Classifications

• • 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
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system

Definitions

• the present invention relates to the use of piperidine benzoderivatives as fungicides .
• KR Pat. 9006522 describes the use of berberine, i.e. a compound comprised in formula I, for the treatment of the pathogen responsible for apple tree canker.
• the description is confined to the effects on individual pathogen and on an individual Apple species, and with a treatment not industrially applicable.
• an object of the present invention is the use of piperidine benzoderivatives of general formula (I)
• R2 H methoxy, ethoxy, propoxy or, together with Rl , a pentatomic dioxole group
• R3 H OH, methoxy, ethoxy, propoxy or, together with R4 , a pentatomic dioxole group
• R4 H OH, methoxy or, together with R3 , a pentatomic dioxole group
• R5 H methyl, ethyl, propyl
• berberine 9 -ethoxy- 13- methyl -berberine, 13 -ethyl -berberine, 13 -methyl - berberine, columbamine, coptisine, j atrorrhizine, palmatine and/or wornnine alone or m mixtures thereof may be mentioned.
• the present invention further relates to the use as fungicides against phytopathogenic fungi of compounds having the formula I wherein the ring A is a saturated ring.
• fungicides against phytopathogenic fungi of compounds having the formula I wherein the ring A is a saturated ring may be mentioned.
• the compounds used as fungicides against phytopathogenic fungi according the present invention may be used as such or in form of salts thereof and/or derivatives, alone or in mixtures thereof.
• mixtures may also comprise all the compounds indicated in the present description.
• a further subject-matter of the present invention are the fungicidal compositions active against phytopathogenic fungi which comprise at least one compound among the above mentioned ones together with carriers and/or additives commonly used in fungicidal formulations .
• the compounds indicated in the present invention are easily available on the market and/or by synthesis or plant extraction with known methods.
• the compounds used according to the present invention are active against fungi belonging to the following classes: Phycomycetes, Ascomycetes, Basidiomycetes, Deuteromycetes .
• Berberine exhibits a fungicidal activity in particular against fungi belonging to the order Oomycetales, family Peronosporaceae, genus Peronospora, species Plasmopara viticola (Bete) Beri et De Toni, genus Phytophthora; against fungi of the order Perisporiales , family Erysiphaceae , genera Uncinula, Erysiphe, Sphaerotecha, fungi of the order Pseudosphaeriales, family Pseudosphaeriaceae, genus Venturia and fungi of the order Helotiales, family Helotiaceae, genera Sclerotinia, Monilia/Monilinia, Botrytis/ Botry
• Berberine whose chemical name is 5-6-dihydro-9 , 10- dimethoxybenzo [g] -1, 3-benzodioxolo [5 , 6-a] -quinolizinium, is a low-toxicity quaternary alkaloid present in a number of vegetal families like the Berberidacee, Papaveracee, Ranuncolacee, Rutacee. The compound is known and is also described in the Merck Index (XII Ed. hereinafter referred to as Merck Index) , under N. 1192; the same source also mentions a method for synthesizing berberine (Kametani et col.) J.Chem. Soc . 1969, 2036).
• Berberine-containing plants have been used as medicaments in the traditional medical systems of several countries, and are still being used in India, China, other Asian areas and in North America. Its therapeutical activity is explicated against malaria and several bacteria.
• berberine is used as an antipyretic, anthelmintic, to expel several parasites, and it demonstrates bitter-tonic stomachic properties (Harborne JB, Baxter H. , 1993) .
• In Western medicine, berberine is used as antibacterial agent (Bruneton, 1995; Reynolds, 1993) .
• Compounds closely related thereto exhibit a colecynetic action, as demonstrated by Sanguinarine, which possesses acetylcholinestherase-inhibiting activities (Wichtl, 1994) .
• Berbine whose chemical name is 5,8,13,13a- tetrahydro-6H-dibenzo [a, g] -quinolizine is a compound described in Merck Index (N. 1195) as parent substance for naming berberine; the reported source also mentions a synthesis, but no use thereof whatsoever.
• Camptothecin whose chemical name is (S) -4-ethyl-4- hydroxy- lH-pyrano- [3 ' , 4 ' : 6, 7] indolizino [1, 2-b] quinoline- 3 , 14 (4H, 12H) -dione, is also described in Merck Index (N. 1783) .
• Canadine whose chemical name is 5, 8, 13, 13a. tetrahydro-9, 10-dimethoxy-6H-benzo [g] -1,3- benzodioxolo [5, 6-a] quinolizine, described in Merck Index (N. 1785) , is also a substance similar to berberine from the plant of Corydalis cava, which may be prepared by reduction of Berberine. No uses thereof are described.
• Chelerythrine 1, 2-dimethoxy-12-methyl [1,3] - benzodioxolo [5 , 6-c] phenanthridinium is a substance described in Merck Index (N. 2093) obtained from root of the plant Chelidonium majus ; the same source reports a synthesis thereof and some pharmacological studies, yet not mentioning any use thereof.
• Columbamine (5, 6-dihydro-2-hydroxy-3 , 9, 10- trimethoxydibenzo [a, g] -quinolizinium) , described in Merck Index (n° 2556) , is obtained from the plant of Berberis Lambertii . A synthesis from Berberine is also possible; for this substance no application is described.
• Coptisine (6, 7-dihydrobis [1,3] -benzodioxolo [5,6- a :4 ', 5' -g] quinolizinium) is described in Merck Index (N. 2591) as obtained from the root of Copthis japonica, citing a publication related to its chemical characterization. No uses thereof are apparent, at least not from the cited source.
• Corycavamine (R) -4,6,7, 14-tetrahydro-5 , 14- dimethylbis [1,3] benzodioxolo [4 , 5-c : 5 ' .6'-g]azin-13(5H)- one) is disclosed in Merck Index (n° 2607) as present in Corydalis Cava plants. The same source cites works on the structure thereof, yet no use thereof is mentioned.
• Corycavidine (R) -5,7,8, 15-tetrahydro-3 , 4-dimethoxy- 6 , 15-dimethyl [1,3] benzodioxolo [5 , 6-e] [2] benzaqueln- 14(6H)one) is disclosed in Merck Index (n° 2608) as obtained from plant of Corydalis Cava ; the same source mentions works describing the structure and the synthesis thereof. In this case as well, no use thereof is reported.
• Corydaline (13S-trans) -5,8,13, 13a-tetrahydro- 2,3,9, 10-tetramethoxy-13-metil-6H- dibenzo [a, g] quinolizine) is described in Merck Index (N. 2610) as an alkaloid isolated from many species of genus Corydalis .
• the same source cites structural, synthesis and toxicity studies .
• Corypalmine (5 , 8 , 13 , 13a-tetrahydro-2 , 9 , 10- trimethoxy-6H-dibenzo [g] quinolizin-3-ol) is cited in Merck Index (N. 2615) as present in Corydalis cava and in other plants belonging to genus Corydalis .
• the same source cites the synthesis thereof and some structural studies, yet not mentioning any use thereof.
• Jatrorrhizine (5, 6-dihydro-3-hydroxy-2 , 9, 10- trimethoxydibenzo [a, g] quinolizinium) is described in Merck Index (N. 5274) , wherein it is indicated to be obtained from root of Jateorhiza palmata; the same source cites structural studies, not reporting any uses thereof. Palmatine (5, 6-dihydro-2 ,3,9, 10-tetra- methoxydibenzo [a, g] quinolizinium) according to Merck Index (N. 7126) was isolated from root of Jateorhiza palmata ; the latter also cites the extraction process and the properties, but no use thereof.
• Tetrahydropalmatine (5, 8, 13 , 13a-tetrahydro-2 , 3,9, 10- tetramethoxy-6H-dibenzo [a, g] quinolizine) is cited in Merck Index (N. 9354) which also reports structure, synthesis and biosynthesis studies, mentioning the presence of a (d) - and of an (l)-form. The same source cites no use thereof.
• Worenine (6 , 6-dihydro-14-methylbis [1 , 3] benzodioxolo [5 , 6-a : 5 ', 6 ' -g] quinolizinium) is also described Merck Index (n° 10187) as an alkaloid similar to berberine isolated from root of Coptis Japonica . The same source cites structural studies, reporting no use thereof .
• Example 1 show the methods followed and the results obtained in some tests conducted to assess and quantify berberine' s fungicidal activity against phytopathogenic fungi. A similar activity was found in the other compounds.
• the dosages indicated in the following examples relate to the quantities used in each individual treatment .
• the first test was conducted on Cucurbitaceae oidium (Erysiphe Cichoracearum DC; Sphaerotheca Fuliginea SHL) present on gourd (Cucurbita Pepo) plants.
• the concentrations adopted were as follows: 2500 ppm, 1250 ppm, 1000 ppm, 500 ppm. Each adopted concentration, apart from the 500 ppm one, had totally devitalized the mycelium within a 48-hour time.
• the 500 ppm solution despite the extremely reduced dosage thereof, showed capable of controlling the fungus, though requiring more time to exhibit its activity (about 4/5 days) .
• the fungicidal activity is highly persistent: 14 days after the treatment, plants treated with a 1000 ppm dose exhibited no reinfection symptoms.
• Example 2 A second test was conducted on Strawberry oidium (Sphaerotheca Macularis Jacz.) ; Strawberry plants located in a nursery cultivated with biological methods were treated with 1000 ppm berberine; after 48 hours the mycelium appeared devitalized. The reference lot, treated exclusively with 0.3% wettable sulfur (compliant to the EEC Norms for biological productions) had instead a marked presence of active mycelium.
• Example 3
• the test was conducted at the end of August in a nursery hosting the apple cultivar denominated Cripps Pink, since, due to the marked susceptibility of such cultivar to the scab, in late summer the pathogen proves difficult to control using the products known by the state of the art.
• Two apical treatments were carried out: - one on 08/28, at a 1000 ppm dose; - - one on 09/08, at a 1250 ppm dose.
• the berberine-treated plants demonstrate fungal infection rates which are constantly lower with respect to those of the plants treated with synthetic fungicides, and, remarkably, the infection rate is 11.8 times lower in plants treated with the natural product with respect to those treated with synthetic products;
• procymidone Trade name: Sumisclex - Sumitomo chem.
• untreated test - 500 ppm procymidone (Trade name: Sumisclex - Sumitomo chem.) ; - untreated test.
• the enclosed photographic reproduction shows the results of the assessment after 4 days from the treatment: the fruit a is the first fruit (as reported in the preceding table) of thesis 1, the fruit b is the fifth fruit of thesis 2, the fruit c is the first fruit of thesis 3, the fruit d is the second fruit of thesis 4, the fruit e is the first fruit of thesis 5, the fruit f is the first fruit of thesis 6.
• the object of this test was comparing the effectiveness of berberine towards the apple scab (Venturia Inaequalis) with that of some products commonly used in the fight against such pathogen.
• the test conducted from 19 April 2000 to 3 June 2000 in a REDCHIEF (RED DELICIOUS) apple orchard, concerned the following theses : THESIS 1 - untreated THESIS 2 - berberine chloride 50 g/hl (equivalent to 500 ppm)
• Berberine provided results similar to those of the traditional products, especially in fruit protection.
• Example 7 The following test was conducted to assess the effectiveness of Berberine towards the pathogen Uncmula necator, causing the vines Oidium.
• the test was conducted from 2000/201710 to 2000/08/21 in a Chardonnay grapevine.
• the theses provided were as follows :
• 50 g/hl and 100 g/hl are equivalent to 500 and 1000 ppm, respectively.
• Each 3 plant -thesis was sprayed with a quantity of solution equivalent to 600 1/ha from April 28, 2000 to May 24, 2000 and with 1000 1/ha thereof from July 6, 2000 to August 8, 2000.
• the assessments on leaves were conducted prior to the treatment and at the onset of ripening; for each of the 3 plants per thesis 50 leaves, i.e., a total of 150 leaves, were assessed.
• the assessments on fruits were conducted on August 8, 2000 on 50 grapes per thesis, and the % of infected grapes was assessed.
• the test was conducted in order to assess berberine' s effectiveness towards Cercospora bieticola, a pathogen causing serious damages to sugar beet .
• the lot examined had already been pretreated with Cu So 4 x 5H 2 0 (25% Cu) at a dose of 700 g/hl.
• Rate of activity mean of untreated plants - mean of treated plants x loo mean of untreated plants Results: decrease of intensity of disease of 75% in Reference Product Thesis and of 60% in Berberine Chloride Thesis
• the object of this test was assessing Berberine 's activity towards the fungus Plasmopara viticola, causing the Vine Peronospora.
• the test was conducted on plants of the variety Sultana, particularly prone to Peronospora attacks. The theses compared were the following:
• Rate activity mean of untreated plants - mean of treated plants x xoo mean of untreated plants
• the first treatment with berberine was conducted with 20 -cm long shoots on May 2, 2000; the subsequent treatments were applied every 10 days until August 04, 2000 for a total of 12 treatments.
• Rate activity mean of untreated plants - mean of treated plants x xoo mean of untreated plants Results: decrease of intensity of disease of 62.3% in reference product thesis and of 58.8% in berberine chloride thesis.
• This test aimed at assessing berberine' s effectiveness towards the collar rot of vegetables caused by Sclerotinia sclerotiorum.
• Sclerotinia mycelium was grown in a Petri plate containing a dextrose potato Agar medium; after 15 days the mycelium with the sclerotia was incorporated in the germination loam placed in plastic containers commonly used in the production of young plants.
• Seeds were immersed in the aqueous solution containing the above mentioned products for 5 minutes, and then sown on September 22, 2000. 3 repetitions per thesis were conducted.
• Rate activit mean of untreated plants - mean of treated plants x 10 o mean of untreated plants
• the example reports the results of the laboratory testing concerning berberine' s effectiveness on mushrooms grown on an artificial substrate.
• the ATCC American Type Culture Collection
• fungi employed in the tests are the following: Botrytis cinerea (n° 48339), Fusarium moniliforme (n° 36541) , Magnaporte grisea (n° 64413) .
• the following fungi were provided from SIAPA Ltd. : Alternaria sp . and Sclerotinia sclerothiorum using the test: measure of the diameter of growth on plate.
• the method for finding the MIC was that of assaying gradually increasing doses of the substance incorporated in the cultural medium of the fungi themselves.
• Exact quantities of berberine - HCl (Fluka) were warm dissolved in the medium; the dosages used started from 10 ⁇ g/ml, then increased to 100 ⁇ g/ml and gradually to 500, 750, 1000, 2000 and 5000 ⁇ g/ml, equivalent to 10, 100, 500, 750, 1000, 2000 and 5000 ppm, respectively.
• Having determined low doses to be less effective, and a stop of growth often not being attainable with higher doses not all the dosages were tested on all fungi.
• the tests comprised the following steps:
• berberine possesses a highly remarkable fungicidal activity, in many instances superior to that of the synthetic fungicides commonly used in agriculture;
• berberine is a wide-spectrum substance, demonstrating active against the main pathogen fungi belonging to the classes Ascomycetes, Phycomicetes , Basidiomycetes and Deuteromycetes .
• berberine demonstrated capable of replacing copper-base products, which, due to the high dosages employed and the age-long use thereof, are creating significant pollution problems to land and water-bearing strata.
• berberine may be successfully used in the fight against several fungal pathologies of primary importance in agriculture. It being a natural product, extractable from several plants as well as by synthesis, the use thereof may be provided both in the traditional and in the biological agriculture.
• a preferred application of the compounds of the present invention and/or of the compounds comprising them is by spraying/nebulizing. This application is particularly suitable for uses in the modern intensive agriculture.
• reference has often been made to berberine chloride it is understood that the fungicidal properties pertain to the berberine compound as such.
• Berberine is quite a common compound in nature, and of age-long use by man, hence, used in lieu of the traditional synthetic fungicides, it may contribute to reduce the hazards for human health and the environment.
• the classification proposed by Gabriele Goidanich ⁇ Manuale di patologia vegetale 2 nd reprint 1978, Edizioni Agricole, Bologna, Italy) was followed.
• other classifications based on different criteria were used, among which that of George N. Agrios in Plant Pathology (Academic Press Inc. 3 rd Ed., 1988) may be mentioned.
• the family of the Peronosporaceae in the classification of Goidanich became the order of the Peronosporales according to Agrios (Genera Phytophthora, Plasmopara)
• the family of the Taphrinaceae became the order of the Taphrinales (genus Taphrina)
• the family of the Erysiphaceae became the order of the Erysiphales (genera Erysiphe, Spaeroteca, Uncinula)
• the family of the Pseudosphaeriaceae became the order of the Pleosporales (genus Venturia)
• the family of the Helotiaceae became the order of the Helotiales (genera Monilia/Monilinia, Sclerotinia)
• the families Mucedinaceae, Dematiaceae, Tuberculariaceae were merged into the order of the Hyphales or Moniliales

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• Life Sciences & Earth Sciences (AREA)
• Dentistry (AREA)
• Pest Control & Pesticides (AREA)
• Plant Pathology (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Agronomy & Crop Science (AREA)
• General Health & Medical Sciences (AREA)
• Wood Science & Technology (AREA)
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• Environmental Sciences (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Hydrogenated Pyridines (AREA)

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Cited By (8)

Citations (5)

• 2000
  • 2000-02-25 IT IT2000RM000093A patent/IT1316994B1/it active
• 2001
  • 2001-02-26 EP EP01912123A patent/EP1265485A1/en not_active Withdrawn
  • 2001-02-26 AU AU2001241037A patent/AU2001241037A1/en not_active Abandoned
  • 2001-02-26 WO PCT/IT2001/000091 patent/WO2001062089A1/en not_active Application Discontinuation

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