PL204957B1 - Silicon organic compounds for hindering the growth of strains of bacteria, fungi and other micro-organisms as well as method for their manufacture - Google Patents

Description

Description of the invention

The subject of the invention is the agent obtained by the Applicant, which is a mixture of new organosilicon compounds, largely soluble in water or in a mixture of water and alcohol, and showing various inhibitory effects on the development of various microorganisms, especially various strains of bacteria and fungal spores.

The agents of the invention are a mixture of polysilsesquioxanes containing secondary, tertiary and / or quaternary ammonium groups connected to the silicon via a hydrocarbon group, preferably via a trimethylene bridge. The invention also relates to a process for the preparation of these compounds.

State of the art

Ammonium salts are known to inhibit the growth of bacteria, fungi and algae. These agents are most often quaternary ammonium salts having one longer alkyl substituent. It is assumed that their action is to break the cell membranes of the microorganism due to the surface tension induced by the amphiphilic biocide. Undoubtedly, the positive charge of the ammonium group plays an important role in this process [E.-R. Kenawy, F.I. Abdel-Hay, A.B.D. El. Raheem, R. El. Shanshoury, M.H. El-Newchy J. Pol. Sci. Part A Polymer Chemistry, 40, 2384 (2002)]. The biological activity of organosilicon compounds is also known in which one of the organic substituents contains an ammonium group bound to silicon through carbon atoms.

The most commonly used agents in this group include [3- (trimethoxysilyl) propyl] octadecyldimethylammonium chloride (Q9-5700) manufactured by Dow Corning. Placing ammonium groups on organosilicon polymers, e.g. polysiloxanes, could increase the antibacterial activity and prolong their biocidal activity [G. Sauvet, S. Dupond, K. Kaźmierski, J. Chojnowski, J. Polym. Sci. 75,1005, (2000)]. Most organic polysiloxanes, such as polydimethylsiloxanes known in pharmacy and medicine as "dimeticone", undergo microbial biodegradation under the influence of various strains of bacteria. [P. Rościszewski, J. Łukasiak, A. Dorosz, J. Galiński: Macromol. Symp. 1998, 130,337; Handbook of Biopolymers, 9, 10, Wiley VCH, Verlag GmbH, Weinheim 2002].

The Polish patent No. 181,411 is known to inhibit the growth of certain bacterial strains of certain haloalkylchlorosilane derivatives and alkoxysilanes, but due to their insolubility in water, they have not been used in practice so far.

During the Applicant's own research on the synthesis of a special class of organic polysiloxanes with a permanent cage structure, the so-called The polysilsesquioxanes surprisingly turned out that some of the newly prepared variants of the ammonium salts of silsesquioxanes clearly inhibit the growth of quite a large group of microorganisms. Such ammonium-substituted oligomeric polysilsquioxanes salts can be obtained by relatively simple syntheses based on low molecular weight polysilsesquioxanes with amino or chlorine groups in organic substituents on silicon. Due to the fact that the compounds obtained by the method according to the invention have a basic cage or ladder structure and molecular weights above 1500 g / mol, most of them should not be absorbed by cell membranes of higher organisms and biodegradable, while showing physiological indifference to humans and animals. These compounds have a compact structure, thanks to which they can more easily penetrate through the outer cover to the walls of the cytoplasm which they destroy.

They do not aggregate easily in aqueous or hydroalcoholic solutions. Unlike various low molecular weight biocidal compounds. The new compounds according to the invention, thanks to the large number of positively charged ammonium groups spatially bound to the silsesquioxane cage, are relatively well soluble in water and water-alcohol mixtures having the ability to strongly affect the negatively charged cell wall.

The essence of the invention

Organosilicon agents inhibiting the growth of various microorganisms, and in particular various bacterial strains and fungal spores, according to the invention are a mixture of polysilsesquioxane oligomers containing secondary and / or tertiary and / or quaternary ammonium groups in an amount of 0.5 to 15% by weight of nitrogen in the molecule, connected to silicon via a hydrocarbon group, preferably via a trimethylene bridge represented by the general formula 1:

PL 204 957 B1

[XSiO3 / 2] p formula 1 where

X represents the ammonium group (CH2) mNRH2 ⁺ Y ^- , (CH2) mNRR'H ⁺ Y ^- and / or (CH2) mNRR'R ⁺ Y ^- and / or the group (CH2) mY or (CH2) mNH2, in which:

R is n-alkyl, preferably CnH2n + 1 (where n = 1 to 20)

R 'and R represent an alkyl, aryl or hydrogen group

Y stands for halogen: Cl, Br or J, m - natural number from 1 to 4, while p means natural number from 6 to 12

The compounds of the invention have a cage structure as shown in the figure, in particular of structure A, structure B, structure C, structure D or ladder structure E where X is selected from the group consisting of ammonium salts of formula: (Y)^-N⁺RR'R, [N (R) H2]⁺Y^- or [NRH (CH2) 2NRH2]²⁺2Y in the organic substituents they contain poly (haloalkyl) -silsesquioxanes obtained by reaction with various alkyl (aryl) amines or by reaction of poly (aminoalkyl) silsesquioxanes with various haloalkanes.

Preferably, the main component of the agent according to the invention is halogen-functional silsesquioxane with a halogen content of 1 to 50% and amine groups with a nitrogen content of 0.5 to 15%, with a T-8 cage structure (n = 8) of the structure cube with silicon atoms in the corners (structure A).

The agents of the invention may also be a mixture of cage compounds having more than 9 to 12 silicon atoms, for example T-10 [X (CH2) mSiO3 / 2] 10. The agent of the invention may also contain compounds with incomplete cage closure, for example T-9-OH or T-8- (OH) 2, [X (CH2) mSiO3 / 2] 9 O1 / 2H (structures C and D) and compounds with a ladder structure-E. All these compounds are represented by the general formula 1, where X is as defined above, R is an alkyl substituent, preferably CnH2n + 1 (where n = 4-20) or hydrogen, and R 'and R are alkyl, aryl or hydrogen groups preferably methyl.

Description of the method

The method of synthesizing organosilicon compounds inhibiting the growth of bacteria and fungi according to the invention consists in reacting suitably prepared poly (halogeno-alkyl) silsesquioxanes with various alkylamines or with ammonia. As a result of this reaction, which is the alkylation of amines (ammonia), and in the case of tertiary amines by quaternizing amines with haloalkyl groups of polysilsesquioxanes, the generation of ammonium salts occurs. The reaction is carried out in a polar solvent, preferably isopropanol, n-butanol, ethyl acetate, dimethylformamide or mixtures of these solvents. The process is performed at the boiling point of the solvents (60-90 ° C). The substitution of the halogen in the polysilsesquioxane with the amino groups may be complete or incomplete.

A second variant of the process according to the invention consists in reacting suitably prepared poly (aminoalkyl) silsesquioxanes with haloalkanes or halogeno-hydrogen. As a result of this alkylation reaction of the amine groups of the polysilsesquioxane there is also generation of ammonium salts on the polysilsesquioxane. The reaction is carried out in solution or in a two-phase system. The reaction can be carried out to complete or partial transformation of the amino group to the ammonium salt.

A third variant of the process according to the invention consists in the hydrolysis and polycondensation of the ammonium salt obtained by reacting the aminoalkyltrialkoxysilane with alkyl halides. The process is carried out in two stages. In the first step, a preliminary hydrolysis is performed which is carried out in a water-organic solvent system, preferably isopropanol, n-butanol, ethyl acetate or DMF. Preferably, a catalyst should be used which is a strong acid, e.g. H2SO4, or a strong base, e.g. tetramethylammonium hydroxide TMAH. The process is carried out at an elevated temperature. At this stage, hydrolysis of the alkoxy groups and partial polycondensation take place. In the second step, there is a further polycondensation to silsesquioxane.

This step is carried out at room or elevated temperature with or without a catalyst. In the final phase, the water is evaporated under reduced pressure and the product is heated to over 100 ° C.

The biological activity of these preparations against gram negative and gram positive bacteria as well as against fungi has been verified by microbiological tests.

PL 204 957 B1

The silsesquioxanes according to the invention are obtained from carbofunctional silsesquioxanes which are hydrolytic polycondensation products of suitable organofunctional alkyltrialkoxysilanes or alkyltrichlorosilanes having functions in the alkyl substituent on silicon, halogen or amino groups. The halogen-containing carbofunctional silsesquioxane is reacted with alkylamines (Scheme I). In contrast, silsesquioxane containing alkylamino groups is reacted with a haloalkane (e.g. scheme 2)

R - alkyl, most often C2H2n + 1 (n = 4-20), or hydrogen

R 'and R - represent an alkyl, aryl or hydrogen group

The substitution may be complete as shown in scheme 1 and scheme 2, or incomplete as shown in scheme 3 and scheme 4. In the case of incomplete halogen substitution (scheme 3), organic groups containing a covalently bonded halogen will be present in addition to the ammonium groups. On the other hand, in the case of incomplete amine conversion (Scheme 4), amino groups will be present next to the ammonium groups.

Embodiments of the invention are illustrated below.

P r z k ł a d I

Silsesquioxane containing 3-aminopropyl substituents on silicon was obtained by the method of two-stage hydrolytic polycondensation of 3-aminopropyltriethoxysilane, initially by heating a solution of this monomer in ethyl acetate, with stoichiometry of water, in the presence of tetramethylammonium hydroxide as a catalyst. The half product obtained was then dosed with stirring into water with the addition of ammonia solution as a catalyst, maintaining the temperature at 15-20 ° C. The resulting poly (3-aminosilsesquioxane) aqueous solution was concentrated by reduced pressure distillation and poured into cuvettes to dry to form a transparent film. The film was dissolved in hot water or a mixture of water with methanol or ethanol and reacted with a stoichiometrically calculated amount of 1-bromobutane by heating in a reflux flask. The obtained solution clearly inhibited the growth of the following bacterial strains: Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Proteus vulgaris, as well as C. Albicans fungal spores.

P r z x l a d II

The hydroalcoholic solution of the ammonium salt prepared analogously to example 1 with the replacement of 1-bromobutane only with 1-bromopentane showed a strong inhibitory effect on the following bacterial strains (measured by the lowest inhibitory concentration): Staphylococcus aureus: 0.015%, Escherichia coli: 0.015-0, 12%, Proteus vulgaris: 0.12-0.24%, Pseudomonas aeruginosa: 0.015-0.12% and for Enterococcus hirae: less than 0.015%

P r z x l a d III

Octa (3-chloropropylisilsesquioxane) with a cage structure and a molecular weight of 1036 g / mol (consistent with the theoretically calculated) was obtained by conducting a two-stage hydrolytic polycondensation similar to that described in Example 1, except that the first stage was carried out by heating a solution of 3-chloropropyltrimethoxysilane in acetate ethyl acetate with the addition of 2 moles of water based on 1 mole of monomer and concentrated hydrochloric acid as a catalyst. After completion of the next polycondensation step in excess water with ammonia, the obtained silsesquioxane was extracted with toluene, washed with water and concentrated by distillation under reduced pressure to a concentration of 40-60%. Additional polycondesation was then carried out by heating this solution to reflux against tetramethylammonium hydroxide. Stripping the solvent under reduced pressure gave octa (3-chloropropylsilsesquioxane) as a low viscosity oil. The obtained silsesquioxane was reacted with N, N-dimethyloctylamine by prolonged heating of the substrate solution in a mixture of isopropanol with dimethylformamide. Upon determination on the basis of ¹ H NMR analysis, desired that the degree of substitution of the chlorine atoms has exceeded 45% of the process was stopped to give, after driving off the solvent and unreacted amine, a suitable seskwioksanową ammonium salt is soluble in water and having similar inhibitory effect on growth of selected strains of bacteria and fungi as described in Examples I and II, namely the minimum bacterial inhibitory concentrations: Enterococcus hirae 0.0157%, Staphylococcus aureus) 0.00198%, Escherichia coli 0.0313%, Proteus vulgaris 0.125% and Pseudomonas aeruginosa 0.125%.

PL 204 957 B1

P r x l a d IV

The oligosilsesquioxane obtained in Example 3 containing 45% of the N, N-dimethyl-n-octylammonium substituted chloropropyl groups was subjected to further heating with an excess of N, N-dimethyl-n-octylamine in solution in dimethylformamide at 80 ° C for 7 days. ¹ H NMR analysis showed an increase of substitution of more than 90% After removal of the solvent and excess amine resulting ammonium salt of the silsesquioxane was analyzed zdolnoś of inhibiting the growth of bacteria finding similar activity Enterococcus hirae - 0.0157%, Staphylococcus aureus - 0.00198% Eshericha coli - 0.25%, Proteus vulgaris - 0.5%, Psudomonas aeruginosa - 0.5%.

P r z k ł a d V

A new silsesquioxane ammonium salt was obtained by refluxing a solution in 200 g of ethyl acetate in 200 g (0.25 mol) of N-2-aminoethyl-3-aminopropyltrimethoxysilane [H2NCH2CH2NHCH2CH2CH2Si (OCH3) 3] with the addition of 96, 5 g (0.5 mol) of 1-bromooctane (C8H17Br). After 7 hours 15 g (0.8 mol) of distilled water was added to heating and reflux was continued for the next 7 hours, then 1 ml of tetramethylammonium hydroxide aqueous solution was added to complete the polycondensation and heated further to reflux until the IR band clearly disappeared at 3630 cm ^-1 , characteristic of HO-Si bonds. The obtained homogeneous colorless solution of silsesquioxane ammonium salt with a pH = 5.9 was subjected to distillation under reduced pressure (approx. 10 torr), removing solvents, water and volatile compounds. 140 g of a yellowish thermoplastic resin highly soluble in ethanol remained. The N content was determined by elemental analysis: 6.03% (calculated 5.19%), C: 46.5% (calculated 46.8%), H: 8.45% (calculated 8.72%). An ethanol solution of the obtained ammonium salt with a concentration of 20%, added in the amount of 1.5% to the silicone-acrylic emulsion paint and subjected to standard tests for the development of fungal spores on the paint coating, effectively protected the coating against fungal growth.

P r x l a d VI

The addition of a 2.5% aqueous solution of the silsesquioxane ammonium salt described in Example 1 to the "Polinil" type emulsion paint used to paint the wall in the laundry effectively prevented the occurrence of dark fungus, common with these paints, for 6 months.

Claims (11)

1. Organosilicon agent inhibiting the growth of strains of bacteria, fungi and other microorganisms is a mixture of polysilsesquioxanes composed of 6-12 silicon atoms linked by oxygen bridges in the structure of regular polyhedron cages or ladders with organic substituents at each silicon atom, represented by the formula 1 [XSiO3 / 2] p pattern 1 in which X represents the ammonium group (CH2) mNRH2 ⁺ Y ^- , (CH2) mNRR'H ⁺ Y ^- and / or (CH2) mNRR'R ⁺ Y ^- and / or the group (CH2) mY or (CH2) mNH2, in which: R is n-alkyl, preferably CnH2n + 1 (where n = 1 to 20) R 'and R represent an alkyl, aryl or hydrogen group Y stands for halogen: Cl, Br or J, m - natural number from 1 to 4, while p means natural number from 6 to 12 2. The agent according to claim. The process of claim 1, wherein it has a cage structure with structure A, structure B, structure C, structure D, or ladder structure E as shown in the drawing, wherein X is selected from the group consisting of ammonium salts of formula: (Y) ^- N + RR'R, [N (R) H2] ⁺ Y ^- or [NRH (CH2) 2NRH2] ²⁺ 2Y ^- , wherein the organic substituents R, R 'and R are as defined above. 3. The agent according to claim. The process of claim 2, characterized in that the main component of the halogen-functional silsesquioxane and the ammonium salt is a T8 (n = 8) cage compound with a cube structure with silicon atoms at the corners (structure A). 4. The agent according to claim. The process according to claim 2, characterized in that it is compounds with a cage structure with more silicon atoms, preferably T10: [X (CH2) 3SiO3 / 2] 10. PL 204 957 B1 5. The measure according to claim A compound according to claim 2, characterized in that it is related to incomplete enclosure of the cage, preferably T-9-OH tub T-8- (OH) 2 (structures C and D) or a compound with a ladder structure - E. Method for the production of organosilicon agents inhibiting the growth of strains of bacteria, fungi and other microorganisms, characterized in that in the first step poly (haloalkyl) -silsesquioxane is produced by hydrolytic polycondensation of haloalkyltrialkoxy (trichloro) silane, and then the isolated silsesquioxane is reacted with the amine of the formula RR'RN where R is an n-alkyl group having from 4 to 20 CH2 groups and R 'and R are alkyl, aryl or hydrogen groups. 7. The method according to p. The process of claim 6, wherein the poly (haloalkyl) silsesquioxane is acetate (3-chloropropyl) silsesquioxane and is reacted under suitable conditions, preferably with dimethylalkylamine having 8-20 methylene groups in the alkyl substituent. 8. A method for the production of organosilicon compounds inhibiting the growth of strains of bacteria, fungi and other microorganisms, characterized in that in the first step poly (aminoalkyl) silsesquioxane is produced by hydrolytic polycondensation of an appropriate aminoalkyltrialkoxysilane, followed by the reaction of the separated silsesquioxane by heating in a suitable solvent with 1-bromo-alkane, with 1-chloroalkane or with 1-iodoalkane containing 4-12 methylene groups. 9. The method according to p. The process as claimed in claim 8, characterized in that 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane and / or N-2-aminoethyl-3-aminopropyltrimethoxysilane are used as monomers for the preparation of poly (aminoalkyl) silsesquioxanes. 10. A method for the preparation of organosilicon compounds inhibiting the growth of strains of bacteria, fungi and other microorganisms, characterized in that in the first step an ammonium salt is prepared by heating a suitable aminoalkyltrialkoxysilane with a selected 1-bromo-alkane, 1-chloroalkane or 1-iodoalkane, and then subjecting it to the obtained hydrolytic polycondensation adduct is obtained under suitable conditions and the obtained silsesquioxane ammonium salt is isolated. 11. The method according to p. The process of claim 10, characterized in that 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane and / or N-2-aminoethyl-3-aminopropyltrimethoxysilane are used as monomers for the preparation of poly (aminoalkyl) silsesquioxanes.