ES2209622B1

ES2209622B1 - FUNGICIDES BASED ON DERIVATIVES OF N- (3-NITROFENIL) -N'-FENIL-, N- (2-CHLOROPIRIDIN-4-IL) -N'-PHENYL-Y N- (1,2,3-TIADIAZOL-5 -IL) -N'-FENIL-UREAS FLUORATED FOR EMPLOYMENT IN HORTICOL CROPS AND ORNAMENTAL PLANTS.

Info

Publication number: ES2209622B1
Application number: ES200201347A
Authority: ES
Inventors: Antonio Abad Somovilla; Consuelo Agullo Blanes; Ana C. Cuñat Romero; Cristina Vilanova Esteve; Raquel Jimenez Briz; Ismael Navarro Fuertes
Original assignee: Universitat de Valencia
Current assignee: Universitat de Valencia
Priority date: 2002-06-06
Filing date: 2002-06-06
Publication date: 2005-06-16
Anticipated expiration: 2022-06-06
Also published as: ES2209622A1

Abstract

Fungicidas a base de derivados de N-(3-Nitrofenil)-N''-Fenil-, N- (2-Cloropiridin-4-Il)-N''-Fenil- y N-(1,2,3-Tiadiazol-5-Il)-N''- Fenil-Ureas Fluoradas para empleo en cultivos hortícolas y de plantas ornamentales. Se describe un procedimiento para proteger plantas frente a enfermedades producidas por hongos fitopatógenos, y que consiste en aplicar a la planta y/o al área de cultivo una cantidad fungicidamente eficaz de una N-(3- nitrofenil)-, N-(2-cloropiridin-4-il)-, ó N-(1,2,3-tiadiazol-5- il)-N''-fluorofenilureas de formulas (I), (II) y (III) respectivamente, en las que R{sup,1}, R{sup,2}, R{sup,3}, R{sup,4} y R{sup,5} son átomos de hidrógeno o flúor en todas las combinaciones posibles. Particularmente destacable es la actividad fungicida de algunas de estas ureas frente a dos de los principales hongos de suelo implicados en el síndrome complejo denominado "colapso" que causa marchitez y la muerte de plantas del melón, monosporascus cannoballus y acremonium cucurbitacearum, cuyo crecimientoinhiben un 100% in vitro a concentraciones de sólo 1 ppm.Fungicides based on derivatives of N- (3-Nitrophenyl) -N '' - Phenyl-, N- (2-Chloropyridin-4-Il) -N '' - Phenyl- and N- (1,2,3-Thiadiazole -5-Il) -N '' - Fluorinated Phenyl-Ureas for use in horticultural and ornamental plant crops. A procedure is described to protect plants against diseases caused by phytopathogenic fungi, and which consists in applying a fungically effective amount of an N- (3- nitrophenyl) -, N- (2-) to the plant and / or crop area. chloropyridin-4-yl) -, or N- (1,2,3-thiadiazol-5- yl) -N '' - fluorophenylureas of formulas (I), (II) and (III) respectively, in which R { sup, 1}, R {sup, 2}, R {sup, 3}, R {sup, 4} and R {sup, 5} are hydrogen or fluorine atoms in all possible combinations. Particularly noteworthy is the fungicidal activity of some of these ureas against two of the main soil fungi involved in the complex syndrome called "collapse" that causes wilting and the death of melon plants, monosporascus cannoballus and acremonium cucurbitacearum, whose growth inhibits 100 % in vitro at concentrations of only 1 ppm.

Description

Fungicidas a base de derivados de N-(3-nitrofenil)-N'-fenil-, N-(2-cloropiridin-4-il)-N'-fenil-y N-(1,2,3-tiadiazol-5-il)-N'-fenil-ureas fluoradas para empleo en cultivos hortícolas y de plantas ornamentales.Fungicides based on derivatives of N - (3-nitrophenyl) - N ' -phenyl-, N - (2-chloropyridin-4-yl) - N' -phenyl- and N - (1,2,3-thiadiazol-5 -il) - Fluorinated N' -phenyl-ureas for use in horticultural and ornamental plant crops.

Technical Field of the Invention

La presente invención se encuadra dentro del campo técnico del control de plagas perjudiciales para el sector agrícola.The present invention fits within the technical field of pest control harmful to the sector agricultural.

Más concretamente, la presente invención se centra en la preparación de derivados mono-, di-, tri-, tetra-, y pentafluorados en el anillo de fenilo de N-(3-nitrofenil)-N'-fenilurea, N-(2-cloropiridin-4-il)-N'-fenilurea y N-(1,2,3-tiadiazol-5-il)-N'-fenilurea y su utilización como ingredientes activos de formulados para el control de enfermedades causadas por hongos en plantas.More specifically, the present invention is focuses on the preparation of mono-, di-, tri-, tetra-, and derivatives pentafluorinated in the phenyl ring of N- (3-nitrophenyl) -N'-phenylurea, N- (2-chloropyridin-4-yl) -N'-phenylurea Y N- (1,2,3-thiadiazol-5-yl) -N'-phenylurea and its use as active ingredients formulated for control of diseases caused by fungi in plants.

State of the art prior to the invention

A pesar de la disponibilidad comercial de un gran número de productos con elevada actividad fungicida frente a los hongos de cultivos agrícolas, hortícolas y de plantas ornamentales, sigue existiendo necesidad de disponer de nuevos productos fungicidas debido a la constante tolerancia que los hongos fitopatógenos desarrollan frente a los fungicidas utilizados. Los compuestos con actividad fungicida utilizados actualmente en los formulados comerciales pertenecen a una gama muy variada de grupos químicos (ver por ejemplo: Compendium of Pesticide Common Names: Fungicides en http://www.hclrss.demon.co.uk/ class_fungicides.html), pero muy pocos pertenecen al grupo de las arilureas, un conocido grupo de pesticidas ampliamente utilizado por sus características como herbicidas. Aunque han sido descritas diversas aril ureas con propiedades fungicidas [ver por ejemplo: Yasuo Yamada y otros, Patente US4127673 (1978) y Patente US4857556 (1989)], sólo la N-[(4-clorofenil)metil]-N ciclopentil-N-fenilurea, comercialmente conocida como pencicurón, parece ser el único compuesto perteneciente al mencionado grupo de las arilureas registrado para su utilización como fungicida. En la amplia literatura disponible sobre la química y actividad de las arilureas se describe que los compuestos con las estructuras (1), (2), y (3), en las que los grupos R^{1} a R^{5} son átomos de hidrógeno, exhiben importante actividad como estimuladores de la división celular y promotores de brotes en numerosas plantas, siendo por lo tanto utilizables como herbicidas y reguladores del crecimiento en determinados tipos de cultivos (Koichi Shudo, ``Chemistry of phenyl urea cytokinin''. En: Mok DWS y Mok MC (eds) Cytokinins: Chemistry, Activity and Functions, Capítulo 3, págs. 35-42. Boca Raton, USA: Ed. CRC Press).Despite the commercial availability of a large number of products with high fungicidal activity against fungi from agricultural, horticultural and ornamental plants, there is still a need for new fungicidal products due to the constant tolerance that phytopathogenic fungi develop against to the fungicides used. Compounds with fungicidal activity currently used in commercial formulations belong to a wide range of chemical groups (see for example: Compendium of Pesticide Common Names: Fungicides at http://www.hclrss.demon.co.uk/ class_fungicides.html ), but very few belong to the arylureas group, a known group of pesticides widely used for their characteristics as herbicides. Although various aryl ureas with fungicidal properties have been described [see for example: Yasuo Yamada et al., US 4127673 (1978) and US4857556 (1989)], only N - [(4-chlorophenyl) methyl] -N cyclopentyl-N -phenylurea, commercially known as pencicuron, appears to be the only compound belonging to the mentioned group of arylureas registered for use as a fungicide. In the extensive literature available on the chemistry and activity of arylureas it is described that compounds with structures (1), (2), and (3), in which the groups R 1 to R 5 they are hydrogen atoms, they exhibit important activity as stimulators of cell division and promoters of sprouts in numerous plants, being therefore usable as herbicides and growth regulators in certain types of crops (Koichi Shudo, `` Chemistry of phenyl urea cytokinin '''In: Mok DWS and Mok MC (eds) Cytokinins: Chemistry, Activity and Functions, Chapter 3, pp. 35-42. Boca Raton, USA: Ed. CRC Press).

22

De hecho, el compuesto (II), (2, R^{1}=R^{2}=R^{3}=R^{4}=R^{5}=H), comercialmente conocido como forclorfenuron, CPPU o KT-30, es ampliamente utilizado en horticultura para incrementar el tamaño y calidad de determinados frutos y el compuesto (III), (3, R^{1}=R^{2}=R^{3}=R^{4}=R^{5}=H), comercialmente conocido como tidiazuron o TDZ, es utilizando como defoliante en cultivos de algodón. También son conocidos algunos derivados fluorados en el anillo de fenilo de estos compuestos. Así, los compuestos (2: R^{1}=F, R^{2}=R^{3}=R^{4}=R^{5}=H), (2: R^{2}=F, R^{1}=R^{3}=R^{4}=R^{5}=H), (2: R^{3}=F, R^{1}=R^{2}=R^{4}=R^{5}=H), y (2: R^{2}=R^{4}=F, R^{1}=R^{2}=R^{4}=H) han sido descritos como promotores de división celular in vitro con potencial actividad fitorreguladora y herbicida [Koichi Shudo y otros, Patente US4193788 (1980); Robert Henrie II y otros, Patente US4787931 (1986); Konishi Kenji y otros, Patente JP62106003 (1987) y Kobayashi Kenji y otros, Patente JP108802 (1987); Robert. Henri II y otros J. Agric. Food Chem. Vol. 36, págs. 626-633, (1988)]. Los compuestos (1, R^{1}=F, R^{2}=R^{3}=R^{4}=R^{5}=H), (1: R^{2}=F, R^{1}=R^{3}=R^{4}=R^{5}=H), (1: R^{3}=F, R^{1}=R^{2}=R^{4}=R^{5}=H) y (1: R^{1}=R^{4}=F, R^{2}=R^{3}=R^{5}=H) también son conocidos [Makoto Miyahara, Chem. Pharm. Bull. Vol. 34, págs. 1950-60 (1986)], pero solamente ha sido descrita la capacidad del derivado meta-fluorado para promover retención de clorofila e iniciar división celular in vitro, lo que también le cualifica como regulador del crecimiento (Michael I. Bruce y otros, Phytochemisty, Vol. 12, págs. 995-1003, 1973). Sin embargo y hasta el momento, es desconocido si alguno de estos compuestos posee actividad fungicida y puede ser utilizado para el control de infecciones producidas por hongos fitopatógenos.In fact, the compound (II), (2, R 1 = R 2 = R 3 = R 4 = R 5 = H), commercially known as forchlorfenuron, CPPU or KT-30, is widely used in horticulture to increase the size and quality of certain fruits and compound (III), (3, R 1 = R 2 = R 3 = R ^ {4 = R5 = H), commercially known as tidiazuron or TDZ, is used as a defoliant in cotton crops. Some fluorinated derivatives in the phenyl ring of these compounds are also known. Thus, the compounds (2: R 1 = F, R 2 = R 3 = R 4 = R 5 = H), (2: R 2 = F, R 1 = R 3 = R 4 = R 5 = H), (2: R 3 = F, R 1 = R ^ 2 = R 4 = R 5 = H), and (2: R 2 = R 4 = F, R 1 = R 2 = R ^ {4} = H) have been described as in vitro cell division promoters with potential phytoregulatory and herbicidal activity [Koichi Shudo et al., US Pat. No. 4193788 (1980); Robert Henrie II et al., US4787931 (1986); Konishi Kenji et al., Patent JP62106003 (1987) and Kobayashi Kenji et al., Patent JP108802 (1987); Robert Henri II and others J. Agric. Food Chem. Vol. 36, p. 626-633, (1988)]. Compounds (1, R 1 = F, R 2 = R 3 = R 4 = R 5 = H), (1: R 2 = F , R 1 = R 3 = R 4 = R 5 = H), (1: R 3 = F, R 1 = R 2 = R 4 = R 5 = H) and (1: R 1 = R 4 = F, R 2 = R 3 = R 5 = H) are also known [Makoto Miyahara, Chem. Pharm. Bull. Vol. 34, p. 1950-60 (1986)], but only the ability of the meta-fluorinated derivative to promote chlorophyll retention and initiate cell division in vitro has been described, which also qualifies it as a growth regulator (Michael I. Bruce et al., Phytochemisty , Vol. 12, pp. 995-1003, 1973). However and until now, it is unknown if any of these compounds have fungicidal activity and can be used to control infections caused by phytopathogenic fungi.

Es conocida la importancia que la sustitución de átomos de hidrógeno por átomos de flúor puede tener en la actividad biológica de los productos orgánicos. Como se ha mostrado recientemente, no sólo el número de posiciones fluoradas sino también el patrón de sustitución puede provocar notables variaciones en la actividad de sistemas arílicos fluorados, no sólo por los cambios que se producen en la lipofilia de estos compuestos sino también por las interacciones específicas que pueden establecerse con los centros enzimáticos receptores (C-Y. Kim, P. P. Chandra, A. Jain y D. W. Chistianson, J. Am. Chem. Soc. Vol. 123, págs. 9620-9627, 2001). En este sentido y en relación con el interés por estudiar la influencia que la fluoración del sistema arílico puede tener en la actividad biológica de las arilureas del tipo de las indicadas anteriormente, los autores de la presente invención han preparado la mayor parte de los compuestos mono-, di-, tri-, tetra-y penta-fluorofenil sustituidos correspondientes a los sistemas (1), (2) y (3) y han realizado un detallado estudio de la actividad de cada uno de ellos. Habiendo encontrado que muchos de los miembros de estas pequeñas librerías de fluorofenil ureas presentan una elevada actividad fungicida, incluso a concentraciones muy bajas, frente a determinados hongos fitopatógenos, lo que hace que puedan ser utilizados para el control de los mismos y las enfermedades que provocan en plantas.It is known the importance that the substitution of hydrogen atoms for fluorine atoms can have in the biological activity of organic products. As it has been shown recently, not only the number of fluorinated positions but also the substitution pattern can cause notable variations in the activity of fluorinated aryl systems, not only because of the changes that occur in the lipophilicity of these compounds but also because of the interactions specific ones that can be established with the receptor enzyme centers (CY. Kim, PP Chandra, A. Jain and DW Chistianson, J. Am. Chem. Soc. Vol. 123, pp. 9620-9627, 2001). In this regard and in relation to the interest in studying the influence that fluorination of the aryl system may have on the biological activity of arylureas of the type indicated above, the authors of the present invention have prepared most of the mono compounds -, di-, tri-, tetra- and penta-fluorophenyl substituted corresponding to the systems (1), (2) and (3) and have carried out a detailed study of the activity of each of them. Having found that many of the members of these small fluorophenyl ureas libraries have a high fungicidal activity, even at very low concentrations, against certain phytopathogenic fungi, which means that they can be used to control them and the diseases they cause in plants.

Description of the invention

La presente invención se refiere a la preparación de N-(3-nitrofenil)-N'-fenil-, N-(2-cloropiridin-4-il)-N'-fenil y N-(1,2,3-tiadiazol-5-il)-N'-fenil ureas fluoradas en el anillo de fenilo y su uso en el control de determinados hongos fitopatógenos.The present invention relates to the preparation from N- (3-nitrophenyl) -N'-phenyl-, N- (2-chloropyridin-4-yl) -N'-phenyl Y N- (1,2,3-thiadiazol-5-yl) -N'-phenyl fluorinated ureas in the phenyl ring and their use in the control of certain phytopathogenic fungi.

Los compuestos activos como fungicidas recogidos en esta invención comprenden N-(3-nitrofenil)-N'-fenil-ureas de fórmula general (1), N-(2-cloropiridin-4-il)-N'-fenil-ureas de fórmula general (2), y N-(1,2,3-tiadiazol-5-il)-N'-fenil-ureas de fórmula general (3), en las que R^{1}, R^{2}, R^{3}, R^{4}, y R^{5} representan átomos de hidrógeno o flúor en todas las combinaciones posibles, siendo la mayoría de estos compuestos desconocidos hasta ahora y, por lo tanto, se describen por primera vez en esta invención. Estos compuestos se listan en las Tablas 1-3, en la que también se recoge la propiedad física (punto de fusión) que les caracteriza.The active compounds as fungicides collected in this invention comprise N- (3-nitrophenyl) -N'-phenyl-ureas of general formula (1), N- (2-chloropyridin-4-yl) -N'-phenyl-ureas of general formula (2), and N- (1,2,3-thiadiazol-5-yl) -N'-phenyl-ureas of general formula (3), in which R 1, R 2, R 3, R 4, and R 5 represent hydrogen or fluorine atoms in all the possible combinations, the majority of these compounds being unknown until now and, therefore, are first described time in this invention. These compounds are listed in the Tables 1-3, in which the property is also collected physical (melting point) that characterizes them.

TABLE 1

33

CompuestoCompound R^{1}R1 R^{2}R2 R^{3}R 3 R^{4}R 4 R^{5}R 5 p.f. (°C)m.p. (° C) Nombre del compuestoCompound Name II HH HH HH HH HH 205-208205-208 1-(3-nitrofenil)-3-fenilurea1- (3-nitrophenyl) -3-phenylurea 1a1st FF HH HH HH HH 189-190189-190 1-(2-fluorofenil)-3-(3-nitrofenil)urea1- (2-fluorophenyl) -3- (3-nitrophenyl) urea 1b1 B HH FF HH HH HH 194-196194-196 1-(3-fluorofenil)-3-(3-nitrofenil)urea1- (3-fluorophenyl) -3- (3-nitrophenyl) urea 1c1 C HH HH FF HH HH 213-214213-214 1-(4-fluorofenil)-3-(3-nitrofenil)urea1- (4-fluorophenyl) -3- (3-nitrophenyl) urea 1d1d FF FF HH HH HH 210-213210-213 1-(2,3-difluorofenil)-3-(3-nitrofenil)urea1- (2,3-difluorophenyl) -3- (3-nitrophenyl) urea 1e1e FF HH FF HH HH 209-211209-211 1-(2,4-difluorofenil)-3-(3-nitrofenil)urea1- (2,4-difluorophenyl) -3- (3-nitrophenyl) urea 1f1f FF HH HH FF HH 210-212210-212 1-(2,5-difluorofenil)-3-(3-nitrofenil)urea1- (2,5-difluorophenyl) -3- (3-nitrophenyl) urea 1g1g FF HH HH HH FF 207-209207-209 1-(2,6-difluorofenil)-3-(3-nitrofenil)urea1- (2,6-difluorophenyl) -3- (3-nitrophenyl) urea 1h1 hour HH FF FF HH HH 210-213210-213 1-(3,4-difluorofenil)-3-(3-nitrofenil)urea1- (3,4-difluorophenyl) -3- (3-nitrophenyl) urea 1i1i HH FF HH FF HH 212-214212-214 1-(3,5-difluorofenil)-3-(3-nitrofenil)urea1- (3,5-difluorophenyl) -3- (3-nitrophenyl) urea 1j1j FF FF FF HH HH 217-219217-219 1-(2,3,4-trifluorofenil)-3-(3-nitrofenil)urea1- (2,3,4-trifluorophenyl) -3- (3-nitrophenyl) urea 1k1k FF FF HH HH FF 204-205204-205 1-(2,3,6-trifluorofenil)-3-(3-nitrofenil)urea1- (2,3,6-trifluorophenyl) -3- (3-nitrophenyl) urea 1l1l FF HH FF FF HH 218-221218-221 1-(2,4,5-trifluorofenil)-3-(3-nitrofenil)urea1- (2,4,5-trifluorophenyl) -3- (3-nitrophenyl) urea 1m1m FF HH FF HH FF 209-212209-212 1-(2,4,6-trifluorofenil)-3-(3-nitrofenil)urea1- (2,4,6-trifluorophenyl) -3- (3-nitrophenyl) urea 1n1n FF FF FF FF HH 203-205203-205 1-(2,3,4,5-tetrafluorofenil)-3-(3-nitrofenil)urea1- (2,3,4,5-tetrafluorophenyl) -3- (3-nitrophenyl) urea 1o1st FF FF FF HH FF 207-209207-209 1-(2,3,4,6-tetrafluorofenil)-3-(3-nitrofenil)urea1- (2,3,4,6-tetrafluorophenyl) -3- (3-nitrophenyl) urea 1p1 p FF FF HH FF FF 213-216213-216 1-(2,3,5,6-tetrafluorofenil)-3-(3-nitrofenil)urea1- (2,3,5,6-tetrafluorophenyl) -3- (3-nitrophenyl) urea 1q1q FF FF FF FF FF 210-212210-212 1-(2,3,4,5,6-pentafluorofenil)-3-(3-nitrofenil)urea1- (2,3,4,5,6-pentafluorophenyl) -3- (3-nitrophenyl) urea

TABLE 2

44

CompuestoCompound R^{1}R1 R^{2}R2 R^{3}R 3 R^{4}R 4 R^{5}R 5 p.f. (°C)m.p. (° C) Nombre del compuestoCompound Name IIII HH HH HH HH HH 172-175172-175 1-(2-cloropiridin-4-il)-3-fenilurea1- (2-Chloropyridin-4-yl) -3-phenylurea 2a2nd FF HH HH HH HH 186-187186-187 1-(2-cloropiridin-4-il)-3-(2-1- (2-Chloropyridin-4-yl) -3- (2- fluorofenil)ureafluorophenyl) urea 2b2b HH FF HH HH HH 193-194193-194 1-(2-cloropiridin-4-il)-3-(3-1- (2-Chloropyridin-4-yl) -3- (3- fluorofenil)ureafluorophenyl) urea 2c2 C HH HH FF HH HH 204-206204-206 1-(2-cloropiridin-4-il)-3-(4-1- (2-Chloropyridin-4-yl) -3- (4- fluorofenil)ureafluorophenyl) urea 2d2d FF FF HH HH HH 205-207205-207 1-(2-cloropiridin-4-il)-3-(2,3-1- (2-Chloropyridin-4-yl) -3- (2,3- difluorofenil)ureadifluorophenyl) urea 2e2e FF HH FF HH HH 212-215212-215 1-(2-cloropiridin-4-il)-3-(2,4-1- (2-Chloropyridin-4-yl) -3- (2,4- difluorofenil)ureadifluorophenyl) urea 2f2f FF HH HH FF HH 219-220219-220 1-(2-cloropiridin-4-il)-3-(2,5-1- (2-Chloropyridin-4-yl) -3- (2,5- difluorofenil)ureadifluorophenyl) urea 2g2 g FF HH HH HH FF 190-193190-193 1-(2-cloropiridin-4-il)-3-(2,6-1- (2-Chloropyridin-4-yl) -3- (2,6- difluorofenil)ureadifluorophenyl) urea 2h2h HH FF FF HH HH 190-192190-192 1-(2-cloropiridin-4-il)-3-(3,4-1- (2-Chloropyridin-4-yl) -3- (3,4- difluorofenil)ureadifluorophenyl) urea 2i2i HH FF HH FF HH 217-219217-219 1-(2-cloropiridin-4-il)-3-(3,5-1- (2-Chloropyridin-4-yl) -3- (3,5- difluorofenil)ureadifluorophenyl) urea 2j2j FF FF FF HH HH 217-219217-219 1-(2-cloropiridin-4-il)-3-(2,3,4-1- (2-Chloropyridin-4-yl) -3- (2,3,4- trifluorofenil)ureatrifluorophenyl) urea 2k2k FF FF HH HH FF 180-182180-182 1-(2-cloropiridin-4-il)-3-(2,3,6-1- (2-Chloropyridin-4-yl) -3- (2,3,6- trifluorofenil)ureatrifluorophenyl) urea 2l2l FF HH FF FF HH 193-194193-194 1-(2-cloropiridin-4-il)-3-(2,4,5-1- (2-Chloropyridin-4-yl) -3- (2,4,5- trifluorofenil)ureatrifluorophenyl) urea 2m2m FF HH FF HH FF 197-201197-201 1-(2-cloropiridin-4-il)-3-(2,4,6-1- (2-Chloropyridin-4-yl) -3- (2,4,6- trifluorofenil)ureatrifluorophenyl) urea 2n2n FF FF FF FF HH 199-201199-201 1-(2-cloropiridin-4-il)-3-(2,3,4,5-1- (2-Chloropyridin-4-yl) -3- (2,3,4,5- tetrafluorofenil)ureatetrafluorophenyl) urea 2o2nd FF FF FF HH FF 174-177174-177 1-(2-cloropiridin-4-il)-3-(2,3,4,6-1- (2-Chloropyridin-4-yl) -3- (2,3,4,6- tetrafluorofenil)ureatetrafluorophenyl) urea 2p2 P FF FF HH FF FF 189-191189-191 1-(2-cloropiridin-4-il)-3-(2,3,5,6-1- (2-Chloropyridin-4-yl) -3- (2,3,5,6- tetrafluorofenil)ureatetrafluorophenyl) urea 2q2q FF FF FF FF FF 211-212211-212 1-(2-cloropiridin-4-il)-3-(2,3,4,5,6-1- (2-Chloropyridin-4-yl) -3- (2,3,4,5,6- pentafluorofenil)ureapentafluorophenyl) urea

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TABLE 3

55

CompuestoCompound R^{1}R1 R^{2}R2 R^{3}R 3 R^{4}R 4 R^{5}R 5 p.f. (°C)m.p. (° C) Nombre del compuestoCompound Name IIIIII HH HH HH HH HH 217-219217-219 1-fenil-3-[1,2,3]tiadiazol-5-il-urea1-phenyl-3- [1,2,3] thiadiazol-5-yl-urea 3a3rd FF HH HH HH HH 242 (desc.)242 (off) 1-(2-fluorofenil)-3-[1,2,3]tiadiazol-5-1- (2-fluorophenyl) -3- [1,2,3] thiadiazol-5- il-ureail-urea 3b3b HH FF HH HH HH 238 (desc.)238 (off) 1-(3-fluorofenil)-3-[1,2,3]tiadiazol-5-1- (3-fluorophenyl) -3- [1,2,3] thiadiazol-5- il-ureail-urea 3c3c HH HH FF HH HH 259 (desc.)259 (off) 1-(4-fluorofenil)-3-[1,2,3]tiadiazol-5-1- (4-fluorophenyl) -3- [1,2,3] thiadiazol-5- il-ureail-urea 3d3d FF FF HH HH HH 229-230229-230 1-(2,3-difluorofenil)-3-[1,2,3]tiadiazol-1- (2,3-difluorophenyl) -3- [1,2,3] thiadiazole- 5-il-urea5-il-urea 3e3e FF HH FF HH HH 225 (desc.)225 (off) 1-(2,4-difluorofenil)-3-1- (2,4-difluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3f3f FF HH HH FF HH 255 (desc.)255 (off) 1-(2,5-difluorofenil)-3-1- (2,5-difluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3g3g FF HH HH HH FF 216 (desc.)216 (off) 1-(2,6-difluorofenil)-3-1- (2,6-difluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3h3h HH FF FF HH HH 239 (desc.)239 (off) 1-(3,4-difluorofenil)-3-1- (3,4-Difluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3i3i HH FF HH FF HH 227 (desc.)227 (off) 1-(3,5-difluorofenil)-3-1- (3,5-difluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3j3j FF FF FF HH HH 263 (desc.)263 (off) 1-(2,3,4-trifluorofenil)-3-1- (2,3,4-trifluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3k3k FF FF HH HH FF 256 (desc.)256 (off) 1-(2,3,6-trifluorofenil)-3-1- (2,3,6-trifluorophenyl) -3- [1,2,3]tiaciiazol-5-il-urea[1,2,3] thiaciiazol-5-yl-urea 3l3l FF HH FF FF HH 245 (desc.)245 (off) 1-(2,4,5-trifluorofenil)-3-1- (2,4,5-trifluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3m3m FF HH FF HH FF 244-245244-245 1-(2,4,6-trifluorofenil)-3-1- (2,4,6-trifluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3n3n FF FF FF FF HH 263-266263-266 1-(2,3,4,5-tetrafluorofenil)-3-1- (2,3,4,5-tetrafluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3o3rd FF FF FF HH FF 255 (desc.)255 (off) 1-(2,3,4,6-tetrafluorofenil)-3-1- (2,3,4,6-tetrafluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3p3p FF FF HH FF FF 255-258255-258 1-(2,3,5,6-tetrafluorofenil)-3-1- (2,3,5,6-tetrafluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea 3q3q FF FF FF FF FF 260-265260-265 1-(2,3,4,5,6-pentafluorofenil)-3-1- (2,3,4,5,6-pentafluorophenyl) -3- [1,2,3]tiadiazol-5-il-urea[1,2,3] thiadiazol-5-yl-urea

La preparación de los compuestos fluorados recogidos en la invención puede efectuarse por alguno de los métodos indicados a continuación.The preparation of fluorinated compounds collected in the invention can be carried out by any of the methods indicated below.

(a) Por reacción de un fenil isocianato mono-, di-, tri-, tetra-o penta-fluorado, preparado por métodos convencionales a partir de la anilina fluorada correspondiente, con 3-nitroanilina (4) para la preparación de los compuestos (1a) a (1q), con 2-cloro-4-aminopiridina (5) para la preparación de los compuestos (2a) a (2q), y con 5-amino[1,2,3]tiadiazol (6) para la preparación de los compuestos (3a) a (3q). Las aminas requeridas para las transformaciones anteriores están disponibles comercialmente, vg. (4), o pueden prepararse por métodos descritos previamente como en el caso de la amina (5) [Robert N. Henrie II y otros, Patente US4808722 (1989)] y la amina (6) [Mamuro Nakai y otros, Patente US4269982 (1981); Katsumasa Harada y otros, Heterocycles, Vol. 44, págs. 197-201 (1997)]. Estas preparaciones pueden representarse por las siguientes reacciones, en las que los grupos R^{1} a R^{5} tienen el mismo significado que en las tablas 1 a 3.(a) By reaction of a phenyl isocyanate mono-, di-, tri-, tetra- or penta-fluorinated, prepared by conventional methods from the corresponding fluorinated aniline, with 3-nitroaniline (4) for the preparation of the compounds (1a) to (1q), with 2-chloro-4-aminopyridine (5) for the preparation of compounds (2a) to (2q), and with 5-amino [1,2,3] thiadiazole (6) for the preparation of the compounds (3a) to (3q). The amines required for the above transformations are commercially available, eg. (4), or they can be prepared by methods described previously as in the case of the amine (5) [Robert N. Henrie II et al., US Pat. No. 4808722 (1989)] and the amine (6) [Mamuro Nakai et al., US Pat. No. 4269982 (1981); Katsumasa Harada and others, Heterocycles , Vol. 44, p. 197-201 (1997)]. These preparations can be represented by the following reactions, in which the groups R 1 to R 5 have the same meaning as in Tables 1 to 3.

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(b) Por reacción de 1-isocianato-3-nitrobenceno (7), 2-cloro-4-isocianatopiridina (8) ó 5-isocianato-[1,2,3]tiadiazol (9) con una anilina mono-, di-, tri-, tetra-o pentafluorada para la preparación de las ureas (1a-1q), (2a-2q) y (3a-3q), respectivamente. Los isocianatos (7), (8) y (9) son compuestos ya descritos en la literatura que pueden prepararse por métodos convencionales por reacción de las aminas (5) y (6) mencionadas en el apartado (a) con fosgeno, trifosgeno, carbonildiimidazol, etc.(b) By reaction of 1-isocyanate-3-nitrobenzene (7), 2-chloro-4-isocyanatopyridine (8) or 5-isocyanate- [1,2,3] thiadiazole (9) with a mono-, di-, tri-, tetra- or pentafluorinated aniline for the preparation of ureas (1a-1q), (2a-2q) and (3a-3q), respectively. Isocyanates (7), (8) and (9) are compounds already described in the literature that can be prepared by conventional methods by reaction of the amines (5) and (6) mentioned in section (a) with phosgene, triphosgene, carbonyldiimidazole, etc.

(c) Por reacción de 3-nitrobenzoil azida (10), 2-cloroisonicotinoil azida (11) ó [1,2,3]tiadiazol-5-carbonil azida (12) con una anilina mono-, di-, tri-, tetra-o pentafluorada para la preparación de las ureas (1a-1q), (2a-2q) y (3a-3q), respectivamente. Las carbonil azidas (10), (11) y (12) ya han sido descritas previamente en la literatura y pueden prepararse utilizando métodos convencionales en dos etapas a partir de los correspondientes ácidos carboxílicos, ácido 3-nitrofenil benzoico, ácido 2-cloroisonicotínico y ácido [1,2,3]tiadiazoil-5-carboxílico, respectivamente. En primer lugar se lleva a cabo la formación del cloruro de ácido por reacción con cloruro de tionilo y a continuación reacción de este con azida sódica.(c) By reaction of 3-nitrobenzoyl azide (10), 2-Chloroisonicotinoyl azide (11) or [1,2,3] thiadiazol-5-carbonyl azide (12) with a mono-, di-, tri-, tetra-o aniline pentafluorinated for the preparation of ureas (1a-1q), (2a-2q) and (3a-3q), respectively. The carbonyl azides (10), (11) and (12) have already been previously described in the literature and can be prepared using conventional two-stage methods to from the corresponding carboxylic acids, acid 3-nitrophenyl benzoic acid 2-chloroisonicotinic acid [1,2,3] thiadiazoyl-5-carboxylic acid, respectively. First, the formation of the acid chloride by reaction with thionyl chloride and a then reaction of this with sodium azide.

(d) Por reacción de (3-nitrofenil)carbamato de fenilo (13), (2-cloropiridin-4-il)-carbamato de fenilo (14) o [1,2,3]tiadiazol-5-il-carbamato de fenilo (15) con una anilina mono-, di-, tri-, tetra-o pentafluorada para la preparación de las ureas (1a-1q), (2a-2q) y (3a-3q), respectivamente. La preparación de los carbamatos (13), (14) y (15) puede efectuarse utilizando procedimientos convencionales por reacción de las aminas (4), (5) y (6), respectivamente, con cloroformiato de fenilo.(d) By reaction of (3-nitrophenyl) phenyl carbamate (13), (2-Chloropyridin-4-yl) -carbamate phenyl (14) or [1,2,3] thiadiazol-5-yl-carbamate of phenyl (15) with a mono-, di-, tri-, aniline tetra-or pentafluorinated for the preparation of ureas (1a-1q), (2a-2q) and (3a-3q), respectively. The preparation of Carbamates (13), (14) and (15) can be made using conventional procedures by reaction of the amines (4), (5) and (6), respectively, with phenyl chloroformate.

Las preparaciones implicadas en los procedimientos descritos en los apartados (b), (c) y (d) pueden representarse por las reacciones químicas recogidas en el siguiente esquema, en el que los grupos R^{1} a R^{5} tienen el mismo significado que en las tablas 1 a 3.The preparations involved in the procedures described in sections (b), (c) and (d) may represented by the chemical reactions collected in the following scheme, in which the groups R1 to R5 have the same meaning as in tables 1 to 3.

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En todas las transformaciones recogidas más arriba es preferible la utilización de cantidades equimoleculares de los reactivos implicados, aunque un ligero exceso de cualquiera de los reactivos puede ser utilizado sin detrimento del rendimiento del proceso. Los disolventes más adecuados para los procedimientos (a), (b) y (c) son benceno, tolueno y xileno. Para el procedimiento recogido en el apartado (d) el disolvente más adecuado es dimetilsulfóxido, aunque otros disolventes como los mencionados previamente pueden ser utilizados con rendimientos inferiores. Las temperaturas adecuadas para efectuar estas transformaciones varían entre 0°C y 150°C, aunque los mejores resultados se obtienen entre 20 y 80°C para los procedimiento (a) y (b) y entre 80 y 90°C para los procedimientos (c) y (d). El tiempo de reacción está comprendido entre 1 h y 24 h, variando considerablemente de unos sistemas a otros y requiriéndose los tiempos más cortos para las transformaciones que implican la condensación de sistemas arílicos poco fluorados, que se incrementan notablemente con el grado de fluoración del mismo, particularmente en el caso de los procedimientos (b), (c) y (d).In all the transformations collected more the use of equimolecular amounts is preferable of the reagents involved, although a slight excess of any of reagents can be used without detriment to performance of process. The most suitable solvents for the procedures (a), (b) and (c) are benzene, toluene and xylene. For the procedure in section (d) the most suitable solvent is dimethylsulfoxide, although other solvents such as those mentioned previously they can be used with lower yields. The suitable temperatures to effect these transformations vary between 0 ° C and 150 ° C, although the best results are obtained between 20 and 80 ° C for procedures (a) and (b) and between 80 and 90 ° C for the procedures (c) and (d). The reaction time is between 1 h and 24 h, varying considerably from about systems to others and requiring the shortest times for transformations that involve the condensation of aryl systems little fluoridated, which increase markedly with the degree of fluoridation thereof, particularly in the case of procedures (b), (c) and (d).

Los siguientes ejemplos ilustran la preparación de los compuestos de la invención.The following examples illustrate the preparation of the compounds of the invention.

(A) Preparation of the 1- (3,5-difluorophenyl) -3- (3-nitrophenyl) urea (1i) from 1-isocyanate-3-nitrobenzene (7)

Una disolución de 1,10 g (8,52 mmol) de la 3,5-difluoroanilina en 3 mL de tolueno seco se añadió bajo condiciones anhidras sobre una disolución 1,27 g (7,74 mmol) de 1-isocianato-3-nitrobenceno (7) disuelto en 3 mL del mismo disolvente. La mezcla se calentó a reflujo con agitación, observando la formación de la urea que se separa de la disolución como un sólido amarillo. Después de 1 hora a reflujo, la mezcla de reacción se enfrió a temperatura ambiente y el sólido se filtró a vacío, lavándose sucesivamente con una mezcla de hexano-tolueno 1:1 y hexano. El sólido amarillo resultante se seca a vacío durante toda la noche, obteniéndose 2,16 g (95%) de 1-(3,5-difluorofenil)-3-(3-nitrofenil)urea (1i). Cristalizada de hexano-acetona, presenta un punto de fusión de 212-214°C. Espectro de IR: 3366, 1678, 1616, 1567, 1523, 1344, 1119 y 843 cm^{-1}; Espectro de masas de alta resolución (EMAR): calcd para C_{13}H_{9}F_{2}N_{3}O_{3} 293,0612, encontrado 293,0615; RMN ^{1}H: (d_{6}-DMSO) \delta 9,39 (1H, s), 9,26 (1H, s), 8,52 (1H, dd), 7,84 (1H, ddd), 7,73 (1H, ddd), 7,57 (1H, dd), 7,21 (2H, dd), 6,82 (1H, dddd).A solution of 1.10 g (8.52 mmol) of the 3,5-Difluoroaniline in 3 mL of dry toluene is added under anhydrous conditions on a solution 1.27 g (7.74 mmol) of 1-isocyanate-3-nitrobenzene (7) dissolved in 3 mL of the same solvent. The mixture was heated to reflux with agitation, observing the formation of urea that separates from the solution as a yellow solid. After 1 hour at reflux, the reaction mixture was cooled to room temperature and the solid was filtered under vacuum, washing successively with a mixture 1: 1 hexane-toluene and hexane. Yellow solid resulting is dried under vacuum overnight, obtaining 2.16 g (95%) of 1- (3,5-difluorophenyl) -3- (3-nitrophenyl) urea (1i). Crystallized hexane-acetone, presents a melting point of 212-214 ° C. IR spectrum: 3366, 1678, 1616, 1567, 1523, 1344, 1119 and 843 cm -1; Spectrum of High resolution masses (EMAR): calcd for C 13 H 9 F 2 N 3 O 3 293.0612, found 293.0615; 1 H NMR: (d 6 -DMSO) δ 9.39 (1H, s), 9.26 (1H, s), 8.52 (1H, dd), 7.84 (1H, ddd), 7.73 (1H, ddd), 7.57 (1H, dd), 7.21 (2H, dd), 6.82 (1H, dddd).

(B) Preparation of 1- (2,3,4-trifluorophenyl) -3- (3-nitrophenyl) urea (1j) from (3-nitrophenyl) carbamate of phenyl (13) (i) Preparation of (3-nitrophenyl) phenyl carbamate (13)

A una disolución agitada de 1,0 g (7,3 mmol) de 3-nitroanilina en 16,2 mL de THF seco se adicionaron bajo condiciones anhidras y de forma consecutiva, 0,74 mL (9,1 mmol) de piridina seca y 0,94 mL (7,5 mmol) de cloroformiato de fenilo. Después de 45 minutos la mezcla de reacción se diluyó con acetato de etilo y la disolución se lavó sucesivamente con disolución 1M de HCl, agua fría, disolución acuosa saturada de NaHCO_{3}, y salmuera. El extracto orgánico se secó sobre MgSO_{4} anhidro. Tras filtrar y evaporar el disolvente a presión reducida se obtuvo un sólido amarillento que se purificó por lavado con una mezcla de hexano-éter 9:1, para obtener 1,75 g (93%) de (3-nitrofenil)carbamato de fenilo (13). Cristalizado de hexano-acetona presentó un punto de fusión de 126-127°C.At a stirred solution of 1.0 g (7.3 mmol) of 3-nitroaniline in 16.2 mL of dry THF is added under anhydrous conditions and consecutively, 0.74 mL (9.1 mmol) of dry pyridine and 0.94 mL (7.5 mmol) of phenyl chloroformate. After 45 minutes the mixture of reaction was diluted with ethyl acetate and the solution was washed successively with 1M solution of HCl, cold water, solution saturated aqueous NaHCO3, and brine. The organic extract is dried over anhydrous MgSO4. After filtering and evaporating the solvent under reduced pressure a yellowish solid was obtained which it was purified by washing with a 9: 1 hexane-ether mixture, to obtain 1.75 g (93%) of (3-nitrophenyl) phenyl carbamate (13). Crystallized hexane-acetone presented a point of melting of 126-127 ° C.

(ii) Preparation of the 1- (2,3,4-trifluorophenyl) -3- (3-nitrophenyl) urea (1j)

Una disolución de 499,6 mg (1,94 mmol) del carbamato de fenilo (13) y 292,5 mg (1,99 mmol) de la 2,3,4-trifluoroanilina en 5,0 mL DMSO seco se calentó a 85°C bajo atmósfera inerte hasta que por cromatografía de capa fina se observó la práctica completa consumición de los materiales (aproximadamente 22 horas). Pasado este tiempo la mezcla de reacción se diluyó con acetato de etilo y se lavó sucesivamente con agua, solución acuosa al 10% de NaHCO_{3} y salmuera. Tras secar la fase orgánica sobre MgSO_{4} anhidro, filtrar y evaporar el disolvente a presión reducida se obtuvo un residuo sólido que se purificó por cromatografía de columna sobre gel de sílice, utilizando una mezcla de hexano-acetato de etilo 7:3 como eluyente, para dar 484,6 mg (80%) de la 1-(2,3,4-trifluorofenil)-3-(3-nitrofenil) urea (1j) como un sólido amarillento. Cristalizada de hexano-acetona presentó un punto de fusión de 217-219°C. Espectro de IR: 3393, 3332, 1662, 1624, 1569, 1515, 1446, 1345, 1258, 1029, 806 y 677 cm^{-1}; EMAR: calcd para C_{13}H_{8}F_{3}N_{3}O_{3} 311, 0518, encontrado 311,0510; RMN ^{1}H: (d_{6}-DMSO) \delta 9,50 (1H, s), 8,77 (1H, s), 8, 51 (1H, dd), 7,81 (1H, ddd), 7,79 (1H, dddd), 7,64 (1H, ddd), 7,54 (1H, dd) y 7,24 (1H, dddd).A solution of 499.6 mg (1.94 mmol) of phenyl carbamate (13) and 292.5 mg (1.99 mmol) of the 2,3,4-trifluoroaniline in 5.0 mL dry DMSO is heated at 85 ° C under an inert atmosphere until by chromatography of thin layer was observed the full practice of eating materials (approximately 22 hours). After this time the mixture The reaction was diluted with ethyl acetate and washed successively with water, 10% aqueous NaHCO3 solution and brine. After Dry the organic phase over anhydrous MgSO4, filter and evaporate the solvent under reduced pressure a solid residue was obtained which purified by column chromatography on silica gel, using a mixture of hexane-ethyl acetate 7: 3 as eluent, to give 484.6 mg (80%) of the 1- (2,3,4-trifluorophenyl) -3- (3-nitrophenyl) urea (1j) as a yellowish solid. Crystallized from hexane-acetone presented a melting point of 217-219 ° C. IR spectrum: 3393, 3332, 1662, 1624, 1569, 1515, 1446, 1345, 1258, 1029, 806 and 677 cm -1; EMAR: calcd for C 13 H 8 F 3 N 3 O 3 311, 0518, found 311.0510; 1 H NMR: (d 6 -DMSO) δ 9.50 (1H, s), 8.77 (1H, s), 8, 51 (1H, dd), 7.81 (1H, ddd), 7.79 (1H, dddd), 7.64 (1H, ddd), 7.54 (1H, dd) and 7.24 (1H, dddd).

(C) Preparation of the 1- (2-Chloropyridin-4-yl) -3- (2,3,6-trifluorophenyl) urea (2k) from 2-Chloroisonicotinoyl azide (11) (i) Acid preparation 2-Chloroisonicotinic

Una disolución de 10,0 g (72 mmol) del N-óxido del ácido isonicotínico en 20 mL de POCl_{3} (215 mmol) se calentó a 110°C durante 3 días. Pasado este tiempo el exceso de POCl_{3} se destiló a vacío (70°C, 20 mmHg) obteniéndose un aceite amarillo que se adicionó lentamente sobre hielo-agua. Se observa la formación del ácido que se separa de la disolución como un sólido blanquecino que se recogió por filtración a vacío. Tras sucesivos lavados con agua fría, el sólido resultante se secó a vacío durante toda la noche, obteniéndose 8,4 g (74%) del ácido 2-cloroisonicotínico. Cristalizado de acetona presentó un punto de fusión de 222-223°C.A solution of 10.0 g (72 mmol) of the N-oxide of the isonicotinic acid in 20 mL of POCl3 (215 mmol) is heated at 110 ° C for 3 days. After this time the excess of POCl3 was distilled under vacuum (70 ° C, 20 mmHg) to obtain a yellow oil that was slowly added over ice water. The formation of the acid is observed that separates from the solution as an off-white solid that was collected by vacuum filtration. After successive washing with cold water, the resulting solid was dried under vacuum overnight, obtaining 8.4 g (74%) of the acid 2-Chloroisonicotinic Crystallized Acetone It had a melting point of 222-223 ° C.

(ii) Preparation of chloride 2-Chloroisonicotinoyl

Una disolución de 8,38 g (53 mmol) del ácido 2-cloroisonicotínico en 30 mL de SOCl_{2} (411 mmol) se calentó a 80°C durante 2 horas. Pasado este tiempo el exceso de SOCl_{2} se destiló a presión reducida (40°C, 210 mmHg) obteniéndose un residuo amarillento sobre el que se añadieron 60 mL de tolueno seco y nuevamente se destiló a presión reducida (85°C, 50 mmHg). El cloruro de 2-cloroisonicotinoilo se empleó en la siguiente etapa sin necesidad de purificación previa.A solution of 8.38 g (53 mmol) of the acid 2-Chloroisonicotinic in 30 mL of SOCl2 (411 mmol) was heated at 80 ° C for 2 hours. After this time the excess SOCl 2 was distilled under reduced pressure (40 ° C, 210 mmHg) obtaining a yellowish residue on which 60 mL was added of dry toluene and again distilled under reduced pressure (85 ° C, 50 mmHg). 2-Chloroisonicotinoyl Chloride is used in the next stage without purification previous.

(iii) Preparation of the 2-Chloroisonicotinoyl azide (11)

Una disolución de 9,17 g (52 mmol) del cloruro de 2-cloroisonicotinoilo en 35 mL de acetona seca se añadió gota a gota, desde un embudo de adición, sobre una disolución de 3,7 g de NaN_{3} (57 mmol) disuelta en 26 mL de agua. Después de 30 minutos la mezcla de reacción fue vertida sobre agua y la disolución se extrajo varias veces con hexano. El extracto orgánico se secó sobre MgSO_{4} anhidro. Tras filtrar y evaporar el disolvente a presión reducida el sólido blanquecino resultante se secó a vacío durante toda la noche, obteniéndose 7,7 g (81%) de la 2-cloroisonicotinoil azida (11). Cristalizada de acetona presentó un punto de fusión de 193-195°C.A solution of 9.17 g (52 mmol) of the chloride 2-Chloroisonicotinoyl in 35 mL of dry acetone is added dropwise, from an addition funnel, on a solution of 3.7 g of NaN3 (57 mmol) dissolved in 26 mL of Water. After 30 minutes the reaction mixture was poured onto water and the solution was extracted several times with hexane. He Organic extract was dried over anhydrous MgSO4. After filtering and evaporate the solvent under reduced pressure the off-white solid resulting was dried under vacuum overnight, obtaining 7.7 g (81%) of the 2-chloroisonicotinoyl azide (11). Crystallized acetone presented a melting point of 193-195 ° C.

(iv) Preparation of 1- (2-chloropi ridin-4-yl) -3- (2,3,6-trifluorophenyl) urea (2k)

Sobre una disolución de 441,2 mg (3,02 mmol) de 2,3,6-trifluoroanilina en 2,5 mL de tolueno seco, a reflujo y con agitación se añadió una disolución de 501,2 mg (2,74 mmol) de la 2-cloroisonicotinoil azida (11) disuelta en 2,5 mL del mismo disolvente. La mezcla se calentó a reflujo con agitación, observando la formación de la urea que se separa de la disolución como un sólido blanquecino. Después de 1 hora a reflujo, la mezcla de reacción se enfrió a temperatura ambiente y el sólido se filtró a vacío, lavándose sucesivamente con una mezcla de hexano-tolueno 1:1 y hexano. El sólido blanco resultante se seca a vacío durante toda la noche, obteniéndose 761,0 mg (92%) de 1-(2-cloropiridin-4-il)-3-(2,3,6-trifluorofenil)urea (2k). Cristalizada de hexano-acetona, presenta un punto de fusión de 180-182°C. Espectro de IR: 3327, 3044, 1668, 1634, 1588, 1535, 1509, 1486, 1381, 1253, 1081, 993 y 815 cm^{-1}; EMAR: calcd para C_{12}H_{7}ClF_{3}N_{3}O 301, 0230, encontrado 301,0228; RMN ^{1}H: (d_{6}-DMSO) \delta 9,73 (1H, s), 8,68 (1H, s), 8,15 (1H, d), 7,58 (1H, d), 7,40 (1H, dddd), 7,32 (1H, dd) y 7,19 (1H, dddd).On a solution of 441.2 mg (3.02 mmol) of 2,3,6-trifluoroaniline in 2.5 mL of dry toluene, a reflux and with stirring a solution of 501.2 mg (2.74 was added mmol) of 2-chloroisonicotinoyl azide (11) dissolved in 2.5 mL of the same solvent. The mixture was heated to reflux with agitation, observing the formation of urea that separates from the solution as an off-white solid. After 1 hour at reflux, the reaction mixture was cooled to temperature environment and the solid was filtered under vacuum, washing successively with a mixture of hexane-toluene 1: 1 and hexane. He resulting white solid is dried under vacuum overnight, obtaining 761.0 mg (92%) of 1- (2-Chloropyridin-4-yl) -3- (2,3,6-trifluorophenyl) urea (2k). Crystallized hexane-acetone, presents a melting point of 180-182 ° C. IR spectrum: 3327, 3044, 1668, 1634, 1588, 1535, 1509, 1486, 1381, 1253, 1081, 993 and 815 cm -1; EMAR: calcd for C 12 H 7 ClF 3 N 3 O 301, 0230, found 301.0228; 1 H NMR: (d_ {6} -DMSO) δ 9.73 (1H, s), 8.68 (1H, s), 8.15 (1H, d), 7.58 (1H, d), 7.40 (1H, dddd), 7.32 (1H, dd) and 7.19 (1H, dddd).

(D) Preparation of 1- (2-Chloropyridin-4-yl) -3- (2,3,4,5,6-pentafluorophenyl) urea (2q) from the 2-chloro-4-isocyanatopyridine (8) (i) Preparation of the 2-chloro-4-isocyanatopyridine (8)

A una disolución agitada de 300,0 mg (2,33 mmol) de la 2-cloro-4-aminopiridina (5) en 16,0 mL de diclorometano, se adicionaron 16,0 mL de una disolución acuosa saturada de NaHCO_{3}. La mezcla bifásica se enfrió a 0°C y se mantuvo con agitación vigorosa durante 30 minutos. Pasado este tiempo se paró la agitación y se añadió sobre la fase orgánica, vía jeringa, 7,4 mL (14 mmol) de una disolución comercial del 20% de fosgeno en tolueno. Finalizada la adición se mantuvo la mezcla de reacción con agitación a 0°C durante 5 horas. Pasado este tiempo la fase orgánica se extrajo con diclorometano y se secó sobre Na_{2}SO_{4} anhidro. Tras filtrar y evaporar el disolvente a presión reducida se obtuvieron 270,3 mg (75%) de la 2-cloro-4-isocianatopiridina (8) como un sólido amarillento.At a stirred solution of 300.0 mg (2.33 mmol) of the 2-chloro-4-aminopyridine (5) in 16.0 mL of dichloromethane, 16.0 mL of a saturated aqueous solution of NaHCO3. The biphasic mixture is cooled to 0 ° C and kept under vigorous stirring for 30 minutes After this time the stirring was stopped and added on the organic phase, via syringe, 7.4 mL (14 mmol) of a solution 20% commercial phosgene in toluene. Finished the addition is kept the reaction mixture with stirring at 0 ° C for 5 hours. After this time the organic phase was extracted with dichloromethane and dried over anhydrous Na2SO4. After filtering and evaporating the solvent under reduced pressure 270.3 mg (75%) of the 2-chloro-4-isocyanatopyridine (8) as a yellowish solid.

(ii) Preparation of the 1- (2-Chloropyridin-4-yl) -3- (2,3,4,5,6-pentafluorophenyl) urea (2q)

Una disolución de 110,3 mg (0,60 mmol) de la 2,3,4,5,6-pentafluoroanilina en 0,5 mL de tolueno seco se añadió bajo condiciones anhidras sobre una disolución de 90,3 mg (0,58 mmol) de la 2-cloro-4-isocianatopiridina (8) disuelta en 0,5 mL del mismo disolvente. La mezcla se calentó a reflujo con agitación, observando la formación de un sólido blanco correspondiente a la urea formada. Después de 1,30 horas a reflujo, la mezcla de reacción se enfrió a temperatura ambiente y el sólido se filtró a vacío, lavándose con hexano. El sólido blanco resultante se cromatografió sobre silicagel, usando hexano-acetato de etilo 8:2 como eluyente, obteniéndose 145,8 mg (7496) de 1-(2-cloropiridin-4-il)-3-(2,3,4,5,6-pentafluorofenil)urea (2q). Cristalizada de hexano-acetona, presenta un punto de fusión de 211-212°C. Espectro de IR: 3242, 3179, 1697, 1594, 1534, 1516, 1493, 1274, 1221, 1010, 994 y 978 cm^{-1}; EMAR: calcd para C_{12}H_{5}ClF_{5}N_{3}O 337,0041, encontrado 337,0035; RMN ^{1}H: (d_{6}-DMSO) \delta 9,81 (1H, s), 8,88 (1H, s), 8,17 (1H, d), 7,58 (1H, d) y 7,33 (1H, dd).A solution of 110.3 mg (0.60 mmol) of the 2,3,4,5,6-pentafluoroaniline in 0.5 mL of toluene dry was added under anhydrous conditions on a solution of 90.3 mg (0.58 mmol) of the 2-chloro-4-isocyanatopyridine (8) dissolved in 0.5 mL of the same solvent. The mixture was heated to reflux with stirring, observing the formation of a white solid corresponding to the urea formed. After 1.30 hours at reflux, the reaction mixture was cooled to room temperature and the solid filtered under vacuum, washing with hexane. White solid resulting was chromatographed on silica gel, using hexane-ethyl acetate 8: 2 as eluent, obtaining 145.8 mg (7496) of 1- (2-Chloropyridin-4-yl) -3- (2,3,4,5,6-pentafluorophenyl) urea (2q). Crystallized hexane-acetone, presents a melting point of 211-212 ° C. IR spectrum: 3242, 3179, 1697, 1594, 1534, 1516, 1493, 1274, 1221, 1010, 994 and 978 cm -1; EMAR: calcd for C 12 H 5 ClF 5 N 3 O 337.0041, found 337.0035; 1 H NMR: (d 6 {-DMSO) δ 9.81 (1H, s), 8.88 (1H, s), 8.17 (1H, d), 7.58 (1H, d) and 7.33 (1H, dd).

(E) Preparation of 1- (3,5-difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3i) from the [1,2,3] thiadiazol-5-carbonyl azide (12) (i) Preparation of the [1,2,3] thiadiazol-5-carbonyl azide (12)

Una disolución de 3,0 g (23 mmol) del ácido 5-[1,2,3] tiadiazolil carboxílico [Preparado según: Friedrich Arndt y otros, Patente US4177054 (1979)] en 10,0 mL de SOCl_{2} (137 mmol) se calentó a 80°C durante 2 horas. Pasado este tiempo el exceso de SOCl_{2} se destiló a presión reducida (40°C, 210 mmHg) obteniéndose un residuo amarillento sobre el que se adicionaron 10,0 mL de tolueno seco y nuevamente se destiló a presión reducida (85°C, 50 mmHg). El aceite amarillo obtenido se empleó en la siguiente etapa sin necesidad de purificación.A solution of 3.0 g (23 mmol) of the acid 5- [1,2,3] thiadiazolyl carboxylic [Prepared according to: Friedrich Arndt et al., US 4177054 (1979)] in 10.0 mL of SOCl2 (137 mmol) was heated at 80 ° C for 2 hours. Past this time excess SOCl 2 was distilled under reduced pressure (40 ° C, 210 mmHg) obtaining a yellowish residue on which 10.0 mL of dry toluene was added and again distilled to reduced pressure (85 ° C, 50 mmHg). The yellow oil obtained is used in the next stage without the need for purification.

Una disolución de 3,4 g (23 mmol) del cloruro de 5-[1,2,3]tiadiazolilo, obtenido en la etapa anterior disuelto en 13,5 mL de acetona seca se adicionó gota a gota sobre una disolución de 1,66 g (26 mmol) de NaN_{3} disuelta en 10 mL de agua. Después de comprobar por cromatografía de capa fina la completa consumición del cloruro de partida (aproximadamente 1 hora), la mezcla de reacción se extrajo con hexano. El extracto orgánico se secó sobre MgSO_{4} anhidro. Tras filtrar y evaporar el disolvente a presión reducida se obtuvieron 2,6 g (74% desde el ácido) de la [1,2,3]tiadiazol-5-carbonil azida (12) como un aceite amarillo.A solution of 3.4 g (23 mmol) of the chloride 5- [1,2,3] thiadiazolyl, obtained in the previous stage dissolved in 13.5 mL of dry acetone was added dropwise on a solution of 1.66 g (26 mmol) of NaN3 dissolved in 10 mL of Water. After checking by thin layer chromatography the complete consumption of starting chloride (approximately 1 hour), the reaction mixture was extracted with hexane. The extract Organic was dried over anhydrous MgSO 4. After filtering and evaporating the solvent under reduced pressure 2.6 g (74% from the acid) of the [1,2,3] thiadiazol-5-carbonyl azide (12) as a yellow oil.

(ii) Preparation of the 1- (3,5-difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3i)

Sobre una disolución de 417,5 mg (3,23 mmol) de 3,5-difluoroanilina en 2,3 mL de tolueno seco, a reflujo y con agitación se añadió una disolución de 455,6 mg (2,94 mmol) de la [1,2,3]tiadiazol-5-carbonil azida (12) disuelta en 2,3 mL del mismo disolvente. La mezcla se calentó a reflujo con agitación, observando la formación de la urea que se separa de la disolución como un sólido blanquecino. Después de 1 hora a reflujo, la mezcla de reacción se enfrió a temperatura ambiente y el sólido se filtró a vacío, lavándose sucesivamente con una mezcla de hexano-tolueno 1:1 y hexano. El sólido blanco resultante se secó a vacío durante toda la noche, obteniéndose 760,3 mg (92%) de 1-(3,5-difluorofenil)-3-[1,2,3]tiadiazol-5-il-urea (3i). Cristalizada de hexano-acetona funde a 227°C con descomposición. Espectro de IR: 3291, 3169, 3106, 2972, 1710, 1616, 1566, 1477, 1310, 1250, 1196, 1120, 977, 730 y 660 cm^{-1}; EMAR: calcd para C_{9}H_{6}F_{2}N_{4}OS 256, 0230, encontrado 256, 0232; RMN ^{1}H: (d_{6}-DMSO) \delta 11,10 (1H, s), 9,86 (1H, s), 8,62 (1H, s), 7,21 (2H, dd), 6,88 (1H, dddd).On a solution of 417.5 mg (3.23 mmol) of 3,5-Difluoroaniline in 2.3 mL of dry toluene, a reflux and with stirring a solution of 455.6 mg (2.94 was added mmol) of the [1,2,3] thiadiazol-5-carbonyl azide (12) dissolved in 2.3 mL of the same solvent. The mixture is heated to reflux with stirring, observing urea formation which separates from the solution as an off-white solid. After 1 hour at reflux, the reaction mixture was cooled to temperature environment and the solid was filtered under vacuum, washing successively with a mixture of hexane-toluene 1: 1 and hexane. He resulting white solid was dried under vacuum overnight, obtaining 760.3 mg (92%) of 1- (3,5-difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3i). Crystallized hexane-acetone melts at 227 ° C With decomposition IR spectrum: 3291, 3169, 3106, 2972, 1710, 1616, 1566, 1477, 1310, 1250, 1196, 1120, 977, 730 and 660 cm -1; EMAR: calcd for C 9 H 6 F 2 N 4 OS 256, 0230, found 256, 0232; 1 H NMR: (d 6 -DMSO) δ 11.10 (1H, s), 9.86 (1H, s), 8.62 (1H, s), 7.21 (2H, dd), 6.88 (1H, dddd).

(F) Preparation of 1- (2,3,4,6-tetrafluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3rd) from the [1,2,3] thiadiazol-5-carbonyl azide (12)

Sobre una disolución de 630 mg (3,816 mmol) de 2,3,4,6-tetrafluoroanilina en 3,5 mL de tolueno seco, a reflujo y con agitación se añadió lentamente una disolución de 536,0 mg (3,458 mmol) de la [1,2,3]tiadiazol-5-carbonil azida (12) disuelta en 3,5 mL del mismo disolvente. Después de 2 horas a reflujo, la mezcla de reacción se enfrió a temperatura ambiente y el sólido formado se filtró a vacío, lavándose sucesivamente con una mezcla de hexano-tolueno 1:1 y hexano. El sólido amarillento obtenido se extrajo varias veces con acetona. Los extractos de acetona se concentraron a presión reducida para obtener 850,7 mg (85%) de la 1-(2,3,4,6-tetrafliiorofenil)-3-[1,2,3]tiadiazol-5-il-urea (3o). Cristalizada de hexano-acetona presentó un punto de fusión de 255°C (desc.); Espectro de IR: 3262, 3228, 3164, 3072, 2967, 1702, 1570, 1499, 1484, 1307, 1072, 816 y 793 cm^{-1}; EMAR: calcd para C_{9}H_{4}F_{4}N_{4}OS 292, 0042, encontrado 292,0050; RMN ^{1}H: (d_{6}-DMSO) \delta 11,36 (1H, s), 9,28 (1H, s), 8,57 (1H, s), 7,66 (1H, dddd).On a solution of 630 mg (3,816 mmol) of 2,3,4,6-tetrafluoroaniline in 3.5 mL of toluene dry, at reflux and with stirring a solution was slowly added of 536.0 mg (3,458 mmol) of the [1,2,3] thiadiazol-5-carbonyl azide (12) dissolved in 3.5 mL of the same solvent. After 2 hours at reflux, the reaction mixture was cooled to temperature ambient and the solid formed was filtered under vacuum, washing successively with a mixture of hexane-toluene 1: 1 and hexane The yellowish solid obtained was extracted several times with acetone. Acetone extracts were concentrated under pressure. reduced to obtain 850.7 mg (85%) of the 1- (2,3,4,6-tetrafliiorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3rd). Crystallized hexane-acetone presented a melting point of 255 ° C (dec.); IR spectrum: 3262, 3228, 3164, 3072, 2967, 1702, 1570, 1499, 1484, 1307, 1072, 816 and 793 cm -1; EMAR: calcd for C 9 H 4 F 4 N 4 OS 292, 0042, found 292.0050; 1 H NMR: (d_ {6} -DMSO) δ 11.36 (1H, s), 9.28 (1H, s), 8.57 (1H, s), 7.66 (1H, dddd).

(G) Preparation of 1- (2,3,4,5,6-pentafluorophenyl) -3- (1,2,3] thiadiazol-5-yl-urea (3q) from the [1,2,3] thiadiazol-5-carbonyl azide (12)

Sobre una disolución agitada de 285,3 mg (1,54 mmol) de la 2,3,4,5,6-pentafluoroanilina en 2 mL de benceno seco a reflujo se añadió lentamente una disolución de 219,6 mg (1,40 mmol) de la [1,2,3]tiadiazol-5-carbonil azida (12) en 2 mL del mismo disolvente. Después de 4 horas a reflujo, el disolvente se eliminó a vacío y el residuo resultante se deposito sobre una pequeña columna de silicagel que se eluyó con acetona. Tras evaporación de la acetona se obtuvieron 313 mg (71%) de la 1-(2,3,4,5,6-pentafluorofenil)-3- [1,2,3]tiadiazol-5-il-urea (3q) como un sólido. Cristalizada de DMSO-H_{2}O presentó un punto de fusión de 260-265°C. Espectro de IR: 3276, 3225, 3006, 1713, 1578, 1528, 1505, 1308, 1197 y 970 cm^{-1}; EMAR: calcd para C_{9}H_{3}FSN_{4}OS 309,9948, encontrado 309,9950; RMN ^{1}H: (d_{6}-DMSO) \delta 11,44 (1H, s), 9,52 (1H, s), 8,59 (1H, s).On a stirred solution of 285.3 mg (1.54 mmol) of 2,3,4,5,6-pentafluoroaniline in 2 mL of dry benzene at reflux a solution of 219.6 was added slowly mg (1.40 mmol) of the [1,2,3] thiadiazol-5-carbonyl azide (12) in 2 mL of the same solvent. After 4 hours at reflux, the solvent was removed in vacuo and the resulting residue it was deposited on a small silica gel column that eluted with acetone After evaporation of acetone, 313 mg was obtained. (71%) of the 1- (2,3,4,5,6-pentafluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3q) as a solid. Crystallized from DMSO-H2O presented a melting point of 260-265 ° C. Spectrum IR: 3276, 3225, 3006, 1713, 1578, 1528, 1505, 1308, 1197 and 970 cm -1; EMAR: calcd for C 9 H 3 FSN 4 OS 309.9948, found 309.9950; 1 H NMR: (d 6 -DMSO) δ 11.44 (1H, s), 9.52 (1H, s), 8.59 (1H, s).

Siguiendo procedimientos análogos a los descritos en los párrafos precedentes se prepararon las siguientes ureas fluoradas:Following procedures analogous to those described in the preceding paragraphs the following ureas were prepared fluoridated:

1- (Fluorophenyl) -3- (3-nitrophenyl) ureas 1- (2-Fluorophenyl) -3- (3-nitrophenyl) urea (1st)

Espectro de IR: 3283, 3081, 1646, 1598, 1563, 1526, 1348, 1252, 1194, 1108 y 758 cm^{-1}; EMAR: calcd para C_{13}H_{10}FN_{3}O_{3} 275,0706, encontrado 275,0697; RMN ^{1}H: (d_{6}-DMSO) \delta 9,52 (1H, s), 8,64 (1H, d), 8,54 (1H, dd), 8,08 (1H, ddd), 7,81 (1H, ddd), 7,63 (1H, ddd), 7,53 (1H, dd), 7,22 (1H, ddd), 7,12 (1H, ddd) y 7,02 (1H, ddd).IR spectrum: 3283, 3081, 1646, 1598, 1563, 1526, 1348, 1252, 1194, 1108 and 758 cm -1; EMAR: calcd for C 13 H 10 FN 3 O 3 275.0706, found 275.0697; NMR 1 H: (d 6 -DMSO) δ 9.52 (1H, s), 8.64 (1H, d), 8.54 (1H, dd), 8.08 (1H, ddd), 7.81 (1H, ddd), 7.63 (1H, ddd), 7.53 (1H, dd), 7.22 (1H, ddd), 7.12 (1H, ddd) and 7.02 (1H, ddd).

1- (3-Fluorophenyl) -3- (3-nitrophenyl) urea (1 B)

Espectro de IR: 3370, 1676, 1561, 1509, 1346, 1272, 1209, 833 y 733 cm^{-1}; EMAR: calcd para C_{13}H_{10}FN_{3}O_{3} 275,0706, encontrado 275,0714; RMN ^{1}H: (d_{6}-DMSO) \delta 9,28 (1H, s), 9,08 (1H, s), 8,54 (1H, dd), 7,83 (1H, ddd), 7,71 (1H, ddd), 7,56 (1H, dd), 7,48 (1H, ddd), 7,31 (1H, ddd), 7,16 (1H, ddd) y 6,81 (1H, dddd).IR spectrum: 3370, 1676, 1561, 1509, 1346, 1272, 1209, 833 and 733 cm -1; EMAR: calcd for C 13 H 10 FN 3 O 3 275.0706, found 275.0714; NMR 1 H: (d 6 -DMSO) δ 9.28 (1H, s), 9.08 (1H, s), 8.54 (1H, dd), 7.83 (1H, ddd), 7.71 (1H, ddd), 7.56 (1H, dd), 7.48 (1H, ddd), 7.31 (1H, ddd), 7.16 (1H, ddd) and 6.81 (1H, dddd).

1- (4-Fluorophenyl) -3- (3-nitrophenyl) urea (1 C)

Espectro de IR: 3292, 3087, 1644, 1599, 1557, 1523, 1347, 1280, 1229, 733 y 686 cm^{-1}; EMAR: calcd para C_{13}H_{10}FN_{3}O_{3} 275,0706, encontrado 275,0705; RMN ^{1}H: (d_{6}-DMSO) \delta 9,21 (1H, s), 8,87 (1H, s), 8,54 (1H, dd), 7,81 (1H, ddd), 7,70 (1H, ddd), 7,55 (1H, dd), 7,48 (2H, dd) y 7,13 (2H, dd).IR spectrum: 3292, 3087, 1644, 1599, 1557, 1523, 1347, 1280, 1229, 733 and 686 cm -1; EMAR: calcd for C 13 H 10 FN 3 O 3 275.0706, found 275.0705; NMR 1 H: (d 6 -DMSO) δ 9.21 (1H, s), 8.87 (1H, s), 8.54 (1H, dd), 7.81 (1H, ddd), 7.70 (1H, ddd), 7.55 (1H, dd), 7.48 (2H, dd) and 7.13 (2H, dd).

1- (2,3-Difluorophenyl) -3- (3-nitrophenyl) urea (1d)

Espectro de IR: 3366, 3097, 1678, 1616, 1567, 1523, 1427, 1344, 1119, 981 y 842 cm^{-1}; EMAR: calcd para C_{13}H_{9}F_{2}N_{3}O_{3} 293, 0612, encontrado 293,0623; RMN ^{1}H: (d_{6}-DMSO) \delta 9,57 (1H, s), 8,86 (1H, d), 8,57 (1H, dd), 7,91 (1H, dddd), 7,85 (1H, ddd), 7,67 (1H, ddd), 7,57 (1H, dd), 7,13 (1H, dddd) y 7,07 (1H, dddd).IR spectrum: 3366, 3097, 1678, 1616, 1567, 1523, 1427, 1344, 1119, 981 and 842 cm -1; EMAR: calcd for C 13 H 9 F 2 N 3 O 3 293 0612, found 293.0623; 1 H NMR: (d 6 -DMSO) δ 9.57 (1H, s), 8.86 (1H, d), 8.57 (1H, dd), 7.91 (1H, dddd), 7.85 (1H, ddd), 7.67 (1H, ddd), 7.57 (1H, dd), 7.13 (1H, dddd) and 7.07 (1H, dddd).

1- (2,4-Difluorophenyl) -3- (3-nitrophenyl) urea (1e)

Espectro de IR: 3397, 3373, 1722, 1562, 1521, 1426, 1341, 1189, 844, 795 y 737 cm^{-1}; EMAR: calcd para C_{13}H_{9}F_{2}N_{3}O_{3} 293,0612, encontrado 293,0613; RMN ^{1}H: (d_{6}-DMSO) \delta 9,51 (1H, s), 8,63 (1H, s), 8,56 (1H, dd), 8,03 (1H, ddd), 7,83 (1H, ddd), 7,66 (1H, ddd), 7,56 (1H, dd), 7,32 (1H, ddd) y 7,06 (1H, dddd).IR spectrum: 3397, 3373, 1722, 1562, 1521, 1426, 1341, 1189, 844, 795 and 737 cm -1; EMAR: calcd for C 13 H 9 F 2 N 3 O 3 293.0612, found 293.0613; 1 H NMR: (d 6 -DMSO) δ 9.51 (1H, s), 8.63 (1H, s), 8.56 (1H, dd), 8.03 (1H, ddd), 7.83 (1H, ddd), 7.66 (1H, ddd), 7.56 (1H, dd), 7.32 (1H, ddd) and 7.06 (1H, dddd).

1- (2,5-Difluorophenyl) -3- (3-nitrophenyl) urea (1f)

Espectro de IR: 3395, 1721, 1557, 1518, 1341, 1212, 800 y 725 cm^{-1}; EMAR: calcd para C_{13}H_{9}F_{2}N_{3}O_{3} 293,0612, encontrado 293,0618; RMN ^{1}H: (d_{6}-DMSO) \delta 9,61 (1H, s), 8,87 (1H, s), 8,56 (1H, dd), 8,01 (1H, ddd), 7,85 (1H, ddd), 7,65 (1H, ddd), 7,57 (1H, dd), 7,30 (1H, ddd) y 6,85 (1H, dddd).IR spectrum: 3395, 1721, 1557, 1518, 1341, 1212, 800 and 725 cm -1; EMAR: calcd for C 13 H 9 F 2 N 3 O 3 293.0612, found 293.0618; 1 H NMR: (d 6 -DMSO) δ 9.61 (1H, s), 8.87 (1H, s), 8.56 (1H, dd), 8.01 (1H, ddd), 7.85 (1H, ddd), 7.65 (1H, ddd), 7.57 (1H, dd), 7.30 (1H, ddd) and 6.85 (1H, dddd).

1- (2,6-Difluorophenyl) -3- (3-nitrophenyl) urea (1g)

Espectro de IR: 3358, 3267, 1668, 1600, 1555, 1468, 1345, 1002, 800 y 720 cm^{-1}; EMAR: calcd para C_{13}H_{9}F_{2}N_{3}O_{3} 293,0612, encontrado 293,0610; RMN ^{1}H: (d_{6}-DMSO) \delta 9,52 (1H, s), 8,52 (1H, dd), 8,33 (1H, s), 7,82 (1H, ddd), 7,75 (1H, ddd), 7,55 (1H, dd), 7,33 (1H, dddd) y 7,16 (2H, dd).IR spectrum: 3358, 3267, 1668, 1600, 1555, 1468, 1345, 1002, 800 and 720 cm -1; EMAR: calcd for C 13 H 9 F 2 N 3 O 3 293.0612, found 293.0610; 1 H NMR: (d 6 -DMSO) δ 9.52 (1H, s), 8.52 (1H, dd), 8.33 (1H, s), 7.82 (1H, ddd), 7.75 (1H, ddd), 7.55 (1H, dd), 7.33 (1H, dddd) and 7.16 (2H, dd).

1- (3,4-Difluorophenyl) -3- (3-nitrophenyl) urea (1 hour)

Espectro de IR: 3368, 1676, 1565, 1515, 1345, 1214, 801 y 734 cm^{-1}; EMAR: calcd para C_{13}H_{9}F_{2}N_{3}O_{3} 293,0612, encontrado 293,0615; RMN ^{1}H: (d_{6}-DMSO) \delta 9,29 (1H, s), 9,06 (1H, s), 8,53 (1H, dd), 7,83 (1H, ddd), 7,71 (1H, ddd), 7,66 (1H, ddd), 7,56 (1H, dd), 7,35 (1H, ddd) y 7,18-7,13 (1H, m).IR spectrum: 3368, 1676, 1565, 1515, 1345, 1214, 801 and 734 cm -1; EMAR: calcd for C 13 H 9 F 2 N 3 O 3 293.0612, found 293.0615; 1 H NMR: (d 6 -DMSO) δ 9.29 (1H, s), 9.06 (1H, s), 8.53 (1H, dd), 7.83 (1H, ddd), 7.71 (1H, ddd), 7.66 (1H, ddd), 7.56 (1H, dd), 7.35 (1H, ddd) and 7.18-7.13 (1H, m).

1- (2,3,6-Trifluorophenyl) -3- (3-nitrophenyl) urea (1k)

Espectro de IR: 3326, 3292, 1671, 1601, 1568, 1529, 1510, 1349, 1238, 955 y 816 cm^{-1}; EMAR: calcd para C_{13}H_{8}F_{3}N_{3}O_{3} 311,0518, encontrado 311,0522; RMN ^{1}H: (d_{6}-DMSO) \delta 9,55 (1H, s), 8,52 (1H, s), 8,47 (1H, dd), 7,79 (1H, ddd), 7,72 (1H, ddd), 7,52 (1H, dd), 7,38 (1H, dddd) y 7,18 (1H, dddd).IR spectrum: 3326, 3292, 1671, 1601, 1568, 1529, 1510, 1349, 1238, 955 and 816 cm -1; EMAR: calcd for C 13 H 8 F 3 N 3 O 3 311.0518, found 311.0522; 1 H NMR: (d 6 -DMSO) δ 9.55 (1H, s), 8.52 (1H, s), 8.47 (1H, dd), 7.79 (1H, ddd), 7.72 (1H, ddd), 7.52 (1H, dd), 7.38 (1H, dddd) and 7.18 (1H, dddd).

1- (2,4,5-Trifluorophenyl) -3- (3-nitrophenyl) urea (1l)

Espectro de IR: 3396, 2361, 2342, 1725, 1560, 1523, 1341, 1276, 1194 y 742 cm^{-1}; EMAR: calcd para C_{13}H_{8}F_{3}N_{3}O_{3} 311,0518, encontrado 311,0512; RMN ^{1}H: (d_{6}-DMSO) \delta 9,51 (1H, s), 8,80 (1H, s), 8,53 (1H, dd), 8,13 (1H, ddd), 7,82 (1H, ddd), 7,70-7,56 (2H, m) y 7,54 (1H, dd).IR spectrum: 3396, 2361, 2342, 1725, 1560, 1523, 1341, 1276, 1194 and 742 cm -1; EMAR: calcd for C 13 H 8 F 3 N 3 O 3 311.0518, found 311.0512; 1 H NMR: (d 6 -DMSO) δ 9.51 (1H, s), 8.80 (1H, s), 8.53 (1H, dd), 8.13 (1H, ddd), 7.82 (1H, ddd), 7.70-7.56 (2H, m) and 7.54 (1H, dd).

1- (2,4,6-Trifluorophenyl) -3- (3-nitrophenyl) urea (1m)

Espectro de IR: 3285, 1662, 1642, 1562, 1529, 1346, 1123, 1031, 999 y 733 cm^{-1}; EMAR: calcd para C_{13}H_{8}F_{3}N_{3}O_{3} 311,0518, encontrado 311,0523; RMN ^{1}H: (d_{6}-DMSO) \delta 9,56 (1H, s), 8,50 (1H, dd), 8,25 (1H, s), 7,83 (1H, ddd), 7,75 (1H, ddd), 7,54 (1H, dd) y 7,28 (2H, dd).IR spectrum: 3285, 1662, 1642, 1562, 1529, 1346, 1123, 1031, 999 and 733 cm -1; EMAR: calcd for C 13 H 8 F 3 N 3 O 3 311.0518, found 311.0523; 1 H NMR: (d 6 -DMSO) δ 9.56 (1H, s), 8.50 (1H, dd), 8.25 (1H, s), 7.83 (1H, ddd), 7.75 (1H, ddd), 7.54 (1H, dd) and 7.28 (2H, dd).

1- (2,3,4,5-Tetrafluorophenyl) -3- (3-nitrophenyl) urea (1n)

Espectro de IR: 3401, 3369, 1714, 1636, 1557, 1523, 1472, 1352, 737 y 669 cm^{-1}; EMAR: calcd para C_{13}H_{7}F_{4}N_{3}O_{3} 329,0424, encontrado 329,0434; RMN ^{1}H: (d_{6}-DMSO) \delta 9,52 (1H, s), 8,97 (1H, s), 8,50 (1H, dd), 7,98 (1H, dddd), 7,81 (1H, ddd), 7,60 (1H, ddd) y 7,53 (1H, dd).IR spectrum: 3401, 3369, 1714, 1636, 1557, 1523, 1472, 1352, 737 and 669 cm -1; EMAR: calcd for C 13 H 7 F 4 N 3 O 3 329.0424, found 329.0434; 1 H NMR: (d 6 -DMSO) δ 9.52 (1H, s), 8.97 (1H, s), 8.50 (1H, dd), 7.98 (1H, dddd), 7.81 (1H, ddd), 7.60 (1H, ddd) and 7.53 (1H, dd).

1- (2,3,4,6-Tetrafluorophenyl) -3- (3-nitrophenyl) urea (1st)

Espectro de IR: 3288, 1666, 1644, 1568, 1529, 1497, 1349, 1068 y 733 cm^{-1}; EMAR: calcd para C_{13}H_{7}F_{4}N_{3}O_{3} 329,0424, encontrado 329,0425; RMN ^{1}H: (d_{6}-DMSO) \delta 9,62 (1H, s), 8,51 (1H, dd), 8,50 (1H, s), 7,84 (1H, ddd), 7,77 (1H, ddd), 7,69-7,55 (1H, dddd) y 7,57 (1H, dd).IR spectrum: 3288, 1666, 1644, 1568, 1529, 1497, 1349, 1068 and 733 cm -1; EMAR: calcd for C 13 H 7 F 4 N 3 O 3 329.0424, found 329.0425; 1 H NMR: (d 6 -DMSO) δ 9.62 (1H, s), 8.51 (1H, dd), 8.50 (1H, s), 7.84 (1H, ddd), 7.77 (1H, ddd), 7.69-7.55 (1H, dddd) and 7.57 (1H, dd).

1- (2,3,5,6-Tetrafluorophenyl) -3- (3-nitrophenyl) urea (1 p)

Espectro de IR: 3358, 3268, 3231, 1680, 1554, 1506, 1480, 1347, 1229 y 938 cm^{-1}; EMAR: calcd para C_{13}H_{7}F_{4}N_{3}O_{3} 329,0424, encontrado 329,0423; RMN ^{1}H: (d_{6}-DMSO) \delta 9,62 (1H, s), 8,77 (1H, s), 8,48 (1H, dd), 7,82 (1H, ddd), 7,79 (1H, dddd), 7,73 (1H, ddd) y 7,54 (1H, dd).IR spectrum: 3358, 3268, 3231, 1680, 1554, 1506, 1480, 1347, 1229 and 938 cm -1; EMAR: calcd for C 13 H 7 F 4 N 3 O 3 329.0424, found 329.0423; 1 H NMR: (d 6 -DMSO) δ 9.62 (1H, s), 8.77 (1H, s), 8.48 (1H, dd), 7.82 (1H, ddd), 7.79 (1H, dddd), 7.73 (1H, ddd) and 7.54 (1H, dd).

1- (2,3,4,5,6-Pentafluorophenyl) -3- (3-nitrophenyl) urea (1q)

Espectro de IR: 3354, 3271, 3228, 1673, 1562, 1529, 1497, 1344, 1010 y 979 cm^{-1}; EMAR: calcd para C_{13}H_{6}F_{5}N_{3}O_{3} 347,0329, encontrado 347,0344; RMN ^{1}H: (d_{6}-DMSO) \delta 9,62 (1H, s), 8,71 (1H, s), 8,47 (1H, dd), 7,82 (1H, ddd), 7,74 (1H, ddd) y 7,54 (1H, dd).IR spectrum: 3354, 3271, 3228, 1673, 1562, 1529, 1497, 1344, 1010 and 979 cm -1; EMAR: calcd for C 13 H 6 F 5 N 3 O 3 347.0329, found 347.0344; 1 H NMR: (d 6 -DMSO) δ 9.62 (1H, s), 8.71 (1H, s), 8.47 (1H, dd), 7.82 (1H, ddd), 7.74 (1H, ddd) and 7.54 (1H, dd).

1- (2-Chloropyridin-4-yl) -3- (fluorophenyl) ureas 1- (2-Chloropyridin-4-yl) -3- (2-fluorophenyl) urea (2nd)

Espectro de IR: 3397, 3250, 3050, 1729, 1595, 1534, 1453, 1309, 1206, 992 y 752 cm^{-1}; EMAR: calcd para C_{12}H_{9}ClFN_{3}O 265,0418, encontrado 265,0428; RMN ^{1}H: (d_{6}-DMSO) \delta 9,67 (1H, s), 8,81 (1H, s), 8,18 (1H, d), 8,05 (1H, ddd), 7,66 (1H, d), 7,28 (1H, dd), 7,25 (1H, ddd), 7,16 (1H, ddd) y 7,09 (1H, ddd).IR spectrum: 3397, 3250, 3050, 1729, 1595, 1534, 1453, 1309, 1206, 992 and 752 cm -1; EMAR: calcd for C 12 H 9 ClFN 3 O 265.0418, found 265.0428; NMR 1 H: (d 6 -DMSO) δ 9.67 (1H, s), 8.81 (1H, s), 8.18 (1H, d), 8.05 (1H, ddd), 7.66 (1H, d), 7.28 (1H, dd), 7.25 (1H, ddd), 7.16 (1H, ddd) and 7.09 (1H, ddd).

1- (2-Chloropyridin-4-yl) -3- (3-fluorophenyl) urea (2b)

Espectro de IR: 3386, 3274, 3088, 3050, 1734, 1625, 1601, 1584, 1564, 1498, 1479, 1445, 1275, 1198, 923 y 774 cm^{-1}; EMAR: calcd para C_{12}H_{9}ClFN_{3}O 265,0418, encontrado 265,0421; RMN ^{1}H: (d_{6}-DMSO) \delta 9,43 (1H, s), 9,22 (1H, s), 8,18 (1H, d), 7,64 (1H, d), 7,46 (1H, ddd), 7,32 (1H, ddd), 7,32 (1H, dd), 7,15 (1H, ddd) y 6,84 (1H, dddd).IR spectrum: 3386, 3274, 3088, 3050, 1734, 1625, 1601, 1584, 1564, 1498, 1479, 1445, 1275, 1198, 923 and 774 cm -1; EMAR: calcd for C 12 H 9 ClFN 3 O 265.0418, found 265.0421; 1 H NMR: (d 6 -DMSO) δ 9.43 (1H, s), 9.22 (1H, s), 8.18 (1H, d), 7.64 (1H, d), 7.46 (1H, ddd), 7.32 (1H, ddd), 7.32 (1H, dd), 7.15 (1H, ddd) and 6.84 (1H, dddd).

1- (2-Chloropyridin-4-yl) -3- (4-fluorophenyl) urea (2 C)

Espectro de IR: 3338, 3274, 3151, 3126, 3075, 1744, 1593, 1548, 1507, 1303, 1252, 1185, 992 y 831 cm^{-1}; EMAR: calcd para C_{12}H_{9}ClFN_{3}O 265,0418, encontrado 265,0411; RMN ^{1}H: (d_{6}-DMSO) \delta 9,37 (1H, s), 9,02 (1H, s), 8,16 (1H, d), 7,63 (1H, d), 7,46 (2H, dd), 7,31 (1H, dd) y 7,14 (2H, dd).IR spectrum: 3338, 3274, 3151, 3126, 3075, 1744, 1593, 1548, 1507, 1303, 1252, 1185, 992 and 831 cm -1; HRMS: calcd for C 12 H 9 ClFN 3 O 265.0418, found 265.0411; 1 H NMR: (d 6 -DMSO) δ 9.37 (1H, s), 9.02 (1H, s), 8.16 (1H, d), 7.63 (1H, d), 7.46 (2H, dd), 7.31 (1H, dd) and 7.14 (2H, dd).

1- (2-Chloropyridin-4-yl) -3- (2,3-difluorophenyl) urea (2d)

Espectro de IR: 3405, 3250, 3152, 3049, 1720, 1630, 1584, 1544, 1510, 1465, 1393, 1307, 1260, 1216, 1178 y 993 cm^{-1}; EMAR: calcd para C_{12}H_{8}ClF_{2}N_{3}O 283,0324, encontrado 283,0315; RMN ^{1}H: (d_{6}-DMSO) \delta 9,67 (1H, s), 8,96 (1H, s), 8,17 (1H, d), 7,82 (1H, dddd), 7,63 (1H, d), 7,27 (1H, dd), 7,14 (1H, dddd): y 7,07 (1H, dddd).IR spectrum: 3405, 3250, 3152, 3049, 1720, 1630, 1584, 1544, 1510, 1465, 1393, 1307, 1260, 1216, 1178 and 993 cm -1; EMAR: calcd for C 12 H 8 ClF 2 N 3 O 283.0324, found 283.0315; 1 H NMR: (d_ {6} -DMSO) δ 9.67 (1H, s), 8.96 (1H, s), 8.17 (1H, d), 7.82 (1H, dddd), 7.63 (1H, d), 7.27 (1H, dd), 7.14 (1H, dddd): and 7.07 (1H, dddd).

1- (2-Chloropyridin-4-yl) -3- (2,4-difluorophenyl) urea (2e)

Espectro de IR: 3405, 3249, 3151, 3049, 1735, 1611, 1592, 1530, 1478, 1319, 1258, 1208, 1189 y 847 cm^{-1}; EMAR: calcd para C_{12}H_{8}ClF_{2}N_{3}O 283,0324, encontrado 283,0319; RMN ^{1}H: (d_{6}-DMSO) \delta 9,60 (1H, s), 8,73 (1H, s), 8,15 (1H, d), 7,94 (1H, ddd), 7,62 (1H, d), 7,30 (1H, ddd), 7,26 (1H, dd) y 7,04 (1H, dddd).IR spectrum: 3405, 3249, 3151, 3049, 1735, 1611, 1592, 1530, 1478, 1319, 1258, 1208, 1189 and 847 cm -1; EMAR: calcd for C 12 H 8 ClF 2 N 3 O 283.0324, found 283.0319; 1 H NMR: (d 6 -DMSO) δ 9.60 (1H, s), 8.73 (1H, s), 8.15 (1H, d), 7.94 (1H, ddd), 7.62 (1H, d), 7.30 (1H, ddd), 7.26 (1H, dd) and 7.04 (1H, dddd).

1- (2-Chloropyridin-4-yl) -3- (2,5-difluorophenyl) urea (2f)

Espectro de IR: 3357, 3288, 3127, 1731, 1637, 1599, 1587, 1553, 1500, 1442, 1392, 1202, 1177, 993, 930, 796 y 736 cm^{-1}; EMAR: calcd para C_{12}H_{8}ClF_{2}N_{3}O 283,0324, encontrado 283,0324; RMN ^{1}H: (d_{6}-DMSO) \delta 9,70 (1H, s), 8,98 (1H, s), 8,17 (1H, d), 7,93 (1H, ddd), 7,63 (1H, d), 7,28 (1H, ddd), 7,25 (1H, dd) y 6,85 (1H, dddd).IR spectrum: 3357, 3288, 3127, 1731, 1637, 1599, 1587, 1553, 1500, 1442, 1392, 1202, 1177, 993, 930, 796 and 736 cm -1; EMAR: calcd for C 12 H 8 ClF 2 N 3 O 283.0324, found 283.0324; 1 H NMR: (d_ {6} -DMSO) δ 9.70 (1H, s), 8.98 (1H, s), 8.17 (1H, d), 7.93 (1H, ddd), 7.63 (1H, d), 7.28 (1H, ddd), 7.25 (1H, dd) and 6.85 (1H, dddd).

1- (2-Chloropyridin-4-yl) -3- (2,6-difluorophenyl) urea (2 g)

Espectro de IR: 3262, 3078, 1703, 1673, 1594, 1525, 1472, 1389, 1247, 1215, 1005 y 782 cm^{-1}; EMAR: calcd para C_{12}H_{8}ClF_{2}N_{3}O 283,0324, encontrado 283,0330; RMN ^{1}H: (d_{6}-DMSO) \delta 9,67 (1H, s), 8,46 (1H, s), 8,14 (1H, d), 7,59 (1H, d), 7,32 (2H, dd), 7,31 (1H, dd) y 7,14 (1H, dd).IR spectrum: 3262, 3078, 1703, 1673, 1594, 1525, 1472, 1389, 1247, 1215, 1005 and 782 cm -1; EMAR: calcd for C 12 H 8 ClF 2 N 3 O 283.0324, found 283.0330; NMR 1 H: (d 6 -DMSO) δ 9.67 (1H, s), 8.46 (1H, s), 8.14 (1H, d), 7.59 (1H, d), 7.32 (2H, dd), 7.31 (1H, dd) and 7.14 (1H, dd).

1- (2-Chloropyridin-4-yl) -3- (3,4-difluorophenyl) urea (2h)

Espectro de IR: 3419, 3250, 3149, 3049, 2985, 1728, 1617, 1582, 1541, 1509, 1475, 1394, 1269, 1204 y 991 cm^{-1}; EMAR: calcd para C_{12}H_{8}ClF_{2}N_{3}O 283,0324, encontrado 283,0325; RMN ^{1}H: (d_{6}-DMSO) \delta 9,41 (1H, s), 9,17 (1H, s), 8,15 (1H, d), 7,61 (1H, ddd), 7,60 (1H, d), 7,34 (1H, ddd), 7,29 (1H, dd) y 7,16-7,08 (1H, m).IR spectrum: 3419, 3250, 3149, 3049, 2985, 1728, 1617, 1582, 1541, 1509, 1475, 1394, 1269, 1204 and 991 cm -1; EMAR: calcd for C 12 H 8 ClF 2 N 3 O 283.0324, found 283.0325; 1 H NMR: (d_ {6} -DMSO) δ 9.41 (1H, s), 9.17 (1H, s), 8.15 (1H, d), 7.61 (1H, ddd), 7.60 (1H, d), 7.34 (1H, ddd), 7.29 (1H, dd) and 7.16-7.08 (1H, m).

1- (2-Chloropyridin-4-yl) -3- (3,5-difluorophenyl) urea (2i)

Espectro de IR: 3366, 3270, 3091, 1734, 1626, 1614, 1584, 1549, 1516, 1472, 1393, 1190, 991 y 833 cm^{-1}; EMAR: calcd para C_{12}H_{8}ClF_{2}N_{3}O 283,0324, encontrado 283,0324; RMN ^{1}H: (d_{6}-DMSO) \delta 9,51 (1H, s), 9,37 (1H, s), 8,16 (1H, d), 7,72 (2H, dd), 7,60 (1H, d), 7,31 (1H, dd) y 6,83 (1H, dddd).IR spectrum: 3366, 3270, 3091, 1734, 1626, 1614, 1584, 1549, 1516, 1472, 1393, 1190, 991 and 833 cm -1; EMAR: calcd for C 12 H 8 ClF 2 N 3 O 283.0324, found 283.0324; 1 H NMR: (d 6 -DMSO) δ 9.51 (1H, s), 9.37 (1H, s), 8.16 (1H, d), 7.72 (2H, dd), 7.60 (1H, d), 7.31 (1H, dd) and 6.83 (1H, dddd).

1- (2-Chloropyridin-4-i1) -3- (2,3,4-trifluorophenyl) urea (2j)

Espectro de IR: 3408, 3249, 3152, 3049, 2988, 1726, 1622, 1585, 1551, 1510, 1463, 1393, 1312, 1293, 1260, 1232, 1186, 1019 y 993 cm^{-1}; EMAR: calcd para C_{12}H_{7}ClF_{3}N_{3}O 301,0230, encontrado 301,0226; RMN ^{1}H: (d_{6}-DMSO) \delta 9,64 (1H, s), 8,92 (1H, s), 8,16 (1H, d), 7,73 (1H, dddd), 7,61 (1H, d), 7,27 (1H, dd) y 7,26 (1H, dddd).IR spectrum: 3408, 3249, 3152, 3049, 2988, 1726, 1622, 1585, 1551, 1510, 1463, 1393, 1312, 1293, 1260, 1232, 1186, 1019 and 993 cm -1; EMAR: calcd for C 12 H 7 ClF 3 N 3 O 301.0230, found 301.0226; 1 H NMR: (d 6 -DMSO) δ 9.64 (1H, s), 8.92 (1H, s), 8.16 (1H, d), 7.73 (1H, dddd), 7.61 (1H, d), 7.27 (1H, dd) and 7.26 (1H, dddd).

1- (2-Chloropyridin-4-yl) -3- (2,4,5-trifluorophenyl) urea (2l)

Espectro de IR: 3372, 3214, 3081, 1719, 1598, 1556, 1506, 1487, 1431, 1392, 1271, 1240, 1211, 1188, 1163, 995 y 871 cm^{-1}; EMAR: calcd para C_{12}H_{7}ClF_{3}N_{3}O 301, 0230, encontrado 301,0234; RMN ^{1}H: (d_{6}-DMSO) \delta 9,63 (1H, s), 8,93 (1H, s), 8,17 (1H, d), 8,07 (1H, ddd), 7,63 (1H, ddd), 7,62 (1H, d) y 7,26 (1H, dd).IR spectrum: 3372, 3214, 3081, 1719, 1598, 1556, 1506, 1487, 1431, 1392, 1271, 1240, 1211, 1188, 1163, 995 and 871 cm -1; EMAR: calcd for C 12 H 7 ClF 3 N 3 O 301, 0230, found 301.0234; 1 H NMR: (d_ {6} -DMSO) δ 9.63 (1H, s), 8.93 (1H, s), 8.17 (1H, d), 8.07 (1H, ddd), 7.63 (1H, ddd), 7.62 (1H, d) and 7.26 (1H, dd).

1- (2-Chloropyridin-4-yl) -3- (2,4,6-trifluorophenyl) urea (2m)

Espectro de IR: 3286, 3045, 1651, 1639, 1589, 1546, 1519, 1448, 1385, 1128, 1040, 999 y 843 cm^{-1}; EMAR: calcd para C_{12}H_{7}ClF_{3}N_{3}O 301,0230, encontrado 301,0231; RMN ^{1}H: (d_{6}-DMSO) \delta 9,71 (1H, s), 8,38 (1H, s), 8,14 (1H, d), 7,58 (1H, d), 7,31 (1H, dd) y 7,26 (2H, dd).IR spectrum: 3286, 3045, 1651, 1639, 1589, 1546, 1519, 1448, 1385, 1128, 1040, 999 and 843 cm -1; EMAR: calcd for C 12 H 7 ClF 3 N 3 O 301.0230, found 301.0231; 1 H NMR: (d 6 -DMSO) δ 9.71 (1H, s), 8.38 (1H, s), 8.14 (1H, d), 7.58 (1H, d), 7.31 (1H, dd) and 7.26 (2H, dd).

1- (2-Chloropyridin-4-yl) -3- (2,3,4,5-tetrafluorophenyl) urea (2n)

Espectro de IR: 3403, 3252, 3154, 3052, 2990, 1729, 1618, 1586, 1552, 1510, 1465, 1394, 1270, 1203, 1180, 927 y 737 cm^{-1}; EMAR: calcd para C_{12}H_{6}ClF_{4}N_{3}O 319,0136, encontrado 319,0124; RMN ^{1}H: (d_{6}-DMSO) \delta 9,66 (1H, s), 9,13 (1H, s), 8,17 (1H, d), 7,94 (1H, dddd), 7,61 (1H, d) y 7,27 (1H, dd).IR spectrum: 3403, 3252, 3154, 3052, 2990, 1729, 1618, 1586, 1552, 1510, 1465, 1394, 1270, 1203, 1180, 927 and 737 cm -1; EMAR: calcd for C 12 H 6 ClF 4 N 3 O 319.0136, found 319.0124; 1 H NMR: (d_ {6} -DMSO) δ 9.66 (1H, s), 9.13 (1H, s), 8.17 (1H, d), 7.94 (1H, dddd), 7.61 (1H, d) and 7.27 (1H, dd).

1- (2-Chloropyridin-4-yl) -3- (2,3,4,6-tetrafluorophenyl) urea (2nd)

Espectro de IR: 3334, 3171, 3048, 1666, 1646, 1582, 1533, 1497, 1387, 1214, 1082, 1070 y 761 cm^{-1}; EMAR: calcd para C_{12}H_{6}ClF_{4}N_{3}O 319,0136, encontrado 319,0126; RMN ^{1}H: (d_{6}-DMSO) \delta 9,77 (1H, s), 8,63 (1H, s), 8,15 (1H, d), 7,61 (1H, dddd), 7,58 (1H, d) y 7,32 (1H, dd).IR spectrum: 3334, 3171, 3048, 1666, 1646, 1582, 1533, 1497, 1387, 1214, 1082, 1070 and 761 cm -1; EMAR: calcd for C 12 H 6 ClF 4 N 3 O 319.0136, found 319.0126; 1 H NMR: (d 6 -DMSO) δ 9.77 (1H, s), 8.63 (1H, s), 8.15 (1H, d), 7.61 (1H, dddd), 7.58 (1H, d) and 7.32 (1H, dd).

1- (2-Chloropyridin-4-yl) -3- (2,3,5,6-tetrafluorophenyl) urea (2 P)

Espectro de IR: 3296, 3036, 1671, 1646, 1582, 1552, 1507, 1480, 1381, 1245, 1191 y 944 cm^{-1}; EMAR: calcd para C_{12}H_{6}ClF_{4}N_{3}O 319,0136, encontrado 319,0125; RMN ^{1}H: (d_{6}-DMSO) \delta 9,80 (1H, s), 8,92 (1H, s), 8,16 (1H, d), 7,80 (1H, dddd), 7,58 (1H, d) y 7,33 (1H, dd).IR spectrum: 3296, 3036, 1671, 1646, 1582, 1552, 1507, 1480, 1381, 1245, 1191 and 944 cm -1; EMAR: calcd for C 12 H 6 ClF 4 N 3 O 319.0136, found 319.0125; NMR 1 H: (d 6 -DMSO) δ 9.80 (1H, s), 8.92 (1H, s), 8.16 (1H, d), 7.80 (1H, dddd), 7.58 (1H, d) and 7.33 (1H, dd).

1- (Fluorophenyl) -3- [1,2,3] thiadiazol-5-yl-ureas 1- (2-Fluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3rd)

Espectro de IR: 3269, 3208, 3028, 1698, 1629, 1561, 1529, 1308, 1184, 755 y 731 cm^{-1}; EMAR: calcd para C_{9}H_{7}FN_{4}OS 238,0325, encontrado 238,0318; RMN ^{1}H: (d_{6}-DMSO) \delta 10,97 (1H, s), 9,16 (1H, s), 8,64 (1H, s), 7,94 (1H, ddd), 7,24 (1H, ddd), 7,15 (1H, ddd) y 7,10 (1H, ddd).IR spectrum: 3269, 3208, 3028, 1698, 1629, 1561, 1529, 1308, 1184, 755 and 731 cm -1; EMAR: calcd for C 9 H 7 FN 4 OS 238.0325, found 238.0318; NMR 1 H: (d 6 -DMSO) δ 10.97 (1H, s), 9.16 (1H, s), 8.64 (1H, s), 7.94 (1H, ddd), 7.24 (1H, ddd), 7.15 (1H, ddd) and 7.10 (1H, ddd).

1- (3-Fluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3b)

Espectro de IR: 3275, 3146, 2940, 1701, 1613, 1556, 1487, 1441, 1301, 1277, 1194, 872, 816 y 794 cm^{-1}; EMAR: calcd para C_{9}H_{7}FN_{4}OS 238,0325, encontrado 238,0331; RMN ^{1}H: (d_{6}-DMSO) \delta 10,92 (1H, s), 9,65 (1H, s), 8,61 (1H, s), 7,43 (1H, ddd), 7,32 (1H, ddd), 7,21 (1H, ddd) y 6,83 (1H, dddd).IR spectrum: 3275, 3146, 2940, 1701, 1613, 1556, 1487, 1441, 1301, 1277, 1194, 872, 816 and 794 cm -1; EMAR: calcd for C 9 H 7 FN 4 OS 238.0325, found 238.0331; 1 H NMR: (d 6 -DMSO) δ 10.92 (1H, s), 9.65 (1H, s), 8.61 (1H, s), 7.43 (1H, ddd), 7.32 (1H, ddd), 7.21 (1H, ddd) and 6.83 (1H, dddd).

1- (4-Fluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3c)

Espectro de IR: 3288, 3146, 3108, 2948, 1702, 1624, 1574, 1509, 1302, 1203, 1187, 1161, 835, 817 y 795 cm^{-1}; EMAR: calcd para C_{9}H_{7}FN_{4}OS 238,0325, encontrado 238,0326; RMN ^{1}H: (d_{6}-DMSO) \delta 10,87 (1H, s), 9,45 (1H, s), 8,59 (1H, s), 7,47 (2H, dd) y 7,13 (2H, dd).IR spectrum: 3288, 3146, 3108, 2948, 1702, 1624, 1574, 1509, 1302, 1203, 1187, 1161, 835, 817 and 795 cm -1; EMAR: calcd for C 9 H 7 FN 4 OS 238.0325, found 238.0326; 1 H NMR: (d 6 -DMSO) δ 10.87 (1H, s), 9.45 (1H, s), 8.59 (1H, s), 7.47 (2H, dd) and 7.13 (2H, dd).

1- (2,3-Difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3d)

Espectro de IR: 3278, 3221, 3040, 1708, 1634, 1577, 1542, 1479, 1314, 1264, 1191 y 975 cm^{-1}; EMAR: calcd para C_{9}H_{6}F_{2}N_{4}OS 256,0230, encontrado 256,0226; RMN ^{1}H: (d_{6}-DMSO) \delta 11,06 (1H, s), 9,39 (1H, s), 8,67 (1H, s), 7,73 (1H, dddd), 718 (1H, dddd) y 7,12 (1H, dddd).IR spectrum: 3278, 3221, 3040, 1708, 1634, 1577, 1542, 1479, 1314, 1264, 1191 and 975 cm -1; EMAR: calcd for C 9 H 6 F 2 N 4 OS 256.0230, found 256.0226; 1 H NMR: (d 6 -DMSO) δ 11.06 (1H, s), 9.39 (1H, s), 8.67 (1H, s), 7.73 (1H, dddd), 718 (1H, dddd) and 7.12 (1H, dddd).

1- (2,4-Difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3e)

Espectro de IR: 3226, 3146, 3039, 2952, 1698, 1576, 1505, 1305, 1301, 1249, 1204, 1107 y 843 cm^{-1}; EMAR: calcd para C_{9}H_{6}F_{2}N_{4}OS 256,0230, encontrado 256,0240; RMN ^{1}H: (d_{6}-DMSO) \delta 11,04 (1H, s), 9,18 (1H, s), 8,63 (1H, s), 7,84 (1H, ddd), 7,33 (1H, ddd) y 7,06 (1H, dddd).IR spectrum: 3226, 3146, 3039, 2952, 1698, 1576, 1505, 1305, 1301, 1249, 1204, 1107 and 843 cm -1; EMAR: calcd for C 9 H 6 F 2 N 4 OS 256.0230, found 256.0240; 1 H NMR: (d 6 -DMSO) δ 11.04 (1H, s), 9.18 (1H, s), 8.63 (1H, s), 7.84 (1H, ddd), 7.33 (1H, ddd) and 7.06 (1H, dddd).

1- (2,5-Difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3f)

Espectro de IR: 3262, 3210, 3022, 1701, 1641, 1579, 1545, 1500, 1320, 1246, 1194, 820 y 746 cm^{-1}; EMAR: calcd para C_{9}H_{6}F_{2}N_{4}OS 256,0230, encontrado 256,0243; RMN ^{1}H: (d_{6}-DMSO) \delta 11,04 (1H, s), 9,36 (1H, s), 8,69 (1H, s), 7,85 (1H, ddd), 7,31 (1H, ddd) y 6,92 (1H, dddd).IR spectrum: 3262, 3210, 3022, 1701, 1641, 1579, 1545, 1500, 1320, 1246, 1194, 820 and 746 cm -1; EMAR: calcd for C 9 H 6 F 2 N 4 OS 256.0230, found 256,0243; 1 H NMR: (d 6 -DMSO) δ 11.04 (1H, s), 9.36 (1H, s), 8.69 (1H, s), 7.85 (1H, ddd), 7.31 (1H, ddd) and 6.92 (1H, dddd).

1- (2,6-Difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3g)

Espectro de IR: 3255, 3174, 2993, 1698, 1561, 1470, 1313, 1245, 1190, 1002, 777 y 702 cm^{-1}; EMAR: calcd para C_{9}H_{6}F_{2}N_{4}OS 256,0230, encontrado 256,0222; RMN ^{1}H: (d_{6}-DMSO) \delta 11,27 (1H, s), 9,10 (1H, s), 8,56 (1H, s), 7,37 (1H, dddd) y 7,17 (2H, dd).IR spectrum: 3255, 3174, 2993, 1698, 1561, 1470, 1313, 1245, 1190, 1002, 777 and 702 cm -1; EMAR: calcd for C 9 H 6 F 2 N 4 OS 256.0230, found 256.0222; NMR 1 H: (d 6 -DMSO) δ 11.27 (1H, s), 9.10 (1H, s), 8.56 (1H, s), 7.37 (1H, dddd) and 7.17 (2H, dd).

1- (3,4-Difluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3h)

Espectro de IR: 3286, 3243, 3143, 3115, 2956, 1702, 1627, 1585, 1547, 1518, 1302, 1272, 1239, 1204, 1192, 854 y 818 cm^{-1}; EMAR: calcd para C_{9}H_{6}F_{2}N_{4}OS 256,0230, encontrado 256,0236; RMN ^{1}H: (d_{6}-DMSO) \delta 10,99 (1H, s), 9,66 (1H, s), 8,61 (1H, s), 7,61 (1H, ddd), 7,36 (1H, ddd) y 7,22-7,19 (1H, m).IR spectrum: 3286, 3243, 3143, 3115, 2956, 1702, 1627, 1585, 1547, 1518, 1302, 1272, 1239, 1204, 1192, 854 and 818 cm -1; EMAR: calcd for C 9 H 6 F 2 N 4 OS 256.0230, found 256.0236; 1 H NMR: (d_ {6} -DMSO) δ 10.99 (1H, s), 9.66 (1H, s), 8.61 (1H, s), 7.61 (1H, ddd), 7.36 (1H, ddd) and 7.22-7.19 (1H, m).

1- (2,3,4-Trifluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3j)

Espectro de IR: 3268, 3013, 1698, 1635, 1518, 1478, 1306, 1251, 1191, 1022, 818 y 685 cm^{-1}; EMAR: calcd para C_{9}H_{5}F_{3}N_{4}OS 274,0136, encontrado 274,0138; RMN ^{1}H: (d_{6}-DMSO) \delta 11,07 (1H, s), 9,37 (1H, s), 8,65 (1H, s), 7,64 (1H, dddd) y 7,29 (1H, dddd).IR spectrum: 3268, 3013, 1698, 1635, 1518, 1478, 1306, 1251, 1191, 1022, 818 and 685 cm -1; EMAR: calcd for C 9 H 5 F 3 N 4 OS 274.0136, found 274.0138; NMR 1 H: (d 6 -DMSO) δ 11.07 (1H, s), 9.37 (1H, s), 8.65 (1H, s), 7.64 (1H, dddd) and 7.29 (1H, dddd).

1- (2,3,6-Trifluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3k)

Espectro de IR: 3211, 3174, 2999, 1708, 1638, 1574, 1557, 1486, 1306, 1254, 1190, 1000 y 815 cm^{-1}; EMAR: calcd para C_{9}H_{5}F_{3}N_{4}OS 274,0136, encontrado 274,0127; RMN ^{1}H: (d_{6}-DMSO) \delta 11,34 (1H, s), 9,32 (1H, s), 8,58 (1H, s), 7,47 (1H, dddd) y 7,23 (1H, dddd).IR spectrum: 3211, 3174, 2999, 1708, 1638, 1574, 1557, 1486, 1306, 1254, 1190, 1000 and 815 cm -1; EMAR: calcd for C 9 H 5 F 3 N 4 OS 274.0136, found 274.0127; 1 H NMR: (d 6 -DMSO) δ 11.34 (1H, s), 9.32 (1H, s), 8.58 (1H, s), 7.47 (1H, dddd) and 7.23 (1H, dddd).

1- (2,4,5-Trifluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3l)

Espectro de IR: 3273, 3034, 2999, 1698, 1650, 1582, 1532, 1506, 1434, 1302, 1213, 1202, 1192, 782 y 737 cm^{-1}; EMAR: calcd para C_{9}H_{5}F_{3}N_{4}OS 274,0136, encontrado 274,0138; RMN ^{1}H: (d_{6}-DMSO) \delta 11,01 (1H, s), 9,34 (1H, s), 8,67 (1H, s), 7,99 (1H, ddd) y 7,66 (1H, ddd).IR spectrum: 3273, 3034, 2999, 1698, 1650, 1582, 1532, 1506, 1434, 1302, 1213, 1202, 1192, 782 and 737 cm -1; EMAR: calcd for C 9 H 5 F 3 N 4 OS 274.0136, found 274.0138; 1 H NMR: (d_ {6} -DMSO) δ 11.01 (1H, s), 9.34 (1H, s), 8.67 (1H, s), 7.99 (1H, ddd) and 7.66 (1H, ddd).

1- (2,4,6-Trifluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3m)

Espectro de IR: 3230, 3142, 3081, 3029, 2967, 1686, 1545, 1514, 1445, 1296, 1244, 1124, 1031, 1000, 866, 823 y 708 cm^{-1}; EMAR: calcd para C_{9}H_{5}F_{3}N_{4}OS 274,0136, encontrado 274,0136; RMN ^{1}H: (d_{6}-DMSO) \delta 11,30 (1H, s), 9,02 (1H, s), 8,55 (1H, s) y 7,31 (2H, dd).IR spectrum: 3230, 3142, 3081, 3029, 2967, 1686, 1545, 1514, 1445, 1296, 1244, 1124, 1031, 1000, 866, 823 and 708 cm -1; EMAR: calcd for C 9 H 5 F 3 N 4 OS 274.0136, found 274.0136; 1 H NMR: (d_ {6} -DMSO) δ 11.30 (1H, s), 9.02 (1H, s), 8.55 (1H, s) and 7.31 (2H, dd).

1- (2,3,4,5-Tetrafluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3n)

Espectro de IR: 3163, 3084, 2999, 1701, 1652, 1591, 1526, 1481, 1308, 1245, 1201, 1184, 1015, 964, 951 y 713 cm^{-1}; EMAR: calcd para C_{9}H_{4}F_{4}N_{4}OS 292,0042, encontrado 292,0033; RMN ^{1}H: (d_{6}-DMSO) \delta 11,07 (1H, s), 9,56 (1H, s), 8,68 (1H, s) y 7,86 (1H, dddd).IR spectrum: 3163, 3084, 2999, 1701, 1652, 1591, 1526, 1481, 1308, 1245, 1201, 1184, 1015, 964, 951 and 713 cm -1; EMAR: calcd for C 9 H 4 F 4 N 4 OS 292.0042, found 292.0033; 1 H NMR: (d 6 -DMSO) δ 11.07 (1H, s), 9.56 (1H, s), 8.68 (1H, s) and 7.86 (1H, dddd).

1- (2,3,5,6-Tetrafluorophenyl) -3- [1,2,3] thiadiazol-5-yl-urea (3p)

Espectro de IR: 3284, 3249, 3189, 3021, 1721, 1567, 1519, 1483, 1309, 1198, 1178 y 937 cm^{-1}; EMAR: calcd para C_{9}H_{4}F_{4}N_{4}OS 292,0042, encontrado 292,0047; RMN ^{1}H: (d_{6}-DMSO) \delta 11,40 (1H, s), 9,55 (1H, s), 8,60 (1H, s) y 7,88 (1H, dddd).IR spectrum: 3284, 3249, 3189, 3021, 1721, 1567, 1519, 1483, 1309, 1198, 1178 and 937 cm -1; EMAR: calcd for C 9 H 4 F 4 N 4 OS 292.0042, found 292.0047; 1 H NMR: (d 6 -DMSO) δ 11.40 (1H, s), 9.55 (1H, s), 8.60 (1H, s) and 7.88 (1H, dddd).

Ha sido determinada la actividad fungicida de los compuestos descritos en la presente invención frente a diferentes hongos fitopatógenos. En particular, la determinación de la actividad fungicida ha sido abordada a través de la influencia ejercida por los diferentes compuestos en el crecimiento miceliar de los siguientes hongos: Rhizoctonia solani, un hongo de suelo que afecta a raíces y cuello de numerosos cultivos hortícolas; Acremonium curcubitacearun y Monosporascus cannonballus, dos de los principales hongos de suelo implicados en el síndrome complejo denominado ``colapso'' que causa marchitez y la muerte de plantas del melón; Verticillium dahliae, el agente casual de la verticilosis en numerosos cultivos hortícolas y leñosos; Botrytis cinerea, un hongo de post-cosecha que también afecta a la parte aérea de numerosos cultivos y que resulta especialmente grave en invernaderos; Sclerotinia sclerotiorum, un hongo de suelo que causa podredumbre del cuello de numerosos cultivos hortícolas; Penicillium digitatum, hongo implicado en podredumbres post-cosecha de cítricos; Alternaria alternata pv. citri, causante de la mancha parda en cítricos; Rosellinia necatrix, que causa también podredumbre de raíces y cuello en numerosos cultivos; Fosarium oxysporum f. sp. Gladioli, el agente causal de la fusariosis del gladiolo; y Fomitiporia punctata, un hongo que contribuye a la aparición de la yesca en el cultivo de la vid.The fungicidal activity of the compounds described in the present invention against different phytopathogenic fungi has been determined. In particular, the determination of fungicidal activity has been addressed through the influence exerted by the different compounds on the mycelial growth of the following fungi: Rhizoctonia solani , a soil fungus that affects roots and neck of numerous horticultural crops; Acremonium curcubitacearun and Monosporascus cannonballus , two of the main soil fungi involved in the complex syndrome called `` collapse '' that causes wilting and the death of melon plants; Verticillium dahliae , the casual agent of verticillosis in numerous horticultural and woody crops; Botrytis cinerea , a post-harvest fungus that also affects the aerial part of numerous crops and is especially serious in greenhouses; Sclerotinia sclerotiorum , a soil fungus that causes rot of the neck of numerous horticultural crops; Penicillium digitatum , fungus involved in post-harvest citrus rot; Alternaria alternata pv. citri , cause of the brown spot in citrus; Rosellinia necatrix , which also causes root and neck rot in numerous crops; Fosarium oxysporum f. sp. Gladioli , the causative agent of gladiolus fusariosis; and Fomitiporia punctata , a fungus that contributes to the appearance of tinder in the cultivation of the vine.

Como medio base para el desarrollo miceliar se utilizó el Agar-patata-dextrosa (PDA). El PDA se esterilizó en autoclave, y a una temperatura de 45-55°C se añadió el compuesto ensayado respectivo, como una alícuota de una disolución en DMSO preparada recientemente, hasta alcanzar las concentraciones requeridas (100, 10 ó 1 ppm) en el medio de cultivo, tras lo cual se vertía en placas petri de 10 cm de diámetro. La concentración de DMSO en el medio no excedió nunca el 0,2%. Para cada urea y concentración se utilizaron cuatro placas de medio de cultivo. Como testigos se utilizaron cuatro placas de PDA sin urea en las que crecían los hongos en las mismas condiciones que en el medio con urea. Tras la siembra del hongo como un disco miceliar de 8 mm de diámetro, las placas se mantuvieron en estufa a 25-27°C. La medición del crecimiento de las colonias se realizó sobre cuatro radios perpendiculares entre sí de cada una de las cuatro placas, obteniéndose el crecimiento radial como media de las mediciones realizadas. Las mediciones se realizaron cada 24 horas, hasta alcanzar el máximo crecimiento posible en las placas testigo, valor que se tomó como referencia para la determinación del porcentaje de inhibición del crecimiento del micelio.As a basis for mycelial development is used the agar-potato-dextrose (PDA). The PDA was sterilized in autoclave, and at a temperature of The respective tested compound was added at 45-55 ° C, as an aliquot of a prepared DMSO solution recently, until reaching the required concentrations (100, 10 or 1 ppm) in the culture medium, after which it was poured into 10 cm diameter petri dishes. The concentration of DMSO in the medium never exceeded 0.2%. For each urea and concentration it They used four plates of culture medium. As witnesses they used four PDA plates without urea in which the fungi under the same conditions as in the middle with urea. Behind the planting the fungus as an 8 mm diameter mycelial disc, the plates were kept in an oven at 25-27 ° C. The Colony growth measurement was performed on four perpendicular radii of each of the four plates, obtaining the radial growth as average of the measurements made. Measurements were made every 24 hours, up to reach the maximum possible growth in the control plates, value which was taken as a reference for the determination of the percentage of mycelium growth inhibition.

En las tablas 4, 5 y 6 aparecen los resultados obtenidos en los estudios sobre crecimiento miceliar de los diferentes hongos, expresados como porcentajes respecto al testigo en cada uno de los compuestos testados. Del análisis de las tablas se desprende que muchas de las ureas ensayadas, incluyendo CPPU y TDZ, presentan in vitro actividad inhibidora de crecimiento miceliar superior al 50% frente a diversos patógenos, resultando particularmente relevante el elevado grado de control ejercido (100% de inhibición), incluso a la dosis más baja ensayada, en Monosporascus cannonballus y Acremonium curcubitacearun, por lo que pueden resultar útiles en el control de enfermedades provocadas por los mismos en cultivos hortícolas y de plantas ornamentales. Más concretamente, y dado el elevado grado de actividad mostrado por algunas de las ureas sobre estos hongos, las mismas pueden ser de gran utilidad para el control de la enfermedad del melón (Cucumis melo L.) conocida como colapso o muerte súbita y que es la responsable del desplazamiento del cultivo de melón por otros cultivos alternativos en zonas de gran tradición melonera como el Levante español.Tables 4, 5 and 6 show the results obtained in the studies on mycelial growth of the different fungi, expressed as percentages with respect to the control in each of the tested compounds. From the analysis of the tables it follows that many of the ureas tested, including CPPU and TDZ, exhibit in vitro mycelial growth inhibitory activity greater than 50% against various pathogens, the high degree of control exerted particularly relevant (100% inhibition ), even at the lowest dose tested, in Monosporascus cannonballus and Acremonium curcubitacearun , so they may be useful in the control of diseases caused by them in horticultural crops and ornamental plants. More specifically, and given the high degree of activity shown by some of the ureas on these fungi, they can be very useful for the control of the melon disease ( Cucumis melo L.) known as collapse or sudden death and that is responsible for the displacement of the melon crop by other alternative crops in areas of great melonera tradition such as the Spanish Levante.

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Es por lo tanto uno de los objetivos de la presente invención proporcionar formulados agrícolas conteniendo como principios activos, uno o más de los compuestos fluorados arriba indicados con las fórmulas (1a-1q), (2a-2q) y (3a-3q), los compuestos de referencia (I), (II) y (III), así como sus sales agrícolamente aceptables, que puedan ser utilizables en el tratamiento de infecciones producidas por los mencionados hongos en cualquier tipo de plantas, particularmente cultivos hortícolas y de plantas ornamentales.It is therefore one of the objectives of the present invention provide agricultural formulations containing as active ingredients, one or more of the fluorinated compounds above indicated with the formulas (1a-1q), (2a-2q) and (3a-3q), the compounds of reference (I), (II) and (III), as well as their agricultural salts acceptable, that can be usable in the treatment of infections caused by the mentioned fungi in any type of plants, particularly horticultural and plant crops Ornamental

Para su utilización como fungicidas en plantas, los compuestos de la presente invención pueden utilizarse por sí mismos. No obstante, los compuestos activos pueden incorporarse en formulados en forma de, por ejemplo, formulado en polvo, polvo mojable, concentrado emulsionable, preparación granular, preparación en pastillas, etc., para lo que se mezclan con soportes sólidos ordinarios, humectantes, emulsionantes, surfactantes, dispersantes, etc por métodos convencionales. Estos preparados pueden ser aplicados directamente o diluidos a una concentración deseada con un diluyente adecuado, preferiblemente agua. La concentración de la sustancia activa en los formulados puede variar de acuerdo con las circunstancias y el tipo de preparado, de tal modo que la concentración final de la sustancia activa después de la dilución se encuentre en el rango de 0,1 a 500 ppm.For use as fungicides in plants, the compounds of the present invention can be used by themselves same. However, the active compounds can be incorporated into formulated in the form of, for example, formulated powder, powder wettable, emulsifiable concentrate, granular preparation, preparation in tablets, etc., for which they are mixed with supports ordinary solids, humectants, emulsifiers, surfactants, dispersants, etc. by conventional methods. These prepared can be applied directly or diluted to a concentration desired with a suitable diluent, preferably water. The concentration of the active substance in the formulations may vary according to the circumstances and the type of preparation, of such so that the final concentration of the active substance after The dilution is in the range of 0.1 to 500 ppm.

Las composiciones fungicidas de la presente invención también pueden contener otros compuestos plaguicidamente eficaces, como insecticidas, otros fungicidas, u otros materiales biológicamente activos que se incluyan en las composiciones para incrementar la gama de especies atacadas. Otros compuestos adicionales que pueden incorporarse a las mencionadas formulaciones son fertilizantes y micronutrientes u otras preparaciones que puedan influir en el desarrollo de las plantas tratadas.The fungicidal compositions of the present invention may also contain other compounds pesticidely effective, such as insecticides, other fungicides, or other materials biologically active that are included in the compositions for increase the range of species attacked. Other compounds additional that can be incorporated into the aforementioned formulations they are fertilizers and micronutrients or other preparations that may influence the development of treated plants.

Claims

1. A method to protect plants against diseases caused by fungi characteristic of horticultural crops and ornamental plants, and which consists in applying a fungicidally effective amount of an N - (nitrophenyl) - N ' to the plant and / or crop area -phenylurea represented by the formula (1)

eleven

in which R 1, R 2, R 3, R 4 and R 5, represent hydrogen atoms or fluorine (compound I), as well as its agriculturally acceptable salts, alone or in combination with other compounds pesticide effective, fertilizers, micronutrients or other preparations that may influence the development of treated plants. For your application, the compound can be applied directly or diluted at a desired concentration with a suitable diluent or can incorporated into formulated in the form of, for example, formulated in powder, wettable powder, emulsifiable concentrate, preparation granular, tablet preparation, etc.

2. The method to protect plants against fungi as mentioned in claim 1, wherein R1 represents a fluorine atom and R2, R3, R4, and R5 represent hydrogen atoms (compound 1a).

3. The method to protect plants against fungi as mentioned in claim 1, wherein R2 represents a fluorine atom and R 1, R 3, R 4, and R 5 represent hydrogen atoms (compound 1b).

4. The method to protect plants against fungi as mentioned in claim 1, wherein R3 represents a fluorine atom and R1, R2, R4 and R5 represent hydrogen atoms (compound 1c).

5. The method to protect plants against fungi as mentioned in claim 1, wherein R1 and R 2 represent fluorine atoms and R 3, R 4 and R 5 represent hydrogen atoms (compound 1d).

6. The method to protect plants against fungi as mentioned in claim 1, wherein R1 and R 3 represents fluorine atoms and R 2, R 4 and R 5 represent hydrogen atoms (compound 1e).

7. The method to protect plants against fungi as mentioned in claim 1, wherein R1 and R 4 represents fluorine atoms and R 2, R 3 and R 5 represent hydrogen atoms (compound 1f).

8. The method to protect plants against fungi as: mentioned in claim 1, wherein R1 and R 5 represents fluorine atoms and R 2, R 3 and R 4 represent hydrogen atoms (compound 1g).

9. The method to protect plants against fungi as mentioned in claim 1, wherein R2 and R 3 represents fluorine atoms and R 1, R 4 and R 5 represent hydrogen atoms (compound 1h).

10. The method to protect plants against fungi as mentioned in claim 1, wherein R2 and R 4 represents fluorine atoms and R 1, R 3 and R 5 represent hydrogen atoms (compound 1i).

11. The method to protect plants against fungi as mentioned in claim 1, wherein R1, R 2 and R 3 represent fluorine atoms and R 4 and R 5 represent hydrogen atoms (compound 1j).

12. The method to protect plants against fungi as mentioned in claim 1, wherein R1, R 2 and R 5 represent fluorine atoms and R 3 and R 4 represent hydrogen atoms (compound 1k).

13. The method to protect plants against fungi as mentioned in claim 1, wherein R1, R 3 and R 4 represent fluorine atoms and R 2 and R 5 represent hydrogen atoms (compound 1l).

14. The method of protecting plants against fungi as mentioned in claim 1, wherein R1, R 3 and R 5 represent fluorine atoms and R 2 and R 4 represent hydrogen atoms (compound 1m).

15. The method to protect plants against fungi as mentioned in claim 1, wherein R1, R 2, R 3 and R 4 represent fluorine atoms and R 5 represents a hydrogen atom (compound 1n).

16. The method of protecting plants against fungi as mentioned in claim 1, wherein R1, R 2, R 3 and R 5 represent fluorine atoms and R 4 represents a hydrogen atom (compound 1o).

17. The method of protecting plants against fungi as mentioned in claim 1, wherein R1, R 2, R 4 and R 5 represent fluorine atoms and R 3 represents an atom of. hydrogen (compound 1p).

18. The method of protecting plants against fungi as mentioned in claim 1, wherein R1, R 2, R 3, R 4 and R 5 represent fluorine atoms (compound 1q).

19. A method to protect plants against fungal diseases characteristic of horticultural crops and ornamental plants, and which consists in applying a fungicidally effective amount of an N - (2-chloropyridine-4) to the plant and / or crop area -il) - N ' -phenylurea represented by the formula (2)

12

in which R 1, R 2, R 3, R 4 and R 5, represent hydrogen atoms or fluorine (compound II), as well as its agriculturally acceptable salts, alone or in combination with other compounds pesticide effective, fertilizers, micronutrients or other preparations that may influence the development of treated plants. For your application, the compound can be applied directly or diluted at a desired concentration with a suitable diluent or can incorporated into formulated in the form of, for example, formulated in powder, wettable powder, emulsifiable concentrate, preparation granular, tablet preparation, etc.

20. The method of protecting plants against fungi as mentioned in claim 19, wherein R1 represents a fluorine atom and R2, R3, R4, and R5 represent hydrogen atoms (compound 2a).

21. The method of protecting plants against fungi as mentioned in claim 19, wherein R2 represents a fluorine atom and R 1, R 3, R 4, and R 5 represent hydrogen atoms (compound 2b).

22. The method of protecting plants against fungi as mentioned in claim 19, wherein R3 represents a fluorine atom and R 1, R 2, R 4, and R 5 represent hydrogen atoms (compound 2c).

23. The method of protecting plants against fungi as mentioned in claim 19, wherein R1 and R 2 represent fluorine atoms and R 3, R 4 and R 5 represent hydrogen atoms (compound 2d).

24. The method of protecting plants against fungi as mentioned in claim 19, wherein R1 and R 3 represents fluorine atoms and R 2, R 4 and R 5 represent hydrogen atoms (compound 2e).

25. The method of protecting plants against fungi as mentioned in claim 19, wherein R1 and R 4 represents fluorine atoms and R 2, R 3 and R 5 represent hydrogen atoms (compound 2f).

26. The method of protecting plants against fungi as mentioned in claim 19, wherein R1 and R 5 represents fluorine atoms and R 2, R 3 and R 4 represent hydrogen atoms (compound 2g).

27. The method of protecting plants against fungi as mentioned in claim 19, wherein R2 and R 3 represents fluorine atoms and R 1, R 4 and R 5 represent hydrogen atoms (compound 2h).

28. The method of protecting plants against fungi as mentioned in claim 19, wherein R2 and R 4 represents fluorine atoms and R 1, R 3 and R 5 represent hydrogen atoms (compound 2i).

29. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 2 and R 3 represent fluorine atoms and R 4 and R 5 represent hydrogen atoms (compound 2j).

30. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 2 and R 5 represent fluorine atoms and R 3 and R 4 represent hydrogen atoms (compound 2k).

31. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 3 and R 4 represent fluorine atoms and R 2 and R 5 represent hydrogen atoms (compound 2l).

32. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 3 and R 5 represent fluorine atoms and R 2 and R 4 represent hydrogen atoms (compound 2m).

33. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 2, R 3 and R 4 represent fluorine atoms and R 5 represents a hydrogen atom (compound 2n).

34. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 2, R 3 and R 5 represent fluorine atoms and R 4 represents a hydrogen atom (compound 2o).

35. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 2, R 4 and R 5 represent fluorine atoms and R 3 represents a hydrogen atom (compound 2p).

36. The method of protecting plants against fungi as mentioned in claim 19, wherein R1, R 2, R 3, R 4 and R 5 represent fluorine atoms (compound 2q).

37. A method to protect plants against diseases caused by fungi characteristic of horticultural crops and ornamental plants, and which consists in applying to the plant and / or to the cultivation area a uniquely effective amount of an N -5- (1,2 , 3-thiadiazoyl) - N ' -phenylurea represented by the formula (3)

13

in which R 1, R 2, R 3, R 4 and R 5, represent hydrogen atoms or fluorine (compound III), as well as its agriculturally acceptable salts, alone or in combination with other compounds pesticide effective, fertilizers, micronutrients or other preparations that may influence the development of treated plants. For your application, the compound can be applied directly or diluted at a desired concentration with a suitable diluent or can incorporated into formulated in the form of, for example, formulated in powder, wettable powder, emulsifiable concentrate, preparation granular, tablet preparation, etc.

38. The method of protecting plants against fungi as mentioned in claim 37, wherein R1 represents a fluorine atom and R2, R3, R4 and R5 represent hydrogen atoms (compound 3a).

39. The method of protecting plants against fungi as mentioned in claim 37, wherein R2 represents a fluorine atom and R 1, R 3, R 4 and R 5 represent hydrogen atoms (compound 3b).

40. The method of protecting plants against fungi as mentioned in claim 37, wherein R3 represents a fluorine atom and R 1, R 2, R 4, and R 5 represent hydrogen atoms (compound 3c).

41. The method of protecting plants against fungi as mentioned in claim 37, wherein R1 and R 2 represent fluorine atoms and R 3, R 4 and R 5 represent hydrogen atoms (compound 3d).

42. The method of protecting plants against fungi as mentioned in claim 37, wherein R1 and R 3 represents fluorine atoms and R 2, R 4 and R 5 represent hydrogen atoms (compound 3e).

43. The method of protecting plants against fungi as mentioned in claim 37, wherein R1 and R 4 represents fluorine atoms and R 2, R 3 and R 5 represent hydrogen atoms (compound 3f).

44. The method of protecting plants against fungi as mentioned in claim 37, wherein R1 and R 5 represents fluorine atoms and R 2, R 3 and R 4 represent hydrogen atoms (compound 3g).

45. The method of protecting plants against fungi as mentioned in claim 37, wherein R2 and R 3 represents fluorine atoms and R 1, R 4 and R 5 represent hydrogen atoms (compound 3h).

46. The method of protecting plants against fungi as mentioned in claim 37, wherein R2 and R 4 represents fluorine atoms and R 1, R 3 and R 5 represent hydrogen atoms (compound 3i).

47. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 2 and R 3 represent fluorine atoms and R 4 and R 5 represent hydrogen atoms (compound 3j).

48. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 2 and R 5 represent fluorine atoms and R 3 and R 4 represent hydrogen atoms (compound 3k).

49. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 3 and R 4 represent fluorine atoms and R 2 and R 5 represent hydrogen atoms (compound 3l).

50. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 3 and R 5 represent fluorine atoms and R 2 and R 4 represent hydrogen atoms (compound 3m).

51. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 2, R 3 and R 4 represent fluorine atoms and R 5 represents a hydrogen atom (compound 3n).

52. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 2, R 3 and R 5 represent fluorine atoms and R 4 represents a hydrogen atom (compound 3o).

53. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 2, R 4 and R 5 represent fluorine atoms and R 3 represents a hydrogen atom (compound 3p).

54. The method of protecting plants against fungi as mentioned in claim 37, wherein R1, R 2, R 3, R 4 and R 5 represent fluorine atoms (compound 3q).