BR102019013424A2 - N-SULPHONYLINDOL DERIVATIVES IN PESTICIDED FORMULATIONS AGAINST INSECTS - Google Patents

Abstract

derivatives of n-sulfonylindole in insect pesticidal formulations are described derivatives of n-sulfonylindole, as specified in formula i, its tautomers, salts, solvates and precursor metabolites such as pesticides. formulations containing the same and methods of use as a pesticide are also described, being, therefore, useful in the control of agricultural pests providing increased production, in combating insects in food storage and in controlling insects of health importance by controlling vector-borne diseases . the compound schc-03, prototype of these derivatives, showed low toxicity in micro crustacean artemia sp. (cl50> 1000 ppm), as well as in marine danish fish (cl50> 25 ppm) indicative of low environmental toxicity.

Description

N-SULPHONYLINDOL DERIVATIVES IN PESTICIDED FORMULATIONS AGAINST INSECTS Field of invention

[001] The present invention includes methods of controlling insects through the use of derivatives of N-sulfonylindole in breeding and development sites of insects.

Background of the invention

[002] Recently two new diseases vectorized by the same vector mosquito of Dengue were introduced in the world, zika and chikungunya. Zika was discovered in 1947 by researchers in the Zika forest in Uganda (Dick, G.W., et al., Transactions of the Royal Society of Tropical Medicine and Hygiene, 1952. 46 (5): p. 509-20). At the time, there was no evidence that this virus could infect humans. However, over time it has been observed that the virus causes a febrile illness and muscle pain. Since last year, a Zika epidemic has plagued much of Brazil. Additionally, the relationship between Zika virus infection in pregnant women and newborn microcephaly has been proven.

[003] On the other hand, Chikungunya was discovered between 1952 and 1953 when an epidemic of a hitherto unknown virus spread in southern Tanzania (Mason, PJ and AJ Haddow, Transactions of the Royal Society of Tropical Medicine and Hygiene, 1957 51 (3): p. 238-40). Similarly, the chikungunya virus was introduced in Brazil in 2014. Zika, chikungunya, yellow fever and dengue are transmitted by the same vector, Aedes aegypti Linn. Tropical and humid regions provide favorable climatic conditions for this vector to thrive and spread diseases transmitted by it, and as there is no vaccine or antiviral agent to fight viruses and cure diseases vectorized by insects, the only way to control epidemics is through insect control. Although actions are taken by governmental control bodies, these diseases still have high levels of contamination (McGraw, E.A. and S.L. O'Neill, Nature reviews. Microbiology, 2013. 11 (3): p. 181-93). These three diseases are an example of a failure in control measures. Larvicides, such as the organophosphate temephos, insect growth regulators (eg pyriproxifene, novaluron and methoprene) and bacteria toxins (eg Bti) have been used in breeding sites (Vontas, J., et al., Pesticide Biochemistry and Physiology, 2012. 104 (2): p. 126-131). However, the disorderly growth of urban areas provides ideal conditions, such as hidden breeding sites, for insect growth.

[004] Larvicidal agents act in specific biochemical pathways. Organophosphates, such as temephos, act on the CNS irreversibly, inhibiting acetylcholinesterase, causing cholinergic hyperstimulation, followed by hyperexcitability, convulsion, paralysis and death (Ozmen, M., et al., Environmental Toxicology and Chemistry, 1999. 18 (2): p. 241-246). Insect growth regulators act by interfering with hormonal regulation or by inhibiting chitin synthesis (Farnesi, L.C., et al., Plos One, 2012. 7 (1)). Digestive proteases cleave the pro-toxins produced by Bti and activate its insecticidal component. The resulting toxic peptides act on the intestinal epithelium of the larvae, promoting a decrease in peristalsis and, consequently, interruption of feeding and death of the larva (Braga, IA and D. Valle, Epidemiol. Serv. Saúde., 2007. 16 ( 4): pp. 279-293). However, resistance caused by the indiscriminate use of larvicides and insecticides has spread this vector, Ae. aegypti, by more than 100 countries in the world. It is estimated that between 50 and 100 million Dengue infections occur worldwide each year (WHO, Dengue and dengue haemorrhagic fever, 2012, Fact sheet 117: Geneva).

[005] Malaria is an ancient disease originating in Africa. Plasmódium is the malaria parasite that is transmitted by the bite of Anopheles mosquitoes. Approximately 40% of the world population is susceptible to malaria, the majority being in tropical and subtropical regions of the world. More than one million deaths and 212 million cases reported in 2015 worldwide (World Health Organization, Malaria Fact Sheet, 2017)

[006] In addition to the diseases mentioned above, other diseases vectorized by insects affect both humans and animals, such as São Luís encephalitis (Diaz, LA, et al. Neuroviral Infections, 2013. p. 239-260 ), transmitted by Culex mosquitoes, LaCross encephalitis (Calisher CH, Clinical microbiology reviews, 1994. 7 (1): p. 89-116), transmitted by Aedes triseriatus, and canine heartworm (Bravo-Barriga, et al Veterinary Parasitology, 2016. 223: p. 173-180), transmitted by insects of various genera.

[007] In addition to being disease transmitters, insects represent significant losses in the production and distribution of food in the world and have grown dramatically in recent years. Similarly, resistance to commercially available insecticides and the indiscriminate use of pesticides lead to the emergence of resistance and the need to rotate the class of pesticide used, with the need for new agents to control production both in the field and in stocking pesticides. agricultural products.

[008] In response to these global threats, researchers are looking for new pesticides as a way to help control measures for insects and, consequently, for the diseases reported here. The search for new pesticides that act by different mechanisms from those mentioned here can give greater support to control programs by reducing the resistance ratios.

[009] Examples of compounds that act on different targets are found in the literature. Aryl triazines that bind to calcium channels with activity against Ae larvae. aegypti have recently been proposed (Tedford, H.W., et al., Pesticide Biochemistry and Physiology, 2013. 106 (3): p. 124-140). Natural products and their derivatives were also tested in order to find new larvicides and insecticides (Ali, A., et al., Journal of Medical Entomology, 2012. 49 (6): p. 1370-1378; Cantrell, CL, et al ., Chemistry & biodiversity, 2010. 7 (7): p. 1681-97; Wang, Z., et al., Pest Management Science, 2012. 68 (7): p. 1041-7). Several classes of organotin compounds with high insecticidal and larvicidal activity are being synthesized and evaluated against Ae. aegypti (Duong, QY, et al., Journal of Organometallic Chemistry, 2006. 691 (8): p. 1775-1779; Song, XQ, et al., Applied Organometallic Chemistry, 2007. 21 (7): p. 545 -550; Hansch, C. and RP Verma, European Journal of Medicinal Chemistry, 2009. 44 (1): p. 260-273)

[010] In order to carry out a study between the Structure and the Activity (SAR), derivatives of the indol tosylates were synthesized.
The carbon 3-substituted derivatives of the tosylated Indians proved to be inactive. However, other derivatives without substitution in this position showed potency in submicromolar concentrations. As an example, the compound SCHC-03 proved to be highly potent against Ae larvae. aegypti LC50 = 0.9 µM (0.2 ppm), larvicidal activity compared to that of malathion (1.2 ppm). Additionally, the compound SCHC-03 showed low toxicity in Artemia salina (> 1000 ppm), which represents a model of environmental toxicity.

DETAILED DESCRIPTION OF THE INVENTION

Onde,
R1 é selecionado dentre o grupo consistindo de H, NH2, NHC1-C6alquila, NH(C1- C6alquila)2, O(C1-C6alquila), S(C1-C6alquila), NHC1-C6cicloalquila, NH(C1- C6cicloalquila)2, O(C1-C6cicloalquila), S(C1-C6cicloalquila), ou R1 é arila que pode ser mono- ou poli substituída por substituintes selecionados dentre o grupo consistindo de C1-C6alquila, C1-C6cicloalquila, NO2, NH2, F, Cl, Br, I, CF3, CN, arila, ou R1 é C1- C6alquila que pode ser mono- ou poli substituída por substituintes selecionados dentre o grupo consistindo de Cl, Br, F, I, NH2, NHC1-C6alquila, NH(C1- C6alquila)2,O(C1-C6alquila), S(C1-C6alquila), ou R1 é C1-C6cicloalquila que pode ser mono- ou poli substituída por substituintes selecionados dentre o grupo consistindo de Cl, Br, F, I, ou R1 é um grupo representado por

onde a seta representa o ponto de ligação com a Fórmula I, sendo X nitrogênio e Y nitrogênio, enxofre, CH2 ou oxigênio (sendo R7 inexistente quando Y é oxigênio ou enxofre). R7 pode ser C1-C6alquila que pode ser mono- ou poli substituída por substituintes selecionados dentre o grupo consistindo de Cl, Br, F, I, ou C1- C6cicloalquila que pode ser mono- ou poli substituída por substituintes selecionados dentre o grupo consistindo de Cl, Br, F, I, ou
R1 é um grupo representado por

onde o ponto de ligação com o anel pode ser via o grupo Z ou um dos carbonos existentes e Z consiste de nitrogênio, enxofre ou oxigênio. O anel aromático pode ser mono- ou poli substituído por substituintes selecionados dentre o grupo consistindo de COOH, CH3NHCOCH3, Br, Cl, I e F; R2 é selecionado dentre o grupo consistindo de H, Cl, Br, I, F, NHC1-C6alquila, NHC1-C6cicloalquila, NHC1-C6halocicloalquila, NH(C1- C6alquila)2, NH(C1-C6cicloalquila)2, CF3, S(C1-C6alquila), S(C1-C6cicloalquila), S(C1- C6halocicloalquila), NO2, CN, OH, CHO, COOH, COO(C1-C6alquila), COO(C1- C6cicloalquila), C1-C6haloalquila, C1-C6alquenila, C1-C6alquinila, C1- C6halocicloalquila, SO2(C1-C6alquila), SO2(C1-C6haloalquila), SO2(C1-C6cicloalquila), SO2(C1-C6halocicloalquila), SO2(C1-C6alquenila), SO2(C1-C6alquinila), O(C1- C6alquila), O(C1-C6haloalquila), e O(C1-C6halocicloalquila);
R3, R4, R5 e R6 são, independentemente um dos outros, selecionados dentre o grupo consistindo de H, Cl, Br, I, F, NHC1-C6alquila, NH(C1-C6alquila)2, CF3, O(C1-C6alquila), S(C1-C6alquila), NO2, CN, OH, CHO, COOH, arila, COO(C1-C6alquila), C1-C6haloalquila, O(C1-C6haloalquila), C1-C6halocicloalquila, C1-C6alquenila, SO2(C1-C6alquila), SO2(C1- C6haloalquila), SO2(C1-C6alquenila), SO2(C1-C6alquinila) e O(C1-C6halocicloalquila).[011] Several derivatives of N-sulfonylindole have been synthesized and shown to be potent larvicides against insects. Consequently this invention includes a method of preventing diseases of humans and animals vectorized by insects, as well as agricultural pests using compounds of Formula I, their tautomers, salts, solvates and metabolite precursors.

Where,
R1 is selected from the group consisting of H, NH2, NHC1-C6alkyl, NH (C1-C6alkyl) 2, O (C1-C6alkyl), S (C1-C6alkyl), NHC1-C6cycloalkyl, NH (C1- C6cycloalkyl) 2, The (C1-C6cycloalkyl), S (C1-C6cycloalkyl), or R1 is aryl which can be mono- or poly substituted by substituents selected from the group consisting of C1-C6alkyl, C1-C6cycloalkyl, NO2, NH2, F, Cl, Br, I, CF3, CN, aryl, or R1 is C1- C6alkyl which can be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, NH2, NHC1-C6alkyl, NH (C1- C6alkyl) 2, O (C1-C6alkyl), S (C1-C6alkyl), or R1 is C1-C6cycloalkyl which can be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, or R1 is a group represented by

where the arrow represents the point of connection with Formula I, where X is nitrogen and Y is nitrogen, sulfur, CH2 or oxygen (where R7 is non-existent when Y is oxygen or sulfur). R7 can be C1-C6alkyl which can be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, or C1- C6cycloalkyl which can be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, or
R1 is a group represented by

where the point of attachment to the ring can be via the group Z or one of the existing carbons and Z consists of nitrogen, sulfur or oxygen. The aromatic ring can be mono- or poly substituted by substituents selected from the group consisting of COOH, CH3NHCOCH3, Br, Cl, I and F; R2 is selected from the group consisting of H, Cl, Br, I, F, NHC1-C6alkyl, NHC1-C6cycloalkyl, NHC1-C6halocycloalkyl, NH (C1- C6alkyl) 2, NH (C1-C6cycloalkyl) 2, CF3, S ( C1-C6alkyl), S (C1-C6cycloalkyl), S (C1- C6halocycloalkyl), NO2, CN, OH, CHO, COOH, COO (C1-C6alkyl), COO (C1- C6cycloalkyl), C1-C6haloalkyl, C1-C6 , C1-C6alkynyl, C1- C6halocycloalkyl, SO2 (C1-C6alkyl), SO2 (C1-C6 haloalkyl), SO2 (C1-C6 cycloalkyl), SO2 (C1-C6halocycloalkyl), SO2 (C1-C6alkyl) (SO2) , O (C1-C6alkyl), O (C1-C6haloalkyl), and O (C1-C6halocycloalkyl);
R3, R4, R5 and R6 are, independently of each other, selected from the group consisting of H, Cl, Br, I, F, NHC1-C6alkyl, NH (C1-C6alkyl) 2, CF3, O (C1-C6alkyl) , S (C1-C6alkyl), NO2, CN, OH, CHO, COOH, aryl, COO (C1-C6alkyl), C1-C6haloalkyl, O (C1-C6haloalkyl), C1-C6halocycloalkyl, C1-C6alkenyl, SO2 (C1- C6alkyl), SO2 (C1- C6haloalkyl), SO2 (C1-C6alkenyl), SO2 (C1-C6alkynyl) and O (C1-C6halocycloalkyl).

[012] Compounds of Formula I that have at least one basic center can form salts by adding mineral acids with, for example, strong inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, perchloric acid, or with a hydrohalogenated acid, and with strong carboxylic acids such as, for example, C1- C4alkylcarboxylic acids substituted with, for example, halogens such as trifluoroacetic acid or unsubstituted, and also with, for example, saturated or unsaturated dicarboxylic acids, such as malonic acid, succinic, maleic acid, tartaric acid or citric acid, and also with, for example, benzoic acids or sulfonic acids, such as C1-C6alkylsulfonic or sulphonyl acid substituted with, for example halogens, or unsubstituted, such as methanesulfonic acid or p-toluenesulfonic.

[013] Compounds of Formula I that have at least one acid center can form salts upon addition of bases, for example, mineral salts such as alkali metals or alkaline earth metals, such as potassium, sodium or magnesium salts or salts with ammonia or organic amines, such as morpholine, piperidine, pyrrolidine, a mono-, di- or trialkylamine, such as ethyl, diethyl, triethyl or dimethylpropylamine, or a mono-, di- or trihydroxyalkylamine, such as a mono-, di-, or triethanolamine.

[014] The terms "C1-Cnalkyl" used in the definitions of the substituents can be straight or branched chains, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert -butyl, pentyl, hexyl, and their position isomers, where the variable “n” is an integer representing the largest number of carbons in this branch.

[015] Halogens are normally fluorine, chlorine, bromine or iodine, which also applies to compounds such as haloalkyl, halocycloalkyl and hydrohalogen.

[016] Haloalkyl groups preferably have a chain length of 1 to 6 carbon atoms. Haloalkyl is, for example, chloromethyl, fluoromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, diiodomethyl, dibromomethyl, trifluoromethyl, tribromomethyl, trichloromethyl, triiodomethyl, trifluorethyl, 2-fluorethyl, 2-chloroethyl, 2,2-chloroethyl, 1,1 , 2-trichloroethyl, 2,2,3,3-tetrafluorethyl and 2,2,2-trichloroethyl.

[017] The term "tautomer" used here refers to compounds that are interconvertible by a formal migration of a hydrogen atom or proton accompanied by the relocation of a single bond and an adjacent double bond. In solutions where tautomerization is possible, a chemical balance of tautomers will be found. The exact ratio of tautomers depends on several factors, such as solvent, pH and temperature.

[018] The term solvate used here means that a compound of Formula I or a salt of a compound of Formula I has molecules of a suitable solvent incorporated into the crystal network.

[019] The terms dengue, zika, chikungunya, malaria, LaCross encephalitis, St. Louis encephalitis and canine heartworm used here refer to infectious diseases of humans and animals caused by their respective parasites.

[020] Additionally, the use of a compound of Formula I for the prevention of infectious diseases vectorized by insects consists of the addition of an adequate amount of this compound in breeding and / or development sites of said insects.

[021] The term "adequate amount" mentioned here refers to a sufficient amount of a Formula I compound to provide lethality for larvae and / or insect vectors for infectious diseases of humans and animals in breeding sites and / or development. In an example, a suitable amount of a compound of this invention ranges from 0.007 to 100 ppm (parts per million) in the liquid to be treated, or to a surface or substrate in order to provide residual effect at the treatment site. The term "parts per million" mentioned here refers to milligrams per liter of solution or substrate to be treated.

[022] An experienced worker will take into account some factors that can influence the concentration to effectively treat the breeding places of insects aiming at the complete eradication of insect larvae as well as the prevention of new larvae in these places and these factors include, among others others, to the total volume of the reservoir, room temperature, potency of the compound and method of delivery of the compound of Formula I. In another example, the compound of Formula I is applied to substrates, such as decomposing organic matter, mud, soil or slime . Other areas of application of the compound of Formula I, according to the invention, are the treatment of foods, such as, for example, fruits, grains or nuts.

[023] In the hygiene sector, the compounds of the present invention can be used against ectoparasites, such as tick larvae, fleas, flies, lice and bird lice at various stages of their life cycles, which includes eggs, larvae, nymphs and adults.

[024] Examples of such insects are: Aedes spp., Anopheles spp., Culex spp., Plutella spp., Lepisma spp., Musca spp., Atta spp., And Periplaneta spp ..

[025] The invention is also related to pesticidal compositions, such as emulsions, microemulsions, suspensions, dispersible oils, solutions, pastes, powders, granules, encapsulated in polymeric compounds that have in their composition at least one active ingredient of this invention. In these compositions the active ingredient is used in pure form, for example a solid with a specific particle size or, preferably, together with at least one of the excipients conventionally used in the art of pharmaceutical technology such as solvents, preservatives, surfactants and carriers solids.

[026] Examples of suitable solvents are: non-hydrogenated or partially hydrogenated aromatic hydrocarbons, preferably with structures between C2 and C12 of alkylbenzenes, such as mixtures of xylenes, alkylated naphthalenes or tetrahydronaphthalene, aliphatic or cycloaliphatic hydrocarbons, such as paraffins or cyclohexane, alcohols such as ethanol, propanol or butanol, glycols and their esters and ethers, such as propylene glycol, dipropylene glycol ether, ethylene glycol or ethylene glycol monomethyl ether, ketones, such as acetone and cyclohexanone, polar solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile and acetonitrile water, vegetable oils such as peanut, soy, canola, silicone and corn oils.

[027] Examples of solid carriers are: calcite, talc, kaolin, montmorillonite, atapulgite, silica gel, polymers, pumice, ceramic granules, sepiolite, betonite, sand or plant residues.

[028] Examples of suitable surfactants may be cationic, anionic, or mixtures that have good emulsification, dispersion and wetting capabilities, such as derivatives of polyglycol ethers or esters of aliphatic and cycloaliphatic alcohols, or of saturated or unsaturated fatty acids that can contain between 3 and 30 glycolic ether groups and 7 to 21 carbons in the hydrocarbon aliphatic radical (cycle) or 6 to 19 carbons in the alkyl portion of alkylphenols, quaternary ammonium salts, fatty acid salts and sulfonic acid salts.

[029] The excipients mentioned herein should be considered as examples only, a large number of excipients that are normally used in the art of formulation and suitable as this invention are available in the literature.

[030] In general, a formulation is composed of 0.1 to 99.9% of the active ingredient and 0.1 to 99.9% of at least one of the adjuvants, whether solid or liquid.
Examples of formulations are: emulsified concentrate, oil / water emulsions, microemulsion, concentrated aqueous suspension, concentrated oil suspension, granules, powders, inclusion complexes and nanocapsules.

[031] Preferred compositions have formulas as follows (% by mass)
after
Active ingredient 0.1 to 10% preferably 0.1 to 2%
Solid carrier 99.9 to 90% preferably 99.9 to 98%
b) Emulsifiable concentrates
Active ingredient 1 to 95% preferably 5 to 20%
Surfactant 1 to 30% preferably 10 to 20%
Solvent 5 to 98% preferably 70 to 85%
c) Wetting powders
Active ingredient 0.5 to 90% preferably 1 to 80%
Surfactant 0.5 to 20% preferably 1 to 15%
Solid carrier 5 to 99% preferably 15 to 98%
d) Concentrated suspensions
Active ingredient 5 to 75% preferably 10 to 50%
Water 94 to 24% preferably 88 to 30%
Surfactant 1 to 40% preferably 2 to 30%
e) Granules
Active ingredient 0.5 to 30% preferably 3 to 15%
Solid carrier 99.5 to 70% preferably 97 to 85%

Example 1. EXAMPLES OF PREPARATION OF THE COMPOUNDS OF THE INVENTION

Esquema 1. Condições das reações: (a) i. BCl3, AlCl3, CNCH2Cl, DCM, ii. HCl; (b) NaBH4, dioxano, H2O; (c) TsCl, TEBA, NaOH, DCM.[032] In accordance with other aspects of this invention, the compounds of the invention can be prepared in a manner analogous to those established in the art.
Example 1.1. Synthesis of N-tosyl 1H-indole (Ia):

Scheme 1. Reaction conditions: (a) i. BCl3, AlCl3, CNCH2Cl, DCM, ii. HCl; (b) NaBH4, dioxane, H2O; (c) TsCl, TEBA, NaOH, DCM.

[033] N-Tosyl 1H-indole (Ia) was synthesized according to Scheme 1 by reacting aniline (I) in the presence of boron chloride, aluminum trichloride, chloroacetonitrile and dichloromethane, followed by hydrolysis with hydrochloric acid under reflux to obtain 2- amino-αchloroacetophenone (II). The 2-amino-α-chloroacetophenone was cyclized in the presence of sodium borohydride in dioxane / water in order to obtain III. Then N-tosyl 1H-indole was obtained by tosylation reaction of indole previously synthesized with tosyl chloride, triethylammonium benzyl chloride, sodium hydroxide and dichloromethane.

(a) Preparation of 2-amino-α-chloroacetophenone (II)

[034] In a 500 mL round-bottom flask with a magnetic stirrer under a nitrogen atmosphere, aluminum trichloride - AlCl3 (8 g, 60 mmol) was added followed by anhydrous dichloromethane - DCM (30 mL) and boron trichloride solution
BCl3 in DCM (1 M, 60 mL, 60 mmol) in an ice bath. In a second 25 ml flask aniline (50 mmol) was added followed by DCM (10 ml), then the solution was transferred, dropwise, to the 500 ml flask, followed by addition of chloroacetonitrile - ClCH2CN (2, 43 g; 7.89 mL - 32.2 mmol). After the addition, the reaction mixture was removed from the ice bath, left under stirring for 30 minutes at room temperature and refluxed for 22 h. After this period, the reaction was removed from heating, cooled to room temperature and acidified with concentrated hydrochloric acid (HCl, 37% 60 mL), then the reaction mixture was again refluxed for 30 minutes and accompanied by CCD. At the end, the reaction mixture was cooled and the organic phase extracted with DCM (3x10 ml), water (3x10 ml), dried with anhydrous sodium sulfate - Na2SO4, filtered and evaporated to dryness. The resulting product was purified by chromatography on silica gel 60 in the 9: 1 Hexane / Acetate system to obtain 2-amino-α-chloroacetophenone. Yield: 57%. IR (KBr, cm-1): 1654. 1H NMR (CDCl3, 400 MHz): δH 7.62 (1H, dd, J1 8.16 Hz and J2 1.35 Hz, H-C6); 7.30 (1H, ddd, J1 8.45 Hz, J2 7.04 Hz and J3 1.47 Hz, H-C4); 6.66 (1H, pt, J 1.13 Hz, H-C5); 6.69 (1H, dd, J1 7.80 Hz and J2 0.99 Hz, H-C6); 6.31 (2H, s, -NH2-); 4.69 (2H, s, -CH2-). NMR13C (CDCl3,100 MHz): δ 192.4; 151.1; 135.3; 130.7; 117.6; 116.0; 115.1; 46.6. MS (ESI) m / z [M + H] +: 170, [M + Na] +: 192.

(b) Preparation of 1H-Indole (III)

[035] In a 500 mL round-bottom flask with magnetic stirring, 2-amino--chloroacetophenone (0.98 mmol), dioxane (5 mL), water (0.5 mL) and NaBH4 (0 , 90 mmol). After the addition was complete, the reaction mixture was refluxed for 24 h with stirring. After this period, the reaction was cooled to room temperature, the organic phase extracted with DCM (3x10 ml) and water (3x10 ml), dried with anhydrous sodium sulfate - Na2SO4 and evaporated to dryness. The resulting product was purified by chromatography on silica gel 60 in the 9: 1 Hexane / Acetate system to obtain 1HIndol. Yield: 64%. 1H NMR (CDCl3, 400 MHz): δ 8.10 (bs, 1H), 7.85 (d, J = 7.25 Hz, 1H), 7.45 (d, J = 7.25 Hz, 1H), 7.35 (t, J = 7.10 Hz, 1H), 7.25 (t, J = 7.15 Hz, 1H), 7.15 (bd, 1H), 6.65 (bd, 1H). NMR13C (CDCl3,100 MHz): δ 135.9, 128.0, 124.4, 122.1, 120.8, 119.9, 111.3, 102.5.

(c) Preparation of N-tosyl 1H-indole (Ia)

Esquema 2. Condições das reações: (a) cloreto de naftaleno-2-sulfonila, TEBA, NaOH, DCM.[036] In a 500 mL round-bottom flask with magnetic stirring, indole (5 g, 42.6 mmol), CH2Cl2 (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4.26 mmol) were added, NaOH (3.06 g, 76.5 mmol) and tosyl chloride (8.13 g, 42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. Wash the organic phase with 100 ml of brine, dry with sodium sulfate, filter and evaporate the solvent in a rotary evaporator, obtaining the final product (Ia).
Yield: 82%. 1H NMR (500 MHz, CDCl3) δ ppm 8.00 (d, J = 8.31 Hz, 1 H) 7.78 (d, J = 8.31 Hz, 2 H) 7.58 (d, J = 3.42 Hz, 1 H) 7.54 (d, J = 7.83 Hz, 1 H) 7.30 - 7.34 (m, 1 H) 7.20 - 7.26 (m, 3 Η) 6.67 (d, J = 3.42 Hz, 1 Η) 2.34 (s, 3 H). 13C NMR (100 MHz, CDCl3) ⍰ ppm 144.9, 135.3, 134.8, 130.7, 129.8, 126.8, 126.3, 124.5, 123.2, 121.3, 113.5, 109.0, 21.5.
Example 1.2. Synthesis of N-naphthalen-2-yl-sulfonyl-1H-indole (Ib)

Scheme 2. Reaction conditions: (a) naphthalene-2-sulfonyl chloride, TEBA, NaOH, DCM.

Esquema 3. Condições das reações: (a) cloreto de 2,4,6 trimetilbenzenosulfonila, TEBA, NaOH, DCM.[037] In a 500 mL round-bottom flask with magnetic stirring, indole (III, 5 g, 42.6 mmol), DCM (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4.26 mmol) were added ), NaOH (3.06 g, 76.5 mmol) and naphthalene-2-sulfonyl chloride (42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2.5 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. Wash the organic phase with 100 mL of brine, dry with sodium sulfate, filter and evaporate the solvent in a rotary evaporator, obtaining the final product (Ib). Yield: 84%. Federal Police. 131-133 ° C. 1H NMR (400 MHz, CDCl3) ⍰ ppm 8.55 - 8.59 (m, 1 H) 8.07 - 8.13 (m, 1 H) 7.97 (dd, J = 7.43, 1.79 Hz, 1 H) 7.81 - 7.88 (m, 2 H ) 7.76 - 7.81 (m, 1 H) 7.68 (d, J = 3.59 Hz, 1 H) 7.57 - 7.66 (m, 2 H) 7.54 (dt, J = 7.86, 0.94 Hz, 1 H) 7.34 (ddd, J = 8.37, 7.26, 1.28 Hz, 1 H) 7.21 - 7.26 (m, 1 H) 6.70 (dd, J = 3.67, 0.77 Hz, 1 H). 13C NMR (100 MHz, CDCl3) ⍰ ppm 135.2, 135.1, 134.9, 131.9, 130.8, 129.7, 129.5, 129.4, 128.6, 127.9, 127.8, 126.4, 124.7, 123.4, 121.5, 121.5, 113.5, 109.2.
Example 1.3. Synthesis of 2,4,6-trimethylbenzenesulfonyl-1H-indole (Ic)

Scheme 3. Reaction conditions: (a) 2,4,6 trimethylbenzenesulfonyl chloride, TEBA, NaOH, DCM.

Esquema 4. Condições das reações: (a) i. BCl3, AlCl3, CNCH2Cl, DCM, ii. HCl; (b) NaBH4, metanol, H2o; (c) NaOCH3, DMF; (d) Cloreto de benzenosulfonila, TEBA, NaOH, DCM.[038] In a 500 mL round-bottom flask with magnetic stirring, indole (III, 5 g, 42.6 mmol), DCM (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4.26 mmol) were added ), NaOH (3.06 g, 76.5 mmol) and 2,4,6-trimethylbenzenesulfonyl chloride (42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 3.5 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. Wash the organic phase with 100 mL of brine, dry with sodium sulfate, filter and evaporate the solvent in a rotary evaporator, obtaining the final product (Ic). Yield: 89%. Federal Police. 98-101 ° C.
1H NMR (400 MHz, CDCl3) ⍰ ppm 7.64 (d, J = 3.76 Hz, 1 H) 7.57 - 7.62 (m, 1 H) 7.34 -7.40 (m, 1 H) 7.17 - 7.25 (m, 2 H) 6.98 (s, 2 H) 6.66 (d, J = 3.59 Hz, 1 H) 2.56 (s, 6 H) 2.31 (s, 3 H). 13C NMR (100 MHz, CDCl3) ⍰ ppm 144.1, 140.3, 134.6, 133.0, 132.4, 130.2, 126.7, 124.1, 122.7, 121.4, 112.4, 106.4, 22.7, 21.1.
Example 1.4. Synthesis of 5-chloro-N-benzenesulfonyl 1H-indole (Id)

Scheme 4. Reaction conditions: (a) i. BCl3, AlCl3, CNCH2Cl, DCM, ii. HCl; (b) NaBH4, methanol, H2O; (c) NaOCH3, DMF; (d) Benzenesulfonyl chloride, TEBA, NaOH, DCM.

[039] 5-Chloro-N-benzenesulfonyl 1H-indole (Id) was synthesized according to Scheme 4 reacting p-chloroaniline (IV) in the presence of boron chloride, aluminum trichloride, chloroacetonitrile and dichloromethane, followed by hydrolysis with hydrochloric acid under reflux to obtain 2-amino-5-chloro-α-chloroacetophenone (V). 2-amino-5-chloro-αchloroacetophenone was reduced with sodium borohydride in order to obtain VI, followed by cyclization in the presence of sodium methoxide in dimethylformamide, obtaining VII. Then 5-Chloro-N-benzenesulfonyl 1H-indole (Id) was obtained by sulfonylation reaction of the indole previously synthesized with benzene sulfonyl chloride, triethylammonium benzyl chloride, sodium hydroxide and dichloromethane according to the following procedures.

(a) Preparation of 2-amino-5-chloro-α-chloroacetophenone (V)

[040] In a 500 mL round-bottom flask with a magnetic stirrer under a nitrogen atmosphere, aluminum trichloride - AlCl3 (8 g, 60 mmol) was added followed by anhydrous dichloromethane - DCM (30 mL) and boron trichloride solution BCl3 in DCM (1 M, 60 mL, 60 mmol) in an ice bath. In a second 25 ml flask p-chloroaniline (50 mmol) was added followed by DCM (10 ml), then the solution was transferred dropwise to the 500 ml flask, followed by the addition of chloroacetonitrile - ClCH2CN ( 2.43 g; 7.89 mL - 32.2 mmol). After the addition, the reaction mixture was removed from the ice bath, left under stirring for 30 minutes at room temperature and refluxed for 22 h. After this period, the reaction was removed from heating, cooled to room temperature and acidified with concentrated hydrochloric acid (HCl, 37% 60 mL), then the reaction mixture was again refluxed for 30 minutes and accompanied by CCD. At the end, the reaction mixture was cooled and the organic phase extracted with DCM (3x10 ml), water (3x10 ml), dried with anhydrous sodium sulfate - Na2SO4, filtered and evaporated to dryness. The resulting product was purified by chromatography on silica gel 60 in the 9: 1 Hexane / Acetate system to obtain 2-amino-5-chloro-a-chloroacetophenone. Yield: 57%. 1H NMR (DMSO-d6) ⍰: 7.74 (d, J = 2.4 Hz, 1H), 7.38 (s, 2H), 7.31 (dd, J = 9.0, 2.5 Hz, 1H), 6.85 (d, J = 9.0 Hz , 1H), 5.06 (s, 2H). 13C NMR (DMSO-d6) ⍰: 192.3, 150.8, 135.1, 130.4, 119.5, 117.9, 115.0, 48.0. IR (KBr): 1654 cm -1. MS (ESI) m / z [M + H] +: 204.

(b) Preparation of α-chloromethyl-2-amino-5-chlorobenzyl alcohol (VI)

[041] To a solution of 2-Amino-5-chloro-α-chloroacetophenone (1 mmol) in methanol (6 mL) containing H2O (0.5 mL) was added sodium borohydride (1 mmol) and the solution was stirred for 5 min at room temperature. An ammonium chloride solution was added to the reaction mixture followed by extraction of the product with DCM, separation of the organic layer and drying (Na2SO4). Concentration of the organic layer resulted in α-chloromethyl-2-amino-5-chlorobenzyl alcohol which was directly used in the next reaction.

(c) Preparation of 5-chlorine 1H-indole (VII)

[042] To a solution of α-chloromethyl-2-amino-5-chlorobenzyl alcohol (1 mmol) in dimethylformamide (4 mL) was added sodium hydride (50 mg, 50% in oil, 1 mmol) in an ice bath . After stirring at room temperature for 1 h under a nitrogen atmosphere, ice was added and the mixture extracted with ether. The extract was suspended in petroleum ether and purified by silica gel column chromatography using hexane: ethyl acetate (9: 1) as the eluent resulting in 5-chlorine 1Hindol. Yield: 55%.

(d) Preparation of N-benzenesulfonyl-5-chlorine 1H-indole (Ib)

Esquema 5. Condições das reações: (a) HNO3, Ac2O, -10°C; (b) cloreto de metanosulfonila, TEBA, NaOH, DCM.[043] In a 500 mL round-bottom flask with magnetic stirring, 5-chloro-1H-indole (42.6 mmol), DCM (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4.26 mmol), NaOH (3.06 g, 76.5 mmol) and benzenesulfonyl chloride (42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. The organic phase is washed with 100 ml of brine, dried with sodium sulfate, filtered and the solvent is evaporated in a rotary evaporator, obtaining the final product (Id). Yield: 85%.
Example 1.5. Synthesis of N-methanesulfonyl-5-nitro 1H-indole (Ie)

Scheme 5. Reaction conditions: (a) HNO3, Ac2O, -10 ° C; (b) methanesulfonyl chloride, TEBA, NaOH, DCM.

[044] N-methanesulfonyl-5-nitro 1H-indole was synthesized from nitration of indole using nitric acid and acetic anhydride followed by sulfonylation with methanesulfonyl chloride, triethylammonium chloride, sodium hydroxide and dichloromethane according to the procedures below .

(a) Preparation of 5-nitro 1H-indole (VIII)

[045] A mixture of 70% nitric acid (2 ml) and acetic anhydride (26.2 ml) cooled to -10 ° C was added dropwise to a mixture of 1H-indole in acetic anhydride (26, 2 mL) at -10 ° C for a period of 30 min with stirring. After stirring at -10 ° C for 2 h the reaction mixture was warmed to room temperature and added to crushed ice. The aqueous mixture was extracted with DCM, the combined organic phases were washed with water, dried (Na2SO4) and the solvent removed. The residue was purified by chromatographic column on silica gel using hexanes: AcOEt (9: 1) as eluent, obtaining 5-nitro-1H-indole. Yield: 45%.

(b) Preparation of N-methanesulfonyl-5-nitro-1H-indole (1e)

Esquema 6. Condições das reações: (a) i. BCl3, AlCl3, CNCH2Cl, DCM, ii. HCl; (b) NaBH4, dioxano, H2O; (c) 2-bromobutanol, zinco em pó, 4,4-di-t-butila-2,2-bipiridina, Nil2, MgCl2, piridina, N,N-dimetilanilina; (d) cloreto de isopropanosulfonila, TEBA, NaOH, DCM; (e) cloreto de tosila, TEBA, NaOH, DCM.[046] In a 500 mL round-bottom flask with magnetic stirring, 5-nitro-1H-indole (42.6 mmol), DCM (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4.26) were added mmol), NaOH (3.06 g, 76.5 mmol) and methanesulfonyl chloride (42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. The organic phase is washed with 100 ml of brine, dried with sodium sulfate, filtered and the solvent is evaporated in a rotary evaporator, obtaining the final product (Ie). Yield: 55%.
Example 1.6: Synthesis of 6- (sec-butyl) -1- (isopropylsulfonyl) -1H-indole (If) and 6- bromo-1-tosyl-1H-indole (1g)

Scheme 6. Reaction conditions: (a) i. BCl3, AlCl3, CNCH2Cl, DCM, ii. HCl; (b) NaBH4, dioxane, H2O; (c) 2-bromobutanol, zinc powder, 4,4-di-t-butyl-2,2-bipyridine, Nil2, MgCl2, pyridine, N, N-dimethylaniline; (d) isopropanesulfonyl chloride, TEBA, NaOH, DCM; (e) tosyl chloride, TEBA, NaOH, DCM.

[047] 6- (sec-butyl) -1- (isopropylsulfonyl) -1H-indole (If) was synthesized according to Scheme 6, reacting m-bromoaniline (IX) in the presence of boron chloride, aluminum trichloride, chloroacetonitrile and dichloromethane , followed by hydrolysis with hydrochloric acid under reflux to obtain 2-amino-4-bromo-α-chloroacetophenone (X). The 2-amino-4-bromoα-chloroacetophenone was cyclized with sodium borohydride in dioxane / water. Then a reductive coupling with 2-bromobutane resulted in 6-sec-butyl-N-tosyl-1H-indole (XII). 6- (sec-butyl) -1- (isopropylsulfonyl) -1H-indole (If) was obtained by tosylation reaction of 6-sec-butyl-N-tosyl-1H-indole previously synthesized with isopropylsulfonyl chloride, triethylammonium benzyl, sodium hydroxide in dichloromethane. The Ig compound was obtained starting from 6-bromoindole (XI) with tosyl chloride, triethylammonium benzyl chloride, sodium hydroxide in dichloromethane.

(a) Preparation of 2-amino-4-bromo-α-chloroacetophenone (X)

[048] In a 500 mL round-bottom flask with a magnetic stirrer under a nitrogen atmosphere, aluminum trichloride - AlCl3 (8 g, 60 mmol) was added followed by anhydrous dichloromethane - DCM (30 mL) and boron trichloride solution BCl3 in DCM (1 M, 60 mL, 60 mmol) in an ice bath. In a second 25 mL flask, 3-bromoaniline (50 mmol) was added, followed by DCM (10 mL), then the solution was transferred dropwise to the 500 mL flask, followed by the addition of chloroacetonitrile - ClCH2CN ( 2.43 g; 7.89 mL, 32.2 mmol). After the addition, the reaction mixture was removed from the ice bath, left under stirring for 30 minutes at room temperature and refluxed for 22 h. After this period, the reaction was removed from heating, cooled to room temperature and acidified with concentrated hydrochloric acid (HCl, 37% 60 mL), then the reaction mixture was again refluxed for 30 minutes and accompanied by CCD. At the end, the reaction mixture was cooled and the organic phase extracted with DCM (3x10 ml), water (3x10 ml), dried with anhydrous sodium sulfate - Na2SO4, filtered and evaporated to dryness. The resulting product was purified by chromatography on silica gel 60 in the 9: 1 Hexane / Acetate system to obtain 2-amino-4-bromo-α-chloroacetophenone. Yield:

(b) Preparation of 6-bromo-1H-indole (XI)

[049] In a 500 mL round-bottom flask with magnetic stirring, 2-amino-4-bromo--chloroacetophenone (0.98 mmol), dioxane (5 mL), water (0.5 mL) were added in this order and NaBH4 (0.90 mmol). After the addition was complete, the reaction mixture was refluxed for 24 h with stirring. After this period, the reaction was cooled to room temperature, the organic phase extracted with DCM (3x10 ml) and water (3x10 ml), dried with anhydrous sodium sulfate - Na2SO4 and evaporated to dryness. The resulting product was purified by chromatography on silica gel 60 in the Hexane / Acetate 9: 1 system to obtain 6-bromo-1H-Indole. Yield: 66%.

(c) Preparation of 6-sec-butyl-1H-indole (XII)

[050] To a flask equipped with a magnetic stirrer was added 2-bromobutane (0.15 mmol), followed by addition in this order of 4,4'-di-t-butyl-2,2'-bipyridine (0.015 mmol), 6-bromo-N-tosyl-1H-indole (0.15 mmol), zinc powder (0.3 mmol), NiI2 (0.015 mmol), MgCl2 (0.15 mmol), pyridine (0.15 mmol) and N, N-dimethylaniline (1 ml) in anhydrous medium. The reaction mixture was stirred for 12 h at room temperature under a nitrogen atmosphere. At the end of the reaction, the product was purified by column chromatography using ethyl acetate and hexanes (9: 1) as eluent, obtaining 6-sec-butyl-1Hindol as a white solid in 60% yield.

(d) Preparation of 6- (sec-butyl) -1- (isopropylsulfonyl) -1H-indole (If)

[051] In a 500 mL round-bottom flask with magnetic stirring, 6 sec-butyl-1H-indole (42.6 mmol), DCM (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4 , 26 mmol), NaOH (3.06 g, 76.5 mmol) and isopropylsulfonyl chloride (42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. Wash the organic phase with 100 ml of brine, dry with sodium sulfate, filter and evaporate the solvent in a rotary evaporator, obtaining the final product (If). Yield: 77%.

(e) Preparation of 6-bromo-1-tosyl-1H-indole (Ig)

Esquema 7. Condições das reações: (a) NaH, Brometo de alila, THF, 0°; (b) 6 N HCl; (c) BF3OEt2, PhCl, refluxo; (d) cloreto de metanosulfonila, TEBA, NaOH, DCM; (e) Nfluorbenzenosulfonimida, difenil diselenideo, tolueno, peneira molecular 4 Å.[052] In a 500 mL round-bottom flask with magnetic stirring, 6-bromo-1H-indole (42.6 mmol), DCM (212.5 mL), triethylammonium benzyl chloride (0.9675 g, 4.26 mmol), NaOH (3.06 g, 76.5 mmol) and tosyl chloride (42.6 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. Wash the organic phase with 100 ml of brine, dry with sodium sulfate, filter and evaporate the solvent in a rotary evaporator, obtaining the final product (Ig) as a violet oil that solidifies with time . Yield: 90%.
Example 1.7. Synthesis of 2-methyl-N-methanesulfonyl-1H-indole (Ih)

Scheme 7. Reaction conditions: (a) NaH, allyl bromide, THF, 0 °; (b) 6 N HCl; (c) BF3OEt2, PhCl, reflux; (d) methanesulfonyl chloride, TEBA, NaOH, DCM; (e) Nfluorbenzenesulfonimide, diphenyl diselenide, toluene, 4 Å molecular sieve.

[053] 2-Methyl-N-methanesulfonyl-1H-indole was synthesized by reacting Boc-aniline (XIII) with sodium hydride and allyl bromide in THF at 0 ° C in order to obtain N-Boc-N-allylaniline (XIV), which was deprotected with 6 N HCl and reacted with borodiethyl etherate trifluoride, refluxing chlorobenzene to obtain o- (prop-1-en-1-yl) -aniline (XVI). Reaction of o- (prop-1-en-1-yl) -aniline with mesyl chloride, triethylammonium benzyl chloride, sodium hydroxide and dichloromethane followed by cyclization with N-fluorbenzenesulfonimide (NFSI), diphenyl diselenide, toluene and molecular sieve 4 Å resulted in the final product Ih. Yield: 56%.

(a) Preparation of N-Boc-N-allylaniline (XVI)

[054] NaH (776 mg, 19.4 mmol) (60% dispersion in mineral oil) was added portionwise to a solution of t-butyl-phenylcarbamate (2.5 g, 12.9 mmol) in DMF (60 mL) and the resulting mixture is stirred for 1.5 h at room temperature. Allyl bromide (1.69 ml, 19.4 mmol) was added dropwise to the previous solution at 0 ° C and the mixture stirred for 20 h at room temperature. The reaction was destroyed with 50 ml of saturated NH4Cl, extracted with ether (3 X 25 ml), washed with brine (3 X 100 ml), dried with Na2SO4 and concentrated to obtain an impure product which was purified by column chromatography. of silica gel using hexane: AcOEt (95: 5) obtaining 2.85 g, 94% of N-Boc-N-allyaniline.

(b) Preparation of N-allylaniline (XV)

[055] Hydrochloric acid (6 N, 20 mL) was added to 2.85 g, 12.2 mmol of N-Boc-N-allyaniline and the resulting suspension stirred for 15 h at room temperature. At the end the reaction mixture was extracted with DCM (3 X 30 ml), the organic phase separated, dried (Na2SO4) and the solvent evaporated. The residue was purified by silica gel column chromatography using hexane: AcOEt (9: 1) to obtain N-allyaniline 1.38 g, 10.3 mmol, 85% yield.

(c) Preparation of o- (prop-1-en-1-yl) -aniline (XVI)

[056] To a 100 mL flask were added N-allylaniline (1.38 g, 10.3 mmol), chlorobenzene (20 mL) and boron trifluoride complexed with diethyl ether (15.8 mL, 51.5 mmol, 46%) under anhydrous conditions. The reaction mixture was refluxed for 24 h and quenched with sat. NaHCO3, extracted with DCM (20 ml X 3), the organic phase was separated, dried with Na2SO4 and evaporated. The residue was purified on a silica gel column chromatography using hexanes: AcOEt (8: 2) to obtain a white solid 0.84 g, 6.3 mmol, 62%.

(d) Preparation of N-methanesulfonyl- o- (prop-1-en-1-yl) -aniline (XVII)

[057] In a 100 mL round-bottom flask with magnetic stirring, o- (prop-1-en-1-yl) -aniline (4.2 mmol), DCM (21 mL), triethylammonium benzyl chloride (96, 7 mg, 0.42 mmol), NaOH (0.3 g, 7.6 mmol) and methanesulfonyl chloride (4.2 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. At the end, the reaction mixture is transferred to a separatory funnel, water (100 ml) is added and the organic phase is extracted, washing the aqueous phase with 10 ml of chloroform. The organic phase is washed with 50 ml of brine, dried with sodium sulfate, filtered and the solvent is evaporated in a rotary evaporator, yielding the product in 84% yield.

(e) Preparation of 2-methyl-N-methanesulfonyl-1H-indole (Ih)

[058] To a suspension of N-methanesulfonyl-o- (prop-1-en-1-yl) -aniline and 4 Å powder molecular sieve (20 mg) in anhydrous toluene under N2 atmosphere were added NFSI (1, 05 equivalents) and diphenyldiselenide (2.5 equivalents). The resulting mixture was stirred at 100 ° C for 16 h. The solvent was removed under reduced pressure and the residue purified by chromatographic column on silica gel using hexanes: AcOEt (9: 1) in order to obtain the final product Ih as a colorless oil and 43% yield.

[059] Other compounds can be synthesized using the above examples as a basis. Most procedures can be found in the literature and can be performed by people with adequate technical knowledge.

Example 2. BIOLOGICAL EXAMPLES Example 2.1. Evaluation of larvicidal activity against Aedes aegypti Linn (Diptera: Culicidae)

[060] The toxicity assessment is carried out by transferring the selected larvae in the third stage (20 per test, in triplicate) to disposable cups containing 20 mL of the test solution. The larvae are exposed to the solutions and monitored for 24 hours. The compounds Ia, Ib, Ic and If mentioned in the examples of this invention resulted in at least 80% mortality at 100 ppm.

Example 2.2. Evaluation of larvicidal activity against Aedes albopictus (Diptera: Culicidae)

[061] The toxicity assessment is carried out by transferring the selected larvae in the third stage to disposable cups containing 20 mL of the test solution. The larvae are exposed to the solutions and monitored for 24 hours. The compounds Ia, Ib, Ic and If mentioned in the examples of this invention resulted in at least 80% mortality at 100 ppm.

Example 2.3. Evaluation of larvicidal activity against Anopheles stephensi

[062] The toxicity assessment is carried out by transferring the selected larvae in the third stage to disposable cups containing 20 mL of the test solution. The larvae are exposed to the solutions and monitored for 24 hours. The compounds Ia, Ib, Ic and If mentioned in the examples of this invention resulted in at least 80% mortality at 100 ppm.

Example 2.4. Evaluation of larvicidal activity against Lepisma saccharina

[063] The toxicity assessment is carried out by transferring adult Lepisma saccharina to petri dishes containing a piece of square filter paper (2 X 2 cm) with varying concentrations of the compound to be evaluated. A few drops of water are added to the bottom of the plates and the plates placed in a growth oven at 26.8 ° C and 90% relative humidity.
The larvae were monitored for 24 hours. All compounds mentioned in the examples of this invention resulted in at least 80% mortality at 100 ppm.

Example 2.5. Evaluation of larvicidal activity against Plutella xylostella

[064] The toxicity assessment is carried out by transferring Plutella xylostella in a second stage to cabbage discs with 2 cm in diameter and then sprayed with solutions of increasing concentrations of test compound (1 mL). Cabbage discs are placed on filter papers moistened in Petri dishes. The plates are placed in a growth oven at 26 ± 1 ° C and 60-70% relative humidity. The larvae were monitored for 72 hours. All compounds mentioned in the examples of this invention resulted in at least 80% mortality at 100 ppm.

Example 2.6. Evaluation of larvicidal activity against Musca domestica

[065] The toxicity validation is carried out by transferring Musca domestica larva to beakers containing growth medium, after immersing them in solutions of different concentrations of the test compound. The beakers are placed in a growth oven at 26 ± 1 ° C and 60-70% relative humidity. The larvae were monitored for 72 h. All compounds mentioned in the examples of this invention resulted in at least 80% mortality at 100 ppm.

Example 2.7. Evaluation of pesticidal activity against Atta opaciceps

[066] Adult workers of the species A. opaciceps collected are exposed to the test compounds in petri dishes lined with moistened filter papers. Each insect receives 1 μL of the test compound solution in the pronotum region, applied with the aid of a microsyringe (10 μL). The plates containing the treated ants are covered with plastic wrap and placed in an incubator type B.O.D. under temperature of 25 ± 1ºC, relative humidity> 70 ± 10% and photoperiod of 12 hours (12L: 12E). Insect mortality assessments are carried out 72 hours after the assembly of the bioassays. All compounds mentioned in the examples of this invention resulted in at least 80% mortality at 100 µg / mg.

Example 2.8. Evaluation of pesticidal activity against American Periplaneta

[067] P. americana are transferred to beakers previously treated with varying amounts of the test compound. The beakers containing the insects were covered with cloth and placed at room temperature and a 12-hour photoperiod (12L: 12E). Insect mortality assessments were performed 24 hours after the assembly of the bioassays. All compounds mentioned in the examples of this invention resulted in at least 80% mortality at 100 µg / mg.

Claims (7)

“USE OF N-SULPHONYLINDOL DERIVATIVES IN PESTICIDAL FORMULATIONS AGAINST INSECTS” Characterized by the use of a compound of Formula I, its tautomers, salts, solvates and metabolic precursors in pesticidal formulations against insects of the genera Aedes, Anopheles, Culex, Plutella, Lepisma, Musca , Atta and Periplaneta

Where,
R1 is selected from the group consisting of H, NH2, NHC1-C6alkyl, NH (C1-C6alkyl) 2, O (C1-C6alkyl), S (C1-C6alkyl), NHC1-C6cycloalkyl, NH (C1- C6cycloalkyl) 2, O (C1-C6cycloalkyl), S (C1-C6cycloalkyl), or
R1 is aryl which can be mono- or poly substituted by substituents selected from the group consisting of C1-C6alkyl, C1-C6cycloalkyl, NO2, NH2, F, Cl, Br, I, CF3, CN, aryl, or
R1 is C1-C6alkyl which can be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, NH2, NHC1-C6alkyl, NH (C1- C6alkyl) 2, O (C1-C6alkyl), S (C1-C6alkyl), or
R1 is C1-C6cycloalkyl which may be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, or
R1 is a group represented by

where the arrow represents the point of connection with Formula I, where X is nitrogen and Y is nitrogen, sulfur, CH2 or oxygen (where R7 is non-existent when Y is oxygen or sulfur) R7 can be C1-C6alkyl which can be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, or C1- C6cycloalkyl which may be mono- or poly substituted by substituents selected from the group consisting of Cl, Br, F, I, or
R1 is a group represented by

where the point of attachment to the ring can be via the group Z or one of the existing carbons and Z consists of nitrogen, sulfur or oxygen The aromatic ring can be mono- or poly substituted by substituents selected from the group consisting of COOH, CH3NHCOCH3, Br, Cl, I and F;
R2 is selected from the group consisting of H, Cl, Br, I, F, NHC1-C6alkyl, NHC1-C6cycloalkyl, NHC1-C6halocycloalkyl, NH (C1-C6alkyl) 2, NH (C1- C6cycloalkyl) 2, CF3, S ( C1-C6alkyl), S (C1-C6cycloalkyl), S (C1-C6halocycloalkyl), NO2, CN, OH, CHO, COOH, COO (C1-C6alkyl), COO (C1-C6cycloalkyl), C1- C6haloalkyl, C1-C6 , C1-C6alkynyl, C1-C6halocycloalkyl, SO2 (C1-C6alkylalkyl), SO2 (C1-C6haloalkyl), SO2 (C1-C6cycloalkyl), SO2 (C1-C6halocycloalkyl), SO2 (C1-C6alkylyl) SO2 , O (C1-C6alkyl), O (C1-C6haloalkyl), and O (C1-C6halocycloalkyl);
R3, R4, R5 and R6 are, independently of each other, selected from the group consisting of H, Cl, Br, I, F, NHC1-C6alkyl, NH (C1-C6alkyl) 2, CF3, O (C1-C6alkyl) , S (C1-C6alkyl), NO2, CN, OH, CHO, COOH, aryl, COO (C1-C6alkyl), C1- C6haloalkyl, O (C1-C6haloalkyl), C1-C6halocycloalkyl, C1-C6alkenyl, SO2 (C1- C6alkyl), SO2 (C1-C6haloalkyl), SO2 (C1-C6alkenyl), SO2 (C1-C6alkynyl) and O (C1- C6halocycloalkyl). “FORMULATIONS OF N-SULPHONYLINDOL DERIVATIVES AS PESTICIDES AGAINST INSECTS” Characterized by a pesticidal composition composed of at least one compound of Formula I, according to the 1st claim or, where appropriate, a free or salt tautomer as an active ingredient and at least one formulation aid. "PEST CONTROL METHOD USING N-SULFONYLINDOL DERIVATIVES IN FORMULATIONS" Characterized by a method of controlling agricultural pests by applying a composition according to the 2nd claim in the pests or in the environment in which they are found. "METHOD FOR THE CONTROL OF DISEASES TRANSMITTED BY PESTES USING N-SULFONYLINDOL DERIVATIVES IN FORMULATIONS" Characterized by a method of controlling diseases transmitted by pests by applying a composition according to the 2nd claim in pests or in the environment in which they are found. "SEED PROTECTION METHOD AGAINST INSECT ATTACK BY THE USE OF N-SULFONYLINDOL IN FORMULATIONS" Characterized by a method of protecting seeds from pests by treating the seeds or the storage location with a composition according to the 2nd claim. "METHOD OF PROTECTING FOOD AGAINST INSECT ATTACK BY THE USE OF N-SULFONYLINDOL IN FORMULATIONS" Characterized by a method of protecting food from pest attack by treating the food or the storage location with a composition according to the 2nd claim. "PROCESS OF PREPARING N-SULPHONYLINDOL PESTICID FORMULATIONS" Characterized by a process for preparing the composition according to the 2nd claim, which consists of intimately mixing and / or crushing at least one active ingredient with at least one formulation aid.