WO1998008387A1 - Plant protectants - Google Patents

Plant protectants Download PDF

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Publication number
WO1998008387A1
WO1998008387A1 PCT/FI1997/000498 FI9700498W WO9808387A1 WO 1998008387 A1 WO1998008387 A1 WO 1998008387A1 FI 9700498 W FI9700498 W FI 9700498W WO 9808387 A1 WO9808387 A1 WO 9808387A1
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Prior art keywords
formula
hydrogen
compound
sch
compounds
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PCT/FI1997/000498
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French (fr)
Inventor
Radii M. Khomutov
Vitalii G. Djavakhia
Alex R. Khomutov
Seppo MÄKINEN
Original Assignee
Khomutov Radii M
Djavakhia Vitalii G
Khomutov Alex R
Maekinen Seppo
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Application filed by Khomutov Radii M, Djavakhia Vitalii G, Khomutov Alex R, Maekinen Seppo filed Critical Khomutov Radii M
Priority to AU40168/97A priority Critical patent/AU4016897A/en
Publication of WO1998008387A1 publication Critical patent/WO1998008387A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
    • A01N57/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing acyclic or cycloaliphatic radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
    • A01N57/22—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing aromatic radicals

Definitions

  • the present invention relates to the synthesis and application of phosphinic acid derivatives, especially to ami- no phosphinic acids.
  • This class of compounds contains both known and earlier unknown representatives.
  • the invention also relates to compositions for use in plant protection containing as active ingredients the above chemicals, as well as the use of said chemicals as plant protectants against phytopathogens, especially against phytopathogenic fungi.
  • the compounds of formula 1 are claimed as new chemicals possessing valuable medicinal and pharma- ceutical properties. They are, for example, antimicrobial agents, which are effective at low concentrations (0.8 to 50 ⁇ g/ml) in inhibiting the growth in vitro of bacteria pathogenic to humans, as for example Escherichia coli, Enterobacter cloacae and other Enterobacteria, Pseudo- monas aeruginosa and yeasts pathogenic for humans, for example Candida albicans and C. tropicalis.
  • antimicrobial agents which are effective at low concentrations (0.8 to 50 ⁇ g/ml) in inhibiting the growth in vitro of bacteria pathogenic to humans, as for example Escherichia coli, Enterobacter cloacae and other Enterobacteria, Pseudo- monas aeruginosa and yeasts pathogenic for humans, for example Candida albicans and C. tropicalis.
  • the compounds of formula 1 are also effective in vivo. At dose levels between 15-100 mg/kg these drugs given subcu- taneously or orally, for example in mice, protect 50% of the animals (ED 50 ) from death following infections with a lethal dose of pathogenic bacteria such as, for example, Klebsiella pneumoniae or Pseudomonas aeruginosa .
  • the present invention describes earlier unknown proper- ties of both known and unknown compounds of formula 1 as plant disease protectants against phytopathogens; it also describes earlier unknown compounds of formula 1A.
  • the compounds of the formula 1 are demonstrated to pos- sess plant disease protecting properties against a set of plant pathogens and suggested as an active ingredient in compositions active against different causal agents of cereal, fruit and vegetable diseases.
  • the present invention is typically employed in agriculture and agrochemistry for treating or preventing plant diseases, especially for the treatment of plant pathogenic fungi.
  • the present invention describes in its broadest sense the use of compounds of formula 1 against phytopathogens and as plant-protectants , the compounds having the general formula
  • R and R are the same or different and are selected from the group consisting of - hydrogen; deuterium;
  • R 2 groups may be the same or different, and are a) hydrogen; b) a lower alkyl, lower alkenyl, lower alkynyl group, which may be substituted with one or two groups se lected from -OH, -
  • R and Rj together form a C 2 -C 7 poly ethylene chain optionally interrupted by an oxygen, nitrogen or sulfur atom; and the salts thereof with organic or inorganic acids and bases, as well as their optical isomers, excluding the compound wherein R is hydrogen and R, is CH 3 , as plant protectants and against phytopatogenic fungi.
  • lower referred to above and hereinafter in connection with organic radicals or compounds respectively, define such with up to 5 carbon atoms.
  • a lower alkyl group of 1 to 5 carbon atoms may be a straight or branched alkyl group and may be, for example, a methyl, ethyl, n-propyl, i-propyl, i-butyl, sec-butyl group.
  • a halogen substituent may be bromine or iodine, but is preferably fluorine or chlorine.
  • a lower alkenyl group may be a C 2 -C 5 straight or branched chain alkenyl group, and may be, for example, a ethenyl, allyl, crotyl, methallyl or methoxyethenyl group.
  • a lower alkynyl group may be a C 2 -C 5 straight or branched chain alkynyl group, and may be, for example, a ethynyl, propynyl or butynyl group.
  • a cycloalkyl group is a cycloalkyl group with 3 to 6 carbon atoms, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • R or R together form a polymethylene chain
  • this may be for example -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, - (CH 2 ) 2 0(CH 2 ) 2 - or -(CH 2 ) 2 NH(CH 2 ) 2 -.
  • the group -COOR 2 is advantageously hydroxycarbonyl, met- hoxycarbonyl, ethoxycarbony1 or i-propoxycarbonyl.
  • the group -OR 2 is advantageously hydroxy, methoxy, ethoxy, i-propoxy.
  • Aryloxy OR 2 is advantageously phenoxy, tolylo- xy, xylyloxy or phenylendihydroxy, and especially benzy- loxy.
  • the group -SR 2 is advantageously thiol, methylthio, ethylthio, and in addition also advantageously benzyl- thio, -S(CH 2 ) n NH 2 , -S(CH 2 ) n 0H, -S (CH 2 ) n 0NH 2 , -S (CH 2 ) n COOH, -S(CH 2 ) n P0 2 H 2 , -S(CH 2 ) n P0 3 H 2 , -S (CH 2 ) m CH (NH 2 ) P0 2 H 2 , -S(CH 2 ) m CH(NH 2 )P0 3 H 2 , -S (CH 2 ) m CH (NH 2 ) COOH, or
  • the group -S(0)-R 2 is advantageously -(CH 2 ) m S(0)R 2 , such as -CH 2 CH 2 S (0) CH 3
  • n may be from 2 to , and m from 1 to 3.
  • the -S(R 2 ) 2 group may be, for example, di ethylsulfonium, methylethylsulfonium, diethylsulfonium, methylpropylsul- fonium, or methylbenzylsulfonium.
  • An aryl group with 6 to 10 carbon atoms as substituent of a lower alkyl, alkenyl or alkynyl group is for example a phenyl, benzyl, tolyl, xylyl, ethylphenyl, propylphenyl , i-propylphenyl or naphthyl group.
  • a heterocyclic ring as a substituent of a lower alkyl, alkenyl or alkynyl group means a saturated or unsaturated cyclic carbon ring, an unsaturated ring containing at least one double bond. Both groups contain one or more oxygen, nitrogen or sulfur atoms, and may be, for example, aziridine, oxetane, thiophene, furan, pyridine, iso- xazole, thiazole, imidazole, pyrimidine, thiadiazole, triazole, triazine, indole, purine or benzofuran.
  • An aryl or heterocyclic ring as defined above is unsubs- tituted or may be substituted by one to three substi- tuents, which are -COOH, -OH, -NH 2 , -N0 2 or -SH groups.
  • R or R is a lower alkyl group substituted by an aryl group with 6 to 10 carbon atoms or a 3 to 9-membered heterocyclic ring
  • the substituted alkyl group will preferably form a C j -C 3 straight or branched alkylene chain, for example, -CH 2 -, -CH(CH 3 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 - or -CH(CH 3 )CH 2 -.
  • the group of compounds of formula 1 includes both known and unknown structures.
  • the invention also relates to earlier unknown compounds formula 1 which are preferably the phosphinic analogues of sulfur containing a ino acids; phosphinic analogues of Asn, Gin, canaline and aminooxy alanine.
  • the object of the invention is thus a novel group of compounds of the formula 1A
  • R is hydrogen, a lower alkyl, lower alkenyl or lower alkynyl group with 1 to 5, or 2 to 5 carbon atoms, respectively
  • ⁇ is selected from the group consisting of -(CH 2 ) ra S + (R 2 ) 2 , "(CH 2 ) m C(0)N(R 2 ) 2 , -(CH 2 ) ffi S(CH 2 ) m CH(NH 2 )COOR 2 , - (CH 2 ) m S (CH 2 ) n ONH 2 ,
  • R is hydrogen or lower alkyl
  • Rj is carboxymethylene, carboxyethylene, dimethylthioethylene, carboxamidomethylene, carboxamidoethylene
  • R t is dimethyltioethylene or carboxymethylene and the salts thereof with inorganic or organic acids or bases, and optical isomers.
  • novel compounds of the formula 1A may be prepared in a manner analogous to those described above for the known compounds, see especially Khomutov et al . , or alternatively Baylis et al .
  • New phosphinic cystat- hionine and lanthionine analogues are derived from phos- phinic cysteine or ho ocysteine analogues by alkylation with corresponding / ⁇ -substituted alanines, ⁇ -substituted butyric acids, their phosphonic and phosphinic analogues; or from corresponding carbonyl precursors in accordance with the above published methods.
  • Novel phosphinic analogues of asparagine and glutamine were prepared by amina- tion of activated distalic carboxyl groups of corresponding phosphinic analogues of aspartic and glutamic acids, respectively.
  • Phosphinic analogues of canaline and amino- oxy alanine are derived from aminooxy-protected derivatives of corresponding aldehydes in accordance with the above published methods.
  • Both known and unknown compounds of formula 1 are demon- strated to possess inhibiting properties against a set of plant pathogens and suggested as an active ingredients of compositions being active against different causal agents of cereal, fruit and vegetable plant diseases.
  • Both known and unknown compounds of formula 1 are demonstrated to possess inhibitor properties against a set of plant pathogens including Pyricularia oryzae; Erysiphe graminis ; Puccinia recondita; Phytophthora infe ⁇ tans ; Venturia inaeqalis; Botrytis cinerea (including strains resistant to Benomyl R and Iprodione R ) ; Septoria nodorum;
  • Pyrenophora tritici-repentis Fusarium graminearum; Fusa- rium moniliforme; Alternaria solani ; Rhizoctonia solani ; and Helminthosporium sativum .
  • the compounds described herein may be used in the form of suitable formulations, especially as solutions with water, or with suitable organic solvents, and subsequently diluted with water.
  • the preparation of such formulations is within the knowledge of a person skilled in the art.
  • concentration of the active agent in the formulation depends on the pathogen, the plant to be treated as well as on the compound to be used. For example a 0.1 % solu- tion of the compound in water has proven acceptable in many field and greenhouse experiments.
  • the amount of active agent to be used can vary, but normally falls within the range of 0.5 to 2.5 kg/ha.
  • Example 14 The results of two-season tests are presented in Example 14. The data presented in Example 14 were obtained according to generally accepted methods. Field experiments were performed in two biologically different seasons. The season II was exceptionally favourable for rice blast disease development that decreased rice productivity. Several varieties of rice were investigated, including those cultivated in different countries. Among these varieties there were such that had a high productivity with good quality of grain, but having low resistance against pathogens, or such possessing opposite combination of pro- perties. The effectivity of the compound 9 was compared with commercial fungicides.
  • Compound 9 demonstrated good in vitro activity against Venturia inaequalis and Botriti ⁇ cinerea .
  • Compounds 2 and 15 also demonstrated good in vitro activity against Bot- ritis cinerea .
  • the compound 9 could overcome the resistance to Benomil R and Ip- rodione R in the case of Botritis cinerea .
  • compound 9 may be valid not only as such, but also as an important additive to commercial fungicidal compositions, for example Score R , in order to prolong the period of their application, which is restricted due to the appearance of resistant populations of pathogens.
  • the compounds 2, 3, 9 and 15 in the form of their 0.1 % water solutions have activity against grape downy mildew caused by Pla ⁇ mopara viticola , under isolated grape lea- ves assay (Example 21) .
  • the compounds 2, 3, 9, and 15 in the form of their 0.003 % water solutions have in vitro activity against Fusarium graminearum; Fusarium monili forme; Alternaria solani; Rhizoctonia solani; and Helminthosporium sativum .
  • the level of activity was structure-dependent, in some cases it was higher than that of the reference Bayletone R ; the results are summarized in Example 20.
  • the activities of the compounds 3, 7 and 15 against the wheat leaf-spotting fungi Pyrenophora tritici-repentis and Septoria nodorum were comparable with those of Tilt R and Polycarbocene R .
  • the compounds 2, 3, 9, and 15 were tested under greenhouse conditions against wheat diseases caused by Pucci- nia recondita and by Erysiphe graminis ; tomato disease caused by Phytophthora infestans and rice blast disease caused by Pyricularia oryzae . These drugs expressed activities which were disease and structure-dependent. Results of the tests are presented in Example 19.
  • R and R j are hydrogen, lower alkyl, lower alkyl substituted by -COOR 2 , -OR 2 , -SR 2 , -N(R 2 ) 2 , -S + (R 2 ) 2 , lower alkyl subs- tituted by aryl or heterocyclic group optionally substituted by one to two hydroxy or lower alkoxy groups and the salts thereof with inorganic or organic acids or bases.
  • R and R j are hydrogen, i-propyl, i-butyl, sec-butyl, hydroxymethylene, aminoethylene, aminopropylene, aminobutylene, thiomethy- lene, thioethylene, carboxymethylene, carboxyethylene, methylthioethylene, ethylthioethylene, dimethylthioethy- lene, carboxamidomethylene, carboxamidoethylene, cyclopentyl, -CH 2 SCH 2 CH(NH 2 )COOH, -CH 2 SCH 2 CH(NH 2 ) P0 2 H 2 , - CH 2 SCH 2 CH (NH 2 ) P0 3 H 2 , -CH 2 SCH 2 CH 2 CH(NH 2 ) COOH, -CH 2 SCH 2 CH 2 CH- (NH 2 )P0 2 H 2 , -CH 2 SCH 2 CH 2 CH(NH 2 )P0 2 H 2 , -CH 2 CH 2 SCH 2 CH (NH 2 CH 2 SCH 2 CH (
  • the nutritional medium contained the following com- pounds per liter of medium: NaN0 3 -2.5 g; KH 2 P0 4 - 1.0 g; MgS0 4 - 0.5 g; Saccarose - 10.0 g; Thiamine - 200 ⁇ g Biotin - 5 ⁇ g; Agar -15 g.
  • the inhibition of radial growth of the mycelium of P . oryzae was estimated by comparing the mycelium growth rate on agar media containing test compounds with control colonies. The influence of the test compounds on conidia germination was estimated on the same agar medium containing the same substances.
  • Example 14 For compounds 10 and 11, see Example 22 and Table 11. For compounds 12 and 13, see Example 23 and Table 12. Example 14 .
  • Seedlings of different rice varieties were sowed in soil of usual rice cultivating field experimental plots and cultivated for 1 or 2 months to obtain seedlings of rice at the 3- to 4-leaves stage.
  • An aqueous dilution of the test compound in the form of emulsifiable concentrate was applied onto the seedlings by foliar treatment.
  • a spore suspension of P. oryzae was sprayed onto the seedlings and covered by polyethylene film for the night.
  • the test compounds treatment was repeated twice in 10 days intervals. Disease development was checked periodically and its development was calculated according to the following equation:
  • the squares of the experimental plots were 1 m 2 . Each experiment was performed in triplicate. Compound effectivi- ties were compared with commercial fungicides. As standards there were used Fujione R , Kitazin P R (Ricide R ) and Cinneb R . The used dosages of testing compounds, each calculated to as the active substance, were 2 kg per hectare during one season applied, as its 0.1% water solution. The dosages of the commercial products were about the same as those calculated for the active compounds content in the fungicidal compositions. The application was carried out by spraying water solutions of the test compounds and standard fungicides. After the end of season the rice grains were collected and the yield was calculated. In the season II the biological conditions were extremely favorable for the disease development, which led to very low yields of the rice crop.
  • Seeds of eggplant were sowed in soil filled in plastic pots and cultivated in a greenhouse to obtain seedlings of eggplant at the 3 to 4-leaves stage.
  • An aqueous solution of the test compound was applied onto the seedlings by foliar treatment. After two days a spore suspension of Botritis cinerea was sprayed onto the seedlings, which were placed at 20°C under humid conditions for 20 hours. Thereafter the seedlings were grown at 20 °C under humid conditions for 6-10 days. The state of infection of the plants was observed, and the disease control value was calculated.
  • the fungicidal activity of 9 could effectively overcome the pathogenicity of Benomyl- and Iprodione-resistant strains of phytopatogenic fungus Botritis cinerea (see Table 5) .
  • Seeds of tomato were sowed in soil in plastic pots and cultivated in a green house for 30 days to obtain seedlings of tomato at the 5-leaved stage.
  • An 0.1% aqueous solution of the test compound in the form of an emulsifiable concentrate was applied onto the seedlings by foliar treatment. On each plant, 0.5 ml of solution was applied. The next day a spore suspension of Phytophthora inf stans was sprayed onto the seedlings, which were placed at 20°C under humid conditions for 20 hrs. Thereafter, the seedlings were grown at 20 °C under humid conditions for 6 days. The state of plant infection was observed and the preventive index was calculated as in Example 14 (see Table 8) .
  • Seeds of wheat were sowed in soil in plastic pots and cultivated in a green house to obtain seedlings of wheat at the 1-leave stage.
  • An 0.1% aqueous solution of the test compound in the form of an emulsifiable concentrate was applied onto the seedlings by foliar treatment. On each plant, 0.5 ml of solution was applied. Then, a spore suspension of Puccinia recondita or Erysiphe graminis were sprayed onto the seedlings, which were placed at 20°C under humid conditions for 24 hrs. Thereafter, the seedlings were grown at 20°C under normal conditions for 6 days. The state of plant infection was observed and the preventive index was calculated as in Example 14 (see Table 8) .
  • Seeds of rice were sowed in soil in plastic pots and cultivated in a green house to obtain seedlings of rice at the 4-leave stage.
  • An 0.1% aqueous solution of the test compound in the form of an emulsifiable concentrate was applied onto the seedlings by foliar treatment. On each plant, 0.5 ml of solution was applied. The next day a spore suspension of Pyricularia oryzae was sprayed onto the seedlings, which were placed at 28 °C under humid conditions for 24 hrs. Thereafter, the seedlings were grown at 28 °C under normal conditions for 10 days. The state of plant infection was observed and the preventive index was calculated as in Example 14 (see Table 8) . Table 8 . .
  • Example 13 In these experiments the method described in Example 13 was used (for data see Table 9) .
  • Freshly isolated grape leaves (variety "Tsolicauri”) were 5 placed in Petri dishes. The bottom of these dishes was covered with wet filter paper for providing moist conditions inside the dish. The leaves were treated with a water solution of the substances. The next day the leaves were inoculated with a zoospore suspension (5.000 spo-
  • Fragments of the first leaf were taken from 7 days old wheat plants (disease-sensitive wheat variety "Thatcher") and were placed in Petri dishes on 1 % agar containing benzimidazole (40 mg/ml) .
  • a spore suspension of wheat rust (Puccinia recondita Rob. ex. Desm. f .sp. tritici Eriks, race 77) with concentration 0.2 mg/ml was used.
  • the applied suspension volume was 0.01 ml, containing the compounds of formula 1 to be tested in different concentrations.
  • the same concentration of wheat rust spores was used in water.

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Abstract

The present invention concerns on the one hand the use of α-amino-phosphinic compounds of formula (1) as plant protectants, as well as a novel subclass of the compounds of formula (1).______

Description

PLANT PROTECTANTS
FIELD OF THE INVENTION
The present invention relates to the synthesis and application of phosphinic acid derivatives, especially to ami- no phosphinic acids. This class of compounds contains both known and earlier unknown representatives. The invention also relates to compositions for use in plant protection containing as active ingredients the above chemicals, as well as the use of said chemicals as plant protectants against phytopathogens, especially against phytopathogenic fungi.
BACKGROUND OF INVENTION
It is well-known that plant diseases caused by different pathogens are the origin of great damages in agriculture. In order to protect plants, a wide range of chemicals, able to inhibit selectively disease development, are used in practical agriculture. At the same time, phytopathogens are capable of adapting to these chemicals and resistant forms of pathogens spontaneously appear. Thus there is a continuous need of new chemicals possessing plant-protecting properties. Another reason is connected with the ecological aspects of agrochemistry, i.e. there is a continuous need of less toxic compounds and a general tendency to decrease the effective plant-protectant dosages.
A set of compounds which are chemically related to the subject of the present invention are known. In German Patent 2, 722, 162 and US Patent 4, 147 , 780, the chemical synthesis of α-amino phosphinic acids of the general for- ula 1 R, O
R - formula 1
Figure imgf000004_0001
is described. The compounds of formula 1 are claimed as new chemicals possessing valuable medicinal and pharma- ceutical properties. They are, for example, antimicrobial agents, which are effective at low concentrations (0.8 to 50 μg/ml) in inhibiting the growth in vitro of bacteria pathogenic to humans, as for example Escherichia coli, Enterobacter cloacae and other Enterobacteria, Pseudo- monas aeruginosa and yeasts pathogenic for humans, for example Candida albicans and C. tropicalis.
The compounds of formula 1 are also effective in vivo. At dose levels between 15-100 mg/kg these drugs given subcu- taneously or orally, for example in mice, protect 50% of the animals (ED50) from death following infections with a lethal dose of pathogenic bacteria such as, for example, Klebsiella pneumoniae or Pseudomonas aeruginosa .
The above two patents contain no information relating to the activity of the compounds of formula 1 against phyto- pathogenic microorganisms nor any data relating to their application in agriculture for the protection of plants as an active ingredient of corresponding compositions.
Chemical syntheses of the compounds of formula 1 are also described in: Khomutov, R.M. & Osipova, T.I. Izv. USSR Acad.Sci., Ser. Khim. No 8, P. 1951 (1978), USSR Patent Application 0,717,062; USSR Patent Application 1,558,921; USSR Patent Application 1,571,996; Baylis, E.K., et.al., j.Chem.Soc.Perkin Trans . I .V .12 , No. 12. P.2845-2853 (1984), Khomutov, A.R., Bioorg . Khim. V. 16, No.9, p. 1290-1293 (1990) , Grobenly, D . , Synthesis, (1987) , 942- 943, Jiao X-Y. et al . , Synthesis, (1994) , 23-24, and McCleery, B . & Tuck, B . J. Chem .Soc . Perkin trans . I V .17, No . 7 , P.1319-1329 (1989) . The last paper also covers stereospecific synthesis of compounds of formula 1 (R=H, Rj =—CH3 ) R=H, R|=—C5H5CH2) «
In EP 0, 002, 031 compounds of formula 1 are documented to have useful plant growth influencing properties, espe- cially of plant growth inhibiting or herbicidal nature, but this invention contains no information relating to protection of plants from diseases by means of these compounds .
In US patent 4, 473, 561 (= EP 0, 063, 464) 1-hydroxyamino ethyl phosphinic acid of the formula 2
O
II /H R - CH - PN formula 2 I OH
wherein R= -CH3; X= -NHOH (2A) or, X= -OH (2B) and their salts are documented as a fungicide against Phycomycetes . For activity comparison, a state-of-the-art compound of the formula 2 was used, wherein X= NH2 and R= CH3. From the disclosure it is evident that 1-hydroxyethyl phosphinic acid (formula 2B; R= -CH3; X= -OH) together with its salts possess fungicidal activity towards the above fami- ly of fungi. However, an alteration in the radical, for example, R=H; -CJHJ; or -C3H77 gives rise to inactive compounds. Similarly, at the optimal meaning of the radical R (R= -CH3) , substitution of the HO- (compound of formula 2B) or of the HONH-group (compound of formula 2A) by a H2N-group (compound of formula 2, X= NH2) has negative effects on the activity, as is evidenced by the test results in the patent. According to the structure-activity relationship laid down in US patent 4, 473 , 561 , compounds of formula 2 wherein R is = -CH3 and X= -NH2 should not be active against phytopathogens. According to the invention, however, it has now surprisingly been found that compounds of such type do in fact possess activity against phytopathogens.
SUMMARY OF INVENTION
The present invention describes earlier unknown proper- ties of both known and unknown compounds of formula 1 as plant disease protectants against phytopathogens; it also describes earlier unknown compounds of formula 1A.
The compounds of the formula 1 are demonstrated to pos- sess plant disease protecting properties against a set of plant pathogens and suggested as an active ingredient in compositions active against different causal agents of cereal, fruit and vegetable diseases.
The present invention is typically employed in agriculture and agrochemistry for treating or preventing plant diseases, especially for the treatment of plant pathogenic fungi.
DETAILED DESCRIPTION OF INVENTION
The present invention describes in its broadest sense the use of compounds of formula 1 against phytopathogens and as plant-protectants , the compounds having the general formula
R 0
I IU H
R, - C - P formula 1
I ^ OH
NH
or the corresponding zwitterion form, in which R and R are the same or different and are selected from the group consisting of - hydrogen; deuterium;
- a lower alkyl, lower alkenyl or lower alkynyl group, which can be substituted with one or two groups selected from 1) -COOR2, -OR2, -SR2, -S+(R2)2, -C(0)N(R2)2, -C(0)NHOR2, -C(0)NHNHR2, -P(O) (H)OR2, -P(0)(OR2)2, -P (0) (R2) OR2, -N(R2)2, -S(0)-R2, -ON(R2)2, -NH-C(MH)-NH2, or halogen atoms, whereby the R2 groups may be the same or different, and are a) hydrogen; b) a lower alkyl, lower alkenyl, lower alkynyl group, which may be substituted with one or two groups se lected from -OH, -SH, -NH2, -COOH, -C(0)NH0H, -C(0)NH2, -ONH2, -P02H2, -P03H2, c) an aryl group with 6 to 10 carbon atoms which may be substituted with -OH, -SH, -NH2, -COOH, -N02 or halogen atoms,
2) an aryl group with 6 to 10 carbon atoms;
3) a 3 to 9 membered heterocyclic ring containing one or more oxygen, nitrogen, or sulfur atoms in the ring;
- a cycloalkyl group with 3 to 6 carbon atoms,
- or R and Rj together form a C2-C7 poly ethylene chain optionally interrupted by an oxygen, nitrogen or sulfur atom; and the salts thereof with organic or inorganic acids and bases, as well as their optical isomers, excluding the compound wherein R is hydrogen and R, is CH3, as plant protectants and against phytopatogenic fungi.
The term "lower", referred to above and hereinafter in connection with organic radicals or compounds respectively, define such with up to 5 carbon atoms.
A lower alkyl group of 1 to 5 carbon atoms may be a straight or branched alkyl group and may be, for example, a methyl, ethyl, n-propyl, i-propyl, i-butyl, sec-butyl group. A halogen substituent may be bromine or iodine, but is preferably fluorine or chlorine.
A lower alkenyl group may be a C2-C5 straight or branched chain alkenyl group, and may be, for example, a ethenyl, allyl, crotyl, methallyl or methoxyethenyl group.
A lower alkynyl group may be a C2-C5 straight or branched chain alkynyl group, and may be, for example, a ethynyl, propynyl or butynyl group.
A cycloalkyl group is a cycloalkyl group with 3 to 6 carbon atoms, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
When R or R, together form a polymethylene chain, this may be for example -(CH2)2-, -(CH2)3-, -(CH2)4-, - (CH2) 20(CH2)2- or -(CH2)2NH(CH2)2-.
The group -COOR2 is advantageously hydroxycarbonyl, met- hoxycarbonyl, ethoxycarbony1 or i-propoxycarbonyl.
The group -OR2 is advantageously hydroxy, methoxy, ethoxy, i-propoxy. Aryloxy OR2 is advantageously phenoxy, tolylo- xy, xylyloxy or phenylendihydroxy, and especially benzy- loxy. The group -SR2 is advantageously thiol, methylthio, ethylthio, and in addition also advantageously benzyl- thio, -S(CH2)nNH2, -S(CH2)n0H, -S (CH2) n0NH2, -S (CH2) nCOOH, -S(CH2)nP02H2, -S(CH2)nP03H2, -S (CH2) mCH (NH2) P02H2, -S(CH2)mCH(NH2)P03H2, -S (CH2)mCH (NH2) COOH, or
-S(CH2)mCH(NH2)C00H. The group -S(0)-R2 is advantageously -(CH2)mS(0)R2, such as -CH2CH2S (0) CH3 The integer n may be from 2 to , and m from 1 to 3.
The -S(R2)2 group may be, for example, di ethylsulfonium, methylethylsulfonium, diethylsulfonium, methylpropylsul- fonium, or methylbenzylsulfonium.
An aryl group with 6 to 10 carbon atoms as substituent of a lower alkyl, alkenyl or alkynyl group is for example a phenyl, benzyl, tolyl, xylyl, ethylphenyl, propylphenyl , i-propylphenyl or naphthyl group.
A heterocyclic ring as a substituent of a lower alkyl, alkenyl or alkynyl group means a saturated or unsaturated cyclic carbon ring, an unsaturated ring containing at least one double bond. Both groups contain one or more oxygen, nitrogen or sulfur atoms, and may be, for example, aziridine, oxetane, thiophene, furan, pyridine, iso- xazole, thiazole, imidazole, pyrimidine, thiadiazole, triazole, triazine, indole, purine or benzofuran.
An aryl or heterocyclic ring as defined above is unsubs- tituted or may be substituted by one to three substi- tuents, which are -COOH, -OH, -NH2, -N02 or -SH groups.
When R or R, is a lower alkyl group substituted by an aryl group with 6 to 10 carbon atoms or a 3 to 9-membered heterocyclic ring, the substituted alkyl group will preferably form a Cj-C3 straight or branched alkylene chain, for example, -CH2-, -CH(CH3)-, -(CH2)2-, -(CH2)3- or -CH(CH3)CH2-.
The group of compounds of formula 1 includes both known and unknown structures.
Known compounds of formula 1 were synthesised in accordance with general methods published earlier, see: Khomu- tov, R .M . & Osipova, T. I . , Izv. USSR Acad.Sci . . Ser.Khim . No . 8, P. 1951 (1978) ; USSR Patent Application 0, 717, 062; USSR Patent Application 1, 558, 921; USSR Patent Application 1, 571, 996; Khurs, E.N. , et . al . Bioorg .Khim . V .15, No . 4, P .552-555 (1989) , Khomutov, A.R . , Bioorg . Khim . V . 16, No.9, p. 1290-1293 (1990). Synthesis of some of these structures may be also performed in accordance with German Patent 2,722 ,162; US Patent 4,147,780; Baylis, E.K., et.al., J.Chem.Soc. Perkin Trans. I V.12, No. 12, P.2845- 2853 (1984); McCleery, B. & Tuck, B. J.Chem.Soc. Perkin Trans. I. V. 17, No. 7, P.1319-1329 (1989); Grobenly, D., Synthesis, (1987), 942-943, Jiao X-Y . et al . , Synthesis, (1994), 23-24, EP 0,181,833; and Dingwall, J.G. , et.al. Tetrahedron V.45, No. 12, P.3787-3808 (1989).
The invention also relates to earlier unknown compounds formula 1 which are preferably the phosphinic analogues of sulfur containing a ino acids; phosphinic analogues of Asn, Gin, canaline and aminooxy alanine.
The object of the invention is thus a novel group of compounds of the formula 1A
R 0
I II ^ H
R,- C - P formula 1A
OH
NH,
or the corresponding zwitterion form in which R is hydrogen, a lower alkyl, lower alkenyl or lower alkynyl group with 1 to 5, or 2 to 5 carbon atoms, respectively, { is selected from the group consisting of -(CH2)raS+(R2)2, "(CH2)mC(0)N(R2)2, -(CH2)ffiS(CH2)mCH(NH2)COOR2, - (CH2) mS (CH2) nONH2,
-(CH2)mC(0)-NHOR2, -(CH2)mONR2R2, - (CH2) mC (0) NHNHR2, -(CH2)mS(CH2)mCH(NH2)P(0) (H)OR2, - (CH2) mS (O) R2, -(CH2)nS(CH2)mCH(NH2)P(0) (OR2)2, wherein R2 is a) hydrogen; b) a lower alkyl, lower alkenyl, lower alkynyl group, which may be substituted with -OH, -SH, -NH2, -COOH, - C(0)NHOH, -C(0)NH2, -ONH2, -P02H2, -P03H2 R3, c) an aryl group with 6 to 10 carbon atoms which may be substituted with -OH, -SH, -NH2, -COOH, -N02 or halogen atoms, and the integers m is independently from 1 to 3 and n is from 2 to 4; and their salts with organic or inorganic acids and bases, and optical isomers.
The meanings of the various substituents and groups are given above.
Especially contemplated in the invention are the compounds wherein R is hydrogen or lower alkyl, and Rj is carboxymethylene, carboxyethylene, dimethylthioethylene, carboxamidomethylene, carboxamidoethylene, or compounds, wherein R is hydrogen, and Rt is dimethyltioethylene or carboxymethylene and the salts thereof with inorganic or organic acids or bases, and optical isomers.
The novel compounds of the formula 1A may be prepared in a manner analogous to those described above for the known compounds, see especially Khomutov et al . , or alternatively Baylis et al . According to known methods a ketone or aldehyde R Rt C(=0) is converted to an oxime and thereafter reacted with phosphinic acid to form the desired compound, or the said ketone or aldehyde with an amine is converted to a Schiff base which on reaction with phosphinic acid and thereafter with an acid is converted to the desired compound. Earlier unknown phosphinic analogues of methylthiomethionine and of related sulfonium- containing substances were synthesized in accordance with known methods of sulfonium compounds preparation, for example, by methylation of 3-methylthio-l-aminopropyl phosphinic acid either by methyl iodide or by methyl ester of p-toluenesulfonic acid. New phosphinic cystat- hionine and lanthionine analogues are derived from phos- phinic cysteine or ho ocysteine analogues by alkylation with corresponding /^-substituted alanines, γ-substituted butyric acids, their phosphonic and phosphinic analogues; or from corresponding carbonyl precursors in accordance with the above published methods. Novel phosphinic analogues of asparagine and glutamine were prepared by amina- tion of activated distalic carboxyl groups of corresponding phosphinic analogues of aspartic and glutamic acids, respectively. Phosphinic analogues of canaline and amino- oxy alanine are derived from aminooxy-protected derivatives of corresponding aldehydes in accordance with the above published methods.
Both known and unknown compounds of formula 1 are demon- strated to possess inhibiting properties against a set of plant pathogens and suggested as an active ingredients of compositions being active against different causal agents of cereal, fruit and vegetable plant diseases.
Both known and unknown compounds of formula 1 are demonstrated to possess inhibitor properties against a set of plant pathogens including Pyricularia oryzae; Erysiphe graminis ; Puccinia recondita; Phytophthora infeεtans ; Venturia inaeqalis; Botrytis cinerea (including strains resistant to BenomylR and IprodioneR) ; Septoria nodorum;
Pyrenophora tritici-repentis ; Fusarium graminearum; Fusa- rium moniliforme; Alternaria solani ; Rhizoctonia solani ; and Helminthosporium sativum .
The compounds described herein may be used in the form of suitable formulations, especially as solutions with water, or with suitable organic solvents, and subsequently diluted with water. The preparation of such formulations is within the knowledge of a person skilled in the art. The concentration of the active agent in the formulation depends on the pathogen, the plant to be treated as well as on the compound to be used. For example a 0.1 % solu- tion of the compound in water has proven acceptable in many field and greenhouse experiments. The amount of active agent to be used can vary, but normally falls within the range of 0.5 to 2.5 kg/ha.
In the case of Pyricularia oryzae, in vitro tests of compounds of formula 1 were performed under simple plate assay on solid agar media containing inorganic salts, sucrose, thiamine and biotin. Test-results were satisfac- tory and compounds of formula 1 inhibited mycelium growth in the concentration range 0.1-200 ppm. Some of the compounds of formula 1 being tested under simple plate assay on solid agar media demonstrated activity also against strains of P. oryzae being different from the wild one.
Compounds of formula 1, especially compounds, 3, 5, 7, 9 and 15 demonstrated activity against different strains of P. oryzae under simple plate assay on solid agar media (Example 13, Table 1, Example 22, Table 11).
Several of these drugs were also field tested. One of the best was the compound of formula 1 (9:R=H, R1=CH3SCH2CH2-) , which possessed high activity with low phytotoxicity. The results of two-season tests are presented in Example 14. The data presented in Example 14 were obtained according to generally accepted methods. Field experiments were performed in two biologically different seasons. The season II was exceptionally favourable for rice blast disease development that decreased rice productivity. Several varieties of rice were investigated, including those cultivated in different countries. Among these varieties there were such that had a high productivity with good quality of grain, but having low resistance against pathogens, or such possessing opposite combination of pro- perties. The effectivity of the compound 9 was compared with commercial fungicides. As standards were chosen: FujioneR, Kitazin PR (RicideR) and CinnebR. In field expe- riments the used dosage of 9 was 2 kg per hectare during one season in the form of its 0.1 % water solution. The dosages of the commercial products were about the same as those calculated for the active compound in the fungici- dal compositions of the invention.
Under the field tests compound 9 demonstrated an activity level comparable with the activity of the commercial fungicides mentioned above; it had low phytotoxicity, it had also low toxic effect towards mice (LD50 2-3 g/kg of body weight at oral administration) .
Compound 9 demonstrated good in vitro activity against Venturia inaequalis and Botritiε cinerea . Compounds 2 and 15 also demonstrated good in vitro activity against Bot- ritis cinerea . In green-house experiments performed on egg-plant it was documented (Example 16) that the compound 9 could overcome the resistance to BenomilR and Ip- rodioneR in the case of Botritis cinerea . These two fun- gicides used to be effective industrial preparations, but their efficiency has diminished during the last years because of the appearance of resistant populations of pathogens .
These data confirm that compound 9 may be valid not only as such, but also as an important additive to commercial fungicidal compositions, for example ScoreR, in order to prolong the period of their application, which is restricted due to the appearance of resistant populations of pathogens.
The compounds 2, 3, 9 and 15 in the form of their 0.1 % water solutions have activity against grape downy mildew caused by Plaεmopara viticola , under isolated grape lea- ves assay (Example 21) .
The compounds 2, 3, 9, and 15 in the form of their 0.003 % water solutions have in vitro activity against Fusarium graminearum; Fusarium monili forme; Alternaria solani; Rhizoctonia solani; and Helminthosporium sativum . The level of activity was structure-dependent, in some cases it was higher than that of the reference BayletoneR; the results are summarized in Example 20.
The compounds of formula 1 (7: R=H, R,=CH2C00H and 3: R=H, R1=CH2CH(CH3) ) were tested in green-house experiments against the wheat leaf-spotting fungus Septoria nodorum under conventionally employed test conditions. As the standards in these trials, the systemic fungicide TiltR and the contact-type fungicide PolycarboceneR were used. Doses for the above representatives of the compound of formula 1. TiltR and PolycarboceneR, were 1.0 kg per hectare. Compounds 7 and 3 were used as pure compounds. The doses for TiltR and PolycarboceneR were calculated based on the active compound content. The results of the greenhouse experiments are presented in Example 17.
The compounds of formula 1 (7: R=H, Rj=CH2COOH and 15: R=H, R,=CH2CH2S (CH3)2) were tested in green-house experiments against the wheat leaf-spotting fungus Pyrenophora tritici-repentis under conventionally employed test con- ditions. As the standard in these trials, the contact- type fungicide PolycarboceneR was used. Doses for the compounds 7, 15 and PolycarboceneR were 2.4 kg per hectare. Drugs 7 and 15 were used as pure compounds. The dose for PolycarboceneR was calculated based on the active compound content. The results of the green-house experiments are presented in Example 18.
The activities of the compounds 3, 7 and 15 against the wheat leaf-spotting fungi Pyrenophora tritici-repentis and Septoria nodorum were comparable with those of TiltR and PolycarboceneR. The compounds 2, 3, 9, and 15 were tested under greenhouse conditions against wheat diseases caused by Pucci- nia recondita and by Erysiphe graminis ; tomato disease caused by Phytophthora infestans and rice blast disease caused by Pyricularia oryzae . These drugs expressed activities which were disease and structure-dependent. Results of the tests are presented in Example 19.
Particularly useful for the above application are com- pounds of formula 1, or the corresponding zwitterion form in which R and Rt mimic side-chains of naturally occuring amino acids, especially proteinogenic amino acids. Thus R and Rj are hydrogen, lower alkyl, lower alkyl substituted by -COOR2, -OR2, -SR2, -N(R2)2, -S+(R2)2, lower alkyl subs- tituted by aryl or heterocyclic group optionally substituted by one to two hydroxy or lower alkoxy groups and the salts thereof with inorganic or organic acids or bases.
Preferred are compounds of formula 1 wherein R and Rj are hydrogen, i-propyl, i-butyl, sec-butyl, hydroxymethylene, aminoethylene, aminopropylene, aminobutylene, thiomethy- lene, thioethylene, carboxymethylene, carboxyethylene, methylthioethylene, ethylthioethylene, dimethylthioethy- lene, carboxamidomethylene, carboxamidoethylene, cyclopentyl, -CH2SCH2CH(NH2)COOH, -CH2SCH2CH(NH2) P02H2, - CH2SCH2CH (NH2) P03H2, -CH2SCH2CH2CH(NH2) COOH, -CH2SCH2CH2CH- (NH2)P02H2, -CH2SCH2CH2CH(NH2)P02H2, -CH2CH2SCH2CH (NH2) COOH, -CH2CH2SCH2CH(NH2) P02H2, -CH2CH2SCH2CH (NH2) P03H2, -CH2SSCH2CH(NH2)P02H2, -NHCNHNH2, -CH2CH2S (O) CH3 and the salts thereof with inorganic or organic acids or bases.
Outstanding are the compounds of formula 1, wherein Rj is hydrogen, i-butyl, sec-butyl, hydroxymethylene, methyl- thioethylene, dimethyltioethylene or carboxymethylene and R is hydrogen, and the salts thereof with inorganic or organic acids or bases. These compounds of formula 1 exhibited plant-protecting activity in field experiments. Especially valuable and suitable for said application are compounds of formula 1, wherein R] is hydrogen, i-butyl, sec-butyl, methylthioethylene, dimethyltioethylene or carboxymethylene and R is hydrogen, and the salts thereof with inorganic or organic acids or bases. These compounds of formula 1 exhibited plant-protecting activity in field experiments. Most preferred are the compounds of formula 1 as listed in the following examples.
EXAMPLES
Example 1. Iodohydrate of (CH)2ScH2CH2CH(NH2) P (0) (H) OH [15].
Freshly distilled methyl iodide 2.5 g (0.04 moles) was added to the solution of 1.7 g (0.01 moles of 3-methyl- thio-1-aminopropyl phosphonous acid [9] in a mixture of 10 ml glacial AcOH and 10 ml 99.9 % HCOOH, and the reaction mixture was kept for 8 days in the dark at 20°C. The reaction mixture was evaporated to dryness in vacuo and the residue was crystallized from 2-propanolether , affording 1.46 g (51%) of iodohydrate of 15; Rf 0.10 (Silufol UV254' Czechoslovakia in n-BuOH-AcOH-H20 = 12:3:5); Rf 0.15 (Silufol UV254, Czechoslovakia in MeOH-2-propanol-H20-25%- NH4OH-F3CCOO".NH4 +. = 100:40:39:20:1); ^-NM (X-100-15 "Va- rian") in D20 (t-BuOH as a ref.): 2.1 (m, 2H, -CH2~) , 2.88 (m, 2H, -CH2-) , 2.92 (d, 6H, -CH3) , 3.45 (m, 1H, -CH-) , 7.05 (d, 1H, P-H; JH.p 520 Hz).
+ Example 2. Tosylate of (CH3)2SCH2CH2CH(NH2)P(θ) (H)OH [15].
The methyl ester of p-toluenesulfonic acid 8.0 g (0.043 moles) was added to the solution of 3.4 g (0.02 moles) of in a mixture of 15 ml glacial AcOH and 15 ml 99.9 % HCOOH and the reaction [9] mixture was kept for 2 weeks at 20°C. The reaction mixture was evaporated to dryness in vacuo and the residue was crystallized from 2-propanolet- her, affording 5.25 g (74%) of the tosylate of [15].
Example 3. HOOCCH,CH(NH;)P(0) (H)OH [7].
1.3 ml of a 2.0 M solution of sodium ethylate in ethanol was added to the solution of 5.73 g (0.025 moles) of N- acetamidomalonic acid diethyl ester in 6.10 g (0.032 moles) of diethoxymethylene phosphonous acid diethyl ester, without cooling but with effective stirring. The addition effected a temperature rise to 55°C. The reaction mixture was kept for three days at 20°C, then 100 ml 20 % HCl (w/v) was added and the resulting solution was refluxed for 3 hr in an Ar atmosphere. The mixture was evaporated to dryness in vacuo, the residue was dissolved in 15% 2- propanol and was purified on Dowex 50x8 resin in H+ form, using 15% water 2-propanol for elution, affording, after crystallization from water-alcohol, 1.4 g (36%) of the desired product; Rf 0.48 (Silufol UV254, Czechoslovakia in MeOH-2-propanol-H20-25%NH4OH-F3CCOO .NH = 100:40:39:20:1); Rf 0.13 (Silufol UV254, Czechoslovakia in 2-propanol-25%- NH4OH-H20 = 7:1:2); Η-NMR (X-100-15) "Varian") in D20 (t-BuOH as a ref.); 3.05 ( , 2H, -CH2-) , 3.48 ( , 1H, -CH-) , 7.00 (d, 1H, P-H; JH.P 510 Hz).
Example 4. H2NC(0)CH2CH(NH2)P(0) (H)OH
The suspension of 0.31 f (0.002 moles) of [7] in 10 ml methanol was saturated with dry HCl and after two days at 20°C solution was evaporated to dryness in vacuo , the residue was dissolved in 10 ml 6 N HCl in methanol and the reaction was again kept for two days at 20°C. The reaction mixture was evaporated to dryness in vacuo , the residue was dissolved in water and the [7] mono-methyl ester was purified on Dowex 50x8 resin in H+ form using water for elution. The resulting mono-methyl ester of [7] was dissolved in 10 ml of water, saturated at 0°C with NH3 and kept for two days at 20°C. The reaction mixture was evaporated to dryness in vacuo , and 2-carboxami- do-1-aminoethyl phosphinic acid was purified on Dowex 50x8 resin in H+ form, using water for elution and affording after crystallization from water-alcohol, 0.19 g (60%) of the desired product:R, 0.26 (Silufol UV254, Czechoslovakia in 2-propanol-25%NH4OH-water = 7:1:2).
Example 5. H2NOCH2CH(NH2)P(0) (H)0H and (CH3)2C=NOCH2CH(NH2)- P(0) (H)0H
To the neutral water solution of 3.3 g (0.01 moles) of hydroxylamine 0.2 ml AcOH was added, and consequently with stirring 15.9 g (0.1 moles) of 3-[ [ (l'-ethoxyethyl- idene) amino]oxy]propanal-l [Karpeiski, M .Ya, et . al . Z .Obsch .Khim . V.32, P.1357-1358 (1962) ] . After 30 min. at 20°C, the resulting mixture was extracted with ether, the ether solution dried affording after the second distillation 8.0 g (45%) of 3-[ [ (1 '-ethoxyethylidene) amino]oxy] - propanal-1-oxime; bp. 107-109°C/1.5 mm Hg; n™ 1.4635.
To the boiling solution of 1.75 g (0.01 moles) of the above 3- [[ (1 '-ethoxyethylidene) amino]oxy]propanal-l oxime in 2.0 ml of ethanol, a solution of 1.32 g (0.02 mol) of H3P02 in 2.0 ml of ethanol was added dropwise and refluxed for additional 3 hrs. The reaction mixture was evaporated to dryness and 3-aminooxy-l-aminopropane phosphinic acid was isolated on Dowex 50x8 resin in H+ form by stepwise elution with water and 2.0% NH40H, affording 0.05 g (3%) of the product; R, 0.22 (Silufol UV254' Czechoslovakia in 2-propanol-25%NH4OH-water = 7:1:2).
With acetone treatment the 3-aminooxy-l-amino-propane phosphinic acid was converted into 3-[ [ (isopropyli- dene]amino]oxy]-l-aminopropane phosphonous acid: R, 0.51 (Silufol UV254, Czechoslovakia in 2-propanol-25%NH4OH-water = 7 : 1 : 2 ) .
Example 6 . H2NO-CH2CH2-S-CH2CH (NH2) P (0) (H) OH
To a boiling solution of 19.8 g (0.3 moles) of H3P02 in 50 ml of abs. ethanol was added dropwise a solution of 27.15 g (0.15 moles) of benzylthioacetaldehyde oxime in 50 ml of abs. ethanol within 30 min in an Ar atmosphere.
The reaction mixture was refluxed for additional 3 hr. and two volumes of 2-propanol, followed with triethylami- ne (up to pH about 5) were added and the precipitated product was collected by filtration after a night at +4°C affording 13 g (38%) of l-amino-2-benzylthioethyl phosphinic acid, Rf 0.65 (Silufol UV^, Czechoslovakia in 2-propanol-25%NH4OH-H20 = 7:1:2).
To a solution of 6.9 g (0.03 moles) of l-amino-2-benzylt- hioethyl phosphinic acid in 300 ml of liquid ammonia small pieces of Na were added with stirring in an Ar atmosphere until the blue colour of the solution remained stable for 15 min. Ammonia was evaporated, the residue was co-evaporated with water in vacuo , dissolved in water and l-amino-2-thioethyl phosphinic acid was isolated by chromatography on Dowex-50x8 in H+ form, affording 3.1 g (74%) of the product, m.p. 195-198°C, Rf 0.39 (Silufol UV254, Czechoslovakia in 2-propanol-25%NH4OH-H20 = 7:1:2), 'H-NMR (XL-100-15 "Varian") in D20 (t-BuOH as a ref.): 2.7-3.5 (m, 3H, -CH2CH-) 7.01 (d, 1H, P-H; J„p538 Hz).
A solution of 1.2 g (0.02 moles) of KOH (85% purity), 2.1 g (0.01 moles) of 2 [[ <1' -ethoxyethylidene) amino]oxy]-l- bromoethane and 1.1 (0.01 moles) of l-amino-2-thioethyl phosphinic acid in 30 ml of a methanol-water cocktail
(8/2, V/V) was left for a few days at +4°C. Methanol was evaporated in vacuo , to the residue was added 20 ml of water and extracted with ether (4x5 ml) . The resulting water solution was neutralised with HCl at -5°C and precipitated S-{2-[ [ (l1 -ethoxyethylidene) amino]oxy]ethyl}-i- amino-2-thioethyl phosphinic acid was recrystallized from water, affording 0.8 g (30%), Rf 0.57 (Silufol UV^, Czechoslovakia in 2 propanol-25% NH4OH-H20 = 7:1:2).
A water solution of 0.54 g (0.002 moles) of S-{2-[[(l'- ethoxyethylene) -amino]oxy]ethyl}-l-amino-2-thioethy1 phosphinic acid was applied on a Dowex-50x8 (+form) column, which was eluted first with water and the required S-{2-[ (l-amino)oxy]ethyl}-l-amino-2-thioethyl phosphinic acid was eluted with 1.0 M NH4OH. Fractions containing the product were evaporated in vacuo to dryness and the pro- duct was crystallised from water-ethanol, affording 0.2 g (50%) of the required α-aminophosphinic acid, Rf 0.16 (Silufol UV^, Czechoslovakia in 2-propanol-25%NH4OH-H20 = 7:1:2), 'H-NMR (XL-100-15 "Varian") in D20 (t-BuOH as a ref.): 2.8-3.6 (m,5H, -CH2CH-, -SCH2CH2-) , 4.22 (t, 2H, - OCH2-) , 7.05 (d, 1H, P-H; J„p 540 Hz).
Example 7.
HO(H) (0)PCH(NH2)CH2CH2CH2-S-CH2CH(NH2)P(0) (H)OH
A solution of 1.8 g (0.03 moles) of KOH (85% purity),
2.65 g (0.01 moles) of l-amino-4-bromobutane phosphinic acid [Baylis, E.K. , et . al . , J. Chem .Soc. Perkin Trns . I . V- 12, No 12, P.2845-2863 (1984) ] and 1.15 g (0.01 moles) of l-amino-2-mercaptoethyl phosphinic acid (see example 6) in 15 ml of water was incubated for a few days at +20°C, then the reaction mixture was neutralised with AcOH and the product was isolated by chromatography on Dowex 50x8 (Py+for ) , elution with 1% Py, affording 0.62 g (25%) of the required product, Rf 0.21 (Silufol UV^, Czechoslova- kia in 2-propanol-25% NH4OH-H20 = 7:1:2). Example 8.
(HO) 2 (O) PCH(NH2) CH2CH2CH2-S-CH2CH2CH (NH2) P (O) (H) OH
To a stirred solution of 3.0 g (0.09 moles) of hydroxyl- amine base in 30 ml of CH3OH, containing 0.25 ml of AcOH and being cooled to +5°C, a solution of 12.0 g (0.09 moles) of 0-acetylthiopropionic aldehyde in 10 ml of CH3OH was added dropwise, stirring was continued for additional 2 hr. at +20°C and the resulting solution was added dropwise to the boiling and stirred solution of 12.0 g (0.18 moles) of H3P02 in 30 ml of CH30H, followed by refluxing for additional 3 hr. The l-amino-3-mercaptopropyl phosphinic acid was isolated by chromatography on Dowex-50x8 (H+form) , eluted with water, affording after drying of the required fractions over P205 in vacuo , 5.0 g (36%) of the product, Rf 0.40 (Silufol UC254, Czechoslovakia in 2- propanol-25%NH4OH-H20 = 7:1:2), Η-NMR (XL-100-15 "Varian") in D20 (t-BuOH as a ref.): 2.09 ( , 2H, -CH2-) , 2.72 (m, 2H, -CH2-) , 3.41 (m, 2H, -CH2-) , 7.02 (d, 1H, P-H; J^ 536 Hz) .
A solution of 2.4 g (0.04 moles) of KOH (85% purity), 2.9 g (0.01 moles) of l-amino-4-bromobutyl phosphonic acid [obtained with quantitative yield by oxidation of the corresponding phosphinic acid with Br2/HBr according to Baylis . E.L . , et al . , J .Chem .Soc .Perkin Trans . I . V .12, No . 12, P.2845-2853 (1984) ] and 1.3 g (0.01 moles) of 1- amino-3-mercaptopropyl phosphinic acid in 15 ml of water, was incubated for a few days at +20°C, then the reaction mixture was neutralised with AcOH and the product was isolated by chromatography on Dowex 50x8 (Py+ form) , eluted with 1% Py, affording after crystallisation 0.52 g (20%) of the required product, Rf 0.06 (Silufol UV2S4, Czechoslovakia in 2-propanol-25% NH4OH-H20 = 7:1:2). Example 9 . HOC (0) CH (NH2) CH2-S-CH2CH2CH (NH2) P (0) (H) OH
To a solution of 1.3 g (0.01 moles) of l-amino-3-mercap- topropyl phosphinic acid and 1.24 g (0.01 moles) of β- chloro alanine in 60 ml of liquid ammonia, Na was added in small pieces until the blue colour of the solution was stable for 15 min. , then stirring at -40°C was continued for additional 5 hr., thereafter ammonia was evaporated and the product was isolated by chromatography on Dowex- 50x8 (Py+ form) , elution first with 1% Py and then with 1.0 M NH40H, affording after crystallisation 0.87 g (33%) of the required product, Rf 0.30 (Silufol UV2J4, Czechoslovakia in 2-propanol-25% NH4OH-H20 = 7:1:2).
Example 10. CH3-S (0) -CH2CH2-CH(NH2) P (0) (H)OH
To the stirred and cooled (+4°C) suspension of 0.91 g (5.4 m ols) of CH3-S-CH2CH2-CH(NH2) P(0) (H) OH [9] in 10 L of AcOH, 0.7 L of 30% H202 was added within 15 min and the reaction mixture was stirred at +4°C for additional 10 min. The solvent was evaporated in vacuo to dryness, the residue was co-evaporated twice with toluene in vacuo , the residual oil was dissolved in MeOH and the product was precipitated after the addition of acetone. The precipitate was treated with a fresh portion of acetone, the resulting crystals were filtered of and dried in vacuo , and gave 0.82 g (82%) of the title compound.
Example 11.
I. C6H5CH20NH-C(O)-CH2CH(NH2)P(O) (H)OH II. p-N02-C<H4-NHNH-C(0)-CH2CH(NH2)P(0) (H)OH
III. o-CH3C6H4-NHNH-C(0)-CH2CH(NH2)P(0) (H)OH
IV. CβHs-NHNH-C(0)-CH2CH(NH2)P(0) (H)OH
To the stirred suspension of 0.29 g (1 mmol) of HOOCCH2CH(NHC(0)OCH2C6H3)P(0) (H)0H (obtained from Asp-α-PH and Cbz-Cl in water in the presence of NaHC03) in 10 mL of dioxane, a solution of 2.0-2.2 mmols of either C6H5CH20NH2, or p-N02C6H4NHNH2, or 0-CH3C6H4NHNH2 or C6HSNHNH2 in 2 mL of dioxane was added followed by the addition of 0.43 g of dicyclohexyl carbodiimide in 8 mL of dioxane and stirring was continued for 16 hr. To the reaction mixture 4 mL of H20 was added, stirring was continued for 1 hr, the precipitated dicyclohexyl urea was filtered off, washed with with EtOH, to the combined filtrates, 3.0 mL of a suspension of Dowex 50x8 in H+-form was added and stirring was continued for 30 min. The Dowex 50x8 was filtered off, the filtrate was evaporated in vacuo to dryness, the residue was coevaporated in vacuo 3 times with AcOH, the last residue was dissolved in 2 mL of AcOH and 1.2 mL of 5.0 M solution of HBr in AcOH was added and the reaction mixture was kept at 20 °C for 30 min. To the resulting solution 20 mL of Et20 was added, the separated oil was washed with Et20, dissolved in water and the titled products were isolated on Dowex 50x8 H+-form (elution with H20 or diluted NH40H) that gave 0.25 g (93%) of compound I; 0.14 g (48%) of compound II: 0.15g (58%) of compound III or 0.08 g (33%) of compound IV.
Example 12. General description of the preparation of the compounds in the Table la
To the boiling solution of 2 equivalents of H3P02 in abs. alcohol, 1 equivalent of the corresponding oxime was added dropwise with stirring. The reaction mixture was ref- luxed for additional 3-6 hours, cooled and the desired products were isolated either by ion-exchange chromato- graphy on cationic exchanging resin or by crystallisation. Yields were from 52 % for the compound 9 to 18 % for the compound 1. The physico-chemical data of the obtained compounds were identical with those of compounds prepared by other methods known from literature. Example 13 .
Small pieces of fungal mycelium of P. oryzae were sowed in the center of Petri dishes containing minimal agar medium. The nutritional medium contained the following com- pounds per liter of medium: NaN03 -2.5 g; KH2P04 - 1.0 g; MgS04 - 0.5 g; Saccarose - 10.0 g; Thiamine - 200 μg Biotin - 5 μg; Agar -15 g. The inhibition of radial growth of the mycelium of P . oryzae was estimated by comparing the mycelium growth rate on agar media containing test compounds with control colonies. The influence of the test compounds on conidia germination was estimated on the same agar medium containing the same substances.
Table la. Activities of COMPOUNDS OF FORMULA 1 against Pyricularia oryzae in Plate Assay in vitro Tests.
Figure imgf000026_0001
For compounds 10 and 11, see Example 22 and Table 11. For compounds 12 and 13, see Example 23 and Table 12. Example 14 .
Seedlings of different rice varieties were sowed in soil of usual rice cultivating field experimental plots and cultivated for 1 or 2 months to obtain seedlings of rice at the 3- to 4-leaves stage. An aqueous dilution of the test compound in the form of emulsifiable concentrate was applied onto the seedlings by foliar treatment. At the next day a spore suspension of P. oryzae was sprayed onto the seedlings and covered by polyethylene film for the night. The test compounds treatment was repeated twice in 10 days intervals. Disease development was checked periodically and its development was calculated according to the following equation:
Degree of Σ^ (Infection index) x (number of diseased leaves) disease deve- = X 100 lopment (%) (Total number of leaves) x 4
Infection index was estimated in accordance with the fol- lowing scheme:
Infection Index State of Infection
0.0 No infection spot on leaf
0.5 Infection spots occupy less than 5% of the leaf
1.0 Infection spots occupy less than 20% of the leaf area
2.0 Infection spots occupy less than 50% of the leaf area 4.0 Infection spots occupy more than 50% of the leaf area
The squares of the experimental plots were 1 m2. Each experiment was performed in triplicate. Compound effectivi- ties were compared with commercial fungicides. As standards there were used FujioneR, Kitazin PR (RicideR) and CinnebR. The used dosages of testing compounds, each calculated to as the active substance, were 2 kg per hectare during one season applied, as its 0.1% water solution. The dosages of the commercial products were about the same as those calculated for the active compounds content in the fungicidal compositions. The application was carried out by spraying water solutions of the test compounds and standard fungicides. After the end of season the rice grains were collected and the yield was calculated. In the season II the biological conditions were extremely favorable for the disease development, which led to very low yields of the rice crop.
Table 2. Activity of COMPOUND OF FORMULA 1(9: R=H,
Figure imgf000028_0001
against Rice Blast Disease Caused by Pyricularia oryzae under Field Tests.
Figure imgf000028_0002
Figure imgf000029_0001
Example 15.
Small pieces of mycelium of B . cinerea or V . inaequalis were sowed in the center of petri dishes on minimal agar medium as in Example 11. Radial growth inhibition of mycelium of B . cinerea and V . inaequalis was estimated by comparing with control colonies. The activity index was estimated according to the following scheme:
3 - excellent radial growth inhibition activity 2 - good radial growth inhibition activity 1 - moderate radial growth inhibition activity. 0 - absence of any activity.
Table 4.. Activity of COMPOUND OF FORMULA 1 (9: R=H) , R,= -CH2CH2SCH3) against Botritis cinerea and Venturia inaequalis under radial plate assay.
Figure imgf000029_0002
Example 16
Seeds of eggplant were sowed in soil filled in plastic pots and cultivated in a greenhouse to obtain seedlings of eggplant at the 3 to 4-leaves stage. An aqueous solution of the test compound was applied onto the seedlings by foliar treatment. After two days a spore suspension of Botritis cinerea was sprayed onto the seedlings, which were placed at 20°C under humid conditions for 20 hours. Thereafter the seedlings were grown at 20 °C under humid conditions for 6-10 days. The state of infection of the plants was observed, and the disease control value was calculated.
The fungicidal activity of 9 could effectively overcome the pathogenicity of Benomyl- and Iprodione-resistant strains of phytopatogenic fungus Botritis cinerea (see Table 5) .
Table 5. Activity of COMPOUND OF FORMULA 1 (9: R=H) , R,= -CH2CH2SCH3) against Iprodione and Benomyl resistant strains of Botri tis cinerea in Green House Experiments
Figure imgf000030_0001
- *) Iprodione (dicarboxamide) resistant strain of Botritis cinerea
- **) Benomyl (benzimidazole) resistant strain of Botritis cinerea.
- ***) Wild strain of Botritis cinerea. Example 17 .
Winter wheat plants (cv. Mironovskaja 808) which had reached the five leaf stage were treated with 0.1% solutions of the fungicides. Twentyfour hours after the treatment the plants were inoculated with a conidial suspension (107 conidia/ml) of three isolates of Septoria nodorum in distilled water with 0.05% of Tween-20 as a surfactant. Inoculated plants were incubated in a mist chamber at 22 °C for 48 hrε. Thereafter the plants were cultivated at 20°C and 16 hr daylength for 20 days and then the percentage of the decrease of photosynthetic surface of the leaves was estimated for each leaf positi- on for each treatment. The mean for each leaf position was calculated, the data summarized and divided by five (see Table 6) .
Table 6 . Chemical Control of Glume Blotch Disease caused by Septoria nodorum on Winter Wheat by Means of
COMPOUNDS OF FORMULA 1 [7:R=H, R,=CH2C00H and 3: R=H Rj= CH2CH(CH3)2] under Greenhouse Experiments
Figure imgf000031_0001
Example lβ. Winter wheat plants (cv. Mironovskaja 808) which had reached the four leaf stage were treated with 0.1% solu- tions of the fungicides. Twentyfour hours after the treatment the plants were inoculated with a conidial suspension (2.103 conidia/ml) of three isolates of Pyrenophora tritici-repentis in distilled water with 0.05% of Tween-20 as a surfactant. Inoculated plants were incubated in a mist chamber at 18-20°C for 60 hrs. Thereafter the plants were cultivated at 18-20°C and 16 hr daylength for 10 days and then the percentage of the decrease of photosynthetic surface of the leaves was estimated for each leaf position for each treatment. The mean for each leaf position was calculated, the data summarized and divided by four (see Table 7) .
Table 1_. Chemical Control of Tan Spot Disease caused by Pyrenophora tritici-repentis on Winter Wheat by
Means of COMPOUNDS OF FORMULA 1 [7:R=H, R,= -CH2COOH and 15: R=H, R,= CH2CH2S (CH3)2] under Greenhouse Experiments.
Figure imgf000032_0001
Example 1 .
Seeds of tomato (species "Talalikhinsky") were sowed in soil in plastic pots and cultivated in a green house for 30 days to obtain seedlings of tomato at the 5-leaved stage. An 0.1% aqueous solution of the test compound in the form of an emulsifiable concentrate was applied onto the seedlings by foliar treatment. On each plant, 0.5 ml of solution was applied. The next day a spore suspension of Phytophthora inf stans was sprayed onto the seedlings, which were placed at 20°C under humid conditions for 20 hrs. Thereafter, the seedlings were grown at 20 °C under humid conditions for 6 days. The state of plant infection was observed and the preventive index was calculated as in Example 14 (see Table 8) .
Seeds of wheat were sowed in soil in plastic pots and cultivated in a green house to obtain seedlings of wheat at the 1-leave stage. An 0.1% aqueous solution of the test compound in the form of an emulsifiable concentrate was applied onto the seedlings by foliar treatment. On each plant, 0.5 ml of solution was applied. Then, a spore suspension of Puccinia recondita or Erysiphe graminis were sprayed onto the seedlings, which were placed at 20°C under humid conditions for 24 hrs. Thereafter, the seedlings were grown at 20°C under normal conditions for 6 days. The state of plant infection was observed and the preventive index was calculated as in Example 14 (see Table 8) .
Seeds of rice were sowed in soil in plastic pots and cultivated in a green house to obtain seedlings of rice at the 4-leave stage. An 0.1% aqueous solution of the test compound in the form of an emulsifiable concentrate was applied onto the seedlings by foliar treatment. On each plant, 0.5 ml of solution was applied. The next day a spore suspension of Pyricularia oryzae was sprayed onto the seedlings, which were placed at 28 °C under humid conditions for 24 hrs. Thereafter, the seedlings were grown at 28 °C under normal conditions for 10 days. The state of plant infection was observed and the preventive index was calculated as in Example 14 (see Table 8) . Table 8.. Chemical control of diseases caused by Puccinia recondita, Eryεiphe graminis, Phytophthora in festans and Pyricularia oryzae by means of 0,1% solutions of COMPOUNDS OF FORMULA 1 [2: R=H,
Ri= -CH(CH3)2; 3: R=H, R,= -CH2CH (CH3)2; 9: R=H,
+ R,= CH2CH2S-CH3; 15: R=H, R]=-CH2CH2S (CH3)2] under green house experiments
Figure imgf000034_0001
Example 20.
In these experiments the method described in Example 13 was used (for data see Table 9) .
Table 9 . Activities of 0.003 % solutions of COMPOUNDS OF FORMULA 1 [2:R=H, R,=CH (CH3) 2; 3: R=H, R1=CH2CH(CH3)2; 9: R=H, R!=-CH2CH2SCH3; 15: R=H, R,=-CH2CH2S (CH3)2] Under Plate Assay in vitro Tests against Fusarium graminearum; Fusarium onili forme; Alter na- ria solani; Rhizoctonia solani; Helminthosporium sativum and Botrytis cinerea .
Figure imgf000035_0001
Example 21.
Freshly isolated grape leaves (variety "Tsolicauri") were 5 placed in Petri dishes. The bottom of these dishes was covered with wet filter paper for providing moist conditions inside the dish. The leaves were treated with a water solution of the substances. The next day the leaves were inoculated with a zoospore suspension (5.000 spo-
10 res/ml) . The inoculated leaves were placed for 2 days at 16 °C in closed dishes. The the dishes were opened, the water drops were dried at room temperature and the dishes were closed and incubated for 5-6 days at room temperature. Commercial fungicide polycarbocine was used as the
15 standard. The state of infection of the plant leaves was observed and the preventive index was calculated according to the following equation: Preventive (Degree of infection in medicated leaves) value = 100 x 100
(% %) (Degree of infection in non-medicated leaves)
(For data see Table 10) .
Table 10. Chemical Control of Grape Mildew caused by
Plasmopara viticola with a 0.1% solution of COMPOUNDS OF FORMULA 1 [2: R=H, R,=-CH (CH3) 2;
Figure imgf000036_0001
es.
Example 22
In this experiment the method described in Example 13 was used.
For data see Table 11.
Table 11. Activities of optical isomers of COMPOUND OF FORMULA 1 9: R=H, R,= -CH2CH2SCH3) against Pyricularia oryzae Under Plate Assay in vitro Tests.
Figure imgf000037_0001
Example 23.
Fragments of the first leaf (about 6 cm long) were taken from 7 days old wheat plants (disease-sensitive wheat variety "Thatcher") and were placed in Petri dishes on 1 % agar containing benzimidazole (40 mg/ml) . For the inoculation a spore suspension of wheat rust (Puccinia recondita Rob. ex. Desm. f .sp. tritici Eriks, race 77) with concentration 0.2 mg/ml was used. The applied suspension volume was 0.01 ml, containing the compounds of formula 1 to be tested in different concentrations. In the control experiments, the same concentration of wheat rust spores was used in water. Petri dishes with inoculated wheat leafs were incubated in the dark for 20 hr. at 20-22 °C and thereafter they were placed under day-type lamps with a light period of 16 hr. - day and 8 hr. - night. Protection index (% of disease development) was determined the tenth day by calculating the amount of pustules on the leaf surface and comparing it with the control, where disease was considered to be 100 %. Table 12. Activities of COMPOUNDS OF FORMULA 1 [1: R=R,=H; 4: R=H, R,=CH2CH(CH3)2; 12: R=H, R,= CH2CH2SCH2CH3; 13: R=CH3, R = CH2CH2SCH3] against wheat rust under isolated-leaf assay in vitro .
Figure imgf000038_0001

Claims

Claims
1. Use of the compounds having the general formula R 0
I II H
R, - C - P ^ formula 1
I OH
NH,
or the corresponding zwitterion form in which R and R, are the same or different and are selected from the group consisting of
- hydrogen; deuterium; - a lower alkyl, lower alkenyl or lower alkynyl group, which can be substituted with one or two groups selected from
1) -C00R2, -0R2, -SR2, -S+(R2)2, -C(0)N(R2)2, -C(0)NHOR2, -C(0)NHNHR2, -P(O) (H)OR2, -P(0)(OR2)2, -P (O) (R2) OR2, -N(R2)2, -S(0)-R2,
-ON(R2)2, -NH-C(NH) -NH2, or halogen atoms, whereby the R2 groups may be the same or different, and are a) hydrogen; b) a lower alkyl, lower alkenyl, lower alkynyl group, which may be substituted with -OH, -SH, -NH2, -COOH,
-C(0)NHOH, -C(0)NH2, -0NH2, -P02H2, -P03H2, c) an aryl group with 6 to 10 carbon atoms which may be substituted with -OH, -SH, -NH2, -COOH, -N02 or halogen atoms, 2) an aryl group with 6 to 10 carbon atoms;
3) a 3 to 9 membered heterocyclic ring containing one or more oxygen, nitrogen, or sulfur atoms in the ring;
- a cycloalkyl group with 3 to 6 carbon atoms;
- or R and R, together form a C2-C7 polymethylene chain op- tionally interrupted by an oxygen, nitrogen or sulfur atom; and the salts thereof with organic or inorganic acids and bases, as well as their optical isomers, excluding the compound wherein R is hydrogen and R, is CH3, as plant protectants and against phytopathogenic fungi.
2. Use according to claim 1 of a compound of formula 1 wherein R and R, are hydrogen, i-propyl, i-butyl, sec-butyl, hydroxymethylene, aminoethylene, aminopropylene, aminobutylene , thiomethylene, thioethylene, carboxymethy- lene, carboxyethylene, methylthioethylene, ethylthioethy- lene, dimethylthioethylene, carboxamidomethylene, carbo- xamidoethylene, cyclopentyl, -CH2SCH2CH(NH2) COOH, •CH2SCH2CH (NH2) P02H2, CH2SCH2CH (NH2) P03H2, -CH2SCH2CH2CH (NH2) COOH, -CH2SCH2CH2CH(NH2)P02H2, -CH2SCH2CH2CH (NH2) P02H2, -CH2CH2SC- H2CH (NH2) COOH , -CH2CH2SCH2CH (NH2) P02H2 , -CH2CH2SCH2CH (NH2) P03H2, -CH2SSCH2CH(NH2)P02H2, -NHC(NH)NH2, -CH2CH2S (O) CH3, and the salts thereof with inorganic or organic acids or bases, and optical isomers.
3. The use according to claim 1 of a compound of formula 1, wherein R is hydrogen or lower alkyl and Rx is hydrogen, lower alkyl optionally substituted with -OH, -SH, -COOH, ethylthio, di ethylthio, cyclopentyl, and the salts thereof with inorganic or organic acids or bases, and optical isomers.
4. The use according to claim 1 of a compound of formula 1, wherein R[ is hydrogen, i-propyl, i-butyl, sec-butyl, hydroxymethylene, methylthioethylene, dimethyltioethylene or carboxymethylene and R is hydrogen, and the salts thereof with inorganic or organic acids or bases, and optical isomers.
5. The use according to claim 1 or 4 against Pyricularia oryzae; Erysiphe graminis; Puccinia recondita; Phytophthora infestans; Venturia inaeqalis; Botrytis cinerea ; Septoria nodorum; Pyrenophora tritici-repentis; Fusarium graminearum; Fusarium moniliforme; Alternaria solani; Rhi- zoctonia solani; and Helminthosporium εativum .
6. The use according to claim 1 or 4 against rice blast disease caused by Pyricularia oryzae , powdery mildew cau- sed by Erysiphe graminis , rust caused by Puccinia recondita on wheat, scab lesions caused by Venturia inaeqaliε and Botrytis cinerea on apple, Botrytiε cinerea on eggplant, glume blotch disease caused by Septoria nodorumon wheat, tan spot disease caused by Pyrenophora tritici- repentis on wheat, damping-off caused by Rhizoctonia solani on tomatoes.
7. The use according to claim 6 of a compound according to the formula 1, wherein R is hydrogen and R, is methylt- hiomethylene .
8. The use according to claim 1 of a compound according to the formula 1, in combination with other fungicides.
9. The use according to claim 8 of a compound according to the formula 1 together with iprodione (3- (3 , 5-dichlo- rophenyl) -N-isopropyl-2 , 4-dioxoimidazolidine-l-carboxami- de) or benomyl (methyl- (butylcarbamoyl) benzimidazol-2-yl carbamate) against Botritis cinerea .
10. The use according to claim 9 of a compound according to the formula 1 wherein R is hydrogen and R, is methylthioethylene.
11. Method for protecting plants comprising applying a plant protecting amount of a compound of the formula 1 as defined in any one of the claims 1 to 4 , to the plant or onto parts thereof.
12. Compound of the formula 1A
R O
I II H i- C - P ^ formula 1A
I OH NH, or the corresponding zwitterion form in which R is hydrogen, a lower alkyl, lower alkenyl or lower alkynyl group with 1 to 5, or 2 to 5 carbon atoms, respectively, R, is selected from the group consisting of -(CH2)mS+(R2)2, -(CH2)mC(0)N(R2)2, -(CH2)mS(CH2)mCH(NH2)COOR2, - (CH2) mS (CH2) π0NH2, -(CH2)mC(0)-NHOR2, -(CH2)m0NR2R2, - (CH2) mC (0) NHNHR2, -(CH2)mS(CH2)mCH(NH2)P(0) (H)OR2, - (CH2) mS (O) R2, -(CH2)nS(CH2)mCH(NH2)P(0) (OR2)2, wherein R2 is a) hydrogen; b) a lower alkyl, lower alkenyl, lower alkynyl group, which may be substituted with -OH, -SH, -NH2, -COOH, -C(0)NHOH, -C(0)NH2, -ONH2, -P02H2 -P03H2, c) an aryl group with 6 to 10 carbon atoms which may be substituted with -OH, -SH, -NH2, -COOH, -N02 or halogen atoms , and the integers m are indendently 1 to 3 and n is 2 to 4; and their salts with organic or inorganic acids and bases, and optical isomers.
13. The compound according to formula 1A in claim 12, wherein R is hydrogen or lower alkyl, and R, is dimethylt- hioethylene, carboxamidomethylene, carboxamidoethylene, or methylethylsulfoxide, and the salts thereof with inorganic or organic acids or bases, and optical isomers.
14. The compound according to claim 13, wherein R is hyd- rogen, and Rj is dimethyltioethylene and the salts thereof with inorganic or organic acids or bases, and optical isomers.
15. Plant-protecting composition comprising an effective amount of a compound of formula 1A as defined in any one of the claims 12 to 14, together with an agrochemically acceptable carrier or diluent.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3160632A (en) * 1961-01-30 1964-12-08 Stauffer Chemical Co Aminomethylenephosphinic acids, salts thereof, and process for their production
US4147780A (en) * 1976-05-21 1979-04-03 Ciba-Geigy Corporation α-Amino-phosphonous acids for inhibiting bacteria and yeast
EP0002031A1 (en) * 1977-11-19 1979-05-30 Ciba-Geigy Ag Methods of inhibiting plant and combating weeds using alpha-aminoalkanephosphonous acids
EP0319471A2 (en) * 1987-12-01 1989-06-07 Ciba-Geigy Ag Resolution process
WO1997009333A1 (en) * 1995-09-06 1997-03-13 Sitra Foundation Novel thio-phosphoorganic compounds with plant protecting activity

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3160632A (en) * 1961-01-30 1964-12-08 Stauffer Chemical Co Aminomethylenephosphinic acids, salts thereof, and process for their production
US4147780A (en) * 1976-05-21 1979-04-03 Ciba-Geigy Corporation α-Amino-phosphonous acids for inhibiting bacteria and yeast
EP0002031A1 (en) * 1977-11-19 1979-05-30 Ciba-Geigy Ag Methods of inhibiting plant and combating weeds using alpha-aminoalkanephosphonous acids
EP0319471A2 (en) * 1987-12-01 1989-06-07 Ciba-Geigy Ag Resolution process
WO1997009333A1 (en) * 1995-09-06 1997-03-13 Sitra Foundation Novel thio-phosphoorganic compounds with plant protecting activity

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DERWENT'S ABSTRACT, No. 91-85420/12, Week 9112; & SU,A,1 558 921 (AS USSR MOLEC BIOL), 23 April 1990. *
STN INTERNATIONAL, File CA, Chemical Abstracts, Volume 108, No. 5, 1 February 1988, (Columbus, Ohio, US), KHOMUTOV R.M. et al., "Inhibition of Polyketide Biosynthesis by 1-Aminoethylphospinic Acid", Abstract No. 33507; & BIOORG. KHIM., (1987), 13(10), 1422-4. *
STN INTERNATIONAL, File CAPLUS, CAPLUS Accession No. 1982:85952, BAYLIS E.K. et al., ".Alpha.-Aminophosphonous Acids: A New Class of Biologically Active Amino Acid Analogs"; & ACS SYMP. SER., (1981), 171 (PHOSPHORUS CHEM.), 183-6. *
XENOBIOTICA, Volume 25, No. 3, March 1995, V.V. SHUMYANTSEVA et al., "Interaction of Organophosphorus Analogues of Amino Acids with P450", pages 219-227. *

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