RU2428419C2 - Novel benzofuroxanes with fungicidal and bactericidal activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: described are novel benzofuroxanes of general formula

, where R is phenylamino-, N-[4-methoxyphenyl]amino-, N-piperidyl-, which have fungicidal and bactericidal activity and which can be used in veterinary, medicine and agriculture.

EFFECT: high efficiency of the compositions.

2 cl, 2 tbl, 3 ex

Description

The invention relates to the field of organic chemistry, in particular to 4-substituted-5-nitro-6-chlorobenzofuroxans of the general formula I:

where R is N-phenylamino, N- [4-methoxyphenyl] amino, N-piperidyl- having fungicidal and bactericidal activity. The invention may find application in the field of veterinary medicine, medicine and agriculture.

Derivatives of benzofuroxanes have a wide spectrum of biological activity, for example, acaricidal and bactericidal [L.M. Yusupova, S.Yu. Garmonov, I.M. Zakharov and others. Biological protective agents based on chlorine derivatives of nitrobenzofuroxan / Bulletin of Kazan Technological University, 2005 ., No. 1, p.103-111].

A known structural analogue of the claimed compounds is 4- or 6-nitro-5,7-dichlorobenzofuroxane of the formula II:

where R ₁ = NO ₂ , R ₂ = H or R ₁ = H, R ₂ = NO ₂ having fungicidal activity [RF patent No. 2032678, publ. 04/10/95]. However, these compounds exhibit only fungicidal activity.

Also known are 5,7-disubstituted-4,6-dinitrobenzofuroxanes of the general formula III

where R ₁ represents

2-chlorophenylamino, 2,5-dichlorophenylamino, 4,5-dichlorophenylamino,

2-hydroxyphenylamino, 4-hydroxyphenylamino, 4-bromophenylamino,

2-methyl-5-chlorophenylamino, 4-aminodiphenyl possessing acaricidal and bactericidal activity [RF patent No. 2255935, publ. 07/10/05], but not possessing fungicidal activity.

The objective of the invention are new compounds in a series of benzofuroxanes having fungicidal and bactericidal activity, expanding the arsenal of known means of this purpose.

EFFECT: new benzofuroxanes possessing both fungicidal and bactericidal activity.

The technical result is achieved by the synthesis of benzofuroxanes of formula I by the interaction of 4,6-dichloro-5-nitrobenzofuroxane with aromatic amines and nitrogen-containing heterocycles in a medium of dimethyl sulfoxide (DMSO) or dioxane according to the scheme:

where R = N-phenylamino, N- [4-methoxyphenyl] amino, N-piperidyl-.

The starting compound, 4,6-dichloro-5-nitrobenzofuroxane, is prepared according to a known method [RF patent No. 2032678, publ. 04/10/95].

For a better understanding of the invention are examples of specific embodiments of the invention.

Example 1. The method of obtaining 4-phenylamino-5-nitro-6-chlorobenzofuroxane

0.125 g (0.0005 mol) of 4,6-dichloro-5-nitrobenzofuroxane in 5 ml of DMSO is dissolved in a flask at room temperature and 0.091 ml (0.001 mol) of aniline are added dropwise with stirring. The reaction mixture is stirred for 0.5 hours, the product is planted with water. The precipitate formed is filtered off, washed with water and dried. Withstand in vacuum (40 ° C, 0.06 Torr) to constant weight. Yield 0.24 g (78.69%). Mp = 160 ° C. IR spectrum, cm ^-1 : 3315 (NH), 3092 (H), 1617 (furoxane ring), 1563 (NO ₂ ). ¹ H NMR (CDCl ₃ ) δ, ppm, (J, Hz): 6.9 s (1H benzofuroxane ring); 7.10-7.13 d (1 H benzene ring, ³ J _HH 11); 7.26-7.28 d (1 H benzene ring, ³ J _HH 8.44); 7.41-7.43 t (3H benzene ring, ³ J _HH 6.6); 8.66 s (1H, NH). C ₁₂ H ₇ ClN ₄ O ₄ (MM 306.5). Found,%: C 46.98; N, 18.27; H 2.28; Cl 11.58. Calculated,%: C 47.00; N, 18.27; H 2.30; Cl 11.56.

Example 2. A method of obtaining 4- [4-methoxyphenylamine] -5-nitro-6-chlorobenzofuroxane

Under the conditions of Example 1, from 0.125 g (0.0005 mol) of 4,6-dichloro-5-nitrobenzofuroxane and 0.123 g (0.001) of p-anisidine, 0.24 g (71%) of 4- [4-methoxyphenylamine] -5- nitro-6-chlorobenzofuroxane. Yield 0.08 g (24.24%), mp. 114 ° C. IR spectrum, ν, cm ^-1 : 3278 (NH), 3082 (H), 1624 (furoxane ring), 1567 (NO ₂ ). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm, (J, Hz): 3.86 s (3H, OCH ₃ ); 6.82 s (1H benzofuroxane ring); 6.91-6.93 d (2H benzene ring, ³ J _HH 8.8); 7.20-7.22 d (2H benzene ring, ³ J _HH 8.8); 8.76 s (1H, NH). C ₁₃ H ₉ ClN ₄ O ₅ MM (336.5). Found,%: C 45.54; H 2.57; N, 16.75; Cl 11.35. Calculated,%: C 46.38; H 2.69; N, 16.64; Cl 10.53.

Example 3. The method of obtaining 4- [piperidyl-N -] - 5-nitro-6-chlorobenzofuroxane

Under the conditions of Example 1, from 0.125 g (0.0005 mol) of 4,6-dichloro-5-nitrobenzofuroxane in 5 ml of dioxane and 0.085 g (0.001 mol) of piperidine, 0.13 g (89%) of the product is obtained. Mp = 160 ° C. IR spectrum, cm ^-1 : 3099 (H), 1622 (furoxane ring), 1563 (NO ₂ ). C ₁₁ H ₁₁ ClN ₄ O ₄ (MM 298.5). Found,%: C 45.61; N, 19.38; H 4.86; Cl 14.30. Calculated,%: C 44.22; N, 18.76; H 3.69; Cl 11.89.

The inventive benzofuroxanes were studied for bacteriostatic, fungistatic and fungicidal activity, the results are shown in tables 1 and 2.

The following microorganisms were used as test objects in the study of biological activity: bacteria (Staphylococcus aureus 209p, Escherichia coli F-50, Pseudamonas aeruginosa 9027, Bacillus cereus 8035), fungi (Aspirgillus niger BKMF-1119, Trichophyton gypseum, Candida-albikans 85565565 gypseum, Candida albikans 85 )

Antibiotics widely used in medical practice were taken as comparison substances: nitroxaline (a derivative of 8-hydroxyquinoline) and amphotericin B (polyene antibiotic fungicide).

Bacteriostatic and fungistatic properties were studied by the method of serial dilutions in a liquid nutrient medium according to the methods (see, for example, Witchina EA, Furer N.M. Guide to Microbiology, Clinic and Epidemiology of Infectious Diseases. - M .: "Medicine", 1964 T.1. S.670-675). In accordance with the guidelines for the study of the biological activity of pharmacological substances (see Milovanova S.N., Stepanishcheva Z.G. // Methods of experimental chemotherapy. - 2nd ed. - M .: "Medicine", 1971. - P. 318-321) the basic solution from which subsequent dilutions are prepared should contain 500 μg / ml of the test drug.

Bacteriostatic and fungistatic effects of drugs are observed with growth retardation of the test microorganism in concentrations not exceeding 500 μg / ml.

For the current dose, take the lowest concentration of the drug that can delay the growth and reproduction of test cultures of microorganisms.

From the results presented in table 1, it can be seen that the compounds studied by us have a bacteriostatic effect in concentrations from 500-3.1 μg / ml and fungistatic effect in concentrations from 500-0.78 μg / ml. The most active against bacteria and fungi is 4- [4-methoxyphenylamine] -5-nitro-6-chlorobenzofuroxane. In experiments with the yeast-like fungus Candida albikans 855-653 and the dermatophyte Trichophyton gypseum, this compound is comparable in activity to the reference substance (nitroxaline).

Table 1 Bacterial and fungistatic activity in μg / ml Compound Microorganisms St.aureus 209p B.cereus 8035 E.coli F-50 Ps.aureus 9027 Asp.niger Trich.gypseum Candida albicans

125 > 500 > 500 > 500 > 500 500 125

15.6 125 125 250 125 15.6 1.9

31.3 250 > 500 > 500 > 500 31.3 3.9 Nitroxaline 3.9 7.8 7.8 > 500 - - 1.9

For 4- [4-methoxyphenylamine] -5-nitro-6-chlorobenzofuroxane, fungicidal activity was determined, that is, the lowest concentration causing complete death of the test strains of fungi. The results are presented in table 2.

table 2 Fungicidal activity in μg / ml Compound Trgipseum Asp.niger Candida albicans

62.5 > 500 5 Amphotericin B 31.3 twenty 0.39

Thus, new compounds have been obtained in a series of benzofuroxans with both fungicidal and bactericidal activity, which expands the arsenal of known agents for this purpose.

Claims (2)

1. New benzofuroxans of General formula I

where R represents:

N-phenylamino, N- [4-methoxyphenyl] amino, N-piperidyl-. 2. The new benzofuroxans according to claim 1, having fungicidal and bactericidal activity.