DE2033749A1 - Use of 4 hydroxybenzophenones to combat harmful microorganisms - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

Case 6821 / E

Germany

Use of 4-hydroxybenzophenones for combating harmful microorganisms.

The invention relates to the use of K -hydroxybenzophenones of the formula

(D

x ~ χ,

H3-

^X 4 ^X 5 ^Y 4

10 9 8 2 5/2199

ο ΑΛ ^0H

where X ,, Xp, Y, and Yp each represent a hydrogen or halogen atom, a trifluoromethyl, alkyl or alkoxy group, X., and Y, each a hydrogen or halogen atom, a cyclohexyl or optionally further substituted benzene radical, X ₁ . j Xp. and Yu. each represents a hydrogen or halogen atom j where at least one of the X or Y radicals is a halogen atom, and where the number of alkyl, alkoxy, trifluoromethyl, benzene and cyclohexyl radicals as substituents together is at most h , for combating harmful Microorganisms.

4-Hydroxybenzophenones of the formula are preferred here

used, in which Xu, X ₁ -, Xg, Yu ₃ Yp and Yg each have a hydrogen or halogen atom, at least one of the radicals being a halogen atom, and X ", Xg and Y" each have a hydrogen atom, a trifluoromethyl, Mean alkyl or alkoxy group.

Halogen atoms for the substituents in formulas (1) and (2) are iodine and, above all, chlorine and bromine into consideration. As alkyl groups for the substituents in

1 ü b H ') R /? 1 9 9

the formulas (1) and (2) come straight-chain as well as branched residues in question, e.g. ethyl, n-propyl, isopropyl, η-butyl or tert. Butyl radicals, but preferably methyl groups. The alkyl groups come as alkoxy groups appropriate groups into consideration.

4-Hydroxybenzophenones of the formula are of particular interest

Xr

wherein X ₁ ,, X ₁ -, Xg, Y ₁ ,, Y ₁ - and Yg each represent a hydrogen or halogen atom, at least one of these radicals being a halogen atom, and X _QJ X ₁₀ and Yg each being a hydrogen atom, a trifluoromethyl group, an alkyl group with 1 to 4 carbon atoms or an alkoxy group with 1 to 4 carbon atoms, where at least 3 of all X and ■ Y radicals represent a hydrogen atom .. 4-Hydroxybenzophenones of the formula ·

108825/7199

wherein Xu, Xj-, Yj, and Y, - each a hydrogen or halogenated, at least one of these radicals represents a halogen atom, X-, X ₁₂ , Yg and Y ₁₀ each represent a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms , whereby

I,

at least 4 of all X and Y radicals represent a hydrogen atom, are particularly suitable.

In the context of the formula (4), particularly those compounds which contain at most 2 alkyl groups are of practical interest.

These 4-hydroxybenzophenones include those of the formula

i ο

wherein at least one of the radicals X ₁ - ** ^ jU * Y ₁ I represents a chlorine or bromine atom and the remaining radicals each represent a methyl group, a hydrogen, chlorine or bromine atom, preferably.

Good results will be especially with

4-hydroxybenzophenones of the formula

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16-

18th

obtained, in which X., _, X .., -, Χ, η, X, _Q and Y, _ each a hydrogen or chlorine atom, X, γ a hydrogen, chlorine or bromine atom and Y-. , j Y ^ i, and Y, g each represent a methyl group, a hydrogen or bromine atom, where at least one of the X or Y radicals represents a chlorine atom and 5 to 6 of all X and Y radicals represent hydrogen atoms. ;

The ^ -hydroxybenzophenones of the formulas (1) to (b) are known or are prepared by methods known per se, for example from the corresponding phenylbenzoates by the so-called Fries reaction. (Compare: "Baltzly et al., Journal of the American Chemical Society TJ_, 2522" or "LF and M. Fieser, Textbook of Organic Chemistry 195ft; <page 728"). The reaction can be carried out in the melt or in the presence of an organic solvent, for example nitrobenzene. When the corresponding phenyl benzoate is heated together with aluminum chloride, the ^ -hydroxybenzophenones of the formula (I) are then formed.

4-Hydroxybenzophenones of formula (1) are by rearrangement of an ester of the formula

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wherein X, to X, - and Y, to Y ^ the meaning given obtained in the presence of aluminum chlorides. Of course, the 4-position in the phenol radical is allowed the compound of the formula (7) -not be substituted, otherwise the rearrangement cannot take place.

The starting products of the formula (7) are prepared according to known methods, for example by reacting a corresponding Obtained benzoyl halide with a corresponding phenol.

Particularly surprising about the connections of the Formula (1) is the broad range of antibacterial activity that extends to both gram-positive and gram-negative bacteria for some of these compounds. Here from an application point of view is the odorlessness and colorlessness of the compounds of formula (I) are of particular value.

The present invention also includes the Use of the compounds of the formula (I) in pest control in general »The use of antimicrobial compounds is on a very broad basis

10982 W? 199

especially to protect organic substrates against the infestation by destructive and pathogenic (also phytopatho.gene) Microorganisms. The aforementioned antimicrobials are therefore suitable both as preservatives and as a disinfectant for technical products of all kinds, in crop protection, in agriculture, in veterinary medicine and in cosmetics.

The 4-hydroxybenzopnenones of formula (1) are so used to equip or protect organic material, especially textiles, by adding the or organic materials to be protected incorporated or at least one of these compounds whose surface applies.

Among the non-textile technical products ^ which can be preserved with the aid of the compounds of the formula (I) are the following as examples singled out: ^

Glues, binders, paints, textile auxiliaries or finishing agents, coloring or printing pastes and similar preparations based on organic and inorganic dyes or pigments, including those that are used as admixtures Contain casein or other organic compounds. Wall and ceiling coatings, e.g. those that contain an proteinaceous dye binder, are prevented by adding the compounds of formula (1)

protected with pests. The use for wood protection

'1098 hp /? ⁴ ! 9 9

is also possible

The compounds of the formula (1) can also be used as preservatives in the pulp and paper industry can be used, among other things, to prevent the well-known slime formation caused by microorganisms in the apparatus used for paper production.

Furthermore, by combining the compounds of the formula (I) with surface-active substances, in particular detergent substances for detergents and cleaning agents with excellent antibacterial or antifungal effects. The compounds of formula (1) can be - 'e.g. can be incorporated into soaps or with soap-free, washable or otherwise surface-active substances, in particular non-ionic or cationic detergents, are combined, or they can be combined together with mixtures of soaps and soap-free detergent actives, whereby in these combinations their antimicrobial effectiveness is fully preserved. With aqueous, .Z, preparations Such detergents and cleaning agents which contain compounds of the formula (I) can, for example, be textile materials be antimicrobial when washing, as the active substance is noun on the textile material able to pull up.

Cleaning agents which contain the compounds of the above formula can also be used in industry and household, as well as in the food

1 0 9 8 2 S ■ /? ι 9 9

advertising, e.g. dairies, breweries, slaughterhouses. Even as a component of preparations which serve the purpose of cleaning or disinfection, the present Connections are used. ·

The effect of the compounds of the formula (I) can also be used in preserving and disinfecting equipment are exploited by plastics. When using plasticizers, it is advantageous to add the antimicrobial additive to be added to the plastic dissolved or dispersed in the plasticizer. It is useful for a uniform as possible Distribution in the plastic must be taken care of. The plastics with antimicrobial properties can be used for everyday objects of all kinds where an effectiveness against various germs, such as bacteria and fungi, is desired, can be used, e.g. in floor mats, bathroom curtains, seating, step gratings in Swimming pools, wall coverings, etc. By incorporation in appropriate wax and polishing compounds, you get Floor and furniture care products with disinfecting properties,

Furthermore, the compounds of the formula (I) can be used for preserving and disinfecting Fibers and textiles are used, whereby they can be applied to natural and artificial fibers and there a permanent effect against harmful (also pathogenic) microorganisms, e.g. fungi and bacteria.

10 9 825/219 9

wrinkles. The addition of the compounds can before, at the same time with or after treating these textiles with other substances, e.g. parquet or printing pastes, finishes etc. take place.

Textiles treated in this way also provide protection against the appearance of white odor, such as that caused by Microorganisms is due to.

The antimicrobial agents can be in the most varied Applied to textile materials to be protected, e.g. by impregnation or spraying with solutions or suspensions which contain the above-mentioned compounds as active ingredients.

The active ingredient content can depending on the application between 1 and 50 g, preferably 1 to 30 g, of active substance per Liters of treatment liquid. '

Most often, textile materials are both synthetic or natural in origin by a content From 0.1 to 3 $ active ingredient sufficient against fungal and bacterial attack protected. The active ingredients mentioned can be used together with other textile auxiliaries such as finishing agents, Anti-crease equipment, etc. are used.

The use forms of the active compounds according to the invention can be the customary formulations of pesticides correspond, for example agents containing said active ingredients, optionally also additives such as solvents, "dispersing, wetting agents

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or contain adhesives, etc., as well as other pesticides. In particular, however, the means in addition to the active ingredient of the formula (I), there is also a solid one

r-

or contain liquid diluent or a solid or liquid carrier.

The active ingredient content of these agents can be between 0.1 and 50 g, preferably between 1 and 30 S * active substance per 1000 g of agent.

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Manufacturing specification

20.9 S 3 ^ dichlorobenzoyl chloride and 16.3 g 2,6-dichlorophenol are in a nitrogen stream during a Stirred hour at 150 ° C, with the elimination of hydrogen chloride practically quantitatively the product of formula

(8th)

forms (melting point 115 to 116 ° C). If the ester is not isolated, 28 g of aluminum chloride will be produced at 140 ° to 150 ° C added for 10 minutes. The mixture is stirred for a further 10 minutes at the same temperature and then added 100 cnr chlorobenzene are added. The solution is poured onto ice and the mixture is then subjected to steam distillation. You suck and dry in a vacuum at 60 ° C.

Yield i 30 g of colorless crystals that have a melting point from 200 ° to 201 ° C.

The analysis product I of the formula

1 0 9 H? fi /? 1 9 9

melts after a single recrystallization from ethanol at 202 ° to 203 ° C.

When the compound of the formula (8) is rearranged, 50 om nitrobenzene is used as a solvent, in this way the compound of the formula (9) is obtained in a similar purity and yield if, for example, during Let react for 24 hours at 75 ° C with stirring.

In a similar way to compound I. the compounds II to XXVIII of the formula

(10)

manufactured,

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• f » O m Ln • W. • ο Λ, O H "^ ^- H cn H 00 P O CM ft H 00 C- 00 VO . VO P * 03 C- H O H CO H H . H H H H H N O
ω ϋ • Η c— 03 03 ^Η CQ CQ 03 03 Oi 'CQ 03 H • Η W. • Η 03 • Η • Η • Η • Η • Η • Η • Η O
approx 03 » • Η , Q cn CM • Η Pl O ^ J- III in 00 O O ω O C- CM C- ω VO VO »Γ vo H H H H H H H H VO W. C- H 00
H H H pi W. H O H O O W. H » H O H W. H Μ H
O H O H H W. H H H Η H H H ιη H « ο O H O O ϋ O O O O Ρ3 ϋ H O H H O W. W. O W. W. O W. < ω φ pc. H H H CM W. hd W. O W. O H Ρ4 W. (U rf « H W. _Μ H
O H
O W. ρΓ
ο H
O H
O ¹ p ϋ H * H rbin H * O H ϋ W. W. W. ω O H H O H H M. ϋ ϋ H O W. ϋ O H ϋ W. d « W. ϋ W. W. H W. W. μ-ι W. H VII VII H H XII > H
H

1 0 9 82S /? 19 9

link H ■ ^R 2 H _R. ^R 5 ^R 6 Cl V ^E 9 Melting point H H in ⁰ C XIII H H Cl Cl Cl ' ' H Br H H 164. to 165 XIV H Cl Cl H .H H • H H H 149 to 150 XV H Cl Cl H H H Cl H H 173 to 174 XVI CH ₅ Cl H H. H H H , 126 to 127 XVII OH ₃ Cl H- H " H H H 138 to 139

O sh 00 ω VO VO ο VO sh KN in O O VO
H H H ίπ H H H CvJ • Η ι ι ι I. I. I. ι I. I. ι I. -P KN LTv LfN ON IXN KN CM CTi I. VO Γ KN VO Ν * Ν (M VO VO VO H H H H H H H H H (M H Η ω W. W. « W. « W. JxJ W. ο M. «' ω W. « W. W. [τ] W. CQ « nT Ö ρΓ ο H
O ο ο Pf W. W. W. _Μ W. * 'W ρΓ » W. W. M. H H P. P. P. Pi ° H _d H H
O βΓ »Γ » W. W. H
O ο • Ο pi H W. W. W. ω W. H H H Sh O W. O P. O H M. M. W. W. H H H H O W. O P. P. O Ph W. H
O Ö If W. H W ' CNJ H H
O H H ' H pi XVII H XXI XXII XXII XXIV G B. XXVI 3. Pi ^H η I. ■ Η ω

1 0 9; ·? ? R /? ι 9 9

Example 1 '

Determination of the minimum inhibitory concentration (MIC) against bacteria and fungi in the gradient plate test ''

The compounds of the formula (10) are used in suitable formulations (e.g. as solutions in methyl sulfoxide) certain concentration with warm Brain Heart Infusion Agar (bacteria) resp. Mycophil agar (mushrooms) mixed. the liquid mixtures are poured onto a solidified, wedge-shaped base agar layer and also allowed to solidify.

Using a Pasteur pipette, the test organisms are then applied in a line perpendicular to the gradient. After incubation for 2k hours at 37 ° C (bacteria) resp. 72 hours at 30 ° C. (mushrooms), the length of the germs grown on the inoculation line is measured and expressed in ppm of active ingredient.

The results are shown in Tables B to E below.

¹ ^ W. Szybalski et al., Science Il6, 26 (1952) ¹ Nuesch and Knuesel, "Sideromycins", in the book of

Gottlieb and Shaw, "Antibiotics, Mechanism of Action". Vol. 1 (1967), Springer Verlag.

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-.18 -

Table B.

Minimal inhibitory concentrations against Staphylococcus aureus (bacteriostasis),

link MIC in ppm link MIC in ppm I. 3 XIV 25th II 20th XV *
2 III 30th XVI 30th IV 2 XVIII V 2 XIX 2 VI 20th XX 2 VII 4.5 XXI 20th VIII 3 XXII 20th IX 25th XXIII 30th X 3 XXIV 28 XI 25th XXV 30th XII 2.5 XXVI 10 XIII 10 XXVII 30th

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/ a

"'Table C

Minimal inhibitory concentrations against 'Escherichia coil (Bacteriostasis).

link MIG in ppm link MIG in ppm VII 10 ' XX 20th IX 30th XXI 40 XIX 20th XXIII 50

Table D.

Minimal inhibitory concentration against Trichophyton menta grophytes (pungistasis)

link MIG in ppm link MIC in ppm I. 10 XVIII 20th II 3 XIX CVJ III 7 ■ XX I- IV 15th XXI 8th V 30th XXII 4th VII 2 XXIII 10 X 2 XXIV 3 XIII 3 XXV 30th XV 10 XXVII 10 XVI. 10

1 0 ί; ■ <? F. / 7 1 QQ

Table E.

Minimal inhibitory concentrations against Aspergillus nigger (Pungistase)

link MIO la ppm link : MIG in ppm II 50 XIX 20 ' V 70 XX ; 20th VII 15th XXI 60 X 10 XXIII 50 XIII 25th XXIV 50 XVIII 20th

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Example 2

Samples of 100 g cotton cretonne are included a solution of compounds of the formula (I) in Isopropanol impregnated at 20 C on a padder and then squeezed off with a lOO ^ igen liquor uptake.

Samples of 100 g of wool cheviot are treated in the same way. *

The fabrics, dried at 30 to 40 ° C, contain 1% active ingredient, based on their own weight.

To test the effect against bacteria, discs with a diameter of 10 mm are placed on the impregnated fabric without water and after soaking for 24 hours 29 ° C placed on Brain Heart Infusion Agar plates, the are pre-inoculated with Staphylococcus aureus. The plates are then incubated at 37 ° C. for 18 hours.

On the one hand, the inhibition zone (HZ in mm) and on the other hand the microscopically detectable growth (W in $>) under or on the tissue are assessed. .

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- "2T -

Table P

Substrate Connect not watered W. watered W. (with Ifo active ingredient) manure HZ (*) HZ (mm) 0 (mm) 0 II ■ 6th 0 2 75 cotton V 10 0 0 0 VII 5 0 4th 0 II 3 0 track 0 Wool V 10 0 5 0 VII 3 10

Similar results are obtained with other compounds in Table A.

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Claims (1)

Attachment to the entry from 25'3 19 ⁷ O within the meaning of the patent application P 20 33 749.9 Our file: 21 715 ' 2Ü33748 Claims 1. Use of 4-hydroxybenzophenones of the formula " ^L 4. -c- in which X., Xp, Y, and Yp each represent a hydrogen or halogen atom, _A trifluoromethyl,. Alkyl or alkoxy groups X, and Y ^ each represent a hydrogen or halogen atom., A cyclohexyl or optionally further substituted benzene radical and -X ^, X ₁ - and Y ₂ each represent a hydrogen or halogen atom, where at least one of the X- or Y radicals represents a halogen atom and where the number of alkyl, alkoxy, trifluoromethyl, benzene and cyclohexyl radicals together is at most 4, for combating harmful microorganisms. · 2. Use of K- hydroxybenzopheones of the formula 109325/2199 in which X ^ ,, X ^, Xg, Y _1. , Y ₅ and Yg each represent a hydrogen or halogen atom, at least one of these radicals being a Hai © - gene atom, and X ₇ , Xg and Y ₇ each being a hydrogen atom, mean a trifluoromethyl, alkyl or alkoxy group for the purpose indicated in claim 1. 3. Use of 4-Hydroxybenzophenonen der formula wherein X ₁ ^, X ^, Xg, Y ₂ ^, Y and Y ^ each represent a hydrogen or halogen atom, at least one of these residues being a halogen atom, and X _g , X ₁₀ and Yo each represent water X _g , X ₁ substance atom, a trifluorine | hy! group, an alkyl group with. ' ..-- ■ --.-- P κ-. "■ - ■ ν , .- ■■) "" 1 to 4 carbon atoms or an alkoxy group with 1 to h carbon atoms, where at least 3 of all 103825/2 199 IMSPECTED ST X and Y radicals represent a hydrogen atom for the purpose specified in claim 1. 4. Use of 4-Hydroxybenzophenonen der formula wherein X ₁ , X ₁ -, Yj, and Y ₁ - each represent a hydrogen or halogen atom, at least one of these radicals being a halogen atom, X ₁₁ , Xi ₀ * Yr. and Y _{1Λ is} each a hydrogen atom IJ. · "· <£ y JU or mean an alfcyl radical with 1 to 4 carbon atoms, where at least 4 of all X and Y radicals are hydrogen represent ato m for the purpose specified in claim 1. 5 »Use of 4-hydroxybenzophenones of the formula ORIGINAL INSPECTED 108325/2199 wherein at least one of the radicals Χ, and Y, , -., X ₁ K, Y ₁₁ and Y _,? represents a chlorine or bromine atom and the remaining radicals each represent a methyl group, a hydrogen, chlorine or bromine atom, for the purpose indicated in claim 1 =. Use of 4-hydroxybenzophenones of the formula where X. ,,., X, g, ^ q * ^x in and ^Y ic J ^{e a} hydrogen or chlorine atom, X, "a hydrogen, chlorine or bromine atom and Y ₁ -., Y ₁₂ , and Y ₁ ^ each represent a methyl group, a hydrogen or bromine atom, where at least one of the X or Y radicals is a chlorine atom and 5 to 7 of all X and Y radicals are hydrogen atoms, for the purpose indicated in claim 1. '· 7. Use according to one of claims 1 to 6, characterized in that organic material, in particular textiles, are given or protected antimicrobial properties. · 109326/2199 ORIGINAL INSPECTED 8y means of combating harmful microorganisms mechanisms containing at least one ¹ ^ - hydroxybenzophenone of the formulas given in one of claims 1 to 6 as active ingredient. 9. Means according to claim 8, which r. Besides the active ingredient nor contain a solid or liquid diluent or a solid or liquid carrier. 10. Means according to claim 8 or 9. » which as washing and cleaning agents with disinfectant properties, characterized in that they are used in addition to the active ingredient contain at least one of the following additives: soaps, surface-active substances such as washing-active substances, Foaming agents, emulsifiers, dispersants or wetting agents, water, organic solvents, light stabilizers, optical brighteners, other fungicidal and bactericidal substances. 11. Means according to claim 8 or 9 * which for protection of non-textile plastics and fibers made from natural and synthetic fibers against attack and damage by using microorganisms. 12. Agent according to one of claims 8 to 10 with a disinfecting and deodorizing effect, which is used for personal hygiene be used. INSPECTED 1 OCoSS, / -? 1-9 9