RU2374233C1 - SUBSTITUTED 2-THIOCARBAMOYL-3-PHENYL-3,3a,4,5,6,7-HEXAHYDRO-2N-INDAZOLES, METHOD OF PRODUCING SAID COMPOUNDS (VERSIONS) AND FUNGICIDE COMPOSITION BASED ON SAID COMPOUNDS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted 2-thiocarbamoyl-3-phenyl-3,3a,4,5,6,7-hexahydro-2N-indazoles with general formula I

, where R1=CH₃, R2=H, CH₃, R1+R2=(CH₂)_m, m=2-5; X=C_kH_2k+1 k=1-4, Hal, NO₂, C_kF_2k+1 n=1-5; R3=CH₃, Alk, Ar, and method of producing them, the first of which involves condensation of 2-arylidenecyclohexanones II with thiosemicarbazides III in aliphatic alcohol in the presence of acid as catalyst while heating (mainly 3,3a-cis-2-thiocarbamoyl-3-phenyl-3,3a,4,5,6,7-hexahydro-2N-indazoles of formula I are obtained using this method); in the second method, through condensation of 2-arylidenecyclohexanones II with hydrazine hydrate while boiling in aliphatic alcohol, intermediate N-unsubstituted hexahydroindazoles IV are obtained, which are acylated with alkyl- or arylisothiocyanates in an inert solvent in the presence of a base catalyst at room temperature (mainly 3,3a-trans-2-thiocarbamoyl-3-phenyl-3,3a,4,5,6,7-hexahydro-2N-indazoles of formula I are obtained using this method).

EFFECT: invention relates to a fungicide composition which contains substituted 2-thiocarbamoyl-3-phenyl-3,3a,4,5,6,7-hexahydro-2N-indazoles with general formula I, for example, 7-methyl- or 7,7-dimethyl-3-(4-chlorobenzylidene)-3,3a,4,5,6,7-hexahydro-2N-indazoles, which exhibits fungitoxicity higher than standard triadimefon.

4 cl, 5 tbl, 5 ex

Description

The invention relates to the chemistry of heterocyclic compounds, namely to substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazolam of the general formula I:

where R1 is a methyl group, R2 is a hydrogen atom or a methyl group, or R1 and R2 together are a polymethylene chain with carbon numbers from 2 to 5; X, identical or different, means an alkyl substituent with the number of carbon atoms from 1 to 4, a halogen atom, a nitro group or a perfluoroalkyl group with the number of carbon atoms from 1 to 4; n is an integer from 1 to 5; R3 means a hydrogen atom, an alkyl or aryl group containing, as substituents, an alkyl group with the number of carbon atoms from 1 to 4, a halogen atom, a nitro group or a perfluoroalkyl group with the number of carbon atoms from 1 to 4. Compounds of the general formula I can be used as agricultural, industrial, medical or veterinary fungicides.

The invention also relates to methods for producing compounds of general formula I, to the use of these compounds in compositions with other active and auxiliary compounds for controlling fungal diseases of plant organisms, animals or humans.

Substituted 7-benzylidene-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula II are known to have a depressant effect on the central nervous system [Krapcho J., Turk Ch.F. Bycyclic pyrazolines. Potential central nervous system depressants and antunflammatory agents. // J. Med. Chem. 1979. - Vol. 22, No. 2 - P.207-210].

R = CH ₃ , (CH ₂ ) ₂ N (CH ₃ ) ₂ , (CH ₂ ) ₃ N (CH ₃ ) ₂ , (CH ₂ ) ₃ N (C ₂ H ₅ ) ₂

The closest to the claimed substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles in structure and biological activity are the compounds described in [Golikov A.G. Synthesis and antimicrobial activity of some (nitro) furfurilidene-containing hexahydroindazoles. / Golikov A.G., Raikova S.V., Bugaev A.A., Krivenko A.P., Shub G.M. // Chem. farm. Journal. - 2005 - T.39 - No. 2, p.22-24] with bactericidal properties, in particular 3- (5-nitrofurfuryl) -7- (5-nitrofurfurilidene) -3,3a, 4,5,6,7 -hexahydro-2H-indazole, showing high antistaphylococcal activity [RF patent No. 2273640, IPC C07D 405/14 stated. 01/11/2005, publ. 04/10/2006].

3- (5-Nitrofurfuryl) -7- (5-nitrofurfurilidene) -3,3a, 4,5,6,7-hexahydro-2H-indazole is prepared by reacting 2,6-di- (5-nitrofurfurilidene) cyclohexanone with hydrazine hydrate in propanol-2 medium with a yield of 80%.

The technical problem is to increase the efficiency and expand the range of fungicidal preparations.

The technical result is to obtain new substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I having fungicidal activity, methods for their preparation, as well as increasing the effectiveness of fungicidal agents for through the use of compounds of general formula I and the expansion of the range of fungicidal preparations.

According to the present invention, substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I, wherein R1 is a methyl group, R2 is a hydrogen atom or a methyl group, or R1 and R2 together means a polymethylene chain with a carbon number of 2 to 5; X, identical or different, means an alkyl substituent with the number of carbon atoms from 1 to 4, a halogen atom, a nitro group or a perfluoroalkyl group with the number of carbon atoms from 1 to 4; n is an integer from 1 to 5; R3 means a hydrogen atom, an alkyl or aryl group containing, as substituents, an alkyl group with a number of carbon atoms from 1 to 4, a halogen atom, a nitro group or a perfluoroalkyl group with a number of carbon atoms from 1 to 4, are obtained by reacting the corresponding 2-arylidenecyclohexanones III with thiosemicarbazides IV, where R1, R2 and R3 have the same meanings as in general formula I, in an aliphatic alcohol medium, for example ethanol, using an acid catalyst, for example hydrochloric acid or n-toluenesulfonic acid, when heated. In this way, mainly 3.3a-cis-2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the formula I are obtained

According to the present invention, substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I by another method are obtained in two stages from 2-arylidenecyclohexanones III by condensation with hydrazine hydrate at boiling in an aliphatic alcohol, for example ethanol, followed by acylation of intermediate N-unsubstituted hexahydroindazoles V with various alkyl or arylisothiocyanates VII in an inert solvent, for example diethyl ether, when catalysed with bases, for example triethylamine, 1,8-diazobicyclo [5.4.0] undec-7- enom (DBU), tetram ethylenediamine (TMEDA) and others. In this way, mainly 3,3a-trans-2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the formula I are obtained

The compounds of formula I and compounds that can be used as intermediates in the processes for their preparation can exist in one or more isomeric forms, both depending on the cis and trans relative positions of 3- and 3a-protons, and depending on the number of asymmetric centers of the molecule. Therefore, the invention also relates to all spatial and optical isomers, to their racemic mixtures and to the corresponding diastereoisomers of the corresponding series.

Substituted 2,2-dimethyl-6-arylidenecyclohexanones III are obtained by Johnson methylation of 2-methyl-6-arylidenecyclohexanones VII with methyl iodide in tyreth-butanol in the presence of potassium tert-butylate [Johnson W. Introduction of the angular methyl group. The preparation of cis- and trans-9-methyldecalone-1. // J. Am. Chem. Soc. - 1943. - Vol. 65, No. 7. - P.1317-1324.]:

Substituted 2-methyl-6-benzylidenecyclohexanones VI are prepared by reacting 2-methylcyclohexanone with aromatic aldehydes in the presence of bases, for example, an aqueous solution of potassium hydroxide by heating [Jonson W. Introduction of the angular methyl group. The preparation of cis- and trans-9- methyldecalone-1.// J. Am. Chem. Soc. - 1943. - Vol. 65, No. 7. - R.1317-1324].

Newly substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I have fungicidal activity.

The technical result of the invention is also the development of fungicidal compositions consisting of substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I at a concentration of 0.1-99% and auxiliary substances that can be successfully used to combat harmful fungal diseases of crops, animals or humans.

The successful use of pesticides to combat various pests largely depends on the formulation of the drug and the conditions under which the active substance is in contact with pests and pathogens of plants. Depending on the physicochemical properties of the preparation, its purpose and method of use, the most effective and economical formulation (composition) is selected, for example, dusts, granules, microencapsulated preparations, wettable powders, emulsion concentrates, ointments, water-dispersible granules, suspension concentrates. Preparative forms, in addition to the active substance, may include excipients, solvents, surfactants, water softeners, synergistic additives, etc. The known drug is cineb, which is used in the form of 70 and 80% wettable powder to combat apple diseases, plums, potato tomatoes, cabbage cucumbers during the growing season, and also as a seed dresser. [Pesticides and plant growth regulators: Ref., Ed. / N.N. Melnikov, K.V. Novozhilov, S.R. Belan. - M .: Chemistry, 1995, p.24, p.316.].

The invention can be illustrated by the following examples:

Example 1. 2-Thiocarbamoyl-3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7 hexahydro-2H-indazole (1)

A mixture of 0.50 g (2.01 mmol) of 2,2-dimethyl-6 (4 chlorobenzylidene) cyclohexanone, 0.366 g (4.02 mmol) of thiosemicarbazide, 20 ml of ethanol and 2 ml (0.0236 mol) of concentrated hydrochloric acid is boiled for 3 hours, cooled evaporate the solvent in a vacuum of a water-jet pump. 15 ml of diethyl ether was added to the residue and boiled for 10 minutes, the precipitate was filtered off, the filtrate was evaporated in a vacuum of a water-jet pump. The residue was recrystallized from isopropanol to give 0.35 g (54%) of 7,7-dimethyl-3- (4-chlorobenzylidene) -3,3a, 4,5,6,7-hexahydro-2H-indazole (1) with mp . 169-170 ° C, R _f = 0.52 (chloroform).

¹ H NMR spectrum (in CDCl ₃ : δ, ppm; J, Hz): 0.52-0.73 m (1H, ⁶ CH ₂ - ⁵ CH ₂ - ⁴ CH ₂ , e), 1.20 s (3H, CH ₃ ), 1.30 s (3H, CH ₃ ), 1.46-1.70 m (5H, ⁶ CH ₂ - ⁵ CH ₂ - ⁴ CH ₂ , a), 3.29-3.42 m (1H, ^3a CH; trans isomer), 3.43 -3.59 m (1H, ^3a CH; cis isomer), 5.27 d (1H, C ³ HN; ³ J = 4.4; trans-isomer), 5.89 d (1H, C ³ HN; ³ J = 11.8; cis isomer ), 6.98 d (2H, 2CH _arom ; ³ J = 7.35), 7.30 d (2H, 2CH _arom ; ³ J = 8.8), 8.32 br. s (1H, NH).

Found,%: C, 60.05; H, 6.45; N, 12.71; Cl, 10.93; S, 10.01. C ₁₆ H ₂₀ ClN ₃ S. Calculated,%: C, 59.70; H, 6.26; N, 13.06; Cl, 11.01; S, 9.96.

IR spectrum (in liquid paraffin; ν, cm ^-1 ): 3404 and 3280 (NH), 1588 (C = N), 1556 (C = S).

Similarly, substituted 2-thiocarbamoyl-3-aryl-3,3a, 4,5,6,7-hexahydro-2H-indazoles are obtained (Table 1)

Table 1.
Melting points and yield of synthesized 2-thiocarbamoyl-3-aryl-3,3a, 4,5,6,7 hexahydro-2H-indazoles

No. R1 R2 R3 X Mp, ° C Exit, % one 2 3 four 5 6 7 one CH ₃ CH ₃ H 4-cl 169-170 54 2 CH ₃ CH ₃ H 4-br 181-183 47 3 CH ₃ CH ₃ H 3,4-Cl ₂ 193-195 27 four CH ₃ CH ₃ H 4-CF ₃ 190-191 28 5 CH ₃ CH ₃ H 2-CH ₃ 230-231 56

one 2 3 four 5 6 7 6 CH ₃ CH ₃ H 2,4-Cl ₂ 195-196 fifteen 7 CH ₃ CH ₃ H 2-br 199-201 13 8 CH ₃ CH ₃ H 2-cl 172-174 22 9 CH ₃ CH ₃ H 4-NO ₂ 164-166 60 10 CH ₃ H H 4-cl 87-89 49 eleven CH ₃ H H 4-br 135-137 twenty 12 (CH ₂ ) ₃ H 4-cl 213-215 63 13 CH ₃ CH ₃ C ₆ H ₅ 4-cl 170-172 67 fourteen CH ₃ CH ₃ C ₆ H ₅ 4-br 184-186 75 fifteen CH ₃ CH ₃ C ₆ H ₅ 2-br 195-196 43 16 CH ₃ CH ₃ C ₆ H ₅ 2-cl 193-194 41 17 CH ₃ H C ₆ H ₅ 4-cl 191-193 68

¹ H NMR spectra were recorded on a Bruker AC-200 instrument (operating frequency 200 MHz), chemical shifts were measured relative to tetramethylsilane, CDCl _{3 was} used as a solvent (for compound * d ₆ DMSO). IR spectra were recorded on a Specord M80 instrument with KBr or NaCl prisms in a thin layer (liquid) or as a suspension in liquid paraffin (crystalline substances).

Example 2. 3- (4-Chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H indazole (18) A solution of 3.73 g (0.015 mol) of 2,2-dimethyl -6- (4-chlorobenzylidene) cyclohexanone and 1.65 g (0.033 mol; 1.65 ml) of hydrazine hydrate in 15 ml of ethanol are boiled for 2 hours, cooled, the precipitate formed is filtered off and washed with 2 ml of ethanol. 3.70 g (94%) of 3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H-indazole (18) are obtained with a mp of 104-106 ° C, R _f = 0.36 (chloroform).

IR (ν, cm ^-1 ): 3354 (NH), 1596 (C = N), 1504 (C = C _arom ).

Example 3. 2- (N-Phenylthiocarbamoyl) -3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H-indazole (19)

To a solution of 1.0 g (0.0038 mol) of 3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H-indazole in 8 ml of diethyl ether is added 1 , 03 g (0.0076 mol) of phenylthioisocyanate and 0.025 g (0.25 mmol) of triethylamine, the reaction mixture was stirred at room temperature for 3 hours, the solvent was evaporated, 5 ml of hexane was added to the residue, stirred, the residue was washed with 2 ml of hexane and recrystallized from a mixture of isopropyl alcohol and DMF (4: 1 by volume) to obtain 1.04 g (56%) of 2- (N-phenylthiocarbamoyl) -3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H-indazole (19) so pl. 168-169 ° C, R _f = 0.61 (chloroform).

Substituted 2-thiocarbamoyl-3-aryl-3,3a, 4,5,6,7-hexahydro-2H-indazoles are similarly prepared (Table 3)

Table 3.
Melting points and yields of synthesized 2-thiocarbamoyl-3-aryl-3,3a, 4,5,6,7 hexahydro-2H-indazoles

No. R1 R2 R3 X Mp. ° C Exit, % 13 CH ₃ CH ₃ C ₆ H ₅ 4-cl 168-169 56 19 CH ₃ CH ₃ CH ₃ 4-cl 206-207 54 twenty CH ₃ CH ₃ 4-ClC ₆ H ₄ 4-cl 194-195 47 21 CH ₃ CH ₃ 4-CF ₃ C ₆ H ₄ 4-cl 175-176 78

Example 4. The composition of the emulsion concentrate

Active ingredient: (substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles) - 70 g

Alkylbenzenesulfonic acid calcium salt (ABSK) - 15 g

Oxyethylated octylphenol (OP-7) - 70 g

Cyclohexanone - 280 g

Xylene mixture - 110 g

1-Methylnaphthalene - 45 g

Kerosene in an amount sufficient to obtain 1 liter of solution.

Example 5. Tests for the fungicidal activity of the compounds was carried out in in vitro experiments. [Guidelines for determining the fungicidal activity of new compounds. Cherkasy: NIITEKHIM. 1984. 34 p.].

The effect of the preparations on the radial growth of mycelium was determined by dissolving the composition of the compound in acetone and adding an aliquot to the potato-sucrose agar at 50 ° C to a concentration of 30 mg / l according to the active substance. The final concentration of acetone in control solutions and in solutions with active substances was 1%. In Petri dishes containing 15 ml of agar medium, a fungal culture needle was applied onto the agar surface. Samples were kept in an incubator at 25 ° C and radial growth was measured after 3 days. The percent inhibition was calculated by Abbot with respect to the untreated control. A commercial fungicide triadimefon in the same concentration was used as a reference. The test results are presented in table 3.

Table 5.
Test results of substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles for fungicidal activity at a concentration of 30 mg / L. Compound Inhibition of the development of microorganisms,% V.i. R.s. F.o. F.m. B.s. S.s. one 40 fifty 46 58 77 26 2 48 52 27 56 67 25 3 28 41 27 47 73 19 four 47 34 9 29th 64 26 5 25 43 6 19 55 24 6 fifty 53 28 48 63 fourteen 7 33 21 10 29th 49 6 8 thirty 36 fifteen fifty 38 eleven 9 25 7 8 - eighteen four 10 45 61 38 55 74 27 eleven 54 42 twenty 45 67 19 12 41 33 19 55 60 eighteen 13* fifteen 0 26 48 54 13 13** 17 17 - - 21 3 fourteen 13 23 31 52 43 7 fifteen thirty 23 7 twenty fourteen 7 16 thirty 55 8 27 12 19 17 23 eighteen 12 58 19 10 19 38 38 24 40 48 13 twenty eighteen 13 6 eleven 2 one 21 10 one fourteen - 0 3 Triadimephone (standard) 41 43 77 87 44 61 * cis-2- [N- (4-chlorophenyl) thiocarbamoyl] -3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H-indazole,
** trans-2- [N- (4-chlorophenyl) thiocarbamoyl] -3- (4-chlorophenyl) -7,7-dimethyl-3,3a, 4,5,6,7-hexahydro-2H-indazole.

Triadimefon-3,3-dimethyl-1- (1,2,4-triazol-1-yl) -1- (4-chlorophenoxy) butanone-2.

Designations of phytopathogenic fungi: V.i. - Venturia inaequalis, R.s. - Rhizoctonia solani, F.o. - Fusarium oxysporum, F.m. - Fusarium moniliforme, B.s. - Bipolaris sorokiniana, S.s. - Sclerotinia sclerotiorum.

The use of compounds of the general formula I both individually and in compositions with other active and auxiliary compounds allows, in the case of using compounds 1, 2, 6, 10, 11, to more effectively fight against fungal diseases of agricultural crops in comparison with the applied agricultural fungicide - triadimefon.

Claims (4)

1. Substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I,

where R1 means a methyl group, R2 means a hydrogen atom or a methyl group, or R1 and R2 together mean a polymethylene chain with the number of carbon atoms from 2 to 5, X, identical or different, mean an alkyl substituent with the number of carbon atoms from 1 to 4, atom halogen, nitro group or perfluoroalkyl group with the number of carbon atoms from 1 to 4, n means an integer from 1 to 5, R3 means a hydrogen atom, an alkyl group with the number of carbon atoms from 1 to 4 or an aryl group containing hydrogen atom as substituents, halogen atom or perf an oralkyl group with the number of carbon atoms from 1 to 4. 2. A method of producing substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I, wherein R1 is a methyl group, R2 is a hydrogen atom or a methyl group, or R1 and R2 together mean a polymethylene chain with carbon numbers from 2 to 5, X identical or different, mean an alkyl substituent with carbon numbers from 1 to 4, a halogen atom, a nitro group or a perfluoroalkyl group with carbon numbers from 1 to 4, n means an integer from 1 to 5, R3 means a hydrogen atom, an alkyl group with the number of carbon atoms from 1 about 4, or an aryl group containing as substituents a hydrogen atom, a halogen atom or a perfluoroalkyl group with carbon number from 1 to 4;
consisting in the fact that the substituted 2-benzylidenecyclohexanones of formula II, where R1, R2, X and n have the same meanings as in formula I, are reacted with thiosemicarbazides of the formula III, where R3 has the same meanings as in the formula I, in an aliphatic alcohol medium in the presence of acid catalysts when heated

3. A method of producing substituted 2-taocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro-2H-indazoles of the general formula I, wherein R1 is a methyl group, R2 is a hydrogen atom or a methyl group, or R1 and R2 together mean a polymethylene chain with carbon numbers from 2 to 5, X identical or different, mean an alkyl substituent with carbon numbers from 1 to 4, a halogen atom, a nitro group or a perfluoroalkyl group with carbon numbers from 1 to 4, n means an integer from 1 to 5, R3 means a hydrogen atom, an alkyl group with the number of carbon atoms from 1 about 4, or an aryl group containing as substituents a hydrogen atom, a halogen atom or a perfluoroalkyl group with carbon number from 1 to 4;
consisting in the fact that 2-arylidenecyclohexanones II, where R1, R2, X and n have the same meanings as in formula I, are condensed with hydrazine hydrate while boiling in an aliphatic alcohol medium to obtain N-unsubstituted hexahydroindazoles of formula IV, where R1 , R2 and Xn have the same meanings as in formula I, which acylate with alkyl or arylisothiocyanates V, where R3 has the same meanings as in formula I, in an inert solvent in the presence of bases as catalysts

4. A fungicidal composition containing the active substance in a concentration of 0.1-99% and auxiliary substances, characterized in that substituted 2-thiocarbamoyl-3-phenyl-3,3a, 4,5,6,7-hexahydro is used as a fungicide -2H-indazoles of the formula I according to claim 1.