MXPA96003754A - Compositions, wide spectrum, active against microb - Google Patents

Abstract

This invention relates to novel compounds active against microbes and their use in controlling or inhibiting the growth of microorganism

Description

COMPOUNDS, OF WIDE SPECTRUM, ACTIVE AGAINST MICROBIOS, This invention relates to novel compounds active against microbes and their use in controlling or inhibiting the growth of microorganisms.

The compounds active against microbes are known and are used to control a broad spectrum of microorganisms in various applications. It is known that compounds active against microbes are frequently active against bacteria, but not against fungi, or vice versa. Many compounds active against microbes are active against both bacteria and fungi, but not against algae, or vice versa. This lack of broad spectrum activity often leads to the need to use a combination of active compounds against microbes to protect a site.

A broad-spectrum, active compound against microbes is desirable to provide protection for a site with a single active compound against microbes.

It is an object of the present invention to provide a method for controlling or inhibiting the growth of microorganisms, comprising introducing into or over a site an antivirally effective amount of an active compound against microbes. It is a further object of the present invention to provide agents against microbes that have fungicidal, bactericidal and / or algicidal activity and function to kill or inhibit the growth of microbial organisms present at various sites.

These and other objects, which will be apparent from the following description, are achieved by the present invention, which, in one aspect, comprises a method for controlling or inhibiting the growth of microorganisms, which comprises introducing into, a, or on a site, an anti-microbially effective amount of an active compound against microbes, of the formula: OR, R wherein: R1 is selected from R2SOy, H and alkyl (C ^^ - C ^^ g) R and R2 are selected, independently from alkyl (CÍ-CÍS); R and R2 can be attached, together with the atoms to which they are attached, to form a 5 or 6 membered saturated or unsaturated ring, this ring optionally being fused to a substituted or unsubstituted phenyl ring; R and R1 can be attached, together with the atoms to which they are attached, to form a ring, saturated or unsaturated, of 5 or 6 members; R3 is selected from H and alkyl (C ^ Cg); R1 and R3 or R and R2 can be attached, together with the atoms to which they are attached, to form a 5 or 6 membered unsaturated ring; x = 1 or 2; and y = 0, 1 or 2.

This invention also relates to compounds active against microbes, according to formula I, with the proviso that when R is methyl, x = 1, and R3 = H, R1 will not be thiomethyl. Substituted phenyl is understood to mean a phenyl group having one or more of its hydrogens replaced with another substituent group. Examples of suitable substituent groups include (C3-C3) alkyl, (Cj-C3) alkoxy, hydroxy, nitro, halogen, cyano, and alkylthio (0 ^ -03). " As used herein, "antimicrobial active compounds" include fungicides, bactericides and algicides, and the activity against microbes is intended to include both the elimination and the inhibition or prevention of the growth of microbial organisms, such as fungi, bacteria and algae. .

U.S. Patent No. 4,028,379, assigned to Smith Kline and French Laboratories, discloses l- (n-methylsulfinyl) -1- (n-methylthio) -2-nitroethene as an intermediate product in the preparation of H2 antagonists. of histamine. This patent does not disclose or suggest the compound that has activity against microbes.

The compounds active against microbes, used in this invention, can be prepared by known methods of alkylation and oxidation. For example, a stirred solution of the potassium salt of 1, 1-dimimercept-2-nitroethene ("PS") in solution with a mixture of solvents, such as methanol and water or chloroform and water, can be react with an alkylating agent, suitably substituted, to provide 1,1-bis- (alkylthio) -2-nitroethene as the product. The alkylation reaction occurs at room temperature in 2 to 48 hours. The product is then oxidized by a variety of procedures known in the literature, to supply the corresponding sulfinyl or sulfonyl derivatives, such as by dissolving in glacial acetic acid, stirring at a temperature of 60 to 70 ° C and adding hydrogen peroxide, or by the treatment with the acid-chloroperbenzoic acid. Typically, the oxidation reaction is completed within 14 hours.

Suitable alkylating agents useful in this invention include the alkyl halides (c? ~ Ci8) and alkyl dihalides (C2-C: L8) • The anti-microbial compounds used in this invention are typically obtained as a mixture of the E and Z isomers. These isomers can be separated from the mixture by any of a variety of known methods, such as column chromatography, high pressure liquid chromatography, recrystallization and EMI milar. The compounds of the invention are effective as anti-microbial agents in the mixture of E and Z isomers, pure E-isomer or pure Z-isomer.

Suitable compounds active against microbes for use in this invention include, for example: 1. 1- (methylsulfinyl) -1- (methylthio) -2-nitroetheno 2. 1- (ethylsulfinyl) -1- (ethylthio) -2-nitroethene 3. 1- (n-butylsulfinyl) -1- (n-but i Lt10) -2-nitroethene 4, 1- (n-hexylsulfinyl) -1- (n-hexylthio) -2-nitroethene 5. 1- (n-octylsulfinyl) -1- (n-octylthio) -2-nitroethene 6. l- (n-decylsulfinyl) -l- (n-deci Itio) -2-nitroethene 7. 1- (n-dodecyl-sulfinyl) -1- (n-dodecyl) -2-nitroethene 8 1- (n-benzylsulfinyl) -1- (n-benzylthio) -2-nitroethene 9. 1,1-bis (methylsulfinyl) -2-nitroethene 10. 2- (Nitromethylene) -1-oxide-l, 3-dithiolane 11. 2- (Nitromethylene) -1-oxide-l, 3-dithiane 12. l-nitro-2- (methylsulfinyl) cyclopentene 13. l-nitro-2- (methylsulfinyl) cyclohexene 14. l-nitro-2- (methylsulfonyl) cyclopentene 15. l-nitro-2- (methylsulfonyl) cyclohexene 16. l-nitro-2- (phenylsulfinyl) cyclopentene 17. l-nitro-2- (phenylsulfinyl) cyclohexene 18. l-nitro-2- (phenylsulfonyl) cyclopentene 19. l-nitro-2- (phenylsulfonyl) cyclohexeno 20. 5-Nitro-3, 4-dihydro-2H-l-oxide-thiopyran 21. 2-nitromethylene-l, 3-benzodithiol-] -S-oxide 22. 2-nitromethylene-6-methyl-l, 3-benzodithiol-l-S-oxide 2. 3 . 2-ethylsulfinyl-1-nitrobutene The use of compound 1 active against microbes is preferred.

The compounds active against the microbes, used in this invention, can be used to inhibit the growth of microbial organisms by introducing an effective amount against the microbes of one or more of the compounds on, at or to the site subject to microbial attack. The sites that can be protected are: woods, paints, adhesives, fillers, mastics, latex, pulp and paper pulp, textiles, leather, plastics, cartons, lubricants, cosmetics, detergents, household products, industrial cooling water, working fluids of metals, aqueous pigment pastes, photographic process fluids, and fuels.

The amount of the active compound against microbes, suitable for inhibiting the growth of mycobial organisms is from about 5 to 300 ppm, based on the weight of said site. In general, the active compound against microbes is applied in a carrier, such as water, solvent, or the like.

It is known in the art that the performance of the compounds active against microbes can be increased by the combination with one or more other compounds active against microbes. Thus, other compounds active against microbes can be advantageously combined with the compounds active against microbes of this invention.

Example 1 - Preparation of i, l-bis (alkylthio) -2- nitroethenes The 1,1-bis (alkylthio) -2-nitro-etenes are prepared according to one of the two general methods described below.

General Method A.

To a stirred solution of 160 ml of methanol, 240 ml of water and 0.16 mol of PS, 0.32 mol of alkyl halide was added dropwise. The mixture was stirred for several hours, after which the reaction mixture was filtered and the solid material was washed with water and then with ethanol, to give the compounds of 1,1-bis (alkylthio) -2-nitroethene.

General Method B.

To a stirred solution of 150 ml of chloroform, 150 ml of water and 0.10 mol of PS, 0.2 mol of alkyl halide was added dropwise. After the addition of the alkyl halide was complete, 0.05 mol of tetrabutylammonium bromide was added. The solution was stirred for up to two days at L5 at room temperature, then the organic layer was separated. The aqueous layer was extracted with chloroform. The organic solutions were combined and washed with water, then dried over anhydrous sodium sulfate. The solution was filtered and the solvent was removed under reduced pressure, then the ; > 0 products were subjected to chromatography on a column of silica gel and eluted with a 1:10 solution of ethyl acetate / petroleum ether, to give the compounds of 1,1-bis (alkylthio) -2-nitroethene.

Example 2 - Oxidation of 1,1-bis (alkylthio) nitrolenes The 1,1-bis (alkylthio) -2-nitroethene compounds, prepared above, were oxidized and isolated according to one of the following methods: General method C To a stirred solution of 10 mmol of 1,1-bis (alkylthio) -2-nitroethene in 45 ml of glacial acetic acid was added 10 mmol of hydrogen peroxide. The mixture was stirred at a temperature of 60 to 65 for 12 hours, then the solvent was removed under reduced pressure.

General method D The compounds were prepared according to method C. After the solvent was removed under reduced pressure, the solution was subjected to chromatography on a silica gel column and eluted with a 1: 7 solution of ethyl acetate / petroleum ether. .

Example 3 - Preparation of l, l-bis- (n-butylthio) -2- nitroethene 1,1-bis- (n-butylthio) -2-n-troethene was prepared according to General Method B, from n-butyl iodide and PS, as starting materials. The product was obtained with a yield of 97%, as a reddish-brown oil and was identified. iH-NMRf CDC13) d 7.10 (s, 1H), 3.03 (t, 3H), 2.94 (t, 3H), 1.40-1.80 (m, 8H), 0.95 (t, 3H), 0.93 ppm (t, 3H) , Analysis, calculated for C10Hi9NO2s2: > 48.16; H 7.68; N 5.61. Found: C, 48.17; H 6.95; N, 5.62.

Example 4 - Preparation of the E- and Z-isomers of l- (n-butylsulfinyl) -l- (n-puttylthio) -2-nitroethene A mixture of the E- and Z-isomers of l- (n-butylsulfinyl) -1- (n-butylthio) -2-nitroethene was prepared from 1,1-bis- (n-butylthio) -2-nitroethene, According to the General Method D. The products were obtained as oils with a yield of 20% (isomer 1) and 45% (isomer 2) and were identified. Isomer 1: iH-NMR (CDCl 3): d 7.66 (s, 1H), 3.02-3.23 (m, 2H), 2.73-2.93 (m, 2H), 1.65-1.95 (m, 4H), 1.40-1.60 (m , 4H), 0.98 (t, 3H), 0.96 ppm (t, 3H), Analysis, calculated for C10H19NO3S2: C, 45, 52; H, 7.21; N, 5.27. Found: C, 45.19; H, 7.27; N, 4.95. Isomer 2: iH-NMR (CDCl 3): d 6.93 (s, 1H), 2.73-3.25 (m, 4H), 1.42-2.05 (m, 8H); 0.97 (t, 3H); 0.96 ppm (t, 3H). Analysis, Found: C, 45.50; H, 7.41; N, 5.26.

Example 5 - Preparation of 1,1-bis (n-dodecylthio) -2- nitrohetene 1, 1-bis- (n-dodecylthio) -2-nitroethene was prepared according to General Method B, from n-dodecyl iodide and PS, as starting materials. The product was obtained in 78% yield as a pale yellow solid and was identified. ^ -H-NMR (CDC13): d 7.08 (s, 1H), 3.04 (t, 2H), 2.94 (t, 2H), 1.20-1.80 (, 40H), 0.85 ppm (t, 6H). Analysis, calculated for C26H5iN02S2: C, 65.91; H, 10.85; N, 2.96. Found. C, 65.72; H, 11.35; N, 2.81.

Example 6 - Preparation of the E Isomers? Z of l- (n-dodecylthio) -2-nitroetheno A mixture of the E and X isomers of 1- (n-dodecylsulfinyl) -1- (n-dodecylthio) -2-nitroethene was prepared from 1,1-bis- (n-dodecylthio) -2-nitroethene, according to the General Method D. The mixture was obtained as a solid with 54% yield and was identified. Analysis, calculated for C26H51N03S2: c > 63.75; H, 10.50; N, 2.86. Found: C, 63.78; H, 9.51; N, 3.07.

Example 7 - Preparation of 2- (nitromethylene) -1,3-dithiolane 2- (Nitromethylene) -1,3-dithiolane was prepared according to General Method B, from 1,2-dibromoethane and PS as starting materials. The product was obtained in 90% yield as yellow crystals and was identified. iH-NMR (CDC13): d 7.57 (s, 1H), 3.54 ppm (s, 4H).

Example 8 - Preparation of the E-isomers? Z of 2- (nitromethylene) -l-oxide-l, 3-dithiolane A mixture of the E and Z isomers of 2- (nitromethylene) -1-oxide was prepared from 2- (nitromethylene) -1,3-dithiolane, according to General Method D. The mixture was obtained as a solid in 37% yield and was identified. Isomer 1: iH-NMR (CDC13): d 7. 85 (s, 1H), 3.95-4.21 (m, 1H), 3.54-3.78 (m, 2H), 3.04-3.21 ppm (m, 1H).

Example 9 - Preparation of 2- (nitromethylene) -i, 3-dithiane 2- (Nitromethylene) -1,3-dithiane was prepared according to General Method A, from trimethylene dibromide and PS, as starting materials. The product was obtained with 82% yield as a solid and was identified. Analysis, calculated for C5H7NO2S2 C, 33.88; H, 3.98; N, 7.90. Found: C, 33.12; H, 3.75; N, 7.58.

Example 10 - Preparation of the E and Z isomers of 2- (nitromethylene) -l-oxide-i, 3-dithiane A mixture of the E- and Z-isomers of 2- (nitromethylene) -1-oxide-1,3-dithiane was prepared from 2- (nitromethylene) -1,3-dithiane, according to the Genercy Method C. The mixture was obtained in 37% yield as a solid and was identified. Analysis, calculated for C5H7N03S2: C, 31.08; H, 3.65; N, 7.25. Found: C, 30.94; H, 3.49; N, 7.07.

Example 11 - Preparation of 2-ethylsulfinyl-1-nitrobutene The 4-nitro-3-butanol was prepared according to the nitroalcohol process, as taught in Organi c Synthesis, Volume 70, page 68, 1991.

The 2-acetoxy-l-nitrobutane was prepared according to the procedure taught in Organic Synthesis, Volume 70, page 68, 1991.

The 2-ethylthio-l-nitrobutane was prepared by the addition, in drops, of a solution of triethylamine (16.77 g, 0.166 mol) and acetonitrile (50 ml) to a stirred solution of 2-acetoxy-1-nitrobutane (26.50 g) g, 0.164 mol) and ethanethiol (11.20 g, 0.164 mol) in 30 minutes at a temperature of 0 to 52C. Upon completion of the addition, the resulting solution was stirred for 1 hour at 0-5dC and then emptied into a dilute aqueous solution of hydrochloric acid (500ml). The organic products were extracted into methylene chloride (3x150 ml) and the combined portions were washed with deionized water (2x200 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled (1.5 Torr., 72-752C, internal), providing a clear oil, 23.03 g, 86% yield. iH-NMR (CDC13): d 1.1 t, 3H, -CH3; 1.29, t, 3H, SCH2CH3; 2.5-2.85, m, 2H, -CH2-; 2.6, q, 2H, SCH2 ~; 3.28, m, 1H, CH; 4.5, d, 2H, -CH2N02. 2-Ethylthio-l-nitrobutene was prepared by adding a solution of sulfuryl chloride (20.16 g, 0.149 mol) in methylene chloride (30 ml) to a stirred solution of 2-ethylthio-1-nitrobutane (20.16 g, 0.141 mol). ) in methylene chloride (100 ml) to ose. The resulting solution was stirred for 15 minutes, after the addition was complete and the volatile components were removed under reduced pressure. The residue was dissolved in methylene chloride (100 mL) and a solution of triethylamine (14.27 g, 0.141 mol) in methylene chloride (30 mL) was added to ose. Once the addition was complete, the solution was stirred for 14 minutes and then emptied into a dilute aqueous solution of hydrochloric acid (400 ml). The organics were separated and washed with deionized water (2 x 75 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (10: L, hexanes / ethyl acetate) provided the product as a yellow oil, 2.85 g, 13% yield. XH-NMR (CDC13): d 1.26,, 3H, -CH3; 1.36, m, 3H, -CH3; 2.55, q, 2H, -CH2-; 2.92, q, 2H, SCH2-; 7.2, s, 1H, olefinic H.

The 2-ethylsulfini 1-1-nitrobutene was prepared by the dropwise addition of aqueous hydrogen peroxide (1.05 g, 0.0093 mol) to a stirred solution of 2-ethylthio-l-nitrobutene (L.50 g, 0.0093 mol ) in formic acid (20 ml). The resulting solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride or, washed successively with saturated aqueous sodium bicarbonate (1 x 50 ml) and deionized water (1 x 50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (2: 1, hexanes / ethyl acetate) provided the isomeric mixture of the product as a yellow oil, 0.42g, 255 yield. ^ -NMR (CDCI3): d 1.26, m, 3H, CH3; 1.5, t, 3H, CH3; 2.5-2.85, m, 2H, -CH2; 2.85 - 3.2, m, 2H, SCH2-¡; 7.2 + 7.3, 2s, 1H, olefinic H.

Example 12 - Physical Data The melting points of some of the compounds of the invention were determined and are the following.

Table 1 - Compound Fusion Points Name of Compound Fusion Point (° C) 1. 1- (n-methylsulfinyl) -1- (n-methylthio) -2-nitroenetene oil 2. 1- (n-ethylsulfinyl) -1- (n-ethylthio) 2-nitroethene oil 3. 1- (n-Butylsulfonyl) -1- (n-butylthio) -2-nitroethene oil 4. 1- (n-Hexylsulfinyl) -1- (n-hexylthio) -2-nitroenetene oil . 1- (n-octylsulfinyl) -1- (n-octylthio) -2-nitroethene semi-solid 6. 1- (n-decylsulfonyl) -1- (n-decylthio) -2-nitroethene 38-41 7, 1- (n-dodecyl-sulfinyl) -1- (n-dodecylthio) -2-n? Troethene 45-48 8. 1- (n-benzylsulfinyl) -1- (n-benzylthio) -2-pitroetene 110-112 9. 1, 1-bis (methylsulfinyl) -2-nitroethene 106-108 2 (nitromethylene) -1-oxido-1,3-dithiolane 86-88 11. 2- (nitromethylene) -1-oxide- 1,3-dithiane 88-90 Example 13 - Test of the Agent against Microbes The activity against microbes and the effect of the anionic surfactant in said activity of the active compounds against microbes of this patent were determined in the tests of the Minimum Inhibitory Concentration (MIC). Lcis CIM were determined by double serial dilutions of a compound in Minimum Means of Salts (M9G), Soy Broth from Tryptocase (TSB) or Tritocasa Soy Broth and anionic surfactant (TSBA). The compounds were tested against Aspergillus niger, Rhodoturola rubra, Escherichia coli and Pseudomonas aeruginosa. Table 2 Minimum Inhibitory Concentration (ppm)

Claims (5)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, it is; claims as propiedcid what is contained in the following: CLAIMS

1. Method for controlling or inhibiting the growth of microorganisms, which comprises introducing into, in, or on a site, an effective amount against the microbes of an active compound against these microbes, from the formula: O, R N? 2"(I) R3 wherein: R1 is selected from R2SOv, H and (C1-C18) alkyl; R and R2 are selected, independently from alkyl. { < \ -Z \%), 'R and R2 can be attached, together with the atoms to which they are attached, to form a ring, saturated or unsaturated, of 5 or 6 members, this ring is optionally fused to a phenyl ring, substituted or unsubstituted; R and R1 can be attached, together with the atoms to which they are attached, to form a ring, saturated or unsaturated, of 5 or 6 members; R3 is selected from H and (C1-C6) alkyl; R1 and R3 or R and R2 can be attached, together with the atoms to which they are attached, to form a 5 or 6 membered unsaturated ring; x = 1 or 2; and y = 0, 1 or 2.

2. Method, according to claim 1, wherein the site is selected from the group consisting of: woods, paints, adhesives, fillers, mastics, latex, pulp and paper pulps, textiles, leather, plastics, cartons, lubricants, cosmetics, detergents, household products, industrial cooling water, metalworking fluids, aqueous pigment pastes, photographic process fluids, and fuels.

3. Method, according to claim 1, wherein the amount of said active compound against microbes, used to inhibit the growth of microbial orqanismos, is from about 5 to 300 ppm, based on the weight of the site. 4. Method, according to claim 1, wherein the compound active against microbes is selected from the group consisting of: 1 ,. 1- (methylsulfinyl) -1- (methylthio) -2-nitroethene 2"l- (ethylsulfinyl) -l- (ethylthio) -2-nitroethene 3. l- (n-butylsulfinyl) -l- (n-but Lithium) -2-nitroethene

4. l- (n-hexylsulfinyl) -1- (n-hex Lithium) -2-nitroethene 5. 1- (n-octylsulfinyl) -1- (n-oct ilt Lo) -2-nitroethene 6. l- (n-decylsulfinyl) -1- (n-dec Lithium) -2-nitroethene 7. 1- (n-dodecylsulfinyl) -1- (n-dodecyl) -2-nitroethene 8. l- (n-benzylsulfinyl) -1- (n-benzylthio) -2-nitroethene 9. 1, 1-bis (methylsulfinyl) -2-nitroethene 10. 2- (nitromethylene) -l-oxide-l, -dithiolane 11. 2- (nitromethylene) -1-oxide-l, -dithiano 12. l-nitro- 2- (metilsulfinil) cic Lopenteno 1. l-nitro-2- (methylsulfinyl) cy Lohexene 14. l-nitro-2- (methylsulfonyl) cy Lopentene 15. l-nitro-2- (methylsulfonyl) cylohexene 16. l-nitro-2- (phenylsulfinyl) cyclopentene 17. l-nitro-2- (phenylsulfinyl) cylohexene 18. l-nitro-2- (phenylsulfonyl) cyclopentene 19. l-nitro-2- (phenylsulfonyl) cylohexene 20. 5-nitro-3,4-dihydro -2H-l-ox ido-thiopyran 21. 2-nitromethylene-l, 3-benzodithiol-l-S-oxide 22. 2-nitromethylene-6-methyl-l, 3-benzodithiol-l -S-oxide 23. 2-ethylsulfinyl-1-nitrobutene.

5. An active compound against microbes, according to formula I, with the proviso that, when R is methyl, x = 1 and R3 = H, R1 will not be thiomethyl.