WO2021089891A1 - Germacrone derivatives for controlling pests - Google Patents

Germacrone derivatives for controlling pests Download PDF

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Publication number
WO2021089891A1
WO2021089891A1 PCT/ES2020/070509 ES2020070509W WO2021089891A1 WO 2021089891 A1 WO2021089891 A1 WO 2021089891A1 ES 2020070509 W ES2020070509 W ES 2020070509W WO 2021089891 A1 WO2021089891 A1 WO 2021089891A1
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Prior art keywords
compounds
control
pests
germacrone
activity
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PCT/ES2020/070509
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Spanish (es)
French (fr)
Inventor
Alejandro FERNÁNDEZ BARRERO
José Francisco QUÍLEZ DEL MORAL
Azucena GONZÁLEZ COLOMA
Maria Fe Andres Yeves
Carmen Elisa DÍAZ HERNÁNDEZ
Ángeles Sonia OLMEDA GARCÍA
Alberto GALISTEO PRETEL
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Universidad De Granada
Consejo Superior De Investigaciones Científicas (Csic)
Universidad Complutense De Madrid
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Publication of WO2021089891A1 publication Critical patent/WO2021089891A1/en

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    • 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
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/06—Oxygen or sulfur directly attached to a cycloaliphatic ring system
    • 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
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals

Definitions

  • the present invention generally falls within the field of organic chemistry and in particular refers to germacrone derivatives that exhibit biocidal activity and as appetite suppressants. In particular, it has been found that these derivatives have greater activity than germachron against some types of mites and insects.
  • Germachron is a sesquiterpene isolated in significant quantities from the essential oil of Geranium macrorhyzum (chemotype from Hungary) [Navarro-Rocha, J .; F. Barrero, A .; Burillo, J .; Olmeda, A.S .; González-Coloma, A. Valorization ofessential oils from two populations (wild and commercial) of Geranium macrorrhizum L. Ind. Crops Prod. 2018, 116, 41-45]
  • This essential oil shows ixodicidal activity against the Hyalomma lusitanicum tick and antifeedant effects against aphids and insect pests Spodoptera littoralis Boisd, Myzus persicae Sulz and Rhopalosiphum padi, being the germacrone, to a great extent, responsible for these activities [Navarro-Rocha, J. ; F. Barrero, A .; Burillo, J .; Olmeda, AS; González-Coloma, A. Valorization ofessential oils from two populations (wild and commercial) of Geranium macrorrhizum L. Ind. Crops Prod. 2018, 116, 41-45].
  • germacrol alcohol resulting from the reduction of the carbonyl group of the germacrone
  • Germachron was also used as a starting material for the synthesis of 9-methylgermacrene to be used in mosquito control compositions.
  • the present invention relates to a group of compounds derived from germacrone that exhibit biocidal activity, in particular improved activity as insecticide or acaricide; and activity as appetite suppressants, in particular insect appetite suppressants.
  • the present invention relates to a biocidal or pesticidal or appetite suppressant composition
  • a biocidal or pesticidal or appetite suppressant composition comprising at least one of the compounds of the first aspect of the invention.
  • the present invention relates to the use of said compounds or of said compositions for the control of pests.
  • the invention refers to its use as an acaricide, preferably ixocide; or as an appetite suppressant, to prevent insect pests, preferably aphids.
  • the present invention relates to the use of the compounds of the first aspect for use as a medicine, in particular as an antiparasitic to prevent parasitosis or to prevent diseases in which parasites (preferably insects or mites) are vectors.
  • parasites preferably insects or mites
  • the invention also relates to pharmaceutical compositions comprising some of the compounds of the first aspect of the invention.
  • “Germacrone” is a sesquiterpene isolated in significant quantities from the essential oil of
  • Geranium macrorhyzum with formula 1:
  • appetite suppressant refers to any product or compound that affects the ability to feed on an animal, in particular insects and / or insect larvae. They are usually organic compounds produced by plants to inhibit the attack of insects and other animals.
  • Appetite suppressants can also be defined as chemicals that have low-concentration properties and that act on very specific sensory cells (anti-food receptors) of the pest. Neurons associated with these antifeedant receptors prevent the animal from feeding (deterrent effect of feeding) or cause the cessation or slowing of subsequent feeding (suppressive effect of feeding). Another mode of action of some appetite suppressants is through an apparent ability to block the function of a herbivore's stimulant food receptors, or by their ability to bind directly to their normal food signals, such as sugars and amino acids. . "Pests" are unwanted plants or animals, such as mites or insects, that interfere with human activity. In particular, pests affect human or animal health or well-being, or affect their economic income, as is the case of agricultural or livestock farms.
  • decimal notation uses the symbol as a decimal separator.
  • the inventors have synthesized up to 23 derivatives in 1-3 steps, achieving different cyclizations and varying the oxidation state of the germacrone.
  • the present invention relates to compounds derived from germacrone ("compounds of the invention”). of formulas 2, 3, 7, 8, 13, 14, 15, 17, 23 and 24, which have biocidal, pesticidal or appetite suppressant activity.
  • the invention relates to compounds of formulas 15, 17, 23 and
  • the compounds of the invention are presented in crystalline form as free or solvated compounds (for example hydrates) or as enantiomers, isomers, or ionic-type derivatives, as salts, of said compounds, all these forms being comprised within the scope of protection of the present invention.
  • the term "compound of the invention” also includes its "pesticidally acceptable salts", understood as such the salts of the anions or cations of which are known and accepted in the art for the formation of salts for use. as a pesticide. Biocidal effects of compounds:
  • the compounds with the highest ixocidal activity are 24, 14, 13 and 3.
  • compound 24 has an LD50 four times higher than germachron 1.
  • compound 2 shows an appetite suppressant effect on Rhopalosiphum padi thousands of times more potent than germacrone, making this substance a very promising selective appetite suppressant against this cereal pest.
  • compositions of the invention are provided.
  • compositions of the invention that comprise as active ingredient at least one of the compounds of the invention, in particular a compound of those detailed in the preferred embodiments of the first aspect of the invention.
  • said formulations may contain any other biocidal ingredient (such as acetylcholinesterase inhibitors, among others), growth inhibitors (such as clofentecin, ethoxazole or hexythiazox, among others) or appetite inhibitors (such as ocryolite, flonicamide or pymetrozine, among others).
  • biocidal ingredient such as acetylcholinesterase inhibitors, among others
  • growth inhibitors such as clofentecin, ethoxazole or hexythiazox, among others
  • appetite inhibitors such as ocryolite, flonicamide or pymetrozine, among others.
  • compositions are characterized by containing as active ingredient only one of the compounds of the invention or a combination of compounds of the invention.
  • compositions of the invention may vary depending on the pest control method used and the type of pest to be controlled.
  • the composition of the invention allows it to be applied and transported by plants. That is, to be absorbed by its roots or aerial parts and circulate through the plant to be ingested by the pest.
  • the composition of the invention comprises one or more compounds of the invention as defined above, in association with, and preferably homogeneously dispersed in one or more diluents or carriers and / or surfactants generally accepted in the art as suitable. for use in pesticidal compositions and that are compatible with the compounds of the invention.
  • a third aspect of the invention consists in the use of the compounds or compositions of the invention as biocides, in particular pesticides, or as appetite suppressants.
  • the present invention relates to the use of the compounds or compositions of the invention for the control of pests.
  • pest control is a method whose objective is to control or eliminate the populations of a pest, preferably mites or insects.
  • the compounds or compositions are useful against mosquitoes, particularly Culex mosquito larvae and preferably against Culex quinquefasciatus larvae and also have acaricidal effects against Tetranychus, particularly Tetranychus urticae or Tribolium, preferably Tribolium castaneum.
  • the invention relates to the use of compounds 2, 3, 7, 8, 13, 14, 15, 19 and 24, or of compositions comprising at least one of them, preferably to the use of the compounds 2, 3, 13, 14 and 24, or of compositions comprising at least one of them, and more preferably of compounds 14 or 24, mixtures of them or of compositions comprising at least one of them, for the control of mite pests belonging to the Hyalomma genus, even more preferred for the control of mite pests belonging to the Hyalomma lusitanicum species.
  • the invention relates to the use of compounds 2, 3, 7, 8, 13, 15, 17 and 23, or of compositions comprising at least one of them, preferably to the use of compounds 2 , 3, 7, 8, 17 and 23 or of compositions comprising at least one of them, and more preferably of compounds 2 or 7, mixtures of them or of compositions comprising at least one of them, for pest control of insects belonging to the genus Spodoptera, even more preferred for the control of pests of insects belonging to the species Spodoptera littoralis
  • the invention relates to the use of compounds 2, 3, 7, 8, 13, 15, 17 and 23, or of compositions comprising at least one of them, preferably to the use of compounds 2 , 3, 7, 8, 17 and 23 or of compositions comprising at least one of them, and more preferably of compounds 2 or 7, mixtures of them or of compositions comprising at least one of them for the control of pests of insects belonging to the genus Myzus, even more preferred for the control of insect pests belonging to the species Myzus persicae,
  • the invention relates to the use of compounds 2, 3, 7, 8, 13, 15, 17 and 23, or of compositions comprising at least one of them, preferably to the use of compounds 2 , 3, 7, 8, 17 and 23 or of compositions comprising at least one of them, and more preferably of compounds 2 or 7, mixtures of them or of compositions comprising at least one of them, for pest control of insects belonging to the species Rhopalosiphum padi.
  • compound 2 shows an appetite suppressant effect on Rhopalosiphum padi thousands of times more potent than germacrone, making this substance a very promising selective appetite suppressant against this cereal pest.
  • the invention describes the use of compound 2 to control a Rhopalosiphum padi pest.
  • the present invention relates to a method of controlling pests using the compounds or compositions of the invention.
  • the present invention also has for its object a method of controlling pests, in particular mites or insects, which comprises contacting a plant affected by said pest with at least one of the compounds of the invention, directly or comprised in one of the compositions of the invention.
  • the methods described in the present invention may further comprise the use of a delivery system for the compounds or compositions of the invention.
  • the pest control methods of the present invention may comprise the use of droppers for dispensing the inventive compounds or compositions.
  • the methods of the present invention may comprise the use of self-compensating drippers, the use of localized irrigation systems (such as micro-sprinklers with rotating elements or diffusers), or the use of sprinklers, for the distribution of the compounds or compositions of the present invention.
  • Localized irrigation systems can be defined as methods of fluid distribution (water, fertilizers, or, in the present case, the compounds or compositions of the invention), which, to maintain an adequate and constant level of the fluid that distributes in the soil, it applies said fluid drop by drop, slowly, locally and uniformly on the root mass of the plant.
  • Localized irrigation systems may comprise drip, bleed, and / or micro-sprinkler systems. The person skilled in the art knows how localized irrigation systems work and how to make use of them.
  • a dropper according to the present invention is defined as a point of emission of the compounds or compositions of the present invention in the proximity of the plants to be treated. The person skilled in the art knows how a dropper works and how to make use of it.
  • the object of the present invention is also a method for the control (prevention) of pests, preferably insects and mites, which comprises contacting a plant using a distribution system for at least one of the compounds of the invention. or for at least one of the compositions of the invention.
  • the compounds or compositions of the invention are used for the control of parasites in animals.
  • the invention also relates to the use of the compounds or compositions of the invention as a medicine or for the preparation of a medicine, in particular a medicine for veterinary use.
  • the compound of the invention and the methods of use thereof are of particular value in the control of pests that are harmful, or that spread or act as vectors of animal diseases, for example, in the control of ticks, mites , lice, fleas, mosquitoes. They are particularly useful in controlling pests that are present in animals or that feed on or on the skin or that suck the blood of animals, for which they can be administered orally, parenterally, percutaneously or topically. or employing any other accepted agent management mode to serve similar utilities.
  • the invention also has as its object a method of prevention and / or treatment of diseases associated with the presence of parasites.
  • This treatment consists of the administration to individuals affected by these diseases of therapeutically effective amounts of at least one of the compounds of the invention, or a pharmaceutical composition that includes them.
  • the term "therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to an animal, is sufficient to produce the treatment.
  • the amount of a compound of the invention that constitutes a therapeutically effective amount will vary, for example, according to the activity of the specific compound employed; the metabolic stability and duration of action of the compound; the species, clinical form of the human disease, age, body weight, general health, sex, and diet of the patient; the route of administration; the mode and time of administration; the rate of excretion, the combination of drugs; the severity of the particular disorder or pathological condition; and the subject undergoing therapy, but can be determined by a person skilled in the art based on his or her own knowledge and that description.
  • Germacrone 1 has an appropriate molecular structure and functionality to be used in a reagent-based approach as a source of chemical diversity.
  • Figure 1 shows some of the transformations planned to be carried out.
  • Epoxides 2 and 3 are also natural products obtained from the rhizomes of various species of Turmeric. [Ulubelen, A .; Góren, N .; Jakupovic, J. Germacrane derivatives from the fruits of Smyrnium creticum. Phytochemistry 1986, 26, 312-313], [Radulovic, N.S .; Zlatkovic, D .; Dekic, M .; Stojanovic-Radic, Z. Further Antibacterial Geranium macrorrhizum L.
  • Isogermacrone 14 was obtained from 1 after NaOEt-mediated isomerization to provide 86% yield of natural product 14 [Bozhkova, N.
  • epoxyeudesmines 23 and 24 were again obtained in just two steps. The first involved a Lewis acid-mediated cyclization of germachron (1) to produce eusdesmadienes 20 (15%) and 21 (24%) and 22 (3%). These three eudesmans are natural products isolated from different essential oils [Coll, JC; Bowden, BF; Tapiólas, DM; Willis, RH; Djura, P .; Streamer, M .; Trott, L. Studies of Australian soft Korais - XXXV: The terpenoid chemistry of soft Koran and its implications.
  • MassLynx v.4.1 software was used for HRMS instrument control, peak detection, and integration. Reactions were monitored by TLC, which was performed on 0.25 mm E. Merck silica gel plates (60F-254) and involves the use of UV light for visualization and solutions of phosphomolybdic acid in EtOH and heat as agents. growth. HPLC with UV light and Rl detection was also used. The reagents were purchased in the highest quality commercially available and used without further purification.
  • compound 14 is closely related to germacrone 1, while compounds 13 and 24 contain an epoxide that closes the carbonyl group instead of a double bond. All this seems to indicate that the presence of an epoxy function located in the a, b position of the carbonyl group enhances the ixodicidal activity.
  • Both substances can be considered analogous to the sesquiterpene ligudicin reported as a potent ixodicide [Ruiz-Vásquez, L .; Olmeda, AS; Z ⁇ iga, G .; From a structure-activity point of view, compound 14 is closely related to germacrone 1, while compounds 13 and 24 contain an epoxide that closes the carbonyl group instead of a double bond. All this seems to indicate that the presence of an epoxy function located in the a, b position of the carbonyl group enhances the ixodicidal activity.
  • Both substances can be considered analogous to the sesquiterpene ligudicin reported as a potent ixodicide [Ruiz-Vásquez, L; Olmeda, AS; Z ⁇ iga, G .; Villarroel, L; Echeverri, LF; González-Coloma, A .; Reina, M. Insect Antifeedant and Ixodicidal Compounds from Senecio adenotrichius. Chem. Biodivers. 2017, 14, e1600155.].
  • the upper surface of the discs or leaf fragments of C. anuum and H. vulgare were treated with 10 ⁇ l of the test substance.
  • the extracts and crude products were tested at an initial dose of 100 or 50 ⁇ g / cm 2 respectively.
  • Extracts and compounds with Fl / Sl> 75% were further tested in a dose-response experiment (3-4 serial dilutions) to calculate their relative potency (EC50, the effective dose to give a 50% reduction in feeding / sedimentation) of regression analysis (% Fl / SI over logarithmic dose) [Burgue ⁇ o-Tapia, E .; Castillo, L .; González-Coloma, A .; Joseph-Nathan, P. Antifeedant and Phytotoxic Activity of the Sesquiterpene p- Benzoquinone Perezone and Some of its Derivatives. 2008]
  • test solution 50 ⁇ l was added to 25 mg of powdered cellulose at different concentrations and the solvent was evaporated. For each test, three replicates with 20 larvae each were used. Dead ticks were counted after 24 h of

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  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

The invention relates to germacrone derivatives that exhibit biocidal activity and can be used as antifeedants. In particular, it has been proven that these derivatives exhibit greater activity than germacrone in relation to certain types of mites and insects.

Description

DERIVADOS DE GERMACRONA PARA EL CONTROL DE PLAGAS GERMACRONE DERIVATIVES FOR PEST CONTROL
SECTOR DE LA TÉCNICA TECHNICAL SECTOR
La presente invención se encuadra en general en el campo de la química orgánica y en particular se refiere a derivados de germacrona que presentan actividad biocida y como inhibidores del apetito. En particular, se ha comprobado que estos derivados presentan mayor actividad que germacrona frente a algunos tipos de ácaros e insectos. The present invention generally falls within the field of organic chemistry and in particular refers to germacrone derivatives that exhibit biocidal activity and as appetite suppressants. In particular, it has been found that these derivatives have greater activity than germachron against some types of mites and insects.
ESTADO DE LA TECNICA STATE OF THE ART
Actualmente, el uso de pesticidas sintéticos es el principal método de protección vegetal aplicado en la agricultura y la horticultura. Sin embargo, su uso excesivo ha provocado el desarrollo de resistencias a los plaguicidas, contaminación del medio ambiente, toxicidad para organismos no objetivo y riesgos para la salud humana. Currently, the use of synthetic pesticides is the main method of plant protection applied in agriculture and horticulture. However, its excessive use has led to the development of resistance to pesticides, environmental contamination, toxicity to non-target organisms and risks to human health.
La germacrona es un sesquiterpeno aislado en cantidades significativas del aceite esencial de Geranium macrorhyzum (quimiotipo de Hungría) [Navarro-Rocha, J.; F. Barrero, A.; Burillo, J.; Olmeda, A.S.; González-Coloma, A. Valorization ofessential oils from two populations (wild and commercial) of Geranium macrorrhizum L. Ind. Crops Prod. 2018, 116, 41-45] Germachron is a sesquiterpene isolated in significant quantities from the essential oil of Geranium macrorhyzum (chemotype from Hungary) [Navarro-Rocha, J .; F. Barrero, A .; Burillo, J .; Olmeda, A.S .; González-Coloma, A. Valorization ofessential oils from two populations (wild and commercial) of Geranium macrorrhizum L. Ind. Crops Prod. 2018, 116, 41-45]
Este aceite esencial muestra actividad ixodicida contra la garrapata Hyalomma lusitanicum y efectos antialimentarios contra pulgones y plagas de insectos Spodoptera littoralis Boisd, Myzus persicae Sulz y Rhopalosiphum padi, siendo la germacrona, en gran medida, responsable de estas actividades [Navarro-Rocha, J.; F. Barrero, A.; Burillo, J.; Olmeda, A.S.; González-Coloma, A. Valorization ofessential oils from two populations (wild and commercial) of Geranium macrorrhizum L. Ind. Crops Prod. 2018, 116, 41-45]. Por otro lado, en [Benelli, G.; Pavela, R.; lannarelli, R.; Petrelli, R.; Cappellacci, L; Cianfaglione, K.; Afshar, F.H.; Nicoletti, M.; Canale, A.; Maggi, F. Synergized mixtures ofApiaceae essential oils and related plant-borne compounds: Larvicidal effectiveness on the filariasis vector Culex quinquefasciatus Say. Ind. Crops Prod. 2017, 96, 186-195] se describe tanto la actividad insecticida de la germacrona contra larvas de mosquito ( Culex quinquefasciatus) como sus efectos acaricidas contra Tetranychus urticae [Benelli, G .; Pavela, R .; Canale, A .; Nicoletti, M .; Petrelli, R .; Cappellacci, L .; Galassi, R .; Maggi, F. Isofuranodieno y germacrona del aceite esencial de Smyrnium olusatrum como acaricidas e inhibidores de la oviposición contra Tetranychus urticae: impacto de la estabilización química del isofuranodieno por interacción con triflato de plata ; Revista de ciencia de plagas. 2016; Vol. 90. p. 693 - 699], This essential oil shows ixodicidal activity against the Hyalomma lusitanicum tick and antifeedant effects against aphids and insect pests Spodoptera littoralis Boisd, Myzus persicae Sulz and Rhopalosiphum padi, being the germacrone, to a great extent, responsible for these activities [Navarro-Rocha, J. ; F. Barrero, A .; Burillo, J .; Olmeda, AS; González-Coloma, A. Valorization ofessential oils from two populations (wild and commercial) of Geranium macrorrhizum L. Ind. Crops Prod. 2018, 116, 41-45]. On the other hand, in [Benelli, G .; Pavela, R .; lannarelli, R .; Petrelli, R .; Cappellacci, L; Cianfaglione, K .; Afshar, FH; Nicoletti, M .; Canale, A .; Maggi, F. Synergized mixtures of Apiaceae essential oils and related plant-borne compounds: Larvicidal effectiveness on the filariasis vector Culex quinquefasciatus Say. Ind. Crops Prod. 2017, 96, 186-195] the insecticidal activity of germacrone against mosquito larvae (Culex quinquefasciatus) and its acaricidal effects against Tetranychus urticae [Benelli, G.; Pavela, R .; Canale, A .; Nicoletti, M .; Petrelli, R .; Cappellacci, L .; Galassi, R .; Maggi, F. Isofuranodiene and germacrone of the essential oil of Smyrnium olusatrum as acaricides and oviposition inhibitors against Tetranychus urticae: impact of the chemical stabilization of isofuranodiene by interaction with silver triflate; Pest Science Magazine. 2016; Vol. 90. p. 693-699],
En cuanto a la toxicidad por contacto de la germacrona contra Tribolium castaneum, en [García, M.; Donadel, O.J.; Ardanaz, C.E.; Tonn, C.E.; Sosa, M.E. Toxic and repellent effects of Baccharis salicifolia essential oil on Tribolium castaneum. Pest Manag. Sci. 2005, 61, 612- 618] se concluye que la germancrona resultó no ser tóxica, mientras que en [Liang, J.Y.; Liu, X.T.; Gu, J.; Liu, Y.; Ma, X.Y.; Lv, N.; Guo, S.S.; Wang, J.L.; Du, S.S.; Zhang, J. Chemical constituents and insecticidal activity of the essential oils extracted from Artemisia giraldii and Artemisia rubripes against two stored product insects. Med. Chem. 2016, 6, 396/1-396/5] se confirma su toxicidad por contacto. La diferencia en las concentraciones usadas puede argumentarse para racionalizar esta discrepancia. Regarding the contact toxicity of germachron against Tribolium castaneum, in [García, M .; Donadel, O.J .; Ardanaz, C.E .; Tonn, C.E .; Sosa, M.E. Toxic and repellent effects of Baccharis salicifolia essential oil on Tribolium castaneum. Pest Manag. Sci. 2005, 61, 612-618] it is concluded that germanchron was not toxic, while in [Liang, J.Y .; Liu, X.T .; Gu, J .; Liu, Y .; Ma, X.Y .; Lv, N .; Guo, S.S .; Wang, J.L .; Du, S.S .; Zhang, J. Chemical constituents and insecticidal activity of the essential oils extracted from Artemisia giraldii and Artemisia rubripes against two stored product insects. Med. Chem. 2016, 6, 396 / 1-396 / 5] its contact toxicity is confirmed. The difference in the concentrations used can be argued to rationalize this discrepancy.
Por otro lado, el germacrol, alcohol resultante de la reducción del grupo carbonilo de la germacrona, resultó activo en bioensayos contra T. castaneum, presentando más actividad que la germacrona [García, M .; Donadel, O.J .; Ardanaz, C.E .; Tonn, C.E .; Sosa, M.E. Efectos tóxicos y repelentes del aceite esencial de Baccharis salicifolia en Tribolium castaneum. Pest Manag. Sci. 2005, 61 , 612-618], La germacrona también se utilizó como material de partida para la síntesis de 9-metilgermacreno que se utilizaría en composiciones para el control de mosquitos. On the other hand, germacrol, alcohol resulting from the reduction of the carbonyl group of the germacrone, was active in bioassays against T. castaneum, presenting more activity than the germacrone [García, M.; Donadel, O.J .; Ardanaz, C.E .; Tonn, C.E .; Sosa, M.E. Toxic and repellent effects of Baccharis salicifolia essential oil in Tribolium castaneum. Pest Manag. Sci. 2005, 61, 612-618], Germachron was also used as a starting material for the synthesis of 9-methylgermacrene to be used in mosquito control compositions.
La importancia de las actividades reportadas para la germacrona llevó a Navarro-Rocha et al a abordar la domesticación y cultivo de su fuente natural, G. macrorhyzum (quimiotipo de Hungría), para la producción sostenible de este producto natural. The importance of the activities reported for the germachron led Navarro-Rocha et al to address the domestication and cultivation of its natural source, G. macrorhyzum (chemotype from Hungary), for the sustainable production of this natural product.
Todas estas referencias indican que germacrona es un buen candidato para el desarrollo de herramientas para un control de plagas más sostenible. Sin embargo la actividad y el espectro de actividad de estos compuestos no son siempre completamente satisfactorios especialmente en el caso de cantidades de aplicación y concentraciones bajas, por lo que sigue siendo necesario encontrar compuestos más efectivos. All these references indicate that germacrona is a good candidate for the development of tools for a more sustainable pest control. However, the activity and spectrum of activity of these compounds are not always completely satisfactory, especially in the case of application amounts and low concentrations, so it is still necessary to find more effective compounds.
BREVE DESCRIPCIÓN DE LA INVENCIÓN BRIEF DESCRIPTION OF THE INVENTION
En el contexto antes mencionado, y después de considerar la funcionalidad particular de la molécula de germacrona [Pérez Morales, M.C.; Catalán, J. V; Domingo, V.; Jaraíz, M.; Herrador, M.M.; Quílez del Moral, J.F.; López-Pérez, J.-L; Barrero, A.F. Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theo retica I-Experimental Study. Chem. - A Eur. J. 2013, 19, 6598-6612.], los inventores han seleccionado germacrone para desarrollar nuevos agentes acaricidas, particularmente ixodicidas; insecticidas, o inhibidores del apetito de los insectos, particularmente frente a pulgones. In the aforementioned context, and after considering the particular functionality of the germachron molecule [Pérez Morales, MC; Catalan, J. V; Domingo, V .; Jaraíz, M .; Herrador, MM; Quílez del Moral, JF; López-Pérez, J.-L; Barrero, AF Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theo retica I-Experimental Study. Chem. -A Eur. J. 2013, 19, 6598-6612.], The inventors have selected germacrone to develop new acaricidal agents, particularly ixodicides; insecticides, or insect appetite suppressants, particularly against aphids.
Así pues, en un primer aspecto, la presente invención se refiere a un grupo de compuestos derivados de germacrona que presentan actividad biocida, en particular actividad mejorada como insecticida o acaricida; y actividad como inhibidores del apetito, en particular inhibidores del apetito de insectos. Thus, in a first aspect, the present invention relates to a group of compounds derived from germacrone that exhibit biocidal activity, in particular improved activity as insecticide or acaricide; and activity as appetite suppressants, in particular insect appetite suppressants.
En un segundo aspecto, la presente invención se refiere a una composición biocida o pesticida o inhibidora del apetito que comprende al menos uno de los compuestos del primer aspecto de la invención. In a second aspect, the present invention relates to a biocidal or pesticidal or appetite suppressant composition comprising at least one of the compounds of the first aspect of the invention.
En un tercer aspecto la presente invención se refiere al uso de dichos compuestos o de dichas composiciones para el control de plagas. In a third aspect the present invention relates to the use of said compounds or of said compositions for the control of pests.
En distintas realizaciones particulares la invención se refiere a su uso como acaricida, preferentemente ixocida; o como inhibidor del apetito, para prevenir plagas de insectos, preferentente áfidos. In different particular embodiments, the invention refers to its use as an acaricide, preferably ixocide; or as an appetite suppressant, to prevent insect pests, preferably aphids.
En otro aspecto, la presente invención se refiere al uso de los compuestos del primer aspecto para su uso como medicamento, en particular como antiparasitario para prevenir la parasitosis o para prevenir enfermedades en las que los parásitos (insectos o ácaros preferentemente) son vectores. In another aspect, the present invention relates to the use of the compounds of the first aspect for use as a medicine, in particular as an antiparasitic to prevent parasitosis or to prevent diseases in which parasites (preferably insects or mites) are vectors.
Por tanto, la invención también se refiere a composiciones farmacéuticas que comprenden alguno de los compuestos del primer aspecto de la invención. Therefore, the invention also relates to pharmaceutical compositions comprising some of the compounds of the first aspect of the invention.
BREVE DESCRIPCIÓN DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
Figura 1. Generación de diversidad estructural a partir de germacrona 1 Figure 1. Generation of structural diversity from germachron 1
Figure 2. Síntesis de los compuestos 2-10 a partir de germacrona 1 Figure 3. Síntesis del epóxido 13 Figure 2. Synthesis of compounds 2-10 from germacrone 1 Figure 3. Synthesis of epoxide 13
Figure 4. Síntesis de derivados de isogermacrona Figure 4. Synthesis of isogermacrone derivatives
Figure 5. Síntesis de epoxieudesmanes 23 and 24 Figure 5. Synthesis of epoxy-eudesman 23 and 24
DESCRIPCION DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
Definiciones Definitions
“Germacrona” es un sesquiterpeno aislado en cantidades significativas del aceite esencial de"Germacrone" is a sesquiterpene isolated in significant quantities from the essential oil of
Geranium macrorhyzum, con fórmula 1 :
Figure imgf000006_0001
Geranium macrorhyzum, with formula 1:
Figure imgf000006_0001
El término “inhibidor del apetito”, "antiapetitivo” o “antialimentario” (del inglés “ antifeedant" ) se refiere a cualquier producto o compuesto que afecte la capacidad para alimentarse de un animal, en particular insectos y/o larvas de insectos. Suelen ser compuestos orgánicos producidos por las plantas para inhibir el ataque de insectos y otros animales. The term "appetite suppressant", "anti-appetitive" or "anti-food" (from English "antifeedant") refers to any product or compound that affects the ability to feed on an animal, in particular insects and / or insect larvae. They are usually organic compounds produced by plants to inhibit the attack of insects and other animals.
Los inhibidores del apetito también pueden definirse como sustancias químicas que tienen propiedades a baja concentración y que actúan sobre células sensoriales muy específicas (receptores antialimentarios) de la plaga. Las neuronas asociadas con estos receptores antialimentarios impiden la alimentación del animal (efecto disuasorio de la alimentación) o provocan el cese o la ralentización de la alimentación posterior (efecto supresor de la alimentación). Otro modo de acción de algunos inhibidores del apetito se lleva a cabo mediante una aparente capacidad de bloquear la función de los receptores estimulantes de la alimentación de un herbívoro, o por su capacidad de unirse directamente a sus señales de alimentación normales, como azucares y aminoácidos. Las “plagas" (en inglés “pest”) son plantas o animales no deseados, como ácaros o insectos, que interfieren con la actividad humana. En particular, las plagas afectan a la salud o al bienestar humano o animal, o afectan a sus ingresos económicos, como es el caso de las explotaciones agrarias o ganaderas. Appetite suppressants can also be defined as chemicals that have low-concentration properties and that act on very specific sensory cells (anti-food receptors) of the pest. Neurons associated with these antifeedant receptors prevent the animal from feeding (deterrent effect of feeding) or cause the cessation or slowing of subsequent feeding (suppressive effect of feeding). Another mode of action of some appetite suppressants is through an apparent ability to block the function of a herbivore's stimulant food receptors, or by their ability to bind directly to their normal food signals, such as sugars and amino acids. . "Pests" are unwanted plants or animals, such as mites or insects, that interfere with human activity. In particular, pests affect human or animal health or well-being, or affect their economic income, as is the case of agricultural or livestock farms.
A lo largo de la descripción y las reivindicaciones el término " comprende ", que también podrá interpretarse como “consiste en", y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Throughout the description and claims the term "comprises", which may also be interpreted as "consists of", and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects Advantages and characteristics of the invention will emerge in part from the description and in part from the practice of the invention.
La notación decimal empleada en la presente memoria emplea el símbolo como separador decimal. The decimal notation used herein uses the symbol as a decimal separator.
Compuestos de la invención Compounds of the invention
Partiendo del producto natural germacrone 1, los inventores han sintetizado hasta 23 derivados en 1-3 pasos, logrando diferentes ciclizaciones y variando el estado de oxidación de la germacrona. Starting from the natural product germacrone 1, the inventors have synthesized up to 23 derivatives in 1-3 steps, achieving different cyclizations and varying the oxidation state of the germacrone.
Algunas de estas sustancias sintetizadas son productos naturales. Some of these synthesized substances are natural products.
Así, en un primer aspecto de la invención, la presente invención se refiere a compuestos derivados de germacrona (“compuestos de la invención ”). de fórmulas 2, 3, 7, 8, 13, 14, 15, 17, 23 y 24, que presentan actividad biocida, pesticida o inhibidora del apetito.
Figure imgf000007_0001
Thus, in a first aspect of the invention, the present invention relates to compounds derived from germacrone ("compounds of the invention"). of formulas 2, 3, 7, 8, 13, 14, 15, 17, 23 and 24, which have biocidal, pesticidal or appetite suppressant activity.
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000008_0001
En una realización preferente, la invención se refiere a compuestos de fórmulas 15, 17, 23 yIn a preferred embodiment, the invention relates to compounds of formulas 15, 17, 23 and
24. En una realización particular, los compuestos de la invención se presentan en forma cristalina como compuestos libres o solvatados (por ejemplo hidratos) o como enantiómeros, isómeros, o derivados de tipo iónico, como sales, de dichos compuestos estando todas estas formas comprendidas en el ámbito de protección de la presente invención. En una realización particular, el término “compuesto de la invención” incluye también a sus “sales pesticidamente aceptables ” entendiendo como tales las sales de los aniones o cationes de las cuales son conocidas y aceptadas en la técnica para la formación de sales para su uso como pesticida. Efectos biocidas de los compuestos: 24. In a particular embodiment, the compounds of the invention are presented in crystalline form as free or solvated compounds (for example hydrates) or as enantiomers, isomers, or ionic-type derivatives, as salts, of said compounds, all these forms being comprised within the scope of protection of the present invention. In a particular embodiment, the term "compound of the invention" also includes its "pesticidally acceptable salts", understood as such the salts of the anions or cations of which are known and accepted in the art for the formation of salts for use. as a pesticide. Biocidal effects of compounds:
Se ha empleado el producto natural germacrona 1 , que posee importante actividad insecticida, como material de partida para la generación de las moléculas 2-24. Algunas de estas moléculas derivadas, como 1,10-epoxigermacrona (2), 4,5-epoxigermacrona (3), gajutsulactona A (7), germacrol (11), isogermacrona (14), 9-hydroxieudesma-3,7(11)dien-6- ona (19), eudesma-4,7(11),dien-8-ona (20), eudesma-3,7(11)-dien-8-ona (21) and eudesma- 4(15),7(11)-dien-8-ona (22), son compuestos naturales. The natural product germacrona 1, which has significant insecticidal activity, has been used as a starting material for the generation of molecules 2-24. Some of these derived molecules, such as 1,10-epoxygermacrone (2), 4,5-epoxygermacrone (3), gajutsulactone A (7), germacrol (11), isogermacrone (14), 9-hydroxieudesma-3.7 (11) dien-6- one (19), eudesma-4.7 (11), dien-8-one ( 20), eudesma-3,7 (11) -dien-8-one (21) and eudesma-4 (15), 7 (11) -dien-8-one (22), are natural compounds.
Los compuestos que presentan mayor actividad ixocida son 24, 14, 13 y 3. The compounds with the highest ixocidal activity are 24, 14, 13 and 3.
Por otro lado, los compuestos 8, 2, 15, 7 y 19, presentan menor actividad ixocida. On the other hand, compounds 8, 2, 15, 7 and 19 have lower ixocidal activity.
Particularmente, el compuesto 24, presenta una LD50 cuatro veces superior que germacrona 1. In particular, compound 24 has an LD50 four times higher than germachron 1.
Desde un punto de vista estructura-actividad, el compuesto 14 está estrechamente relacionado con germacrona 1, mientras que los compuestos 13 y 24 contienen un epóxido que cierra el grupo carbonilo en lugar de un doble enlace. Todo esto parece indicar que la presencia de una función epoxi ubicada en la posición a,b del grupo carbonilo potencia la actividad ixodicida. Ambas sustancias pueden considerarse análogas del sesquiterpeno ligudicina reportado como un potente ixodicida [Ruiz-Vásquez, L.; Olmeda, A.S.; Zúñiga, G.; Villarroel, L; Echeverri, L.F.; González-Coloma, A.; Reina, M. Insect Antifeedant and Ixodicida! Compounds from Senecio adenotrichius. Chem. Biodivers. 2017, 14, e1600155.]. From a structure-activity point of view, compound 14 is closely related to germacrone 1, while compounds 13 and 24 contain an epoxide that closes the carbonyl group instead of a double bond. All this seems to indicate that the presence of an epoxy function located in the a, b position of the carbonyl group enhances the ixodicidal activity. Both substances can be considered analogous to the sesquiterpene ligudicin reported as a potent ixodicide [Ruiz-Vásquez, L .; Olmeda, A.S .; Zúñiga, G .; Villarroel, L; Echeverri, L.F .; González-Coloma, A .; Reina, M. Insect Antifeedant and Ixodicida! Compounds from Senecio adenotrichius. Chem. Biodivers. 2017, 14, e1600155.].
Por otro lado, la presencia de un epóxido en C4-C5 3 no afecta la actividad de estos compuestos, ni la existencia de un grupo ceto en un anillo ciclooctano 8. En estos casos, la funcionalidad enona debe ser la responsable de la actividad observada. Finalmente, otras modificaciones estructurales en 1 como la presencia de una lactona en lugar de la cetona, o la isomerización del doble enlace provocan una disminución significativa de la actividad. On the other hand, the presence of an epoxide in C4-C5 3 does not affect the activity of these compounds, nor the existence of a keto group in a cyclooctane ring 8. In these cases, the enone functionality must be responsible for the observed activity. . Finally, other structural modifications in 1 such as the presence of a lactone instead of the ketone, or the isomerization of the double bond cause a significant decrease in activity.
Nueve de las moléculas sintetizadas 4-6, 9-10 y 17-21 resultaron inactivas. En este caso, la desaparición de la enona 9-10 o la presencia del sistema de espirano muy tenso pueden ser las causas de la inactividad. Nine of the synthesized molecules 4-6, 9-10 and 17-21 were inactive. In this case, the disappearance of the enone 9-10 or the presence of the very tense spiral system may be the causes of inactivity.
Efectos como inhibidores del apetito También se probaron los efectos antialimentarios de estos derivados de germacrona contra la plaga de insectos S. littoralis Boisd, M. persicae Sulz y R. padi L. Ninguno de los compuestos ensayados mejora la actividad moderada-alta de la germacrona contra S. littoralis. Sólo la dicetona 8 presentó una actividad similar, mientras que los derivados 2 y 3, el diepóxido 17 y los triciclos acetilados 9 y 10 resultaron ser menos activos que la germacrona. Se encontraron resultados similares para M. persicae. Por tanto, sólo 15 mostró una actividad comparable a la de la germacrona. Cuatro compuestos, 2, 8, 10 y 13, presentaron actividad antialimentaria baja-moderada y los restantes estaban inactivos o mostraron actividad muy baja. Effects as appetite inhibitors The antifeedant effects of these germacrone derivatives were also tested against the insect plague S. littoralis Boisd, M. persicae Sulz and R. padi L. None of the compounds tested improves the moderate-high activity of germacrone against S. littoralis. Only diketone 8 showed similar activity, while derivatives 2 and 3, diepoxide 17 and acetylated tricycles 9 and 10 were less active than germachron. Similar results were found for M. persicae. Therefore, only 15 showed an activity comparable to that of the germacron. Four compounds, 2, 8, 10 and 13, showed low-moderate antifeedant activity and the rest were inactive or showed very low activity.
No obstante, de forma sorprendente, el compuesto 2 muestra un efecto inhibidor del apetito en Rhopalosiphum padi miles de veces más potente que germacrona, lo que convierte a esta sustancia en un inhibidor del apetito selectivo muy prometedor contra esta plaga del cereal. However, surprisingly, compound 2 shows an appetite suppressant effect on Rhopalosiphum padi thousands of times more potent than germacrone, making this substance a very promising selective appetite suppressant against this cereal pest.
Composiciones de la invención Compositions of the invention
En un segundo aspecto, la invención proporciona formulaciones o composiciones aptas para el control de plagas, ya sea composiciones biocidas, en particular pesticidas, o composiciones inhibidoras del apetito, en adelante “composiciones de la invención" que comprenden como ingrediente activo al menos uno de los compuestos de la invención, en particular un compuesto de los detallados en las realizaciones preferidas del primer aspecto de la invención. In a second aspect, the invention provides formulations or compositions suitable for the control of pests, either biocidal compositions, in particular pesticides, or appetite-suppressing compositions, hereinafter "compositions of the invention" that comprise as active ingredient at least one of the compounds of the invention, in particular a compound of those detailed in the preferred embodiments of the first aspect of the invention.
En una realización particular, dichas formulaciones puede contener cualquier otro ingrediente biocida (como inhibidores de la acetilcolinesterasa, entre otros), inhibidores del crecimiento (como clofentecina, etoxazol o hexitiazox, entre otros) o inhibidores del apetito (como ocriolita, flonicamida o pimetrocina, entre otros). In a particular embodiment, said formulations may contain any other biocidal ingredient (such as acetylcholinesterase inhibitors, among others), growth inhibitors (such as clofentecin, ethoxazole or hexythiazox, among others) or appetite inhibitors (such as ocryolite, flonicamide or pymetrozine, among others).
En otra realización particular, dichas composiciones se caracterizan por contener como ingrediente activo únicamente uno de los compuestos de la invención o una combinación de compuestos de la invención. In another particular embodiment, said compositions are characterized by containing as active ingredient only one of the compounds of the invention or a combination of compounds of the invention.
Las cantidades de sustancias activas contenidas en las composiciones de la invención pueden variar en función del método de control de plagas empleado y del tipo de plaga que se desea controlar. The amounts of active substances contained in the compositions of the invention may vary depending on the pest control method used and the type of pest to be controlled.
En una realización particular, la composición de la invención permite ser aplicada y transportada por las plantas. Es decir, ser absorbida por sus raíces o partes aéreas y circular por la planta para ser ingerida por la plaga. En otra realización particular, la composición de la invención comprende uno o más compuestos de la invención según lo definido anteriormente, en asociación con, y preferentemente homogéneamente dispersos en uno o varios diluyentes o portadores y/o agentes tensioactivos generalmente aceptados en la técnica como adecuados para su uso en composiciones pesticidas y que sean compatibles con los compuestos de la invención. In a particular embodiment, the composition of the invention allows it to be applied and transported by plants. That is, to be absorbed by its roots or aerial parts and circulate through the plant to be ingested by the pest. In another particular embodiment, the composition of the invention comprises one or more compounds of the invention as defined above, in association with, and preferably homogeneously dispersed in one or more diluents or carriers and / or surfactants generally accepted in the art as suitable. for use in pesticidal compositions and that are compatible with the compounds of the invention.
Uso para el control de plaqas de los compuestos de la invención Use for plaque control of the compounds of the invention
Un tercer aspecto de la invención consiste en el uso de los compuestos o composiciones de la invención como biocidas, en particular pesticidas, o como inhibidores del apetito. A third aspect of the invention consists in the use of the compounds or compositions of the invention as biocides, in particular pesticides, or as appetite suppressants.
Preferiblemente, la presente invención se refiere al uso de los compuestos o composiciones de la invención para el control de plagas. Preferably, the present invention relates to the use of the compounds or compositions of the invention for the control of pests.
En el contexto de la presente invención, el control de plagas es un procedimiento cuyo objetivo es controlar o eliminar las poblaciones de una plaga, preferentemente ácaros o insectos. In the context of the present invention, pest control is a method whose objective is to control or eliminate the populations of a pest, preferably mites or insects.
Adicionalmente, los compuestos o composiciones son útiles frente a mosquitos, particularmente larvas de mosquito Culex y preferiblemente contra larvas de Culex quinquefasciatus y también tienen efectos acaricidas contra Tetranychus, particularmente Tetranychus urticae o Tríbolium, preferentemente Tribolium castaneum. Additionally, the compounds or compositions are useful against mosquitoes, particularly Culex mosquito larvae and preferably against Culex quinquefasciatus larvae and also have acaricidal effects against Tetranychus, particularly Tetranychus urticae or Tribolium, preferably Tribolium castaneum.
Así, en una realización particular, la invención se refiere al uso de los compuestos 2, 3, 7, 8, 13, 14, 15, 19 y 24, o de composiciones que comprenden al menos uno de ellos, preferentemente al uso de los compuestos 2, 3, 13, 14 y 24, o de composiciones que comprenden al menos uno de ellos, y más preferentemente de los compuestos 14 o 24, mezclas de ellos o de composiciones que comprenden al menos uno de ellos, para el control de plagas de ácaros pertenecientes al género Hyalomma, aún más preferente para el control de plagas de ácaros pertenecientes a la especie Hyalomma lusitanicum. Thus, in a particular embodiment, the invention relates to the use of compounds 2, 3, 7, 8, 13, 14, 15, 19 and 24, or of compositions comprising at least one of them, preferably to the use of the compounds 2, 3, 13, 14 and 24, or of compositions comprising at least one of them, and more preferably of compounds 14 or 24, mixtures of them or of compositions comprising at least one of them, for the control of mite pests belonging to the Hyalomma genus, even more preferred for the control of mite pests belonging to the Hyalomma lusitanicum species.
Así, en una realización particular, la invención se refiere al uso de los compuestos 2, 3, 7, 8, 13, 15, 17 y 23, o de composiciones que comprenden al menos uno de ellos, preferentemente al uso de los compuestos 2, 3, 7, 8, 17 y 23 o de composiciones que comprenden al menos uno de ellos, y más preferentemente de los compuestos 2 o 7, mezclas de ellos o de composiciones que comprenden al menos uno de ellos, para el control de plagas de insectos pertenecientes al género Spodoptera, aún más preferente para el control de plagas de insectos pertenecientes a la especie Spodoptera littoralis Thus, in a particular embodiment, the invention relates to the use of compounds 2, 3, 7, 8, 13, 15, 17 and 23, or of compositions comprising at least one of them, preferably to the use of compounds 2 , 3, 7, 8, 17 and 23 or of compositions comprising at least one of them, and more preferably of compounds 2 or 7, mixtures of them or of compositions comprising at least one of them, for pest control of insects belonging to the genus Spodoptera, even more preferred for the control of pests of insects belonging to the species Spodoptera littoralis
Así, en otra realización particular, la invención se refiere al uso de los compuestos 2, 3, 7, 8, 13, 15, 17 y 23, o de composiciones que comprenden al menos uno de ellos, preferentemente al uso de los compuestos 2, 3, 7, 8, 17 y 23 o de composiciones que comprenden al menos uno de ellos, y más preferentemente de los compuestos 2 o 7, mezclas de ellos o de composiciones que comprenden al menos uno de ellos para el control de plagas de insectos pertenecientes al género Myzus, aún más preferente para el control de plagas de insectos pertenecientes a la especie Myzus persicae, Thus, in another particular embodiment, the invention relates to the use of compounds 2, 3, 7, 8, 13, 15, 17 and 23, or of compositions comprising at least one of them, preferably to the use of compounds 2 , 3, 7, 8, 17 and 23 or of compositions comprising at least one of them, and more preferably of compounds 2 or 7, mixtures of them or of compositions comprising at least one of them for the control of pests of insects belonging to the genus Myzus, even more preferred for the control of insect pests belonging to the species Myzus persicae,
Así, en una realización particular, la invención se refiere al uso de los compuestos 2, 3, 7, 8, 13, 15, 17 y 23, o de composiciones que comprenden al menos uno de ellos, preferentemente al uso de los compuestos 2, 3, 7, 8, 17 y 23 o de composiciones que comprenden al menos uno de ellos, y más preferentemente de los compuestos 2 o 7, mezclas de ellos o de composiciones que comprenden al menos uno de ellos, para el control de plagas de insectos pertenecientes a la especies Rhopalosiphum padi. Thus, in a particular embodiment, the invention relates to the use of compounds 2, 3, 7, 8, 13, 15, 17 and 23, or of compositions comprising at least one of them, preferably to the use of compounds 2 , 3, 7, 8, 17 and 23 or of compositions comprising at least one of them, and more preferably of compounds 2 or 7, mixtures of them or of compositions comprising at least one of them, for pest control of insects belonging to the species Rhopalosiphum padi.
Dos compuestos, 2 y 7, resultaron ser muy activos contra este pulgón (valores EC50: 6 x 10- 3 y 2 x 10-2). Estos datos convierten estas dos sustancias en inhibidores del apetito selectivos prometedores contra esta plaga de cereales. Otras cuatro moléculas (3, 8, 17 y 23) mostraron una alta actividad. Finalmente, los compuestos 13 y 15 presentaron una actividad moderada, mientras que el resto de compuestos no mostraron ningún efecto relevante. Two compounds, 2 and 7, turned out to be very active against this aphid (EC50 values: 6 x 10-3 and 2 x 10-2). These data make these two substances promising selective appetite suppressants against this cereal pest. Four other molecules (3, 8, 17 and 23) showed high activity. Finally, compounds 13 and 15 showed moderate activity, while the rest of compounds did not show any relevant effect.
Sorprendentemente, el compuesto 2 muestra un efecto inhibidor del apetito en Rhopalosiphum padi miles de veces más potente que germacrona, lo que convierte a esta sustancia en un inhibidor del apetito selectivo muy prometedor contra esta plaga de cereales. Por tanto, en su aspecto más preferible, la invención describe el uso del compuesto 2 para controlar una plaga de Rhopalosiphum padi. Surprisingly, compound 2 shows an appetite suppressant effect on Rhopalosiphum padi thousands of times more potent than germacrone, making this substance a very promising selective appetite suppressant against this cereal pest. Thus, in its most preferred aspect, the invention describes the use of compound 2 to control a Rhopalosiphum padi pest.
En otro aspecto, la presente invención se refiere a un método de control de plagas mediante el uso de los compuestos o las composiciones de la invención. In another aspect, the present invention relates to a method of controlling pests using the compounds or compositions of the invention.
La presente invención tiene también por objeto un procedimiento de control de plagas, en particular ácaros o insectos, que comprende poner en contacto una planta afectada por dicha plaga con al menos uno de los compuestos de invención, directamente o comprendido en una de las composiciones de la invención. Los procedimientos descritos en la presente invención pueden además comprender el uso de un sistema de distribución de los compuestos o las composiciones de la invención. Por ejemplo, los procedimientos de control de plagas de la presente invención pueden comprender el uso de goteros para la distribución de los compuestos o composiciones invención. Por ejemplo, los procedimientos de la presente invención pueden comprender el uso de goteros autocompensantes, uso de sistemas de riego localizado (como por ejemplo microaspersores con elementos giratorios o difusores), o el uso de aspersores, para la distribución de los compuestos o composiciones de la presente invención. The present invention also has for its object a method of controlling pests, in particular mites or insects, which comprises contacting a plant affected by said pest with at least one of the compounds of the invention, directly or comprised in one of the compositions of the invention. The methods described in the present invention may further comprise the use of a delivery system for the compounds or compositions of the invention. For example, the pest control methods of the present invention may comprise the use of droppers for dispensing the inventive compounds or compositions. For example, the methods of the present invention may comprise the use of self-compensating drippers, the use of localized irrigation systems (such as micro-sprinklers with rotating elements or diffusers), or the use of sprinklers, for the distribution of the compounds or compositions of the present invention.
Los sistemas de riego localizado se pueden definir como métodos de distribución de fluidos (agua, fertilizantes, o, en el caso que nos ocupa, los compuestos o composiciones de la invención), que, para mantener un nivel adecuado y constante del fluido que distribuye en el suelo, aplica dicho fluido gota a gota, de manera lenta, localizada y uniforme en la masa radicular de la planta. Localized irrigation systems can be defined as methods of fluid distribution (water, fertilizers, or, in the present case, the compounds or compositions of the invention), which, to maintain an adequate and constant level of the fluid that distributes in the soil, it applies said fluid drop by drop, slowly, locally and uniformly on the root mass of the plant.
Los sistemas de riego localizado pueden comprender sistemas de goteo, de exudación y/o de microaspersión. La persona experta en la materia conoce cómo funcionan los sistemas de riego localizado y cómo hacer uso de ellos. Localized irrigation systems may comprise drip, bleed, and / or micro-sprinkler systems. The person skilled in the art knows how localized irrigation systems work and how to make use of them.
Un gotero de acuerdo con la presente invención se define como un punto de emisión de los compuestos o composiciones de la presente invención en la proximidad de las plantas que se quieren tratar. La persona experta en la materia conoce cómo funciona un gotero y cómo hacer uso de él. A dropper according to the present invention is defined as a point of emission of the compounds or compositions of the present invention in the proximity of the plants to be treated. The person skilled in the art knows how a dropper works and how to make use of it.
Por lo tanto, también es objeto de la presente invención un procedimiento para el control (prevención) de plagas, preferiblemente insectos y ácaros, que comprende poner en contacto una planta utilizando para ello un sistema de distribución para al menos uno de los compuestos de invención o para al menos una de las composiciones de la invención. Therefore, the object of the present invention is also a method for the control (prevention) of pests, preferably insects and mites, which comprises contacting a plant using a distribution system for at least one of the compounds of the invention. or for at least one of the compositions of the invention.
Uso como medicamento Use as a medicine
En un aspecto de la invención, los compuestos o las composiciones de la invención se utilizan para el control de parásitos de animales. Así, la invención se refiere también al uso de los compuestos o las composiciones de la invención como medicamento o para la preparación de un medicamento, en particular un medicamento de uso veterinario. In one aspect of the invention, the compounds or compositions of the invention are used for the control of parasites in animals. Thus, the invention also relates to the use of the compounds or compositions of the invention as a medicine or for the preparation of a medicine, in particular a medicine for veterinary use.
Además, el compuesto de la invención y los procedimientos de uso del mismo son de particular valor en el control de plagas que son perjudiciales, o que se propagan o actúan como vectores de enfermedades de animales, por ejemplo, en el control de garrapatas, ácaros, piojos, pulgas, mosquitos. Son particularmente útiles en el control plagas que están presentes en animales o que se alimentan en o sobre la piel o que chupan la sangre de los animales, para los cuales se pueden administrar por vía oral, parenteral, por vía percutánea o por vía tópica, o empleando cualquier otro modo de administración de agentes aceptados para servir a similares utilidades. Furthermore, the compound of the invention and the methods of use thereof are of particular value in the control of pests that are harmful, or that spread or act as vectors of animal diseases, for example, in the control of ticks, mites , lice, fleas, mosquitoes. They are particularly useful in controlling pests that are present in animals or that feed on or on the skin or that suck the blood of animals, for which they can be administered orally, parenterally, percutaneously or topically. or employing any other accepted agent management mode to serve similar utilities.
La invención también tiene como objeto un método de prevención y/o tratamiento de enfermedades asociadas a la presencia de parásitos. Este tratamiento consiste en la administración a los individuos afectados por estas enfermedades de cantidades terapéuticamente efectivas de al menos uno de los compuestos de la invención, o una composición farmacéutica que los incluya. The invention also has as its object a method of prevention and / or treatment of diseases associated with the presence of parasites. This treatment consists of the administration to individuals affected by these diseases of therapeutically effective amounts of at least one of the compounds of the invention, or a pharmaceutical composition that includes them.
En el sentido utilizado en esta descripción, la expresión “cantidad terapéuticamente efectiva ” se refiere a aquella cantidad de un compuesto de la invención que cuando se administra a un animal, es suficiente para producir el tratamiento. La cantidad de un compuesto de la invención que constituye una cantidad terapéuticamente efectiva variará, por ejemplo, según la actividad del compuesto específico empleado; la estabilidad metabólica y duración de la acción del compuesto; la especie, la forma clínica de la enfermedad humana, la edad, el peso corporal, el estado general de salud, el sexo y la dieta del paciente; la vía de administración; el modo y el tiempo de administración; la velocidad de excreción, la combinación de fármacos; la gravedad del trastorno o la condición patológica particulares; y el sujeto que se somete a terapia, pero puede ser determinada por un especialista en la técnica según su propio conocimiento y esa descripción. In the sense used in this description, the term "therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to an animal, is sufficient to produce the treatment. The amount of a compound of the invention that constitutes a therapeutically effective amount will vary, for example, according to the activity of the specific compound employed; the metabolic stability and duration of action of the compound; the species, clinical form of the human disease, age, body weight, general health, sex, and diet of the patient; the route of administration; the mode and time of administration; the rate of excretion, the combination of drugs; the severity of the particular disorder or pathological condition; and the subject undergoing therapy, but can be determined by a person skilled in the art based on his or her own knowledge and that description.
Procedimiento de síntesis de los compuestos de la invención Germacrone 1 presenta una estructura molecular y una funcionalidad apropiadas para ser utilizado en un enfoque basado en reactivos como fuente de diversidad química. En la figura 1 se muestran algunas de las transformaciones previstas a realizar. Synthesis procedure of the compounds of the invention Germacrone 1 has an appropriate molecular structure and functionality to be used in a reagent-based approach as a source of chemical diversity. Figure 1 shows some of the transformations planned to be carried out.
Algunos de los compuestos probados se sintetizaron siguiendo protocolos previamente informados por algunos de los inventores, e incluyeron solo uno o dos pasos sintéticos de germacrone (1) [ Pérez Morales, M.C.; Catalán, J. V; Domingo, V.; Jaraíz, M.; Herrador, M.M.; Quílez del Moral, J.F.; López-Pérez, J.-L; Barrero, A.F. Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theoretical- Experimental Study. Chem. - A Eur. J. 2013, 19, 6598-6612.7], Some of the tested compounds were synthesized following protocols previously reported by some of the inventors, and included only one or two synthetic germacrone steps (1) [Pérez Morales, M.C .; Catalan, J. V; Domingo, V .; Jaraíz, M .; Herrador, M.M .; Quílez del Moral, J.F .; López-Pérez, J.-L; Barrero, A.F. Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theoretical- Experimental Study. Chem. -A Eur. J. 2013, 19, 6598-6612.7],
La síntesis de los compuestos 2-10 se resume en la Figura 2. La epoxidación directa de germacrone 1 con mCPBA produce una mezcla de epóxidos 2-3 en una proporción de 4: 1. Los epóxidos 2 y 3 también son productos naturales obtenidos de los rizomas de varias especies de Cúrcuma. [Ulubelen, A.; Góren, N.; Jakupovic, J. Germacrane derivatives from the fruits of Smyrnium creticum. Phytochemistry 1986, 26, 312-313], [Radulovic, N.S.; Zlatkovic, D.; Dekic, M.; Stojanovic-Radic, Z. Further Antibacterial Geranium macrorrhizum L. Metabolites and Synthesis of Epoxygermacrones. Chem. Biodivers. 2014, 11, 542-550] y [Yoshihara, M.; Shibuya, H.; Kitano, E.; Yanagi, K.; Kitagawa, I. The absolute stereostructure of (4s, 5s)-(+)-germacrone 4, 5-epoxide from zedoariae rhizoma cultivated in yakushima island. Chem. Pharm. Bull. (Tokyo). 1984, 32, 2059-2062], La apertura iónica de 1 (10) - epoxigemacrona (2) desencadenada por el ácido de Lewis lnBr3 dio como resultado la generación de los espiro-alcoholes 4-5 (30%). La oxidación de Dess-Martin de 4-5 produjo la correspondiente cetona 6 con un rendimiento aceptable. El tratamiento de 4,5- epoxygermacrone (3) con GaCI3 como ácido de Lewis provocó la apertura de 2 para dar un producto natural conocido como gajutsulactona A (7) (72%) (7) (72%) [Matsuda, H.; Morikawa, T.; Toguchida, I.; Ninomiya, K.; Yoshikawa, M. Medicinal Foodstuffs. XXVIII. Inhibitors of Nitric Oxide Production and New Sesquiterpenes, Zedoarofuran, 4-Epicurcumenol, Neocurcumenol, Gajutsul aciones A and B, and Zedoarolides A and B, from Zedoariae Rhizoma. Chem. Pharm. Bull. 2001, 49, 1558-156], junto con cantidades menores de dicetona 8 (18%). Por otro lado, el tratamiento de 3 con monocloruro de titanoceno y la acetilación posterior produjo la mezcla de acetatos 9-10. The synthesis of compounds 2-10 is summarized in Figure 2. Direct epoxidation of germacrone 1 with mCPBA produces a mixture of epoxides 2-3 in a 4: 1 ratio. Epoxides 2 and 3 are also natural products obtained from the rhizomes of various species of Turmeric. [Ulubelen, A .; Góren, N .; Jakupovic, J. Germacrane derivatives from the fruits of Smyrnium creticum. Phytochemistry 1986, 26, 312-313], [Radulovic, N.S .; Zlatkovic, D .; Dekic, M .; Stojanovic-Radic, Z. Further Antibacterial Geranium macrorrhizum L. Metabolites and Synthesis of Epoxygermacrones. Chem. Biodivers. 2014, 11, 542-550] and [Yoshihara, M .; Shibuya, H .; Kitano, E .; Yanagi, K .; Kitagawa, I. The absolute stereostructure of (4s, 5s) - (+) - germacrone 4, 5-epoxide from zedoariae rhizoma cultivated in yakushima island. Chem. Pharm. Bull. (Tokyo). 1984, 32, 2059-2062], The ionic opening of 1 (10) -epoxygemacrone (2) triggered by Lewis acid lnBr3 resulted in the generation of the spiro-alcohols 4-5 (30%). Dess-Martin oxidation of 4-5 produced the corresponding ketone 6 in acceptable yield. Treatment of 4,5-epoxygermacrone (3) with GaCl3 as Lewis acid caused the opening of 2 to give a natural product known as gajutsulactone A (7) (72%) (7) (72%) [Matsuda, H. ; Morikawa, T .; Toguchida, I .; Ninomiya, K .; Yoshikawa, M. Medicinal Foodstuffs. XXVIII. Inhibitors of Nitric Oxide Production and New Sesquiterpenes, Zedoarofuran, 4-Epicurcumenol, Neocurcumenol, Gajutsul aciones A and B, and Zedoarolides A and B, from Zedoariae Rhizoma. Chem. Pharm. Bull. 2001, 49, 1558-156], along with minor amounts of diketone 8 (18%). On the other hand, treatment of 3 with titanocene monochloride and subsequent acetylation produced the mixture of acetates 9-10.
Los intentos de lograr la epoxidación quimioselectiva del doble enlace exocíclico de 1 utilizando H2O2 / NaOH en diferentes disolventes fueron infructuosos, ya que la isomerización del doble enlace 1 , (10) tuvo lugar antes del inicio del proceso de epoxidación. El compuesto 13 se obtuvo por tanto siguiendo el protocolo descrito por Enev y Tsankova [13], aunque variando las especies de vanadio utilizadas para la epoxidación selectiva C7-C11 de 11 (Figura 3). Attempts to achieve chemoselective epoxidation of the exocyclic double bond of 1 using H2O2 / NaOH in different solvents were unsuccessful, since the isomerization of the double bond 1, (10) took place before the start of the epoxidation process. Compound 13 was therefore obtained following the protocol described by Enev and Tsankova [13], although varying the vanadium species used for the selective C7-C11 epoxidation of 11 (Figure 3).
El isogermacrona 14 se obtuvo a partir de 1 después de la isomerización mediada por NaOEt para proporcionar un rendimiento del 86% del producto natural 14 [Bozhkova, N.Isogermacrone 14 was obtained from 1 after NaOEt-mediated isomerization to provide 86% yield of natural product 14 [Bozhkova, N.
V; Stoev, G.; Orahovats, A.S.; Rizov, N.A. Sesquiterpene ketones from geranium macrorrhizum. Phytochemistry 1984, 23, 917-918], La epoxidación quimioselectiva del doble enlace conjugado de 14 empleando H2O2 alcalino en EtOH produce epóxido 15 (20%) (Figura 4). La reducción de isogermacrona 14 mediada por LAH produjo isogermacrol 16 (54%). Los espectros de RMN de esta molécula solo mostraron una resolución aceptable cuando se realizaron a alta temperatura. La falta de resolución a temperatura ambiente se puede atribuir a la existencia de fenómenos de coalescencia a esta temperatura. La epoxidación del isogermacrol 16 no fue selectiva y el diepóxido 17 se originó después de una doble epoxidación catalizada por vanadio. El tratamiento de isogermacrona 14 con mCPBA condujo selectivamente a 4,5-epoxiderivado 18, que se convirtió en eudesmanona 19, mediante un proceso de ciclación desencadenado por cloruro de dietilaluminio [Radulovic, N.S.; Zlatkovic, D.; Dekic, M.; Stojanovic-Radic, Z. Further Antibacterial Geranium macrorrhizum L. Metabolites and Synthesis of Epoxygermacrones. Chem. Biodivers. 2014, 11, 542-550], El compuesto 19 es un producto natural aislado de Cúrcuma phaeocaulis [Liu, Y.; Ma, J.; Wang, Y.; Donkor, P.O.;V; Stoev, G .; Orahovats, A.S .; Rizov, N.A. Sesquiterpene ketones from geranium macrorrhizum. Phytochemistry 1984, 23, 917-918], Chemoselective epoxidation of the conjugated double bond of 14 using alkaline H2O2 in EtOH produces epoxide 15 (20%) (Figure 4). LAH-mediated reduction of isogermacrone 14 produced isogermacrol 16 (54%). The NMR spectra of this molecule only showed acceptable resolution when performed at high temperature. The lack of resolution at room temperature can be attributed to the existence of coalescence phenomena at this temperature. The epoxidation of isogermacrol 16 was not selective and diepoxide 17 originated after a double epoxidation catalyzed by vanadium. Treatment of isogermacrone 14 with mCPBA selectively led to 4,5-epoxy derivative 18, which was converted to eudesmanone 19, by a cyclization process triggered by diethylaluminum chloride [Radulovic, N.S .; Zlatkovic, D .; Dekic, M .; Stojanovic-Radic, Z. Further Antibacterial Geranium macrorrhizum L. Metabolites and Synthesis of Epoxygermacrones. Chem. Biodivers. 2014, 11, 542-550], Compound 19 is a natural product isolated from Turmeric phaeocaulis [Liu, Y .; Ma, J .; Wang, Y .; Donkor, P.O .;
Li, Q.; Gao, S.; Hou, Y.; Xu, Y.; Cui, J.; Ding, L.; et al. Eudesmane-Type Sesquiterpenes from Cúrcuma phaeocaulis and Their Inhibitory Activities on Nitric Oxide Production in RAW 264.7 Cells. European J. Org. Chem. 2014, 2014, 5540-5548], Li, Q .; Gao, S .; Hou, Y .; Xu, Y .; Cui, J .; Ding, L .; et al. Eudesmane-Type Sesquiterpenes from Turmeric phaeocaulis and Their Inhibitory Activities on Nitric Oxide Production in RAW 264.7 Cells. European J. Org. Chem. 2014, 2014, 5540-5548],
Finalmente, se obtuvieron nuevamente epoxyeudesmenos 23 y 24 en solo dos pasos. El primero implicó una ciclación de germacrona (1) mediada por ácido de Lewis para producir eusdesmadienos 20 (15%) y 21 (24%) y 22 (3%). Estos tres eudesmanos son productos naturales aislados de diferentes aceites esenciales [Coll, J.C.; Bowden, B.F.; Tapiólas, D.M.; Willis, R.H.; Djura, P.; Streamer, M.; Trott, L. Studies of australian soft coráis — XXXV: The terpenoid chemistry of soft coráis and its implications. Tetrahedron 1985, 41, 1085-1092], [Nazaruk, J.; Kalemba, D.; Nazaruk, J.; Kalemba, D. Chemical Composition of the Essential Oils from the Roots of Erigeron acris L and Erigeron annuus (L.) Pers. Molecules 2009, 14, 2458-2465] y [Endo, K.; Taguchi, T.; Taguchi, F.; Hikino, H.; Yamahara, J.; Fujimura, H. Antiinflammatory Principies of Atractylodes Rhizomes. Chem. Pharm. Bull. (Tokyo). 1979, 27, 2954-2958], La epoxidación de 20 y 21 con el sistema de peróxido alcalino H2O2 / NaOH produjo epóxidos 23 y 24 con rendimientos aceptables (Figura 5). Finally, epoxyeudesmines 23 and 24 were again obtained in just two steps. The first involved a Lewis acid-mediated cyclization of germachron (1) to produce eusdesmadienes 20 (15%) and 21 (24%) and 22 (3%). These three eudesmans are natural products isolated from different essential oils [Coll, JC; Bowden, BF; Tapiólas, DM; Willis, RH; Djura, P .; Streamer, M .; Trott, L. Studies of Australian soft Korais - XXXV: The terpenoid chemistry of soft Koran and its implications. Tetrahedron 1985, 41, 1085-1092], [Nazaruk, J .; Kalemba, D .; Nazaruk, J .; Kalemba, D. Chemical Composition of the Essential Oils from the Roots of Erigeron acris L and Erigeron annuus (L.) Pers. Molecules 2009, 14, 2458-2465] and [Endo, K .; Taguchi, T .; Taguchi, F .; Hikino, H .; Yamahara, J .; Fujimura, H. Antiinflammatory Principles of Attractiveylodes Rhizomes. Chem. Pharm. Bull. (Tokyo). 1979, 27, 2954-2958], Epoxidation of 20 and 21 with the alkaline peroxide H2O2 / NaOH system produced epoxides 23 and 24 in acceptable yields (Figure 5).
MODOS DE REALIZACIÓN REALIZATION MODES
Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención: The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention:
Instrumentos y productos químicos Instruments and chemicals
Se usó gel de sílice SDS 60 (35-70 μm) para cromatografía en columna ultrarrápida. Los espectros de RMN se adquirieron con Varían Direct-Drive 600 (1H 600 MHz / 13C 150 MHz), Varían Direct-Drive 500 (1H 500 MHz / 13C 125 MHz) y Varían Direct-Drive 400 (1H 400 MHz / 13C 100 MHz). Se lograron determinaciones de masa precisas con un espectrómetro de masas de tiempo de vuelo cuadrupolo SYNAPT G2-Si (Waters, Milford, MA, EE. UU.) equipado con movilidad iónica T-Wave de alta eficiencia y una fuente de ionización por electropulverización ortogonal Z-spray ™ (ESI ) que se utilizó para análisis masivos. Se utilizó el software MassLynx v.4.1 para el control del instrumento HRMS, la detección de picos y la integración. Las reacciones se controlaron mediante TLC, que se realizaron en placas de gel de sílice E. Merck de 0,25 mm (60F-254) e implica el uso de luz UV para visualización y soluciones de ácido fosfomolíbdico en EtOH y calor como agentes de desarrollo. También se utilizó HPLC con luz UV y detección de Rl. Los reactivos se compraron con la más alta calidad disponible comercialmente y se usaron sin purificación adicional. Silica gel SDS 60 (35-70 µm) was used for flash column chromatography. NMR spectra were acquired with Varian Direct-Drive 600 ( 1 H 600 MHz / 13 C 150 MHz), Varian Direct-Drive 500 ( 1 H 500 MHz / 13 C 125 MHz) and Varian Direct-Drive 400 ( 1 H 400 MHz / 13 C 100 MHz). Accurate mass determinations were achieved with a SYNAPT G2-Si quadrupole time-of-flight mass spectrometer (Waters, Milford, MA, USA) equipped with high-efficiency T-Wave ion mobility and an orthogonal electrospray ionization source. Z-spray ™ (ESI) that was used for massive analysis. MassLynx v.4.1 software was used for HRMS instrument control, peak detection, and integration. Reactions were monitored by TLC, which was performed on 0.25 mm E. Merck silica gel plates (60F-254) and involves the use of UV light for visualization and solutions of phosphomolybdic acid in EtOH and heat as agents. growth. HPLC with UV light and Rl detection was also used. The reagents were purchased in the highest quality commercially available and used without further purification.
Síntesis Synthesis
Los compuestos 1-6, 9-10, 14, y 18-19 se prepararon de acuerdo a la descripción previa en [Pérez Morales, M.C.; Catalán, J. V; Domingo, V.; Jaraíz, M.; Herrador, M.M.; Quílez del Moral, J.F.; López-Pérez, J.-L; Barrero, A.F. Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theoretical-Experimental Study. Chem. - A Eur. J. 2013, 19, 6598-6612.7], Compounds 1-6, 9-10, 14, and 18-19 were prepared according to the previous description in [Pérez Morales, M.C .; Catalan, J. V; Domingo, V .; Jaraíz, M .; Herrador, M.M .; Quílez del Moral, J.F .; López-Pérez, J.-L; Barrero, A.F. Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theoretical-Experimental Study. Chem. -A Eur. J. 2013, 19, 6598-6612.7],
Ciclación de 4,5-epoxigermacrona (3) con GaCh. Cyclization of 4,5-epoxygermacrone (3) with GaCh.
A una solución de 4,5-epoxigermacrona (3) (150 mg, 0,64 mmol) en DCM seco (10 mi) se añadió GaCl3 (11 mg, 0,1 mmol) en atmósfera de argón a -20°C. Esta mezcla se agitó durante 90 min y se controló mediante análisis de cromatografía en capa fina. Tras el consumo del material de partida, la mezcla se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 7: 3) para obtener 108 mg de 7 (72%) y 27 mg de 8 (18%). Los compuestos 7 y 8 se describieron previamente. To a solution of 4,5-epoxygermacrone (3) (150 mg, 0.64 mmol) in dry DCM (10 ml) was added GaCl 3 (11 mg, 0.1 mmol) under argon atmosphere at -20 ° C . This mixture was stirred for 90 min and monitored by thin layer chromatography analysis. After consumption of the starting material, the mixture was evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 7: 3) to obtain 108 mg of 7 (72%) and 27 mg of 8 (18%). Compounds 7 and 8 were previously described.
Síntesis de 7,11-epoxigermacrona 13 Synthesis of 7,11-epoxygermacrone 13
A una solución de 1 (1,5 g, 6,8 mmol) en THF seco (20 ml) bajo atmósfera de argón se le añadieron 200 mg de LiAlH4 a -10 °C. La mezcla de reacción se agitó a esta temperatura durante 10 min y se controló mediante análisis de cromatografía en capa fina. T ras el consumo del material de partida, se añadieron gota a gota 0,15 mi de agua, una solución de NaOH 6 N (0,15 mi) y 0,6 mi de agua. La mezcla se filtró sobre gel de sílice y Na2SO4 (2:1) y se lavó con MTBE. La reacción se evaporó al vacío para obtener 1 ,4 g de 11 (94%). Los datos espectroscópicos de germacrol (11) fueron descritos previamente[ García, M.; Donadel, O.J.; Ardanaz, C.E.; Tonn, C.E.; Sosa, M.E. Toxic and repellen t effects of Baccharis salicifolia essential oil on Tribolium castaneum. Pest Manag. Sci. 2005, 61, 612-618] To a solution of 1 (1.5 g, 6.8 mmol) in dry THF (20 ml) under argon atmosphere was added 200 mg of LiAlH 4 at -10 ° C. The reaction mixture was stirred at this temperature for 10 min and monitored by thin layer chromatography analysis. After consumption of the starting material, 0.15 ml of water, a 6N NaOH solution (0.15 ml) and 0.6 ml of water were added dropwise. The mixture was filtered over silica gel and Na 2 SO 4 (2: 1) and washed with MTBE. The reaction was evaporated in vacuo to obtain 1.4 g of 11 (94%). The spectroscopic data of germacrol (11) were previously described [García, M .; Donadel, OJ; Ardanaz, CE; Tonn, CE; Sosa, ME Toxic and repellen t effects of Baccharis salicifolia essential oil on Tribolium castaneum. Pest Manag. Sci. 2005, 61, 612-618]
A una solución de germacrol (11) (1000 mg, 4,54 mmol) en benceno (25 mi) en atmósfera de argón, se le añadieron 37 mg de VOSO4 (0,23 mmol). Después de calentar la mezcla de reacción a la temperatura de reflujo durante 10 min, se añadieron 1 ,6 mi de t-BuOOH (9,08 mmol). Después, la reacción se calentó a reflujo durante 30 min más y se controló mediante cromatografía en capa fina. Tras el consumo del material de partida, la mezcla se diluyó con 250 mi de EtOAc, se lavó con una solución saturada de NaHC03 (3 x 100 mi) y salmuera (3 x 100 mi). La capa orgánica se secó sobre Na2S04 y se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 9: 1) para obtener 616 mg de 12 (60%). 1H NMR (400 MHz, CDCl3) d 4.82 (dd, J = 11.8, 3.1 Hz, 1 H), 4.51 (d, J = 11.3 Hz, 1H), 4.00 (d, J = 10.0 Hz, 1 H), 2.63 (dd, J = 14.8, 11.3 Hz, 1 H), 2.52 (d, J = 10.1 Hz, 1H), 2.44 (d, J = 13.0 Hz, 1H), 2.34 (td, J = 12.3, 4.9 Hz, 1 H), 2.29 - 2.19 (m, 2H), 2.09 (dd, J = 12.4, 5.0 Hz, 1 H), 2.00 (td, J = 12.1, 5.4 Hz, 1 H), 1.60 (s, 3H), 1.56 (d, 6H), 1.46 (s, 3H). 13C NMR (100 MHz, CDCl3) d 134.52, 133.32, 129.78, 123.98, 72.48, 70.46, 63.38, 46.27, 38.73, 35.25, 25.22, 22.26, 21.20, 16.66, 16.39. HRMS TOF (ES+) m/z calculado para C15H24O2 [M+H]+, en 237.1838. To a solution of germacrol (11) (1000 mg, 4.54 mmol) in benzene (25 ml) under argon atmosphere, 37 mg of VOSO 4 (0.23 mmol) was added. After heating the reaction mixture at reflux temperature for 10 min, 1.6 ml of t-BuOOH (9.08 mmol) was added. The reaction was then refluxed for an additional 30 min and monitored by thin layer chromatography. After consumption of the starting material, the mixture was diluted with 250 ml of EtOAc, washed with a saturated solution of NaHCO3 (3 x 100 ml) and brine (3 x 100 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 9: 1) to obtain 616 mg of 12 (60%). 1 H NMR (400 MHz, CDCl 3 ) d 4.82 (dd, J = 11.8, 3.1 Hz, 1 H), 4.51 (d, J = 11.3 Hz, 1H), 4.00 (d, J = 10.0 Hz, 1 H) , 2.63 (dd, J = 14.8, 11.3 Hz, 1H), 2.52 (d, J = 10.1 Hz, 1H), 2.44 (d, J = 13.0 Hz, 1H), 2.34 (td, J = 12.3, 4.9 Hz , 1H), 2.29 - 2.19 (m, 2H), 2.09 (dd, J = 12.4, 5.0 Hz, 1H), 2.00 (td, J = 12.1, 5.4 Hz, 1H), 1.60 (s, 3H) , 1.56 (d, 6H), 1.46 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) d 134.52, 133.32, 129.78, 123.98, 72.48, 70.46, 63.38, 46.27, 38.73, 35.25, 25.22, 22.26, 21.20, 16.66, 16.39. HRMS TOF (ES +) m / z calculated for C 15 H 24 O 2 [M + H] + , at 237.1838.
A una solución de 12 (160 mg, 0,68 mmol) en DMF seco (3,5 mL) bajo atmósfera de argón, se le añadieron 1,8 g de PDC (4,78 mmol) a 0 °C. La mezcla de reacción se agitó a esta temperatura durante 30 min y se controló mediante cromatografía en capa fina. Tras el consumo del material de partida, la reacción se diluyó en 35 ml de MTBE y se lavó con 35 ml de agua. Después, la capa acuosa se lavó con MTBE (3 x 20 ml). La capa orgánica combinada se lavó con salmuera (3 x 20 ml), se secó sobre Na2SO4 y se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 6: 1) para obtener 101 mg de 7,11-epoxigemacrona (13) (41%). 1H NMR (500 MHz, CD2CI2, -10 °C). Señales asignadas a conformador UU: δ 5.09 (d, J= 12.3 Hz, 1H), 4.95 (d, J= 11.9 Hz, 1H), 3.8 (d, J= 9,6 Hz, 1 H), 2.92 (t, J = 12.8 Hz, 1 H), 2,38 (m, 1H), 2,29 (d, 9.5 Hz, 1 H), 2.16 (m, 1 H), 2.07 (m, 1 H), 1.93 (dd, J = 13.9, 2.7 Hz, 1 H), 1.6 (s, 3H), 1.35 (s, 3H);. Señales asignadas a conformador DD: δ 4.87 ( J = 12.5 Hz, 1H), 4.83 (dd, J= 10.7, 7.0 Hz, 1H), 3.02-1.92 (m, 2H), 2.76 (dd, J = 14.3, 6.1 Hz, 1 H), 2.41 (m, 1H), 2.17 (m,1H), 2.12 (m, 1H), 2.07 (m, 1 H), 1.82 (s, 3H), 1.56 (s, 3H).; Señales asignadas a conformador UD: δ 5.45 (t, J = 7.5 Hz,1H) 4.74 (dd, J = 10.4,5.6 Hz,1H), 3.78 (d, J = 9.6 Hz, 1H), 2.72 (dd, J= 13.5, 5.9 Hz, 1H), 2.35 (d, J= 9,3 Hz, 1 H), 2.34 (m,1H), 2.18 (m, 2H), 2.10 (m, 1H), 1.55 (s, 3H), 1.5 (s, 3H). 13C NMR (125 MHz, CD2CI2) Señales asignadas a conformador UU: d 207.5, 133.3, 122.4, 48.2, 37.8, 27.6, 23.5, 16.0, 15.3.; Señales asignadas a conformador DD: d 207.0, 132.9, 122.9, 50.2, 28.5, 24.5, 23.3, 19.5, 15,7.; Señales asignadas a conformador UD: d 206.9, 130.7, 121.4, 49.9, 28.7, 23.4, 15.8, 15.6. HRMS TOF (ES+) m/z calculado para C15H22O2 [M+H]+, en 235.1698. To a solution of 12 (160 mg, 0.68 mmol) in dry DMF (3.5 mL) under argon atmosphere, 1.8 g of PDC (4.78 mmol) was added at 0 ° C. The reaction mixture was stirred at this temperature for 30 min and monitored by thin layer chromatography. Behind the Consuming the starting material, the reaction was diluted in 35 ml of MTBE and washed with 35 ml of water. The aqueous layer was then washed with MTBE (3 x 20 ml). The combined organic layer was washed with brine (3 x 20 mL), dried over Na 2 SO 4, and evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 6: 1) to obtain 101 mg of 7,11-epoxygemacrone (13) (41%). 1 H NMR (500 MHz, CD 2 CI 2 , -10 ° C). Signals assigned to UU shaper: δ 5.09 (d, J = 12.3 Hz, 1H), 4.95 (d, J = 11.9 Hz, 1H), 3.8 (d, J = 9.6 Hz, 1 H), 2.92 (t, J = 12.8 Hz, 1H), 2.38 (m, 1H), 2.29 (d, 9.5 Hz, 1H), 2.16 (m, 1H), 2.07 (m, 1H), 1.93 (dd , J = 13.9, 2.7 Hz, 1H), 1.6 (s, 3H), 1.35 (s, 3H); Signals assigned to conformer DD: δ 4.87 (J = 12.5 Hz, 1H), 4.83 (dd, J = 10.7, 7.0 Hz, 1H), 3.02-1.92 (m, 2H), 2.76 (dd, J = 14.3, 6.1 Hz , 1H), 2.41 (m, 1H), 2.17 (m, 1H), 2.12 (m, 1H), 2.07 (m, 1H), 1.82 (s, 3H), 1.56 (s, 3H); Signals assigned to the UD conformer: δ 5.45 (t, J = 7.5 Hz, 1H) 4.74 (dd, J = 10.4,5.6 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H), 2.72 (dd, J = 13.5, 5.9 Hz, 1H), 2.35 (d, J = 9.3 Hz, 1H), 2.34 (m, 1H), 2.18 (m, 2H), 2.10 (m, 1H), 1.55 (s, 3H) , 1.5 (s, 3H). 13 C NMR (125 MHz, CD 2 CI 2 ) Signals assigned to UU shaper: d 207.5, 133.3, 122.4, 48.2, 37.8, 27.6, 23.5, 16.0, 15.3 .; Signals assigned to conformer DD: d 207.0, 132.9, 122.9, 50.2, 28.5, 24.5, 23.3, 19.5, 15.7 .; Signals assigned to UD shaper: d 206.9, 130.7, 121.4, 49.9, 28.7, 23.4, 15.8, 15.6. HRMS TOF (ES +) m / z calculated for C 15 H 22 O 2 [M + H] + , at 235.1698.
Síntesis de 9,10-epoxyisoqermacrona 15 Synthesis of 9,10-epoxyisoqermacrone 15
A una solución de 1 (200 mg, 0,92 mmol) en EtOH (50 mi) se le añadieron 0,5 ml de H2O2 (30%) y 0,5 ml de una solución de NaOH 5 N gota a gota. La mezcla de reacción se agitó durante 40 días a temperatura ambiente y se controló mediante análisis de cromatografía en capa fina. Tras el consumo del material de partida, la mezcla se diluyó con 75 mi de MTBE, se lavó con salmuera (3 x 20 ml), se secó sobre Na2S04 y se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 9: 1) para obtener 90 mg de 14 (41%) y 64 mg de 15 (20%). 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 5.17 (dd, J = 9.1, 6.5, 1H), 3.59 (s, 1H), 2.98 (dd, J= 15.1, 6.5 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.14 (ddd, J= 13.6, 8.6, 6.1 Hz, 1 H), 1.98 (dt, J = 12.9, 6.0 Hz, 1 H), 1.75 (s, 3H), 1.73 - 1.63 (m, 3H), 1.68 (bs, 3H), 1.68 - 1.66 (m, 1H), 1.48 (s, 3H), 1.39 (s, 3H), 1.28- 1.19 (m, 1 H). 13C NMR (125 MHz, DMSO-d6, 85 °C) d 204.98, 136.74, 135.68, 130.70, 123.17, 67.99, 65.33, 37.58, 28.30, 27.39, 22.11, 21.72, 21.52, 19.97, 15.24. To a solution of 1 (200 mg, 0.92 mmol) in EtOH (50 ml) were added 0.5 ml of H2O2 (30%) and 0.5 ml of a 5N NaOH solution dropwise. The reaction mixture was stirred for 40 days at room temperature and monitored by thin layer chromatography analysis. After consumption of the starting material, the mixture was diluted with 75 ml of MTBE, washed with brine (3 x 20 ml), dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 9: 1) to obtain 90 mg of 14 (41%) and 64 mg of 15 (20%). 1 H NMR (500 MHz, DMSO-d 6, 85 ° C) δ 5.17 (dd, J = 9.1, 6.5, 1H), 3.59 (s, 1H), 2.98 (dd, J = 15.1, 6.5 Hz, 1H) , 2.93-2.83 (m, 1H), 2.14 (ddd, J = 13.6, 8.6, 6.1 Hz, 1H), 1.98 (dt, J = 12.9, 6.0 Hz, 1H), 1.75 (s, 3H), 1.73 - 1.63 (m, 3H), 1.68 (bs, 3H), 1.68-1.66 (m, 1H), 1.48 (s, 3H), 1.39 (s, 3H), 1.28-1.19 (m, 1H). 13 C NMR (125 MHz, DMSO-d 6 , 85 ° C) d 204.98, 136.74, 135.68, 130.70, 123.17, 67.99, 65.33, 37.58, 28.30, 27.39, 22.11, 21.72, 21.52, 19.97, 15.24.
Síntesis del compuesto 17 A una solución de 14 (419 mg, 1,9 mmol) en THF seco (23 mi) bajo atmósfera de argón, se le añadieron 108 mg de LiAIH4 a -10 °C. La mezcla de reacción se agitó a esta temperatura durante 100 min y se controló mediante cromatografía en capa fina. Una vez consumido el material de partida, la mezcla de reacción se diluyó con MTBE y luego se añadieron gota a gota 1 mi de agua, 1 mi de NaOH 6 N y 3 mi de agua. Luego, la reacción se filtró sobre gel de sílice y Na2SO4 (2:1) y se lavó con EtOAc. El disolvente se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 4:1) para obtener 227 mg de isogermacrol (16) (54%). 1H NMR (600 MHz, DMSO-d6, 80 °C) δ 5.26 (d, J= 9.7 Hz, 1 H), 4.97 (bs, 1H), 4.75 (d, J = 9.6 Hz, 1H), 2.94 (dd, J = 14.5, 5.2 Hz, 1 H), 2.65 (t, J = 12.3 Hz, 1H), 2.37 (ddd, J= 14.1 , 9.9, 4.4 Hz, 1 H), 2.02 (dp, J= 26.4, 6.5 Hz, 2H), 1.87 (d, J = 2.1 Hz, 3H), 1.84 - 1.70 (m, 1H), 1.64 (s, 3H), 1.62 (s, 3H), 1.61 - 1.57 (m, 2H), 1.50 (s, 3H). 13C NMR (125 MHz, DMSO-d6, 80 °C): d 132.4, 128.5, 72.6, 43.5, 41.3, 34.4, 31.5, 25.6, 24.6, 24.5, 22.5, 18.0. Synthesis of compound 17 To a solution of 14 (419 mg, 1.9 mmol) in dry THF (23 ml) under argon atmosphere, 108 mg of LiAIH4 was added at -10 ° C. The reaction mixture was stirred at this temperature for 100 min and monitored by thin layer chromatography. After the starting material was consumed, the reaction mixture was diluted with MTBE and then 1 ml of water, 1 ml of 6N NaOH and 3 ml of water were added dropwise. Then the reaction was filtered over silica gel and Na 2 SO 4 (2: 1) and washed with EtOAc. The solvent was evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 4: 1) to obtain 227 mg of isogermacrol (16) (54%). 1 H NMR (600 MHz, DMSO-d 6 , 80 ° C) δ 5.26 (d, J = 9.7 Hz, 1H), 4.97 (bs, 1H), 4.75 (d, J = 9.6 Hz, 1H), 2.94 (dd, J = 14.5, 5.2 Hz, 1H), 2.65 (t, J = 12.3 Hz, 1H), 2.37 (ddd, J = 14.1, 9.9, 4.4 Hz, 1H), 2.02 (dp, J = 26.4 , 6.5 Hz, 2H), 1.87 (d, J = 2.1 Hz, 3H), 1.84-1.70 (m, 1H), 1.64 (s, 3H), 1.62 (s, 3H), 1.61-1.57 (m, 2H) , 1.50 (s, 3H). 13 C NMR (125 MHz, DMSO-d 6 , 80 ° C): d 132.4, 128.5, 72.6, 43.5, 41.3, 34.4, 31.5, 25.6, 24.6, 24.5, 22.5, 18.0.
A una solución de 16 (227 mg, 1 ,04 mmol) en benceno seco (10 mi) en atmósfera de argón, se le añadieron 14 mg de VO(acac)2. La mezcla de reacción se agitó durante 10 min a temperatura de reflujo. Luego, se añadieron 0,37 mi de t-BuOOH (3,2 mmol). La reacción se agitó durante 30 min a temperatura de reflujo y se controló mediante cromatografía en capa fina. Tras el consumo del material de partida, la mezcla se diluyó con 180 mi de EtOAc, se lavó con una solución saturada de NaHC03 (3 x 50 mi), salmuera (3 x 50 mi), se secó sobre Na2SO4 y se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 3: 2) para obtener 100 mg de 17 (39%). 1H NMR (500 MHz, CDCl3): δ 4.97 (d, J = 12.4 Hz, 1 H), 3.56 (d, J= 9.2 Hz, 1 H), 2.80 (dd, J= 9.2, 0.9 Hz, 1 H), 2.61 (dd, J = 13.9, 12.5 Hz, 1H), 2.50 (s, 1 H), 2.26 - 2.11 (m, 3H), 1.92 - 1.72 (m, 3H), 1.67 (s, 3H), 1.65 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.34 - 1.24 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 138.20, 119.75, 69.41, 67.03, 66.96, 63.28, 62.47, 36.80, 31.86, 27.91, 22.29, 22.03, 21.95, 21.44, 15.28. To a solution of 16 (227 mg, 1.04 mmol) in dry benzene (10 ml) under argon atmosphere, 14 mg of VO (acac) 2 was added . The reaction mixture was stirred for 10 min at reflux temperature. Then, 0.37 ml of t-BuOOH (3.2 mmol) was added. The reaction was stirred for 30 min at reflux temperature and monitored by thin layer chromatography. After consumption of the starting material, the mixture was diluted with 180 ml of EtOAc, washed with a saturated solution of NaHCO3 (3 x 50 ml), brine (3 x 50 ml), dried over Na 2 SO 4 and evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 3: 2) to obtain 100 mg of 17 (39%). 1 H NMR (500 MHz, CDCl 3 ): δ 4.97 (d, J = 12.4 Hz, 1 H), 3.56 (d, J = 9.2 Hz, 1 H), 2.80 (dd, J = 9.2, 0.9 Hz, 1 H), 2.61 (dd, J = 13.9, 12.5 Hz, 1H), 2.50 (s, 1H), 2.26 - 2.11 (m, 3H), 1.92 - 1.72 (m, 3H), 1.67 (s, 3H), 1.65 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.34-1.24 (m, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 138.20, 119.75, 69.41, 67.03, 66.96, 63.28, 62.47, 36.80, 31.86, 27.91, 22.29, 22.03, 21.95, 21.44, 15.28.
Ciclación de qermacrona (1) con GaCl3. Cyclization of qermacrone (1) with GaCl3.
A una solución de 1 (150 mg, 0,69 mmol) en DCM seco (7 mi) en atmósfera de argón, se le añadieron 12 mg de GaCI3 (0,069 mmol). La mezcla de reacción se agitó durante 40 min a temperatura ambiente y se controló mediante cromatografía de capa fina. Tras el consumo del material de partida, la reacción se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 95: 5) para obtener 22 mg de 20 (15%), 37 mg de 21 (24%) y 4 mg de 22 (3%). Los compuestos 20 y 21 se describieron previamente [Pérez Morales, M.C.; Catalán, J. V; Domingo, V.; Jaraíz, M.; Herrador, M.M.; Quílez del Moral, J.F.; López-Pérez, J.-L; Barrero, A.F. Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theoretical-Experimental Study. Chem. - A Eur. J. 2013, 19, 6598-6612.7], To a solution of 1 (150 mg, 0.69 mmol) in dry DCM (7 ml) under argon atmosphere, 12 mg of GaCl3 (0.069 mmol) was added. The reaction mixture was stirred for 40 min at room temperature and monitored by thin layer chromatography. After consumption of the starting material, the reaction was evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 95: 5) to obtain 22 mg of 20 (15%), 37 mg of 21 (24%) and 4 mg of 22 (3%). Compounds 20 and 21 were previously described [Pérez Morales, MC; Catalan, J. V; Domingo, V .; Jaraíz, M .; Herrador, MM; Quílez del Moral, JF; López-Pérez, J.-L; Barrero, AF Structural Diversity from the Transannular Cyclizations of Natural Germacrone and Epoxy Derivatives: A Theoretical-Experimental Study. Chem. -A Eur. J. 2013, 19, 6598-6612.7],
Epoxidación de 20 con NaOH y H2O2. Epoxidation of 20 with NaOH and H2O2.
A una solución de 20 (298 mg, 1,37 mmol) en MeOH (45 mL), se le añadió 1 mL de NaOH 2 N y 2,7 mL de H2O2 (30% en agua) a 0 °C. La mezcla de reacción se agitó a esta temperatura durante 22 h y se controló mediante cromatografía en capa fina. Tras consumir el material de partida, la mezcla se diluyó con 155 mi de MTBE, se lavó con salmuera (3 x 50 ml), se secó sobre Na2SO4 y se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 4: 1) para obtener 137 mg de 23 (36%). 1H NMR (500 MHz, CDCl3): δ 2.77 (d, J = 17.3 Hz, 1 H), 2.68 (d, J = 17.3 Hz, 1H), 2.37 (s, 2H), 2.04 - 1.95 (m, 2H), 1.79 - 1.61 (m, 2H), 1.59 (s, 3H), 1.56 - 1.48 (m, 1 H), 1.43 (s, 3H), 1.42 - 1.36 (m, 1 H), 1.31 (s, 3H), 1.14 (s, 3H). 13C NMR (125 MHz, CDCl3): d 207.98, 128.75, 128.51 , 68.31 , 65.64, 53.77, 37.83, 35.00, 31.65, 29.80, 26.53, 20.12, 19.32, 19.17, 18.63. HRMS TOF (ES+) m/z calculado para C15H23O2[M + H]+ 235.1698, en 235.1687. To a solution of 20 (298 mg, 1.37 mmol) in MeOH (45 mL), 1 mL of 2N NaOH and 2.7 mL of H2O2 (30% in water) were added at 0 ° C. The reaction mixture was stirred at this temperature for 22 h and was monitored by thin layer chromatography. After consuming the starting material, the mixture was diluted with 155 ml of MTBE, washed with brine (3 x 50 ml), dried over Na 2 SO 4 and evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 4: 1) to obtain 137 mg of 23 (36%). 1 H NMR (500 MHz, CDCl 3 ): δ 2.77 (d, J = 17.3 Hz, 1 H), 2.68 (d, J = 17.3 Hz, 1H), 2.37 (s, 2H), 2.04 - 1.95 (m, 2H), 1.79-1.61 (m, 2H), 1.59 (s, 3H), 1.56-1.48 (m, 1H), 1.43 (s, 3H), 1.42-1.36 (m, 1H), 1.31 (s, 3H), 1.14 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ): d 207.98, 128.75, 128.51, 68.31, 65.64, 53.77, 37.83, 35.00, 31.65, 29.80, 26.53, 20.12, 19.32, 19.17, 18.63. HRMS TOF (ES +) m / z calculated for C 15 H 23 O 2 [M + H] + 235.1698, at 235.1687.
Epoxidación de 21 con NaOH v H2O2. Epoxidation of 21 with NaOH v H2O2.
A una solución de 21 (98 mg, 0,45 mmol) en MeOH (15 mL), se le añadieron 0,5 mL de solución de NaOH 2 N y 0,8 mL de H202 (30% en agua) a una temperatura de 0 °C. La mezcla de reacción se agitó a esa temperatura durante 22 h y se controló mediante análisis de cromatografía en capa fina. Tras el consumo del material de partida, la mezcla se diluyó luego en 60 mi de MTBE, se lavó con salmuera (3 x 20 ml), se secó sobre Na2SÜ4 y se evaporó al vacío. El producto bruto se purificó mediante cromatografía ultrarrápida (H: MTBE, 4: 1) para obtener 42 mg de 24 (40%). 1H NMR (500 MHz, CDCl3): δ 5.44 (bs, 1 H) 2.44 - 2.29 (m, 2H), 2.20 (d, J = 17.7 Hz, 1H), 2.11 (d, J = 6.0 Hz, 1H), 2.09 - 1.96 (m, 2H), 1.95 - 1.90 (m, 1 H), 1.63 (s, 3H), 1.55 - 1.49 (m, 1 H), 1.47 - 1.42 (m, 1 H), 1.41 (s, 3H), 1.27 (s, 3H), 0.99 (s, 3H). 13C NMR (126 MHz, CDCl3): d 208.18, 133.14, 122.25, 68.14, 65.18, 54.62, 43.22, 37.01, 33.62, 29.47, 22.46, 21.13, 20.68, 19.61 , 18.62. HRMS TOF (ES+) m/z calculado para C15H23O2 [M + H]+ 235.1698, en 235.1697. To a solution of 21 (98 mg, 0.45 mmol) in MeOH (15 mL), 0.5 mL of 2 N NaOH solution and 0.8 mL of H2O2 (30% in water) were added at a temperature 0 ° C. The reaction mixture was stirred at that temperature for 22 h and monitored by thin layer chromatography analysis. After consumption of the starting material, the mixture was then diluted in 60 ml of MTBE, washed with brine (3 x 20 ml), dried over Na 2 SÜ 4 and evaporated in vacuo. The crude product was purified by flash chromatography (H: MTBE, 4: 1) to obtain 42 mg of 24 (40%). 1 H NMR (500 MHz, CDCl 3 ): δ 5.44 (bs, 1 H) 2.44 - 2.29 (m, 2H), 2.20 (d, J = 17.7 Hz, 1H), 2.11 (d, J = 6.0 Hz, 1H ), 2.09-1.96 (m, 2H), 1.95-1.90 (m, 1H), 1.63 (s, 3H), 1.55-1.49 (m, 1H), 1.47-1.42 (m, 1H), 1.41 ( s, 3H), 1.27 (s, 3H), 0.99 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ): d 208.18, 133.14, 122.25, 68.14, 65.18, 54.62, 43.22, 37.01, 33.62, 29.47, 22.46, 21.13, 20.68, 19.61, 18.62. HRMS TOF (ES +) m / z calcd for C 15 H 23 O 2 [M + H] + 235.1698, at 235.1697.
Ejemplos de ensayos con los compuestos de la invención
Figure imgf000022_0001
Examples of tests with the compounds of the invention
Figure imgf000022_0001
Tabla 2. Actividad acaricida de derivados de germacrona frente a H. lusitanicum Koch. a Datos corregidos según la fórmula de Schenider Orelli. b Dosis necesaria para obtener un 50% y un 90% de mortalidad (95% Confidence Limits) Los compuestos ixodicidas más activos resultaron ser epoxyeudesmenona. 24 e isogermacrona 14, seguidos de germacrona (1), y los compuestos 13 y 3. Los compuestos 8, 2, 15, 7 y 19 fueron los derivados menos activos. El compuesto 24, presenta una LD50 cuatro veces mayor que la de germacrona (1), puede considerarse un candidato ixodicida prometedor. Table 2. Acaricidal activity of germacrone derivatives against H. lusitanicum Koch. a Data corrected according to the Schenider Orelli formula. b Dose required to obtain 50% and 90% mortality (95% Confidence Limits) The most active ixodicidal compounds were found to be epoxyeudesmenone. 24 and isogermacrone 14, followed by germacrone (1), and compounds 13 and 3. Compounds 8, 2, 15, 7 and 19 were the least active derivatives. Compound 24, with an LD 50 four times higher than that of germacrone (1), can be considered a promising ixodicidal candidate.
Desde un punto de vista estructura-actividad, el compuesto 14 está estrechamente relacionado con germacrona 1, mientras que los compuestos 13 y 24 contienen un epóxido que cierra el grupo carbonilo en lugar de un doble enlace. Todo esto parece indicar que la presencia de una función epoxi ubicada en la posición a,b del grupo carbonilo potencia la actividad ixodicida. Ambas sustancias pueden considerarse análogas del sesquiterpeno ligudicina reportado como un potente ixodicida [Ruiz-Vásquez, L.; Olmeda, A.S.; Zúñiga, G.; Desde un punto de vista estructura-actividad, el compuesto 14 está estrechamente relacionado con germacrona 1, mientras que los compuestos 13 y 24 contienen un epóxido que cierra el grupo carbonilo en lugar de un doble enlace. Todo esto parece indicar que la presencia de una función epoxi ubicada en la posición a,b del grupo carbonilo potencia la actividad ixodicida. Ambas sustancias pueden considerarse análogas del sesquiterpeno ligudicina reportado como un potente ixodicida [Ruiz-Vásquez, L; Olmeda, A.S.; Zúñiga, G.; Villarroel, L; Echeverri, L.F.; González-Coloma, A.; Reina, M. Insect Antifeedant and Ixodicidal Compounds from Senecio adenotrichius. Chem. Biodivers. 2017, 14, e1600155.]. From a structure-activity point of view, compound 14 is closely related to germacrone 1, while compounds 13 and 24 contain an epoxide that closes the carbonyl group instead of a double bond. All this seems to indicate that the presence of an epoxy function located in the a, b position of the carbonyl group enhances the ixodicidal activity. Both substances can be considered analogous to the sesquiterpene ligudicin reported as a potent ixodicide [Ruiz-Vásquez, L .; Olmeda, AS; Zúñiga, G .; From a structure-activity point of view, compound 14 is closely related to germacrone 1, while compounds 13 and 24 contain an epoxide that closes the carbonyl group instead of a double bond. All this seems to indicate that the presence of an epoxy function located in the a, b position of the carbonyl group enhances the ixodicidal activity. Both substances can be considered analogous to the sesquiterpene ligudicin reported as a potent ixodicide [Ruiz-Vásquez, L; Olmeda, AS; Zúñiga, G .; Villarroel, L; Echeverri, LF; González-Coloma, A .; Reina, M. Insect Antifeedant and Ixodicidal Compounds from Senecio adenotrichius. Chem. Biodivers. 2017, 14, e1600155.].
Por otro lado, la presencia de un epóxido en C4-C5 3 no afecta la actividad de estos compuestos, ni la existencia de un grupo ceto en un anillo ciclooctano 8. En estos casos, la funcionalidad enona debe ser la responsable de la actividad observada. Finalmente, otras modificaciones estructurales en 1 como la presencia de una lactona en lugar de la cetona, o la isomerización del doble enlace provocan una disminución significativa de la actividad. On the other hand, the presence of an epoxide in C4-C5 3 does not affect the activity of these compounds, nor the existence of a keto group in a cyclooctane ring 8. In these cases, the enone functionality must be responsible for the observed activity. . Finally, other structural modifications in 1 such as the presence of a lactone instead of the ketone, or the isomerization of the double bond cause a significant decrease in activity.
Nueve moléculas (4-6, 9-10 y 17-21) resultaron inactivas. En este caso, la desaparición de la enona (9-10) o la presencia del sistema de espirano muy tenso pueden ser las causas de la inactividad. Nine molecules (4-6, 9-10 and 17-21) were inactive. In this case, the disappearance of the enone (9-10) or the presence of the very tense spinal system may be the causes of inactivity.
También se ensayaron los efectos antialimentarios de estos derivados de germacrona contra la plaga de insectos S. littoralis Boisd, M. persicae Sulz (Tabla 3) y R. padi L (Tabla 4). Ninguno de los compuestos ensayados mejora la actividad moderada-alta de germacrona contra S. littoralis. Sólo la dicetona 8 presentó una actividad similar, mientras que los epoxiderivados 2 y 3, el diepóxido 17 y los triciclos acetilados 9 y 10 resultaron ser menos activos que el germacrona. Se encontraron resultados similares cuando M. persicae. Por tanto, sólo 15 mostraron actividad comparable a la del germacrone. Cuatro compuestos, 2, 8, 10 y 13, presentaron actividad baja-moderada y los restantes estaban inactivos o mostraron actividad muy baja.
Figure imgf000023_0001
Figure imgf000024_0002
The antifeedant effects of these germacrone derivatives were also tested against the insect pest S. littoralis Boisd, M. persicae Sulz (Table 3) and R. padi L (Table 4). None of the compounds tested improves the moderate-high activity of germacrone against S. littoralis. Only diketone 8 showed similar activity, while epoxy derivatives 2 and 3, diepoxide 17 and acetylated tricycles 9 and 10 were less active than germacrone. Similar results were found when M. persicae. Therefore, only 15 showed activity comparable to that of germacrone. Four compounds, 2, 8, 10 and 13, showed low-moderate activity and the rest were inactive or showed very low activity.
Figure imgf000023_0001
Figure imgf000024_0002
Tab e 3. Efecto antialimentario (a una dosis de 5 mg / ml) de derivados de germacrona contra S. littoralis y M. persicae a% Fl / SI = (1 — (T / C)) x 100, donde T y C se alimentan / sedimentan en tratamiento y discos de hojas de control a 5 mg / mL. bEC50, dosis eficaz para producir una inhibición del 50% (límites de confianza del 95%). Tab e 3. Antifeedant effect (at a dose of 5 mg / ml) of germacrone derivatives against S. littoralis and M. persicae at% Fl / SI = (1 - (T / C)) x 100, where T and C they are fed / sedimented in treatment and control leaf discs at 5 mg / mL. b EC 50 , effective dose to produce 50% inhibition (95% confidence limits).
Mucho más interesantes fueron los resultados obtenidos contra R. padi (Tabla 4). Así, dos compuestos, 1 , 10-epoxygermacrona (2) y gajutsulactona A (7), resultaron ser muy activos contra ese áfido (valores de EC50: 6 x 10-3 y 2 x 10-2). Estos datos convierten estas dos sustancias en antialimentarios selectivos prometedores contra esta plaga de cereales. Otras cuatro moléculas (3, 8, 17 y 23) mostraron una alta actividad. Finalmente, los compuestos 13 y 15 presentaron una actividad moderada, los compuestos de escariado no mostraron ningún efecto relevante.
Figure imgf000024_0001
Figure imgf000025_0001
Much more interesting were the results obtained against R. padi (Table 4). Thus, two compounds, 1, 10-epoxygermacrone (2) and gajutsulactone A (7), turned out to be very active against this aphid (EC 50 values: 6 x 10 -3 and 2 x 10 -2 ). These data make these two substances promising selective antifeedant against this pest of cereals. Four other molecules (3, 8, 17 and 23) showed high activity. Finally, compounds 13 and 15 showed moderate activity, the reaming compounds did not show any relevant effect.
Figure imgf000024_0001
Figure imgf000025_0001
Tabla 4. Efecto antialimentario (a una dosis de 5 mg/ml) def derivados de germacrona contra R. padi a % Fl / SI = (1-(T/C)) x 100, donde T y C se alimentan / sedimentan en discos de hojas tratados y de control a 5 mg / mL. bEC50, dosis eficaz para producir una inhibición del 50% (límites de confianza del 95%). Table 4. Antifeedant effect (at a dose of 5 mg / ml) of germacrone derivatives against R. padi at% Fl / SI = (1- (T / C)) x 100, where T and C feed / settle in treated and control leaf discs at 5 mg / mL. b EC 50 , effective dose to produce 50% inhibition (95% confidence limits).
Evaluación biológica Biological evaluation
Las colonias de S. littoralis, M. persicae y R. padi se criaron con dieta artificial [ Poitout, S.; Bues, S. Elevage de plusieurs espéces de lépidotéres Noctundiae sur milieu artificiel riche et sur milieu artificiel simplifié. Ann. Zool. Ecol. Anim. 1970, 2, 79-91], de pimiento morrón ( Capsicum annuum ) y cebada ( Hordeum vulgare ), respectivamente. Las plantas se cultivan a partir de semillas en macetas con sustrato comercial. Las plantas para la cría de pulgones se infectan regularmente (plantas de pimiento con 4 hojas, plantas de cebada de 10 cm de longitud). Las colonias de insectos y plantas hospedadoras se mantuvieron a 22 ± 1 ° C,> 70% de humedad relativa con un fotoperiodo de 16: 8 h (L: D) en una cámara de crecimiento. Actividad antialimentaria The colonies of S. littoralis, M. persicae and R. padi were reared with an artificial diet [Poitout, S .; Bues, S. Elevage de plusieurs espéces de lepidores Noctundiae sur milieu artificiel riche et sur milieu artificiel simplifié. Ann. Zool. Ecol. Anim. 1970, 2, 79-91], of bell pepper (Capsicum annuum) and barley (Hordeum vulgare), respectively. The plants are grown from seeds in pots with commercial substrate. Plants for rearing aphids are regularly infected (pepper plants with 4 leaves, barley plants 10 cm long). The insect colonies and host plants were kept at 22 ± 1 ° C,> 70% relative humidity with a photoperiod of 16: 8 h (L: D) in a growth chamber. Anti-food activity
La superficie superior de los discos o fragmentos de hojas de C. anuum y H. vulgare (1 ,0 cm2) se trataron con 10 pl de la sustancia de ensayo. Los extractos y productos brutos se probaron a una dosis inicial de 100 o 50 μg / cm2 respectivamente. Se permitió que cinco placas de Petri (9 cm de diámetro) o veinte cajas de plástico ventiladas (2 x 2 cm) con dos larvas de S. littoralis L6 recién mudadas (<24 h) o diez áfidos adultos (24-48 h de edad) alimentados a temperatura ambiente para S. litoralis (<2 h) o en una cámara de crecimiento para los pulgones (24 h, condiciones ambientales como arriba). Cada experimento se repitió 2-3 veces (SE <10%) y se terminó cuando el consumo de los discos de control alcanzó el 65-75% para S. litoralis o después de 24 h para los pulgones. El área consumida del disco foliar se midió en sus imágenes digitalizadas (Imagen J, http://imagej.nih.gov/ij). La sedimentación se midió contando el número de pulgones sedimentados en cada fragmento de hoja. La inhibición por alimentación o sedimentación (% Fl o% SI) se calculó como% Fl /% SI = [1 - (T / C) x 100], donde T y C son el consumo / sedimentación de los discos foliares tratados y de control, respectivamente. Los efectos antialimentarios (% Fl / SI) se analizaron para determinar su significación mediante la prueba no paramétrica de rangos con signo de Wilcoxon. Los extractos y compuestos con un Fl / Sl> 75% se probaron adicionalmente en un experimento de dosis-respuesta (3-4 diluciones en serie) para calcular su potencia relativa (EC50, la dosis efectiva para dar una reducción del 50% de alimentación / sedimentación) de análisis de regresión (% Fl / SI sobre dosis logarítmica) [Burgueño-Tapia, E.; Castillo, L.; González- Coloma, A.; Joseph-Nathan, P. Antifeedant and Phytotoxic Activity of the Sesquiterpene p- Benzoquinone Perezone and Some of its Derivatives. 2008] The upper surface of the discs or leaf fragments of C. anuum and H. vulgare (1.0 cm2) were treated with 10 µl of the test substance. The extracts and crude products were tested at an initial dose of 100 or 50 µg / cm 2 respectively. Five Petri dishes (9 cm in diameter) or twenty ventilated plastic boxes (2 x 2 cm) with two newly molted S. littoralis L6 larvae (<24 h) or ten adult aphids (24-48 h of age) fed at room temperature for S. litoralis (<2 h) or in a growth chamber for aphids (24 h, ambient conditions as above). Each experiment was repeated 2-3 times (SE <10%) and ended when the consumption of the control discs reached 65-75% for S. litoralis or after 24 h for aphids. The consumed area of the leaf disk was measured in its digitized images (Image J, http://imagej.nih.gov/ij). Sedimentation was measured by counting the number of aphids settled on each leaf fragment. Inhibition by feeding or sedimentation (% Fl or% SI) was calculated as% Fl /% SI = [1 - (T / C) x 100], where T and C are the consumption / sedimentation of the treated leaf discs and of control, respectively. Antifeedant effects (% Fl / SI) were analyzed for significance using Wilcoxon's nonparametric signed rank test. Extracts and compounds with Fl / Sl> 75% were further tested in a dose-response experiment (3-4 serial dilutions) to calculate their relative potency (EC50, the effective dose to give a 50% reduction in feeding / sedimentation) of regression analysis (% Fl / SI over logarithmic dose) [Burgueño-Tapia, E .; Castillo, L .; González-Coloma, A .; Joseph-Nathan, P. Antifeedant and Phytotoxic Activity of the Sesquiterpene p- Benzoquinone Perezone and Some of its Derivatives. 2008]
Actividad ixodicida Ixodicidal activity
Se recolectaron garrapatas hembras ingurgitadas de H. lusitanicum en el centro de España (Finca La Garganta, Ciudad Real) de su hospedador (ciervo) y se mantuvieron a 22-24 °C y 70% de HR hasta la oviposición y eclosión de los huevos. Para los bioensayos se utilizaron larvas resultantes (4-6 semanas de edad) [Ruiz-Vásquez, L Olmeda, A.S Zúñiga, G Villarroel, L Echeverri, L.F González-Coloma, A Reina, M. Antialimentadoras y compuestos ixodicidas de insectos de Senecio adenotrichius. Chem. Biodiversidad. 2017, 14, e1600155.] Brevemente, se agregaron 50 μl de solución de prueba a 25 mg de celulosa en polvo a diferentes concentraciones y se evaporó el solvente. Para cada prueba, se utilizaron tres réplicas con 20 larvas cada una. Las garrapatas muertas se contaron después de 24 h de Ingested female H. lusitanicum ticks were collected in central Spain (Finca La Garganta, Ciudad Real) from their host (deer) and kept at 22-24 ° C and 70% RH until oviposition and hatching of the eggs. . Resulting larvae (4-6 weeks old) were used for the bioassays [Ruiz-Vásquez, L Olmeda, AS Zúñiga, G Villarroel, L Echeverri, LF González-Coloma, A Reina, M. Anti-aging agents and ixodicidal compounds of Senecio insects adenotrichius. Chem. Biodiversity. 2017, 14, e1600155.] Briefly, 50 μl of test solution was added to 25 mg of powdered cellulose at different concentrations and the solvent was evaporated. For each test, three replicates with 20 larvae each were used. Dead ticks were counted after 24 h of

Claims

REIVINDICACIONES
1.- Uso para el control de plagas de un compuesto derivado de germacrona seleccionado del grupo formado por los compuestos de fórmulas 2, 3, 7, 8, 13, 14, 15, 17, 23 y 24.
Figure imgf000027_0001
1.- Use for pest control of a compound derived from germacrone selected from the group formed by the compounds of formulas 2, 3, 7, 8, 13, 14, 15, 17, 23 and 24.
Figure imgf000027_0001
2.- Uso, según reivindicación 1, en el que el compuesto se selecciona del grupo formado por compuestos de fórmula 15, 17, 23 y 24. 2. Use according to claim 1, in which the compound is selected from the group consisting of compounds of formula 15, 17, 23 and 24.
3.- Uso, según reivindicaciones 1 , para el control de plagas de mosquitos, particularmente control de larvas de mosquito Culex y preferiblemente control de larvas de Culex quinquefasciatus. 3.- Use, according to claims 1, for the control of mosquito pests, particularly control of Culex mosquito larvae and preferably control of Culex quinquefasciatus larvae.
4 - Uso, según reivindicación 1, para el control de plagas de ácaros. 4 - Use, according to claim 1, for the control of mite pests.
5.- Uso, según reivindicación anterior para el control de plagas de Tetranychus, particularmente Tetranychus urticae, 5.- Use, according to the previous claim, for the control of Tetranychus pests, particularly Tetranychus urticae,
6.- Uso, según reivindicación 4, para el control de plagas de Tribolium , preferentemente Tribolium castaneum. 6.- Use, according to claim 4, for the control of Tribolium pests, preferably Tribolium castaneum.
1 - Uso, según reivindicación 4, en el que los compuestos se seleccionan del grupo formado por compuestos de fórmula 2, 3, 1 - Use according to claim 4, in which the compounds are selected from the group consisting of compounds of formula 2, 3,
7, 8, 13, 14, 15, 19 y 24, preferentemente del grupo formado por compuestos de fórmula 2, 3, 13, 14 y 24, y más preferentemente de los compuestos 14 o 24, para el control de plagas de ácaros pertenecientes al género Hyalomma, aún más preferente para el control de plagas de ácaros pertenecientes a la especie Hyalomma lusitanicum. 7, 8, 13, 14, 15, 19 and 24, preferably from the group formed by compounds of formula 2, 3, 13, 14 and 24, and more preferably from compounds 14 or 24, for the control of mite pests belonging to to the genus Hyalomma, even more preferred for the control of mite pests belonging to the species Hyalomma lusitanicum.
8.- Uso, según reivindicación 1 para el control de plagas de insectos, preferentemente áfidos. 8. Use according to claim 1 for the control of insect pests, preferably aphids.
9.- Uso, según reivindicación 4, en el que los compuestos se seleccionan del grupo formado por compuestos de fórmula 2, 3, 7, 8, 13, 15, 17 y 23, preferentemente al uso de los compuestos 2, 3, 7, 8, 17 y 23, y más preferentemente de los compuestos 2 o 7, para el control de plagas de insectos pertenecientes al género Spodoptera, aún más preferente para el control de plagas de insectos pertenecientes a la especie Spodoptera littoralis. 9.- Use, according to claim 4, in which the compounds are selected from the group consisting of compounds of formula 2, 3, 7, 8, 13, 15, 17 and 23, preferably to the use of compounds 2, 3, 7 , 8, 17 and 23, and more preferably of compounds 2 or 7, for the control of insect pests belonging to the genus Spodoptera, even more preferred for the control of insect pests belonging to the species Spodoptera littoralis.
10.- Uso, según reivindicación 4, en el que los compuestos se seleccionan del grupo formado por compuestos de fórmula 2, 3, 7, 8, 13, 15, 17 y 23, preferentemente al uso de los compuestos 2, 3, 7, 8, 17 y 23, y más preferentemente de los compuestos 2 o 7, para el control de plagas de insectos pertenecientes al género Myzus, aún más preferente para el control de plagas de insectos pertenecientes a la especie Myzus persicae, 10.- Use, according to claim 4, in which the compounds are selected from the group formed by compounds of formula 2, 3, 7, 8, 13, 15, 17 and 23, preferably to the use of compounds 2, 3, 7 , 8, 17 and 23, and more preferably of compounds 2 or 7, for the control of insect pests belonging to the genus Myzus, even more preferred for the control of insect pests belonging to the species Myzus persicae,
11.- Uso, según reivindicación 4, en el que los compuestos se seleccionan del grupo formado por compuestos de fórmula 2, 3, 7, 8, 13, 15, 17 y 23, preferentemente al uso de los compuestos 2, 3, 7, 8, 17 y 23, y más preferentemente de los compuestos 2 o 7, para el control de plagas de pulgones pertenecientes a la especies Rhopalosiphum padi. 11.- Use, according to claim 4, in which the compounds are selected from the group consisting of compounds of formula 2, 3, 7, 8, 13, 15, 17 and 23, preferably to the use of compounds 2, 3, 7, 8, 17 and 23, and more preferably compounds 2 or 7, for the control of aphid pests belonging to the species Rhopalosiphum padi.
12.- Uso, según reivindicación 1, para el control del plagas de Rhopalosiphum padi, en el que el compuesto empleado es el compuesto 2. 12.- Use, according to claim 1, for the control of Rhopalosiphum padi pests, in which the compound used is compound 2.
13.- Uso, según reivindicación 1, para el control de plagas de ixoideos en el que los compuestos de seleccionan del grupo de compuestos con fórmulas 24, 14, 13 y 3. 13. Use, according to claim 1, for the control of ixoid pests in which the compounds are selected from the group of compounds with formulas 24, 14, 13 and 3.
14.- Método de prevención y/o tratamiento de enfermedades asociadas a la presencia de parásitos que consiste en la administración a los individuos afectados por estas enfermedades de cantidades terapéuticamente efectivas de al menos un derivado de germacrona seleccionado del grupo formado por los compuestos de fórmulas 2, 3, 7, 8, 13, 14, 15, 17, 23 y 24. 14.- Method of prevention and / or treatment of diseases associated with the presence of parasites that consists in the administration to the individuals affected by these diseases of therapeutically effective amounts of at least one germacrone derivative selected from the group formed by the compounds of formulas 2, 3, 7, 8, 13, 14, 15, 17, 23 and 24.
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