MXPA00002415A - Heterocyclic substituted isoxazolidines and their use as fungicides - Google Patents

Abstract

Compounds with fungicidal properties having formula X isCH or nitrogen;R is (C1-C12)alkyl, halo(C1-C12)alkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, halo(C2-C8)alkynyl, (C1-C12)alkoxy(C1-C12)alkyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aralkyl, aryloxy(C1-C4)alkyl or heterocyclic;R1 is aryl, heterocyclic or C(R6R7R8). R2 and R3 are each selected from hydrogen, (C1-C12)alkyl, halo(C1-C12)alkyl, (C1-C12)alkoxy, halo(C1-C12)alkoxy, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aralkyl, heterocyclic;cyano, and (C1-C4)alkoxycarbonyl;R4 and R5 are each selected from hydrogen, (C1-C12)alkyl, halo(C1-C12)alkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, halo(C2-C8)alkynyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryloxy(C1-C4)alkyl, aralkyl, heterocyclic, cyano, and (C1-C4)alkoxycarbonyl such that R4 and R5 are not both hydrogen;R6, R7, and R8 are each selected from hydrogen, (C1-C12)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C12)alkoxy(C1-C12)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aralkyl, and heterocyclic(C1-C4)alkyl.

Description

ISO ^ AZOLIDINES, SUBSTITUTE HETEROCYCLIC AND ITS USE AS FUNGICIDES The present invention relates to isoxazolidine, substituted heterocyclic compounds, compositions containing these compounds and methods for controlling fungi by the use of a fungitoxic amount of these compounds. It is known that compounds having certain 2-aryl-3- (3'-pyridyl) isoxazolidines, US Patent Number 4,066,770, are useful as furgics. We have discovered new isoxazolidine derivatives that have a 3, 3 '-disubstitution, one of which is a 3-pyridyl or 5-pyrimidinyl, and the other is a substituent that does not carry hydrogen, and in C-5 at least a substituent that carries carbon. The novel substituted, heterocyclic isoxazolidine compounds of the present invention have the Formula (I) wherein X is CH or nitrogen; R is selected from a group consisting of alkyl (Ci-C 2 2), halo alkyl (C -C -C 2 2), alkenyl (C2-C8), halo alkenyl (C2-C8), alkynyl (C2-C8) , halo aüquimlo (C2-C8), alkoxy (C? ~ C? 2) alkyl (C? -C? 2), cycloalkyl (C3-C7), halo cycloalkyl (C3-C7), cycloalkyl (C3-C7) alkyl (C? -C4), aralkyl, aryloxyalkyl (C? -C4) and heterocyclic; Ri is selected from the group consisting of aryl, heterocyclic and C (R6 7Re). R2 and R3 are each independently selected from the group consisting of alkyl (C? -C? 2), halo alkyl (C? -C? 2), alkoxy (C? -C? 2),. Halo alkoxy (C1-C1.J, halo alkoxy (C3-C7), cycloalkyl (C3-C7) alkyl (C? -C), aryl, aralkyl, heterocyclic, cyano and alkoxycarbonyl (C? -C); R4 and R5 each is selected from the group consisting of alkyl (C? -C? 2), halo alkyl (C? -C? 2), alkenyl (C2-C8), halo alkenyl (C2-C8), alkynyl (C2-C8) ), (C2-C8) haloalkynyl, (C3-C7) cycloalkyl, (C3-C7) alkyl cycloalkyl, (C3-C7) cycloalkyl (C1-C4) alkyl, aryl, aryloxy (C1-C4) alkyl , aralkyl, heterocyclic, cyano and alkoxycarbonyl, such that R4 and R5 are not both hydrogen.

Rd, R7 and R8 are each independently selected from the group consisting of hydrogen, (C? -C12) alkyl, alkenyl (C2-C8), alkynyl (C? -C? 2), alkoxy (C? -C12) alkyl (C1-C12), cycloalkyl (C3-C7), cycloalkyl (C3-C7) alkyl (C1-C4), aryl, aralkyl and heterocyclic alkyl (Ci-CJ; The aforementioned alkyl group (C? -C? 2), alkenyl (C2-Cs) (C2-C8) alkynyl and (C3-C7) cycloalkyl can be optionally substituted with up to three substitutes selected from the group consisting of nitro, thihalomethyl, and cyano. The term "alkyl" includes both branched chain and straight chain alkyl groups of one to 12 carbon atoms. Typical alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl , undecyl, dodecyl and the like. The term "haloalkyl" refers to an alkyl group substituted with 1 to 3 halogens. The term "alkenyl" refers to an unsaturated, straight or branched ethylene glycol hydrocarbon group with a chain length of 2 to 12 carbon atoms and 1 or 2 ethylenic bonds. The term "haloalkenyl" refers to an alkenyl group substituted with 1 to 3 halogen atoms. The term "alkynyl" refers to an unsaturated hydrocarbon group, straight or branched, having a chain length of 2 to 12 carbon atoms and 1 or 2 acetylenic bonds. The term "cycloalkyl" refers to a saturated ring system having from 3 to 7 carbon atoms. It is understood that the term "aryl" is phenyl or naphthyl, which can be further substituted with up to three substitutes independently selected from the group consisting of halogen, cyano, nitro, trihalomethyl, phenyl, phenoxy, (C 1 -C 4) alkyl, alkoxy (C 1) -C4), alkylthio (C1-C4), alkylsulfoxide (C1-C4), alkoxy (Ci-C6) and haloalkyl (C1-C4). Typical substitutes for aryl include, but are not limited to, 4-chlorophenyl, 4-fluoro-phenyl, 4-bromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 2,4-b-trichlorophenyl, 4-methoxy-phenyl, 2-chloronaphthyl, 2, 4 -methoxyphenyl, 4- (trifluoromethyl) phenyl and 2-iodo-4-methylphenyl. The term "heterocyclic" refers to a substituted unsubstituted or unsubstituted 5 or 6-membered unsaturated chain, two or three heteroatoms, preferably one, two or three heteroatoms independently selected from oxygen, nitrogen and sulfur or a bicyclic unsaturated closed chain system containing up to 10 atoms includes a heteroatom selected from oxygen, nitrogen and sulfur. Highlights among the examples of heterocycles, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyridimidinyl, pyridazinyl, pyrazole, triazolyl, imidazolyl, 2 or 3-thienyl, 2 or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl and isoquinolyl. The heterocyclic closed chain can be optionally substituted with up to two substitutes independently selected from (C? -C4) alkyl, halogen, cyano, nitro and trialomethyl. The term "aralkyl" is used to describe a group in which the alkyl chain has from 1 to 10 carbon atoms and can be a branched or straight chain, preferably a straight chain, forming the aryl portion, as defined above, a terminal portion of the aralkyl moiety. Typical aralkyl moieties are benzyl, phenethyl, phenpropyl and phenbutyl moieties optionally substituted. Typical benzyl moieties are 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-trifluoromethylbenzyl, 2,4-dichlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 3 -methylbenzyl and 4-methylbenzyl. Typical phenethyl moieties are 2- (2-chlorophenyl) ethyl, 2- (3-chlorophenyl) ethyl, 2- (4-chlorophenyl) ethyl, 2- (2-fluorophenyl) ethyl, 2- (3-fluorophenyl) ethyl , 2- (4-fluorophenyl) ethyl, 2- (2-methylphenyl) ethyl, 2- (3-methyl-phenyl) ethyl, 2- (4-methylphenyl) ethyl, 2- (4-trifluoromethylphenyl) ethyl, 2- (2,4-dichlorophenyl) -ethyl, 2- (3,5-dimethoxyphenyl) ethyl. Typical phenpropyl moieties are 3-phenylpropyl, 3- (2-chlorophenyl) propyl, 3- (3-chlorophenyl) propyl, 3- (4-chlorophenyl) propyl, 3- (2,4-dichloro-phenyl) propyl, 3- (2-fluorophenyl) propyl, 3- (3-fluorophenyl) propyl, 3- (4-fluorophenyl) propyl, 3- (2-methylphenyl) propyl, 3- (3-methylphenyl) propyl, 3- (4- methylphenyl) ethyl, 3- (4-trifluoromethylphenyl) propyl, 3- (2,4-dichlorophenyl) propyl and 3- (3,5-dimethylphenyl) propyl. Typical phenbutyl moieties include 4-phenylbutyl, 4- (2-chlorophenyl) butyl, 4- (3-chlorophenyl) butyl, 4- (4-chlorophenyl) butyl, 4- (2-fluorophenyl) butyl, 4- (3 -fluorophenyl) butyl, 4- (4-fluorophenyl) butyl, 4- (2-methylphenyl) butyl, 4- (3-methylphenyl) butyl, 4- (4-methylphenyl) butyl and 4- (2,4-dichlorophenyl) butyl, 4- (2-methoxyphenyl) butyl, 4- (3-methoxyphenyl) butyl and 4- (4-methoxyphenyl) butyl. f Halogens or halo are defined as halves iodine, fluorine, bromine and chlorine. Those skilled in the art will recognize that the groups R2, R3 and R4, R5 can exist as cis or trans isomers relative to the heterocyclic ring and Ri to C-3. These isomers can be separated into individual components by conventional methods. Both the individual isomeric compounds and mixtures thereof are part of the invention and have fungicidal properties. A preferred embodiment of the present invention are the compounds, enantiomorphs, salts and complexes of the Formula (I ') wherein R2, R3, R5 are hydrogen, Ri is aryl or C (RdR7R8), R is (C1-) alkyl C12) and R4 is independently aryl, aryloxyalkyl (C? -C4), aralkyl, heterocyclic cyano, or (C1-C4) alkoxycarbonyl.

A more preferred form of the present invention are the compounds, enantiomorphs, salts and complexes of Formula (I ") wherein X is CH, R is methyl and Ri is C (R6R7R8), wherein R6, R7 / and R8 are hydrogen.

Typical compounds encompassed by the present invention with Formula I include those compounds presented in Table 1 of Formula II wherein X is CH, R2 and R3 are hydrogen, Ri is C (ReR7 8), wherein R4, R5, d , R7 and R8 are defined in Table 1.

Table I Table i Continuation) Typical compounds encompassed by the present invention with Formula I include those compounds presented in Table 2 of Formula III wherein X is nitrogen, R2 and R3 are hydrogen, Ri is C (R6R7R8) wherein R6, R7 and R8 are defined in Table II.

(III) Typical compounds encompassed by the present invention with Formula I include those compounds presented in Table 3 of Formula IV, R2, R3 and R5 are hydrogen, and Ri, R4 and X are defined in Table 3.

(TV) As used in Tables 1 to 3, it is understood that Ph is phenyl. Scheme A describes the general procedure for the preparation of the compounds of Formula (I). These 3, 4, 5-substituted-3-heterocyclic isoxazolidines are prepared by the reaction of nitrones (V) with substituted alkenes (SAW). The 1,3-dipolar cycloaddition of nitrones with alkenes is described in Advances in Heterocyclic Chemistry, Vol. 21., pp.207-251, 1997; Angewandte Chem. Int. Ed. Vol. 2, 565-598, 1963; Synthesis, 205-221, 1975 and in J. Org. Chemistry, Vol.49, 276-1281, 1984 and in the references cited therein. The cycloaddition can proceed to provide two regioisomers one of which is shown in Scheme A of the formula I wherein R4 and R5 are bonded to the carbon adjacent to the oxygen of the isoxazolidine. Another regioisomer in which R2 and R3 are bonded to the carbon adjacent to the oxygen of the isoxazolidine are also object of the present invention. The regioisomers, when formed, can be separated by conventional techniques such as thin layer or column chromatography. The reaction of the N-substituted-3, 3-disubstituted nitrones of formula V or V is conducted in solvents such as benzene, toluene and chlorobenzene at temperatures of 50 ° C to the boiling point of the solvent and preferably to reflux in toluene. The olefins used can be tetrasubstituted olefins (VI), as shown in scheme A, but are more often olefins OI, α-disubstituted (VI where R2, R3 = H) and monosubstituted olefins (VI 'where R4 = H) such as styrenes, allylethers and substituted acrylates. The isoxazolidines of the present invention may exist in diastereomeric forms. For example, when monosubstituted olefins are used, the substitutes H and R5 can be cis or trans with respect to the C-3 heterocycle. The cis and trans isomers can be separated by normal chromatographic techniques. When separated, the isomers are designated isomer A or isomer B possessing isomer A the highest Rf in thin layer chromatography.

Scheme A where Ri is C (R6R7Rs) Scheme B describes the general procedure for the preparation of nitrones V and V. The nitrones of the present invention are N-substituted-, a-disubstituted, in such a way that the alpha substitutes must be substitutes that are not hydrogen. The chemical composition of the nitrones, both of the preparations and the reactions, is described in Chem Reviews, Vol. 64, 473-495, 1964. The nitrones of the present invention are derived from the ketones that transport a ring-shaped heterocycle. of 3-pyridyl or 5-pyrimidinyl and the other substitute as RL previously defined. The nitrones are prepared from the corresponding ketone in a hydroxyl solvent, for example, methanol or ethanol, preferably ethanol, at room temperature under reflux, preferably at room temperature, by reaction with an R-NHOH for example N-methylhydroxylamine in salt form of hydrochloride in the presence of sodium acetate. The nitrone is isolated by removing the solvent followed by trituration of the resulting wet solid with methylene chloride with isolation of the nitrone from the filtrate. Nitrones are used directly in the cycloaddition reactions described in Scheme A. Scheme B where Ri is C (R6R7R8) Ketones of formula VII and VII 'which carry substitutes of 3-pyridyl or 5-pyrimidinyl can be prepared by normal synthesis techniques or in the case of 3-acetylpyridine, is commercially available. For example, Advanced Organic Chemistry, 4th Ed, pp. 963-965, and references cited therein, describe the preparation of the ketones from nitriles by the addition of a Grignard reagent, RMgBr or an organolithium, for example RLi. Pyridyl ketones can be prepared by the Fridel Crafts acylation as described in Organic Synthesis, Vol. 37, 1957, by magnesium catalyzed acylation to form acetylpyridines as described in Tetrahedron, Vol. 48, pp. 9233-9236, 1992 , and from pyridyl esters through classical Claisen condensation as described in JACS, Vol. 69, 119 and Vol. 76, 5452, 1954. When the reaction of nitrones, V and V, with olefins (VI and VI ') provides incomplete conversion to isoxazolidines (I), mixtures (I) and (VII) are isolated. To remove the unwanted ketones VII and VII 'the mixture is exposed to an alkylhydroxylamine in an alcoholic solvent in the presence of sodium acetate and stirred at room temperature. The solvent is removed and the residue is dissolved in an organic solvent which is thoroughly washed with water. The water-soluble nitrone is removed in the aqueous phase and the resulting organic phase contains the desired pure product. The compounds of the present invention can be manufactured according to the following procedures: Example 1 5- (4-chlorophenyl) -2,3-dimethyl-3- (3-pyridyl) isoxazolidine (Compounds 1.4, 1-4A and 1.4B of the Table I) To a 500-ml 3-inlet round bottom flask were added 35g (0.233mol) of N-oxide 3-pyridyl-N-methyl ethylimine and 32.3 p-chlorostyrene (0.233mol, leq.) In 200mL of toluene. and was heated to reflux (110 ° C) for 5 hours. The reaction was monitored through thin layer chromatography (TLC) (1: 1 Hex / EtOAc). After the p-chlorostyrene was consumed the reaction was cooled to room temperature. Toluene was extracted with 300mL of 10% HCl, then 100mL of 10% HCl. The acid layer was then washed once with 100 ml of toluene. The toluene portion was discarded and the acid portion was brought to a pH of 6 with 10% NaOH. This aqueous portion was extracted with several 200ml portions of ethyl acetate. The EtOAc was washed with water and brine, dried over anhydrous sodium sulfate, filtered and extracted to provide 32 g of an orange oil which was the mixture of the desired product and 3-acetylpyridine. The crude mixture of the reaction was purified through the following process. 32 g of the crude mixture in the form of orange oil were treated with 10 g of N-methylhydroxylamine hydrochloride, and 20 g of sodium acetate in a 500 ml round bottom flask with 100 ml of absolute ethanol. The reaction mixture was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in 150 mL of ethyl acetate which was washed with 2 x 100 mL of water and 1 x 100 mL of brine. The solvent was dried over anhydrous sodium sulfate, filtered and extracted to yield 15.6g of a yellow oil whose 300MHz "" "H NMR (Nuclear Magnetic Resonance) was congruent with 5- (4-chlorophenyl) ) -2, 3-dimethyl-3- (3-pyridyl) isoxazolidine as a 2: 1 mixture of isomer A (higher Rf 'in TLC): isomer B (lower Rf in TLC).

NMR (XH 200MHz) of compound 1.04: 1.6-1.7 (two singlet, 3H), 2.6 (two singlet, 3H), 2.3-2.9 (m, 2H), 4.9-5.4 (two dd, 1H), 7.0-7.4 ( m 5H), 7.8-8.0 (two dd, 1H), 8.5-8.6 (two dd, 1H) and 8.75 and 8.85 (two dd, 1H) 8g of the crude mixture were purified by column chromatography on silica gel with 1 : 1 hexane: EtAOc and 1.2g of 9: 1 isomers A: B was produced as clear oil, 0.4 of 4: 1 isomers A: B, clear oil, 0.2g of 1: 6 isomers A: B, as a white solid, mp. 75 ° C-80 ° C and 2.0g of 4: 5 mixture of the A: B isomers as a mixture of solid and oil (yield of 52.5% based on 8g purified). NMR (1H 200MHz) 9: 1 isomers A: B, major isomer A, Compound 1.04A: 1.6 (s, 3H), 2.6 (s, 3H), 2.5-2.9 (m, 2H), 5.2-5.4 (dd, 1H), 7.0-7.4 (m, 5H), 7.8-7.9 (d, 1H), 8.5 (d, 1H) and 8.75 (d, 1H). NMR ("" "H 200MHz) 1: 5 isomers A: B, major isomer B, Compound 1.04B: 1.55 (s, 3H), 2.6 (s, 3H), 2.3-2.9 (m, 2H), 4.85-5.0 (t, 1H), 7.0-7.4 (m, 5H), 7.9-8.0 (d, 1H), 8.6 (d, 1H) and 8.85 (d, 1H) Synthesis of Nitrona, N-oxide of 3-pyridyl- N-methyl ethylimine. 3-Acetylpyridine (80g, 0.661mol), N-methylhydroxylamine hydrochloride (84g, l.Oldmol, 1.5eq) and sodium acetate (164.8g, 2.01mol, 3eq) were combined in a round bottom flask. with 450mL of absolute ethanol, allowed to stir overnight, the mixture was monitored by TLC (1: 1 EtAc / Hexanes), the disappearance of the 3-acetylpyridene stain and the formation of a stain on the line was monitored. base (presumably nitrone) The ethanol was removed, the residue was taken in 400 mL of methylene chloride, the remaining residue was filtered, dried over anhydrous sodium sulfate, filtered and extracted to produce a light yellow oil. for this run it was 94g (95%) Example 2 Isoxazolidine 5-fe noxymethyl-3-phenyl-3- (3-pyridyl) -2-methyl Compounds 3.22A, 3.22B of Table 3. In a 300 ml 3-inlet round bottom flask under nitrogen 2.1 (1.0 eq. mmol) of 3-pyridyl-N-methyl benzylimine N-oxide in 25 ml of toluene and 4.0 g (3.0eq., 30 mmole) of allyl phenyl ether in 25 ml of toluene and heated to reflux (110 ° C). After one day, the following additional initial reagents were added to the flask: 1.05g (1.0 eq., 5 mmol) of N-oxide and 2.0g (3.0 eq., 15 mmol) of ether. It was heated to reflux for 6 days and worked. Work of the reaction solution was concentrated in a rotary vaporizer at 50 ° C to provide 6.6 g of wet solid containing a mixture of the stereoisomers. The wet solid was triturated with ethyl acetate / hexane and filtered under vacuum to provide 1.8 isomer A (top spot, Rf = 0.59 ethyl acetate / hexane 1: 1) as a solid product, mp = 145 ° C-147 ° C). NMR (XH 200MHz) of Compound 3.22A: 2.5 (s, 3H); 3.0 (s, 1H); 3.3 (s, 1H); 3.7-4.1 (m, 2H); 4.65 (s, 1H); 6.8-7.4 (m 11H); 7.85 (d, 1H); 8.5 (dd, 1H); 8.65 (d, 1H). The filtrate was concentrated to provide 4.5g of yellow oil and chromatography (ethyl acetate / hexane 1: 1) was made to give 0.7g of isomer B (Rf = 0.47 ethyl acetate / hexane 1: 1) the product was a yellow oil). NMR ^ H 200MHz) of Compound 3.22B: 2.5 (s, 3H); 3.1 (s, 2H); 4.1 (s, 2H); 4.4 (s, 1H); 6.85-7.4 (m, 11H); 7.9 (s 1H); 8.5 (dd, 1H); 8.65 (d, 1H). Preparation of 3-pyridyl-N-methyl benzylimine N-oxide In a 300 ml 3-inlet 3-necked round bottom flask under N2 were added 9.15 g (1.0 eq., 0.050 mmol) 3-benzoylpyridine in 50 ml of absolute ethanol and they dissolved. 5.0 g net (1.2 eq., 0.060 mole) of N-methyl hydroxylamine hydrochloride were added followed by 9.84 g (2.4 eq., 0.12 mole) of acetic acid, sodium salt. The reaction was stirred for 88 h at room temperature and brought to reflux (78 ° C) for 20 h followed by work. The reaction solution was made basic to pH 8 with potassium carbonate, the solid was filtered and the filtrate was concentrated to give an orange wet solid. The wet solid was triturated in methylene chloride, filtered, the filtrate was dried over anhydrous magnesium sulfate and concentrated to provide 11.3 g of orange solid, 60% product and 40% of initial ketone by GC. The crude solid is triturated with ethyl acetate and filtered to provide 2.4 g of product as a white solid, mp = 143 ° C-146 ° C. A second batch of 1.5g was isolated with a slightly higher purity of the filtrate after concentration and grinding. The total product was 3.9g (36.8% yield). NMR ^ H 200MHz): 3.8 (s, 3H); 7.2-7.6 (m, 6H); 8.6 (d, 1H); 8.8 (dd, 1H); 8.9 (d, 1H). Example 3 Proton NMR data (200 MHz) are provided in Table IV for representative compounds typical of Tables I and II.

Table IV: Table IV Continuation) Table IV (Continued) Note: The 1HNRM spectrum was recorded using CDC13. The following codes were used: s = singlet, d doublets, t = triplets, m = multiplets, br = broad peak. Example 4 Several compounds of the present invention were tested for fungicidal activity in vivo against the diseases described below. The compounds were dissolved in a 1: 1 mixture of acetone and methanol 2: 1: 1 or N, N-dimethylformamide and diluted with a mixture of water, acetone and methanol (by volume) 2: 1: 1 to reach the concentration adequate The solution was sprayed on the plants and allowed to dry for two hours. The plants were inoculated with fungal spores. Each test used control plants that were sprayed with the proper solvent and inoculated. For these protection tests, the plants were inoculated one day after being treated with the compounds of the present invention. The rest of the technique of each of the tests is mentioned below together with the results of several compounds described herein by the number of compound compared to the various fungi at a dose of 100 or 150 grams per hectare. The results are the percentage of disease control compared to untreated verification, where A is 90-100% disease control, B is 70-89% control, C is 50-69% control, and D is less than 50% control of the disease. The application of the test fungal spores to these test plants was as follows: Scalding of Wheat Leaves (SNW) Septoria nodorum cultures were maintained on V-8 Czapek-Dox juice agar plants in a 20 ° incubator C with alternating periods of 12 hours of light and 12 hours of darkness for 2 weeks. A suspension of water from the spores was obtained by stirring the portion of the plate with fungal material in deionized water and filtering through cheesecloth. The suspension of water containing spores was diluted to a spore concentration of 3.0 x 106 spores per ml. The inoculum was dispersed by a DeVilbiss atomizer over one week old Fielder wheat plants that had previously been sprayed with the fungicide compound. The inoculated plants were placed in a humidity cabinet at 20 ° C with 12 hours of light and 12 hours of alternating darkness for 7 days. The inoculated seedlings were then transferred to a room with controlled environment at 20 ° C for 2 days of incubation. Disease control values were recorded as percentage control. Powdery mildew (WPM) Erysiphe graminis (f.t. tri tici) was grown in wheat seedlings, Fielder variety obtained by selection, in a temperature controlled room at 18 ° C. Mildeu spores were agitated from the culture plants in the mildew spores were shaken from the crop plants on the 7-day wheat seedlings that had previously been sprayed with the fungicide compound. The inoculated seedlings were kept in a room with controlled temperature at 18 ° C and rose up. The percentage of disease control was classified 7 days after the inoculation. The control values of the disease were recorded as a percentage of control. Powdery mildew of the Cucurbitaceae (CPM) Sphaerotheca fulginea was maintained in cucumber plants, Bush Champion variety obtained by selection, in the greenhouse. The inoculum was prepared by placing five to ten leaves with many mildeus in a glass container with 500 ml of water containing one drop of Twee 80 (polyoxyethylene monooleate) per 100 ml. After shaking the liquid and the leaves, the inoculum was filtered through cheesecloth and sprayed on the plants with a nebulizer bottle. The spore count was 100,000 spores / ml. The plants were then placed in the greenhouse for infection and incubation. The plants were assigned a score 7 days after inaction. The control values of the disease were recorded as a percentage of control. Blight of Rice (RB). Cultures of Pylicularia oyrzae were maintained on potato dextrose agar for two to three weeks. The spores were washed from the agar with water containing one drop of Tween 80 per 100. After filtering the suspension of the spores through two layers of cheesecloth, the spore count was adjusted to 5 x 105. The suspension of the spores was sprayed on 12-day rice plants, variety M-l obtained by selection, using a De Vilbiss atomizer. The inoculated plants were placed in a humid chamber at 20 ° C for 36 hours to allow infection. After the period of infection, the plants were placed in the greenhouse. After 6 days, a score was assigned to the plants in terms of disease control. The control values of the disease were recorded as a percentage of control. Gray rot of cucurbits (BOT) Cucumber plants were maintained in the greenhouse. The large, fully expanded leaves were collected from the plates. The stems were wrapped in cotton, the leaves were placed in a large petri dish (15-cm diameter) and the leaves were supported with glass rods. The top cover of the plate was removed and the top surface of the separated cucumber sheet was sprayed with the compounds of the present invention. The sheet was allowed to air dry for about 2 hours. Botrytis cinerea cultures were maintained on potato dextrose agar for two or three weeks. 6 mm diameter agar plugs were cut from the periphery of the margin of the fungal colony with an internal diameter of cork. These agar plugs were placed with the fungal surface in contact with the treated upper surface of the cucumber leaf. Each leaf received two miscellar plugs. After placing the petri dish on the leaves, the plates were returned to a controlled environmental chamber at 20 ° C and a humidity of 90% for three or four days. After this time, the diameter of the lesions produced by the miscellar plug was measured. The average size of the lesion was compared with the size of the lesion produced in the control leaves. The data were expressed as a percentage of control. Mildeu de la Cucurbitaceae (CDM) Cucumber plants were kept in the greenhouse. The large, fully expanded leaves were collected from the plates. The stems were wrapped in cotton, the leaves were placed in a large petri dish (15-cm diameter) and the leaves were supported with glass rods. The top cover of the plate was removed and the top surface of the separated cucumber sheet was sprayed with the compounds of the present invention. The sheet was allowed to air dry for about 2 hours. Cultures of Pseudoperonospora cuhenis were maintained in cucumber plants. After extracting the spores by shaking the leaves in water, the lower surface of the treated cucumber leaves were sprayed with a spore concentration of 100,000 spores per ml. The plates were returned to a chamber with controlled environment at 20 ° C and 90% humidity for five days. After this time, the leaves were examined in view of the development of the disease. The control values of the disease were recorded as a percentage of control.

When tested against the scald of wheat leaves at 300 grams per hectare, compound 1.7 showed a control located in classification group B. When tested against wheat powdery mildew at 300 grams per hectare, compounds 1.04A , 1.10, and 1.51 showed control in the classification group A and compounds 1.7, 1.13 and 1.63 showed control in the classification group B. When tested against the powdery mildew of the cucurbits at a dose of 300 grams per hectare, 1.04 showed control in the classification group A and 1.23 in the classification group B. When tested against grape powdery mildew at 300g per hectare, compounds 1.04, 1.10, 1.39 and 1.51 showed control in the classification group B. When were tested against the rice stubble at 300g per hectare compounds 1.04A, 1.9 and 1.10 showed control in the classification group A and 1.13, 1.39 and 1.51 showed control in the classification group. B. When tested against the gray speck of cucurbits at 300 grams per hectare, compounds 1.04A, 1.15 and 1.51 showed control in the classification group A.

The compounds of the present invention are useful as agricultural fungicides, and as such they can be applied to several places, for example, the seed, soil or foliage of the plants to be protected. The compounds of the present invention can be applied as fungicide sprays by commonly employed methods, for example, conventional high volume hydraulic sprays, low volume sprays, air blast sprays, sprays and air jets. The dissolution and the rate of application will depend on the type of equipment used, the method of application, the plants to be treated and the diseases to be controlled. In general, the compounds of the present invention will be applied in an amount of from about 0.005 kilograms to about 50 kilograms per hectare and preferably from about 0.025 to about 25 kilograms per hectare of active ingredient. As a seed protector, the amount of toxicant coated in the seed is generally from a dosage rate of from about 0.05 to about 20, preferably from about 0.05 to about 4, more preferably from about 0.1 to about 1 gram per one hundred kilograms of seed. As a soil fungicide the chemical compound can be incorporated into the soil or applied to the surface generally at a rate of from about 0.02 to about 20, preferably from about 0.05 to about 10, and more preferably from 0.1 to about 5 kilograms per hectare. As a foliar fungicide, the toxicant is generally applied to growing plants at a rate of from about 0.01 to about 10, preferably from 0.02 to about 5, and more preferably from 0.25 to about 1 kilogram per hectare. While the compounds of the present invention exhibit fungicidal activity, these compounds can be combined with other known fungicides to provide broad spectrum activity. Suitable fungicides include, but are not limited to, the compounds listed in U.S. Patent No. 5,252,594 (see in particular columns 14 and 15). Other known fungicides which can be combined with the compounds of the invention are dimethomorph, ciymoxanil, trifluzamide, furalaxyl, ofurace, benalaxyl, oxadixyl, propamocarb, ciprofuram, phenpiclonil, fludioxonil, pyrimethanil, cyprodinil, triticonazole, fluquinconazole, metconazole, spiroxamine, carpropamide, azoxystrobin , queroxim-de methyl, metominoestrobin and trifloxeistrobin.

The compounds of the present invention can be advantageously employed in various ways. Since these compounds possess a broad spectrum fungicidal activity, they can be used in the storage of cereal grains. These compounds can also be used as fungicides in cereals including wheat, barley and rye, in rice, peanuts, beans and grapes, in grass, in fruits, nuts and vegetables orchards, and applications for golf courses. Examples of the diseases against which the compounds of the invention are useful are helminthosporiosis of wheat and barley, powdery mildew of wheat and barley, rusts of the leaf and stem of wheat, spot blotch and rust. of barley leaves, early tomato blight, tomato late blight, early peanut leaf spot, grape powdery mildew, rot of grape leaves, apple scab, apple powdery mildew, powdery mildew Cucurbitaceae, fruit rot, gray rot, powdery mildew of beans, anthragnosis of cucurbits, septoria of wheat, blight of rice pod and rice blight. The compounds of the present invention can be applied in the form of compositions or formulations. An example of the preparation of compositions and formulations can be found in the publication of the American Chemical Society "Pesticidal Formulation Research" (1969), Series of Advances in Chemistry No. 86, written by Wade Van Valkenburg and in the publication of Marcel Dekker, Inc . "Pesticide Formulations" / (1973) edited by Wade Van Valkenburg. In these compositions and formulations, the active substance is mixed with the conventional inert element acceptable from the agronomic point of view (ie, compatible with the plant or inert from the point of view of the pesticide, or both), diluents or extenders of pesticides, for example solid carrier material or liquid carrier material, of the type usable in conventional pesticide compositions or formulations. By "agronomically acceptable carrier" is meant any substance that can be applied to dissolve, disperse or diffuse the active ingredient in the composition without hindering the effectiveness of the active ingredient and which by itself has no significant harmful effect on the soil , equipment, desirable plants or agronomic environment. If desired, adjuvants can also be combined, for example, sulfactants, stabilizers, antifoaming agents and anti-aging agents.

Examples of compositions and formulations according to the invention are aqueous solutions and dispersions, oily solutions and oil dispersions, pastes, dusting powders, wettable powders, emulsifiable concentrates, flowable elements, granules, baits, invert emulsions, aerosol compositions and Fumigating candles. Moisturizing powders, pastes, flowable elements, emulsifiable concentrates are concentrated preparations that are diluted with water before or during their use. In such formulations, the compounds are expanded with a liquid or solid carrier and, where desired, suitable surfactants are incorporated. Decoys are preparations that generally comprise a food or other substance attractive to insects, which includes at least one compound of the instant invention. Usually, it is desirable, particularly in the case of formulations for foliar spray, to include adjuvants, such as wetting agents, spreading agents, dispersing agents, stickers, adhesives and the like in accordance with a list of adjuvants commonly used in the The technique, and an analysis thereof, can be found in many references, for example in the publication of John W. McCutcheon, "Detergents and Emulsifiers, Annual".

The active compounds of the present invention can be used only in the form of mixtures with one another or with solid or liquid dispersible carrier vehicles, or other compatible active agents, especially plant protection agents, for example insecticides, arthropodicides, nematicides , fungicides, bactericides, rodenticides, herbicides, fertilizers, growth regulation agents and synergists. In the composition of the invention, the active compound is present in an amount substantially between about 0.0001 (1: 999,999) -99 (99: 1)% by weight. For compositions suitable for storage or transportation, the amount of the active ingredient is preferably between about 0.5 (1: 199) 90 (9: 1)% by weight, and more preferably between about (1:99) -75 (3 : 1)% weight of the mixture. Compositions suitable for direct filtration or field application generally contain the active compound in an amount substantially between 0.0001 (1: 999.999) -95 (19: 1)%, and more preferably between about 0.0005 (1: 199.999) -75 (3: 1)% by weight of the mixture. The composition can also be designated as a proportion of the compound with respect to the carrier. In the present invention, the weight ratio of these materials (active compound / carrier) can vary from 99: 1 (99%) to 1: 4 (20%) and more preferably from 10: 1 (91%) to 1: 3 (25%). In general, the compounds of the present invention can be dissolved in certain solvents, for example, acetone, methanol, ethanol, dimethylformamide, pyridine or dimethylsulfoxide and the solutions can be diluted with water. The concentrations of the solution may vary from about 1% to about 90% with a preferred range of about 5% to about 50%. For the preparation of emulsifiable concentrates, the composition can be dissolved in suitable organic solvents, or a mixture of solvents, together with an emulsifying agent to improve the dispersion of the compound in water, the concentration of the active ingredient in the emulsifiable concentrates is generally about 10. % to about 90%, and in fluid emulsion concentrates it can be up to about 75%. Wettable powders suitable for sprinkling, can be prepared by mixing the compound with a finely divided solid, such as clay, inorganic silicate and carbonate, and silica and incorporating wetting agents, sticking agents or dispersing agents in mixtures. The concentration of the active ingredients of the formulations is generally in the range of about 20% to about 99%, preferably from about 40% to about 75%. A typical wetting powder is made by mixing 50 parts of a compound of Formula I, 45 parts of a hydrated silicone dioxide and synthetic precipitate, such as that sold under the tradename HI-Si R, available from PPG Industries, Pittsburgh, PA and 5 parts of sodium lingosulfonate. In another preparation a kaolin clay (Barden) is used in place of synthetic precipitated hydrated silicone dioxide in the above wetting powder, and in another preparation 25% is replaced with a synthetic sodium silicoaluminate, sold under the trade name Zeolex ®3 .. The powders are prepared with the compounds of Formula I, or the enantiomorphs, salts and complexes thereof with finely divided inert solids which may be organic or inorganic in nature. Useful materials for this purpose include botanical flours, silica, silicates, carbonates and clays. A convenient method for preparing a powder is to dilute a wetting powder with a finely divided carrier. Powder concentrates containing from about 20% to about 80% active ingredient are commonly manufactured and are subsequently diluted from about 1% to about 10% to be used in the concentration. The active compounds can be applied as sprays and insecticides by commonly used methods, for example high-gallonage hydraulic sprays, low-gallonage sprays, ultra-low volume sprays, air-spray sprays, aerial sprays and powders. The present invention also contemplates methods for killing, combating or controlling pests comprising contacting the pests with a combative or toxic amount. (that is, a pesticidally effective amount) of at least one active compound of the invention alone or together with a transported vehicle (composition or formulation) as noted above. The term "contacting" as used in the present specification and the claims means applying at least one of (a) said pests and (b) the corresponding habitat thereof (ie, the place to be protected, by example, a crop being grown or an area where a crop will be grown) the active compound of the present invention alone or as a constituent of a composition or formulation. In addition to the aforementioned ingredients, the preparations according to the invention may also include other substances commonly used in preparations of this type. For example, a lubricant, for example calcium stearate or magnesium stearate, can be added to the wetting powder or to a mixture to be granulated. In addition, for example, "adhesives" may be added, for example, polyvinyl alcohol-based cellulose derivatives or other colloidal materials, for example caffeine to improve the adhesion of the plasmicide to the surface to be protected.

Claims (10)

1. CLAIMS A compound of the formula: ' wherein X is CH or nitrogen; R is selected from a group consisting of alkyl (Ci- C? 2), haloalkyl (C? -C? 2), alkenyl (C2-C8), haloalkenyl (C2-C8), alkynyl (C2-C8), halo alkynyl (C2-C8), alkoxy (Cx-C2) alkyl (C? -C? 2), cycloalkyl (C3-C7), halo cycloalkyl (C3-C7), (C3-C7) cycloalkyl (C1-C4) alkyl, aralkyl, aryloxyalkyl (C1-C4) and heterocyclic; Ri is selected from the group consisting of aryl, heterocyclic and C (ReR7R8). R2 and R3 are each independently selected from the group consisting of alkyl (C? -C? 2), halo alkyl (C? ~ C? 2), alkoxy (C? -C12), halo alkoxy (C? ~ C12) , halo (C3-C7) alkoxy, (C3-C7) cycloalkyl (C1-C4) alkyl, aryl, aralkyl, heterocyclic, cyano and alkoxycarbonyl (C? -C4); R4 and Rs are each selected from the group consisting of alkyl (C? ~ C? 2), haloalkyl (C? -C? 2), alkenyl (C2-C8), halo alkenyl (C2-C8), alkynyl ( C2-C8), haloalkynyl (C2-C8), cycloalkyl (C3-C7), halo cyclo (C3-C7) alkyl, cycloalkyl (C3-C7) alkyl (C? ~ C4) aryl, aryloxy (C1-C4) alkyl , aralkyl, heterocyclic, cyano and alkoxycarbonyl, such that R 4 and R 5 are not both hydrogen. R6, R7 and R8 are each independently selected from the group consisting of hydrogen, alkyl (C? -C? 2), alkenyl (C2-C8), alkynyl (C? -C? 2), alkoxy (C? -C 2) alkyl (C x -C 2), cyclo (C 3 -C 7) alkyl, (C 3 -C 7) cycloalkyl (C 1 -C 4) alkyl, aryl, aralkyl and (C 1 -C 4) heterocyclic alkyl; And enantiomers, stereoisomers and agronomically acceptable salts thereof.
2. 2. The compound of claim 1, wherein R is selected from the group consisting of alkyl (C? -C? 2) and haloalkyl (C? -C? 2), Ri is selected from the group consisting of aryl and C (R6, R7, R8) and R is selected from the group consisting of substituted phenyltriallymethyl and substituted halo phenyl.
3. 3. The compound of claim 2, wherein R is (C? -C4) alkyl, Ri is selected from the group consisting of phenyl, substituted halo phenyl and C (Rd, R7, R8), and R4 is selected from the group which consists of 2-chlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl and 2,4-dichlorophenyl.
4. 4. The compound of claim 2, wherein R is alkyl (C? -C), R4 is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, -trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl and 2,4-dichlorophenyl, and Re, R7 and Rs are each independently selected from the group consisting of hydrogen and (C1-C4) alkyl.
5. The compound of claim 3, wherein R is methyl, Ri is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and R 4 is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl and 2, -dichlorophenyl.
6. 6. The compound of claim 4, wherein R is methyl, R4 is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl and 2,4-dichlorophenyl, and Re, R7 and Rs are hydrogen.
7. 7. The compound of claim 5, wherein Ri is selected from the group consisting of phenyl, 4-chlorophenyl, R4 is selected from the group consisting of 4-chlorophenyl and 4-fluorophenyl.
8. 8. The compound 5- (4-chlorophenyl) -2,3-dimethyl-3- (3-pyridyl) isoxazolidine.
9. 9. A fungicide composition for controlling phytopathogenic fungi, which comprises an agronomically acceptable carrier and the compound of the claim 1 wherein the ratio between the carrier and the compound is between 99.1 and 1: 4.
10. 10. A method for controlling phytopathogenic fungi, which comprises applying the compound of claim 1 at the point of location where the control is desired, at a rate of

    0. 005 to 50 kilograms per hectare. SUMMARY OF THE INVENTION Compounds with fungal properties that the formula has i wherein X is CH or nitrogen; R is selected from a group consisting of alkyl (C? -C? 2), halo alkyl (C? -C? 2), alkenyl (C2-C8), halo alkenyl (C2-C8), alkynyl (C2-C8), halo alkynyl (C2-C8), alkoxy (C? -C12) alkyl (C? -C12), cycloalkyl (C3-C7) , cycloalkyl halo (C3-C7), cycloalkyl (C3-C7) alkyl (C? ~ C), aralkyl, aryloxyalkyl (C1-C4) and heterocyclic; Ri is selected from the group consisting of aryl, heterocyclic and C (R6R7R8) R2 v3 are each independently selected from the group consisting of alkyl (Ci- C? 2), haloalkyl (C? -C12), alkoxy (C ? -C? 2), halo alkoxy (C? C? 2), halo alkoxy (C3-C7), cycloalkyl (C3-C7) alkyl (C1-C4), aryl, aralkyl, heterocyclic, cyano, and alkoxycarbonyl (Ci-? C4) R4 and R5 are each selected from the group consisting of alkyl (C? -C? 2), halo alkyl (C? -C? 2), alkenyl (C2-C8), halo alkenyl (C2-C8), (C2-C8) alkynyl, (C2-C8) haloalkynyl, (C3-C7) cycloalkyl, (C3-C7) alkyl cycloalkyl, (C3-C7) cycloalkyl (C? -C) alkyl, aryl, aryloxy alkyl (C1) -C4), aralkyl, heterocyclic, cyano and alkoxycarbonyl, such that R4 and R5 are not both hydrogen. Rβ, R7 and R8 are each independently selected from the group consisting of hydrogen, alkyl (C? -C? 2), alkenyl (C2-C8), alkynyl (C? -C? 2), alkoxy (C? -C12) ) alkyl (C? -C? 2), cycloalkyl (C3-C7), cycloalkyl (C3-C7) alkyl (C1-C4), aryl, aralkyl and heterocyclic alkyl (C1-C4)