BR102013030329B1 - quinoxaline compounds, pharmaceutical compositions containing them and use of said compositions - Google Patents

Abstract

QUINOXALIN COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USE OF THESE COMPOSITIONS. Quinoxaline compounds are described according to the formula where R1 is selected from the group consisting of Cl, Arila, or NHR, where R is selected from the group consisting of Me, Et, NBu, IBu, Cyclohexyl, Phenyl, CH2CH2OH; R2 is selected from the group consisting of Arila, NHR, SMe, SOMe, SO2Me; R3 is selected from the group consisting of H, F, Cl, Br, OMe; and R4 is selected from the group consisting of H, OMe, Cl. Pharmaceutical compositions containing compounds according to the invention, with activity for epimastigote, intracellular amastigote and trypomastigote forms of Trypanosoma cruzi and promastigote and intracellular amastigote forms of Leishmania amazonensis, are also described.

Description

FIELD OF THE INVENTION

The present invention belongs to the field of quinoxaline compounds, more specifically, quinoxaline derivatives with activity in the treatment of leishmaniasis and Chagas disease.

BACKGROUND OF THE INVENTION

Quinoxalins and their derivatives represent one of the most important classes of biologically active compounds. They are found, for example, in drugs with antiglaucoma activity (Brimonidine), help to quit smoking (Varenicline), with bactericidal property (Quinacillin) and in many natural products (Figure 1).

Leishmaniasis is still considered a disease without efficient treatment, because the compounds currently used are very toxic, causing several side effects. In this context, Guillon. J. et al. Bioorg. Med. Chem. 15, 194, 2007, reported the synthesis and evaluation of the in vitro antiparasitic activity of a series of 4-substituted pyrrolo [1,2a] quinoxalins on Leishmania amazonensis and L. infantum. Although some pyrroloquinoxalins A and B have shown excellent activities, they also showed a high profile of cytotoxicity (Figure 2).

Hui, X. et al .; Bioorg. Med. Chem.Lett. 16, 815, 2006 prepared several quinoxaline derivatives, which were tested against the promastigote forms of Leishmania donovani, trypanosoma brucei brucei trypomastigote and Trichomonas vaginalis. The compounds showed activity only against L. donovani, with compound C (Figure 2) being the most active with an IC50 of 8.2 pM.

Grande, F. et al .; Bioorg. Med. Chem. 15, 288, 2007 carried out a study of the structure-activity relationship of quinoxalinohydrazines on breast and cervical cancer cells, noting that compound D (Figure 3) had an IC50 less than 1 μM in several tumor lines.

Romeiro, N. C. et al .; Bioorg. Med. Chem. 17, 641, 2009 synthesized N-acilhydrazonaquinoxaline, designed to inhibit the cruzain enzyme. The compounds were evaluated against epimastigotes of Trypanosoma cruzi (strain Tulahuen 2). The most active compound E (Figure 3) showed an IC50 of 15.9 pM.

Recently, Chen, Q. et al., Bryant, V. C .; Lopez, H .; Kelly, D. L .; Luo, X .; Natarajan, A .; Bioorg. Med. Chem. Lett. 21, 1929, 2011 carried out a study of the structure-relationship antiproliferative activity of 6-aminoquinoxaline 2,3- disubstituted in cancer cells. Compound F was the one with the best results with IC50 in the range of 5.9 -17.3 μM in 7 types of tumor cells (Figure 4 illustrating Scheme 1).

Derivatives of quinoxaline substituted in position 2 were evaluated against mycobacteria by Seitz, L. E et al. J. Med. Chem. 45, 5604, 2002, and compound G, 4-acetoxybenzyl quinoxaline-2-carboxylate, showed good inhibition results, with MIC = 0.5 pg / mL against Micobacterium tuberculosis (Figure 5).

In the patent literature several documents are found.

Published international application W02002 / 094796A2 reports the synthesis of benzo [g] quinoxaline derivatives and their use in the treatment of infectious diseases and opportunistic infections such as diabetes, cancer and inflammation. This work presents the activity of some compounds on cancer cells, fungi and viruses.

The published Brazilian application BR0516754-0 A refers to benzoxazine and quinoxaline derivatives, as well as their use for the preparation of drugs useful in the treatment of disorders of the central nervous system and gastrointestinal tract.

Published international application WO1998 / 54158A1 deals with derivatives of quinolines and quinoxalins that inhibit platelet growth factor or inhibit tyrosine kinase activity p56lck. This international document also deals with pharmaceutical compositions comprising these compounds for the treatment of disorders involving cell differentiation and proliferation.

European publication EP 0149802 reports the synthesis of quinoxaline derivatives and their application as photoconductors.

Published international application W02009 / 027820A1 reports compositions employing quinoxaline derivatives containing piperidine as a substitute, for the treatment of pain.

Published international application W02008 / 101979A1 refers to the use of quinoxaline derivatives for the treatment of autoimmune disorders and / or anti-inflammatory, cardiovascular, neurodegenerative diseases, bacterial and viral infections, asthma, pancreatitis, organ failure, liver diseases, aggregation of platelets, cancer, lung damage and erythrocyte deficiency. This work presents some derivatives of quinoxalins that inhibit the action of phosphokinases of the PI3Ks type.

However, the crossing and analysis of these documents shows that only the publication WO 2012/096556 A1 refers to quinoxaline derivatives active in T. cruzi, and no patent document presents quinoxaline derivatives active in L. amazonensis.

Published international application WO2012 / 096556A1 refers to 1,4-dioxo derivatives of 3-trifluoromethylquinoxaline containing the ester or amide function in position 2, with selectivity in Trypanosoma cruzi. The compounds were tested only in the epimastigote form of the protozoan, this is not an infectious form of the parasite, and are derived from oxidized quinoxaline, structurally different from those present in this invention. In the present invention, the trypomastigote form was tested in addition to forms of Leishmania amazonensis.

Therefore, it would be useful if the technique had quinoxaline derivatives with activity in the treatment of infectious diseases such as leishmaniasis and Chagas disease.

SUMMARY OF THE INVENTION

Broadly speaking, the present invention comprises a series of 2,3-disubstituted quinoxaline derivatives containing sulfide, sulfoxide, sulfone, aromatics or amine groups (Figure 6).

The quinoxalins of the invention are synthesized from 3-chloro-2- (methylsulfanyl) -quinoxaline.

The synthetic route starts from the reaction of 1,1-dimethylsulfanyl-2-nitroethene with anilines substituted with different donor and electron withdrawers groups, such as fluoro and methoxy, using ethanol as a solvent and under microwave irradiation for 90 minutes to take the nitroethenes / V, S-arylaminoacetals.

Nitrocetenes A /, S-arylaminoacetals are cyclized using phosphoryl chloride (POCI3) to provide 3-chloro-2-methylsulfonyl-quinoxaline.

Then, using oxidation, nucleophilic substitution and cross-coupling reactions, the 2,3-disubstituted quinoxaline derivatives are prepared.

Another series of quinoxalins is synthesized using condensation reactions of o-phenylenediamines and a-diketones under ultrasound irradiation.

The antiparasitic activity of these quinoxalins was assessed against epimastigote, intracellular amastigote and trypomastigote forms of Trypanosoma cruzi and promastigote and intracellular amastigote forms of Leishmania amazonensis. Benzonidazole and amphotericin B were used as reference drugs against T. cruzi and L. amazonensis, respectively.

Thus, the present invention provides 2,3-disubstituted quinoxalins containing sulfide, sulfoxide, sulfone, aromatics or amine groups.

The present invention also provides quinoxaline derivatives containing the sulfoxide and sulfone functions in position 2 of the highly active quinoxaline ring and with high levels of selectivity.

The present invention provides 2,3-disubstituted quinoxalins with high activity and selectivity for epimastigote, intracellular amastigote and trypanosoma cruzi trypomastigote forms and Lemamania amazonensis promastigote and intracellular amastigote forms.

The present invention further provides 2,3-disubstituted quinoxalins useful in pharmaceutical compositions with activity in infectious diseases, mainly antiparasitic activity.

The present invention also provides pharmaceutical compositions containing a pharmaceutically effective proportion of the 2,3-disubstituted quinoxalins of the invention.

The present invention is further directed to the use of said pharmaceutical compositions to prepare a medicament to treat diseases caused by the parasites Leishmania amazonensis and Trypanosoma cruzi. BRIEF DESCRIPTION OF THE DRAWINGS The attached FIGURE 1 shows a set of formulas for Drugs and natural products derived from quinoxalins. The attached FIGURE 2 illustrates the 4- substituted Pyrrolo [1,2a] quinoxaline formulas active on L amazonensise L. infantum. The attached FIGURE 3 shows the structure of a quinoxalinehydrazone active on tumor lines. The attached FIGURE 4 shows Scheme 1 with 2,3-disubstituted 6-Aminoquinoxalines tested against tumor cell proliferation. The attached FIGURE 5 shows the 4-acetoxybenzyl Quinoxaline-2-carboxylate formula, active against M. tuberculosis. The attached FIGURE 6 shows the general formula of the quinoxalins synthesized and evaluated during the research that gave rise to the present application. The attached FIGURE 7 shows Scheme 2 illustrating the synthesis of nitroethene- / V, S-acetals (2) and 3-chloro-2-methylsulfanylquinoxaline (3). The attached FIGURE 8 shows Scheme 3 illustrating the synthesis of 3-aryl-2-methylsulfanylquinoxalins (4) and 2,3-diarylquinoxalins (5) via cross-coupling reactions. The attached FIGURE 9 shows Scheme 4 illustrating the synthesis of 2,3-diarylkinoxalins (5) by the annealing method. The attached FIGURE 10 shows Scheme 5 illustrating the synthesis of 3-chloro-2-methylsulfoxylquinoxaline (6) and 3-chloro-2-methylsulfonylquinoxaline (7). The attached FIGURE 11 shows Scheme 6 illustrating the synthesis of 3-phenyl-2-methylsulfonyl-6-methoxyquinoxaline (8a), used in substitution reactions under microwave irradiation to produce the 3-aryl-2-aminoquinoxaline (14). The attached FIGURE 12 shows Scheme 7 illustrating a sequence of two nucleophilic substitution reactions to produce 3-chloro-2-aminoquinoxaline (9) and 2,3-diaminoquinoxaline (10). The attached FIGURE 13 shows Scheme 8 where the synthesis of a series of 3-amino-2-methylsulfanylquinoxaline (11) from 3-chloroquinoxaline (3) in nucleophilic substitution reactions. The attached FIGURE 14 shows Scheme 9 where the methylsulfanyl groups of quinoxalins 11 were oxidized to sulfone and sulfoxide in quinoxalins 12 and 13.

DETAILED DESCRIPTION OF THE INVENTION

The present invention deals with 2,3-disubstituted quinoxalins with high activity and selectivity for epimastigote, intracellular amastigote and trypanosoma cruzi trypomastigote forms and Leishmania amazonensis promastigote and intracellular amastigote forms.

onde R1 é selecionado dentre o grupo consistindo de Cl, Arila, ou NHR, onde R é selecionado dentre o grupo consistindo de Me, Et, nBu, 'Bu, Ciclohexila, Fenila, CH2CH2OH; R2 é selecionado dentre o grupo consistindo de Arila, SMe, SOMe, SO2Me NHR, onde R é selecionado dentre o grupo consistindo de Me, Et, nBu, 'Bu, Ciclohexila, Fenila, CH2CH2OH; R3 é selecionado dentre o grupo consistindo de H, F, Cl, Br, OMe; e R4 é selecionado dentre o grupo consistindo de H, OMe, Cl.The quinoxaline compounds according to the invention correspond to the general formula

where R1 is selected from the group consisting of Cl, Arila, or NHR, where R is selected from the group consisting of Me, Et, nBu, 'Bu, Ciclohexila, Fenila, CH2CH2OH; R2 is selected from the group consisting of Arila, SMe, SOMe, SO2Me NHR, where R is selected from the group consisting of Me, Et, nBu, 'Bu, Ciclohexila, Fenila, CH2CH2OH; R3 is selected from the group consisting of H, F, Cl, Br, OMe; and R4 is selected from the group consisting of H, OMe, Cl.

The present invention also deals with pharmaceutical compositions containing a pharmaceutically effective proportion of the 2,3-disubstituted quinoxalins, added by conventional vehicles.

Next, the stages of the synthesis of the active and selective products according to the invention and the tests to which they were subjected in determining the activity and selectivity for the tested parasites will be detailed, always with reference to the attached Figures.

Initially, the method developed by Venkatesh, C. et al., Org. Lett., 7, 2169, 2005 was used for the synthesis of quinoxalins.

This method consists of a vinyl substitution reaction of anilines to bis-1,1-dimethylsulfanyl-2-nitroethene (1), under microwave irradiation (MW), as reported by Sangi, D. P .; Correa, A. G. J. Braz. Chem. Soc., 21, 795, 2010 leading to the formation of nitroethene- / V, S-acetals (2), which subsequently undergo a cyclization step with phosphoryl chloride, producing 3-chloro-2-methylsulfanylquinoxaline (3) (Figure 7, showing Scheme 2).

Synthesis of 1,1-dimethylsulfanyl-2-nitroethene (1) as per article by Guo, W. X. et al .; J. Braz. Chem. Soc., 20, 1674, 2009.

To a flask containing ethanol (25 ml), under magnetic stirring at room temperature, nitromethane (0.163 mol) and carbon disulfide (0.250 mol) were added. After keeping the mixture under stirring for 15 minutes, a solution of potassium hydroxide (0.350 mol) in ethanol (100mL) was added dropwise. Stirring was continued for 30 minutes at the same temperature.

The formed red precipitate was filtered, washed with ethanol (30 ml) and diethyl ether (20 ml) and solubilized in 40% aqueous methanol (200mL), without previous purification. The solution was cooled to 0 ° C and dimethyl sulfate (0.224 mol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature. The reaction was ended by adding water (200 ml), the precipitate formed was filtered, washed with water and dried under reduced pressure. Compound 1 (see Figure 6, Scheme 2) was obtained as a yellow solid in 54% yield and PF: 123 - 125 ° C.

Synthesis of nitroetenes A /, S-acetals (2) according to Sangi, D. P .; Correa, A. G. J. Braz. Chem. Soc., 21, 795, 2010.

A suspension of compound 1 (0.182mmol) in ethanol (1mL) was prepared in a tube already equipped with a magnetic bar. Then the corresponding aniline (0.182 mmol) was added and the tube which was introduced into the microwave oven was closed. The oven parameters were set to 70 watts of power, 110 ° C and continuous agitation. The irradiation was maintained for 90 minutes. After irradiation, the solvent was evaporated under reduced pressure and the product

purified by flash silica gel column chromatography, using a mixture of ethyl acetate - hexane (2: 3 v / v) as eluent. 3-Methoxy-N- [1 - (methylsulfanyl) -2-nitroetenyl] -benzenamine (2a), as

Venkatesh, C .; Singh, B .; Mahata, P. K .; Ila, H .; Junjappa, H.; Org. Lett., 7, 2169, 2005.

N-[1-(metilsulfanil)-2-nitroetenil]-benzenamina (2b), conforme Venkatesh citado acima. O rendimento foi de 85%.

4-Metoxi-N-[1 -(meilsulfanil)-2-nitroetenil]-benzenamina (2c). O rendimento foi de 99%.

N-[1 -(Metilsulfanil)-2-nitroetenil]-1,3-benzodioxol-5-amina (2d), conforme ensinado na publicação internacional WO 2000016766. O rendimento foi de 93%.

3,4,5-Trimetoxí-N-[1-(metilsulfanil)-2-nitroeteníl]-benzenamina (2e), preparado conforme ensinado na publicação francesa FR 2730733. O rendimento foi de 80%.

4-[[1-(Metilsulfanil)-2-nitroetenil]amino]-fenol (2f), preparado conforme ensinado nas publicações WO 2000016766 e FR 2730733. O rendimento foi de 89%.

3,5-Dimetoxi-N-[1 -(metilsulfanil)-2-nitroetenil]-benzenamina (2g), preparado conforme Venkatesh citado acima. O rendimento foi de 87%.

4-Bromo-N-[1 -(metilsulfanil)-2-nitroetenil]-benzenamina (2h), preparado conforme o artigo por Zou, Y.; Feng, J.; Li, J.; Ye, C.; Synth. Met., 71, 1743, 1995. O rendimento foi de 97%.

A/-[1-(metiltio)-2-nitroetenil]-cicloexanamina (2i), preparado conforme o artigo por Masereel, B.; J. Med. Chem., 41, 3239, 1998. O rendimento foi de 98%.

2,5-Dimetoxi-N-[1 -(metilsulfanil)-2-nitroethenil]-benzenamina (2j), preparado conforme Venkatesh citado acima. O rendimento foi de 51%.

4-Fluoro-N-[1 -(metilsulfanil)-2-nitroetenil]-benzenamina (2k) preparado conforme o artigo por Kearney, T.; Joule, J. A.; Jackson, A.; Heterocycles, 33, 757, 1992. 5 O rendimento foi de 98%.

5-((1 -(metilsulfanil)-2-nitroetenil)amino)pentan-1 -ol (2I) O rendimento foi de 93%.

10 4-((1-(metilsulfanil)-2-nitroetenil)arnino)butan-1-ol (2m), preparado conforme a publicaçã W02000/016766A1. O rendimento foi de 77%.

N1,N1-dimethyl-N4-(1-(metilsulfanil)-2-nitroetenil)benzeno-1,4-diamino (2n) 15 O rendimento foi de 94%.

2-fluoro-N-(1-(metilsulfanil)-2-nitroetenil)anilina (2o), preparado conforme o artigo Kearney, T.; Joule, J. A.; Jackson, A.; Heterocycles, 33, 757, 1992. O rendimento foi de 65%.

4-cloro-N-(1-(metilsulfanil)-2-nitroetenil)aniline (2p), preparado conforme Venkatesh citado acima. O rendimento foi de 55%.

Procedimento geral de síntese de 3-cloro-2-metilsulfanilquinoxalinas (3). Preparou-se uma suspensão com o nitroeteno A/,S-acetal 2 (0,208 mmol) e acetonitrila (1 ml_). A mistura foi resfriada a 0°C e em seguida adicionou-se POCI3 (0,625 mmol), gota a gota, por 15 minutos. A mistura foi aquecida até 80 °C e mantida sob agitação por 4 horas. A mistura foi resfriada e neutralizada com solução saturada de bicarbonato de sódio (2,5 ml_). Em seguida realizou-se uma extração com clorofórmio (3x2 ml_).A fase orgânica foi lavada com água (2x2 mL) e solução saturada de NaCI (2 mL) e seca com sulfato de sódio anidro. O solvente foi destilado a pressão reduzida, obtendo-se o produto impuro. A purificação foi realizada por cromatografia em coluna de sílica gel flash, utilizando hexano: acetato de etila (9:1) como eluente. 3-Cloro-7-metoxi-2-metilsulfanilquinoxalina (3a) preparado conforme Venkatesh citado acima. Os dados analíticos do composto 3a são como segue. O rendimento foi de 54%, PF : 109-111 °C.

3-Cloro-2-metilsulfanilquinoxalina (3b) preparado conforme Venkatesh citado acima. O rendimento foi de 36%.

3-Cloro-6-metoxi-2-metilsulfanilquinoxalina (3c) preparado conforme Venkatesh citado acima. O rendimento de 31%.

6-Bromo-3-cloro-2-metilsulfanilquinoxalina (3d) O rendimento foi de 30%.

3,6-Dicloro-2-metilsulfanilquinoxalina (3e) preparado conforme Venkatesh citado acima. O rendimento foi de 32%.

As quinoxalinas 3 foram utilizadas em uma série de duas reações de acoplamento cruzado mediadas por metais de transição, primeiramente produzindo as 3-aril-2-metilsulfanilquinoxalinas (4a e 4b) e posteriormente as 2,3-diarilquinoxalinas (5a e 5b) (Figura 8, Esquema 3), conforme descrito por Venkatesh, C. e col. Org. Lett., 7, 2169, 2005. Procedimento geral para a síntese de 3-aril-2-metilsulfanilquinoxalinas (4a e 4b). A um balão de fundo redondo equipado com uma barra magnética, adicionou-se a quínoxalina (3a) (1mmol), tris-(acetilacetonato)ferro(lll) (0,10 mmol) e THF anidro (5 ml_), deixando-se sob agitação a -30 °C em atmosfera de nitrogênio. Uma solução de brometo de fenilmagnésio (2,2 mmol) foi adicionada à mistura reacional, e a agitação foi mantida por mais 10 minutos. Adicionou-se solução saturada de NaCI (5 ml_) e extraiu-se a matéria orgânica com diclorometano (3x5 mL). A fase orgânica foi lavada com água (10 ml_) e solução saturada de NaCI (2x10 mL) e seca com sulfato de sódio anidro. O produto bruto foi obtido pela evaporação do solvente a pressão reduzida. As 3-fenilquinoxalinas foram purificadas em coluna cromatográfica utilizando mistura de hexano - acetato de etila (9:1) como eluente. 3-Fenil-7-metoxi-2-metilsulfanilquinoxalina (4a), preparado conforme Venkatesh citado acima. O rendimento de foi de 31%.

3-Fenil-2-metilsulfanilquinoxalina (4b), preparada conforme ensinado na publicação alemã DD144054. O rendimento foi de 36%.

Síntese de quinoxalinas 2,3-diarilsubstituídas Procedimento para reação de acoplamento cruzado usando catalisador de Níquel: síntese dos compostos (5a) e (5b). A um balão de duas vias, equipado com uma barra magnética, adicionou-se dicloro-bis-(trifenilfosfino)níquel(ll) (0,027 mmol) e benzeno anidro (3 mL), de forma a obter uma suspensão que foi mantida em atmosfera de argônio, sob agitação e em refluxo. Adicionou-se à suspensão brometo de benzil / aril magnésio (0,018 mmol) e manteve-se em refluxo por 15 min para promover a redução do catalisador. Em seguida adicionou-se novamente brometo de benzil / aril (0,16 mmol) e uma solução de 3-fenil-7-metoxi-2-metilsulfanilquinoxalina (4a) (0,089 mmol) em benzeno anidro (2mL), mantendo-se a mistura reacional sob refluxo por mais 12 horas. A reação foi finalizada pela adição de solução saturada de cloreto de amónio (5 mL), em seguida extraiu-se com diclorometano (3 x 50 mL), secou-se a fase orgânica com sulfato de sódio anidro e evaporou-se o solvente a pressão reduzida. O produto da reação foi purificado por coluna cromatográfica utilizando mistura de hexano e acetato de etila (19:1) como eluente. 2,3-difenil-7-metoxiquinoxalina (5a), preparada conforme o artigo por Zhou, J. F.;Gong, G. X.; Zhi, S. J.; Duan, X. L; Synth. Comm. 39, 3743, 2009.

O rendimento foi de 69%. 3-fenil-7-metoxi-2-(4-metoxifenil)quinoxalina (5b), preparada conforme o artigo de Venkatesh citado acima.

Rendimento de 31%. As 2,3-diarilquinoxalinas 5c-k foram sintetizadas empregando a anelaçâo de a-dicetonas e o-fenilenediaminas sob ultrassom (Esquema 4, Figura 9), conforme artigo por Guo, W. X. et al.; J. Braz. Chem. Soc., 20, 1674, 2009. Procedimento para reações de condensação de o-fenilenodiaminas e ct- dicetonas. Adicionou-se 1,2-fenilenediamina (1mmol) a uma solução formada por uma 1,2-dicetona (1 mmol) e uma mistura de etanol/ácido acético (4 mL / 0,4mL). A solução resultante foi irradiada com ultrassom por 1 hora. Evaporou- se o solvente e purificou-se o produto por cromatografia em coluna usando diclorometano como solvente. 2,3-difenilquinoxalina (5c), preparada conforme procedimento relatado por Zhou citado acima.

Rendimento de 82% 2-(metilfenil)-3-fenilquinoxalina (5d) preparada conforme procedimento relatado por Zhou citado acima.

Rendimento de 86% 6-cloro-2-(metilfenil)-3-fenilquinoxalina e 7-cloro-2-(metilfenil)-3- 10 fenilquinoxalina (5e)

Rendimento de 87% RMN 1H (400 MHz, CDCI3) δ : 8,15 (d, J= 2,32 Hz, 1H); 8,09 (d, J- 8,98 Hz, 1H); 7,71 - 7,67 (m, 1H); 7,54 - 7,49 (m, 2H); 7,42 - 7,32 (m, 5H); 7,14 (d, J= 8,26 15 Hz, 2H); 2,36 (s, 3H). IV (vmax KBr): 3043, 2918, 1597, 1466, 1340, 1066 cm'1. EM (m/z) : 330 (M+, 100), 329 (65), 315(40) , 165 (34), 75 (30). Anal. Elem. Calc, para C21H15N2CI : C 76,24%, H 4,57%, N 8,47%; Encontrado : C 76,49%, H 4,61%, N 8,47%. 20 2-(4-metoxifenil)-3-fenilquinoxalina (5f), conforme procedimento relatado por Islami, M. R.; Hassani, Z.; Arkivoc XV, 280, 2008.

Rendimento de 98% 6-cloro-2-(metoxifenil)-3-fenilquinoxalina e 7-cloro-2-(metoxifenil)-3- fenilquinoxalina (5g)

Rendimento de 98% RMN1H (400 MHz, CDCI3) δ : 8,16 - 8,13 (m, 1H); 8,07 (d, J= 8,90 Hz, 2H); 7,69 - 7,66 (m, 1H); 7,54 - 7,51 (m, 2H); 7,48 - 7,45 (m, 2H); 7,39 - 7,33 (m, 3H); 6,85 (d, J= 8,90 Hz, 2H); 3,82 (s, 3H). IV (vmax diclorometano): 3061,2933, 1608, 1514, 1466, 1342, 1252, 1175 cm'1. EM (m/z) : 346 (M+ , 100), 345 (49), 331 (34), 178 (25), 75 (26). Anal. Elem. Calc. paraC2iHisN2OCI : C 72,73%, H 4,36%, N 8,08%; Encontrado : C 72,75%, H 4,61 %, N 7,72%. 6-cloro-2,3-difenilquinoxalina (5h), conforme procedimento relatado por Castellanos, J. J. M.; Hernandez, K. R.; Flores, N. S. G.; Suarez, O. O. R.; Cruz, J. P.; Molecules, 17, 5164, 2012

Rendimento de 95% 6,7-dicloro-2,3-difenilquinoxalina (5i) conforme procedimento relatado por Shaabani, A.; Rezayan, A. H.; Behnam, M.; Heidary, M.; C. R. Chimie, 12, 1249, 2009.

Rendimento de 87% 6,7-dicloro-2-(4-metilfenil)-3-fenilquinoxalina (5j)

Rendimento de 96% RMN 1H (400 MHz, CDCI3) δ : 8,23 (s, 2H); 7,52 - 7,48 (m, 2H); 7,41 - 7,32 (m, 5H); 7,14 - 7,10 (m, 2H); 2,35 (s, 3H). RMN 13C (100 MHz, CDCI3) δ : 154,49; 140,02; 139,82; 139,48; 138,65; 135,53; 134,28; 134,15; 130,06; 129,93; 129,81; 129,24; 129,09; 128,37; 21,40. IV (vmax diclorometano): 3055, 2920, 1609, 1450, 1439, 1337, 1107, 879 cm’1. EM (m/z) : 364 (M+, 100), 363 (60), 349 (43), 177 (25), 109 (26). Anal. Elem. Cale. paraCs-iHu^Cfe : C 69,06%, H 3,86%, N 7,67%; Encontrado : C 69,28%, H 3,97%, N 7,16%. 2,3-di-(4-met°xifenil)-quinoxalina (5k), preparado conforme procedimento descrito em artigo por Islami et al., citado acima.

Rendimento de 94% Procedimento para a síntese das 2,3-diarilquinoxalinas (5fa) e (5fb) Em uma solução de (5f) (1,5 mmol) em diclorometano (20 mL) sob atmosfera de argônio, adicionou-se uma solução 1M de BBr3 em diclorometano (6 mmol, 6 mL), a 0 °C por 10 minutos. Elevou-se a temperatura até a ambiente e deixou-se sob agitação por 20 horas. Finalizou-se a reação pela adição de uma solução saturada de bicarbonato de sódio (100 mL), extraiu-se com diclorometano (3 x 50 mL), secou-se com sulfato de sódio anidro e evaporou-se o solvente. Preparou-se uma suspensão contendo o produto bruto da reação anterior (1,75 g), DMF (15 mL), o cloreto de alquila apropriado (1,65 mmol), carbonato de césio (3,3 mmol) e iodeto de potássio (0,075 mmol) e deixou-se sob agitação por 20 horas a 70 °C. Evaporou-se o solvente a pressão reduzida, adicionou-se água (25 mL) e extraiu-se com diclorometano (3 x 50 mL). Secou-se com sulfato de sódio anidro e evaporou-se o solvente sob pressão reduzida. O produto foi purificado por cromatografia em coluna usando diclorometano/metanol (8:2) como eluente. 2-[4-(2-piperidina)etoxifenil]-3-fenilquinoxalina (5fa)

Rendimento de 82%. RMN 1H (400 MHz, CDCI3) δ: 8,16 - 8,13 (m, 2H); 7,76 - 7,72 (m, 2H); 7,55 - 7,52 (m, 2H); 7,46 (d, J= 8,90 Hz, 2H); 7,37 - 7,34 (m, 3H); 6,85 (d, J= 8,90 Hz, 2H); 4,13 (t, J= 6,05 Hz, 2H); 2,78 (t, J= 6,05 Hz, 2H); 2,55 - 2,49 (m, 4H); 1,62 (quint, J= 6,05 Hz, 4H); 1,49 -1,41 (m, 2H). RMN13C (100 MHz, CDCI3) δ: 159,46; 153,43; 153,04; 141,31; 141,00; 139,42; 131,46; 131,35; 129,85; 129,75; 129,59; 129,16; 129,06; 128,74; 128,33; 114,41; 65,99; 57,83; 55,08; 25,85; 24,13. IV (vmax, diclorometano): 3057, 2932, 1605, 1512, 1466, 1344, 1250 cm’1. EM (m/z) : 409 (M+, 1), 98 (100), 96 (7), 70 (5). Anal. Elem. Cale. paraCzyH^NsO : C 79,19%, H 6,65%, N 10,26%; Encontrado : C 78,96%, H 6,91%, N 10,00%. 2-[4-(2-morfolina)etoxifenil]-3-fenilquinoxalina (5fb)

Rendimento de 60%. RMN 1H (400 MHz, CDCI3) δ: 8,17 - 8,13 (m, 2H); 7,76 - 7,69 (m, 2H); 7,55 - 7,52 (m, 2H); 7,46 (d, J= 8,75 Hz, 2H); 7,39 - 7,32 (m, 3H); 6,85 (d, J= 8,75 Hz, 2H); 4,11 (t, J= 5,65 Hz, 2H); 3,73 (t, J= 4,76 Hz, 4H); 2,79 (t, 5,65 Hz, 2H); 2,57 (t, J= 4,76 Hz, 4H). RMN 13C (100 MHz, CDCI3) δ: 159,21; 153,24; 152,80; 141,15; 140,85; 139,27; 131,45; 131,24; 129,74; 129,62; 129,50; 129,01; 128,90; 128,60; 128,18; 114,24; 67,77; 65,72; 57,44; 53,98. IV (vmax, diclorometano): 3059, 2922, 1637, 1607, 1250, 1117 cm’1. EM (m/z): 411 (M+, 1), 100 (100), 70 (4), 56 (8). Anal. Elem. Calc. paraC26H2δN302: C 75,89%, H 6,12%, N 10,21%; Encontrado : C 75,22%, H 5,91%, N 10,08%. Procedimento para a síntese de 2-[4-(2-piperidina)etoxifenil]-3-(4- hidroxifenil)quinoxalina (5ka) A uma solução de (5k) (1,5 mmol) em diclorometano (20 mL) em atmosfera de argônio, adicionou-se uma solução 1M de BBr3 em diclorometano (12 mmol, 12 mL), a 0 °C por 10 minutos. Elevou-se a temperatura até a ambiente e deixou-se sob agitação por 20 horas. Finalizou-se a reação pela adição de uma solução saturada de bicarbonato de sódio (150 mL), extraiu-se com diclorometano (3 x 50 mL), secou-se com sulfato de sódio anidro e evaporou-se o solvente. Preparou-se uma suspensão contendo o produto bruto da reação anterior (1,95 g), acetona (15 mL), 2-cloroetilpiperidina (1,65 mmol), carbonato de césio (3,3 mmol) e iodeto de potássio (0,075 mmol), e deixou-se sob agitação por 20 horas a 70 °C. Evaporou-se o solvente sob pressão reduzida, adicionou-se água (50 mL) e extraiu-se com diclorometano (3 x 75 mL). Secou-se com sulfato de sódio anidro e evaporou-se o solvente sob pressão reduzida. A purificação foi realizada por cromatografia em coluna usando diclorometano/metanol (8:2) como eluente e o produto obtido com 60% de rendimento.

RMN 1H (400 MHz, CDCI3) δ: 8,10 - 8,07 (m, 2H); 7,70 - 7,68 (m, 2H); 7,51 - 7,43 (m, 2H); 7,32 (d, J= 8,54 Hz, 2H); 6,89 - 6,79 (m, 4H); 4,46 - 4,44 (m, 2H); 3,35 - 3,32 (m, 2H); 3,20 - 3,10 (m, 4H); 2,05 - 1,95 (m, 2H); 1,70 - 1,62 (m, 2H). RMN 13C (100 MHz, CDCI3) δ: 157,94; 157,46; 153,24; 152,76; 140,94; 139,27; 131,46; 131,36; 129,80; 129,65; 128,91; 128,80; 115,66; 114,34; 63,00; 56,49; 54,23; 23,16; 22,09. EM (m/z): 426,3 (eletrospray / iontrap).Compound 2a was synthesized according to the general method described above. The yield was 91%.

N- [1- (methylsulfanyl) -2-nitroetenyl] -benzenamine (2b), according to Venkatesh mentioned above. The yield was 85%.

4-Methoxy-N- [1 - (meylsulfanyl) -2-nitroethyl] -benzenamine (2c). The yield was 99%.

N- [1 - (Methylsulfanyl) -2-nitroetenyl] -1,3-benzodioxol-5-amine (2d), as taught in the international publication WO 2000016766. The yield was 93%.

3,4,5-Trimethoxy-N- [1- (methylsulfanyl) -2-nitroethyl] -benzenamine (2e), prepared as taught in French publication FR 2730733. The yield was 80%.

4 - [[1- (Methylsulfanyl) -2-nitroetenyl] amino] -phenol (2f), prepared as taught in publications WO 2000016766 and FR 2730733. The yield was 89%.

3,5-Dimethoxy-N- [1 - (methylsulfanyl) -2-nitroetenyl] -benzenamine (2g), prepared according to Venkatesh mentioned above. The yield was 87%.

4-Bromo-N- [1 - (methylsulfanyl) -2-nitroetenyl] -benzenamine (2h), prepared according to the article by Zou, Y .; Feng, J .; Li, J .; Ye, C .; Synth. Met. 71, 1743, 1995. The yield was 97%.

A / - [1- (methylthio) -2-nitroetenyl] -cyclohexanamine (2i), prepared according to the article by Masereel, B .; J. Med. Chem., 41, 3239, 1998. The yield was 98%.

2,5-Dimethoxy-N- [1 - (methylsulfanyl) -2-nitroethenyl] -benzenamine (2j), prepared according to Venkatesh mentioned above. The yield was 51%.

4-Fluoro-N- [1 - (methylsulfanyl) -2-nitroetenyl] -benzenamine (2k) prepared according to the article by Kearney, T .; Joule, JA; Jackson, A .; Heterocycles, 33, 757, 1992. 5 The yield was 98%.

5 - ((1 - (methylsulfanyl) -2-nitroetenyl) amino) pentan-1-ol (2I) The yield was 93%.

10 4 - ((1- (methylsulfanyl) -2-nitroetenyl) amine) butan-1-ol (2m), prepared according to publication W02000 / 016766A1. The yield was 77%.

N1, N1-dimethyl-N4- (1- (methylsulfanyl) -2-nitroetenyl) benzene-1,4-diamino (2n) 15 The yield was 94%.

2-fluoro-N- (1- (methylsulfanyl) -2-nitroetenyl) aniline (2o), prepared according to the article Kearney, T .; Joule, JA; Jackson, A .; Heterocycles, 33, 757, 1992. The yield was 65%.

4-chloro-N- (1- (methylsulfanyl) -2-nitroetenyl) aniline (2p), prepared according to Venkatesh mentioned above. The yield was 55%.

General procedure for the synthesis of 3-chloro-2-methylsulfanylquinoxaline (3). A suspension was prepared with nitroethene A /, S-acetal 2 (0.208 mmol) and acetonitrile (1 ml). The mixture was cooled to 0 ° C and then POCI3 (0.625 mmol) was added dropwise over 15 minutes. The mixture was heated to 80 ° C and kept under stirring for 4 hours. The mixture was cooled and neutralized with saturated sodium bicarbonate solution (2.5 ml). Then an extraction with chloroform (3x2 ml) was carried out. The organic phase was washed with water (2x2 ml) and saturated NaCI solution (2 ml) and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, obtaining the impure product. Purification was carried out by flash silica gel column chromatography, using hexane: ethyl acetate (9: 1) as the eluent. 3-Chloro-7-methoxy-2-methylsulfanylquinoxaline (3a) prepared according to Venkatesh mentioned above. The analytical data for compound 3a is as follows. The yield was 54%, PF: 109-111 ° C.

3-Chloro-2-methylsulfanylquinoxaline (3b) prepared according to Venkatesh mentioned above. The yield was 36%.

3-Chloro-6-methoxy-2-methylsulfanylquinoxaline (3c) prepared according to Venkatesh mentioned above. The yield of 31%.

6-Bromo-3-chloro-2-methylsulfanylquinoxaline (3d) The yield was 30%.

3,6-Dichloro-2-methylsulfanylquinoxaline (3e) prepared according to Venkatesh mentioned above. The yield was 32%.

Quinoxalins 3 were used in a series of two cross-coupling reactions mediated by transition metals, first producing the 3-aryl-2-methylsulfanylquinoxalins (4a and 4b) and then the 2,3-diarylquinoxalins (5a and 5b) (Figure 8, Scheme 3), as described by Venkatesh, C. et al. Org. Lett., 7, 2169, 2005. General procedure for the synthesis of 3-aryl-2-methylsulfanylquinoxaline (4a and 4b). To a round-bottom flask equipped with a magnetic bar, quinoxaline (3a) (1mmol), tris- (acetylacetonate) iron (lll) (0.10 mmol) and anhydrous THF (5 ml) were added, leaving under stirring at -30 ° C in a nitrogen atmosphere. A solution of phenylmagnesium bromide (2.2 mmol) was added to the reaction mixture, and stirring was continued for another 10 minutes. Saturated NaCl solution (5 ml) was added and the organic matter was extracted with dichloromethane (3x5 ml). The organic phase was washed with water (10 ml) and saturated NaCl solution (2x10 ml) and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent under reduced pressure. The 3-phenylquinoxalins were purified on a chromatographic column using a mixture of hexane - ethyl acetate (9: 1) as eluent. 3-Phenyl-7-methoxy-2-methylsulfanylquinoxaline (4a), prepared according to Venkatesh mentioned above. The yield was 31%.

3-Phenyl-2-methylsulfanylquinoxaline (4b), prepared as taught in German publication DD144054. The yield was 36%.

Synthesis of 2,3-diaryl substituted quinoxalins Procedure for cross-coupling reaction using Nickel catalyst: synthesis of compounds (5a) and (5b). To a two-way flask, equipped with a magnetic bar, dichloro-bis- (triphenylphosphino) nickel (ll) (0.027 mmol) and anhydrous benzene (3 mL) were added, in order to obtain a suspension that was maintained in an atmosphere argon, under agitation and reflux. Benzyl / aryl magnesium bromide (0.018 mmol) was added to the suspension and refluxed for 15 min to promote the reduction of the catalyst. Then benzyl / aryl bromide (0.16 mmol) and a solution of 3-phenyl-7-methoxy-2-methylsulfanylquinoxaline (4a) (0.089 mmol) in anhydrous benzene (2 mL) were added again, maintaining reaction mixture under reflux for another 12 hours. The reaction was completed by adding saturated ammonium chloride solution (5 ml), then extracted with dichloromethane (3 x 50 ml), the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated at reduced pressure. The reaction product was purified by chromatographic column using a mixture of hexane and ethyl acetate (19: 1) as eluent. 2,3-diphenyl-7-methoxyquinoxaline (5a), prepared according to the article by Zhou, JF; Gong, GX; Zhi, SJ; Duan, X. L; Synth. Comm. 39, 3743, 2009.

The yield was 69%. 3-phenyl-7-methoxy-2- (4-methoxyphenyl) quinoxaline (5b), prepared according to the article by Venkatesh cited above.

Yield 31%. The 2,3-diarylkinoxalins 5c-k were synthesized using the annealing of a-diketones and o-phenylenediamines under ultrasound (Scheme 4, Figure 9), according to an article by Guo, WX et al .; J. Braz. Chem. Soc., 20, 1674, 2009. Procedure for condensation reactions of o-phenylenediamines and ket ketones. 1,2-Phenylenediamine (1 mmol) was added to a solution formed by a 1,2-diketone (1 mmol) and an ethanol / acetic acid mixture (4 mL / 0.4 mL). The resulting solution was irradiated with ultrasound for 1 hour. The solvent was evaporated and the product was purified by column chromatography using dichloromethane as the solvent. 2,3-diphenylquinoxaline (5c), prepared according to the procedure reported by Zhou mentioned above.

Yield 82% 2- (methylphenyl) -3-phenylquinoxaline (5d) prepared according to the procedure reported by Zhou mentioned above.

Yield of 86% 6-chloro-2- (methylphenyl) -3-phenylquinoxaline and 7-chloro-2- (methylphenyl) -3-10 phenylquinoxaline (5e)

Yield 87% NMR 1H (400 MHz, CDCl 3) δ: 8.15 (d, J = 2.32 Hz, 1H); 8.09 (d, J-8.98 Hz, 1H); 7.71 - 7.67 (m, 1H); 7.54 - 7.49 (m, 2H); 7.42 - 7.32 (m, 5H); 7.14 (d, J = 8.26 15 Hz, 2H); 2.36 (s, 3H). IR (vmax KBr): 3043, 2918, 1597, 1466, 1340, 1066 cm -1. MS (m / z): 330 (M +, 100), 329 (65), 315 (40), 165 (34), 75 (30). Anal. Elem. Calc, for C21H15N2CI: C 76.24%, H 4.57%, N 8.47%; Found: C 76.49%, H 4.61%, N 8.47%. 20 2- (4-methoxyphenyl) -3-phenylquinoxaline (5f), according to the procedure reported by Islami, MR; Hassani, Z .; Arkivoc XV, 280, 2008.

98% yield 6-chloro-2- (methoxyphenyl) -3-phenylquinoxaline and 7-chloro-2- (methoxyphenyl) -3-phenylquinoxaline (5g)

Yield 98% NMR1H (400 MHz, CDCl3) δ: 8.16 - 8.13 (m, 1H); 8.07 (d, J = 8.90 Hz, 2H); 7.69 - 7.66 (m, 1H); 7.54 - 7.51 (m, 2H); 7.48 - 7.45 (m, 2H); 7.39 - 7.33 (m, 3H); 6.85 (d, J = 8.90 Hz, 2H); 3.82 (s, 3H). IR (vmax dichloromethane): 3061.2933, 1608, 1514, 1466, 1342, 1252, 1175 cm -1. MS (m / z): 346 (M +, 100), 345 (49), 331 (34), 178 (25), 75 (26). Anal. Elem. Calc. paraC2iHisN2OCI: C 72.73%, H 4.36%, N 8.08%; Found: C 72.75%, H 4.61%, N 7.72%. 6-chloro-2,3-diphenylquinoxaline (5h), according to the procedure reported by Castellanos, JJM; Hernandez, KR; Flores, NSG; Suarez, OOR; Cruz, JP; Molecules, 17, 5164, 2012

Yield of 95% 6,7-dichloro-2,3-diphenylquinoxaline (5i) according to the procedure reported by Shaabani, A .; Rezayan, AH; Behnam, M .; Heidary, M .; CR Chimie, 12, 1249, 2009.

87% yield 6,7-dichloro-2- (4-methylphenyl) -3-phenylquinoxaline (5j)

Yield 96% 1H NMR (400 MHz, CDCl3) δ: 8.23 (s, 2H); 7.52 - 7.48 (m, 2H); 7.41 - 7.32 (m, 5H); 7.14 - 7.10 (m, 2H); 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 154.49; 140.02; 139.82; 139.48; 138.65; 135.53; 134.28; 134.15; 130.06; 129.93; 129.81; 129.24; 129.09; 128.37; 21.40. IR (vmax dichloromethane): 3055, 2920, 1609, 1450, 1439, 1337, 1107, 879 cm -1. MS (m / z): 364 (M +, 100), 363 (60), 349 (43), 177 (25), 109 (26). Anal. Elem. Shut up. paraCs-iHu ^ Cfe: C 69.06%, H 3.86%, N 7.67%; Found: C 69.28%, H 3.97%, N 7.16%. 2,3-di- (4-met ° xiphenyl) -quinoxaline (5k), prepared according to the procedure described in an article by Islami et al., Cited above.

94% yield Procedure for the synthesis of 2,3-diarylquinoxaline (5fa) and (5fb) In a solution of (5f) (1.5 mmol) in dichloromethane (20 mL) under an argon atmosphere, a solution was added 1M BBr3 in dichloromethane (6 mmol, 6 mL), at 0 ° C for 10 minutes. The temperature was raised to room temperature and left under stirring for 20 hours. The reaction was completed by adding a saturated sodium bicarbonate solution (100 ml), extracted with dichloromethane (3 x 50 ml), dried with anhydrous sodium sulfate and the solvent was evaporated. A suspension was prepared containing the crude product from the previous reaction (1.75 g), DMF (15 ml), the appropriate alkyl chloride (1.65 mmol), cesium carbonate (3.3 mmol) and potassium iodide (0.075 mmol) and left under stirring for 20 hours at 70 ° C. The solvent was evaporated under reduced pressure, water (25 ml) was added and extracted with dichloromethane (3 x 50 ml). It was dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The product was purified by column chromatography using dichloromethane / methanol (8: 2) as an eluent. 2- [4- (2-piperidine) ethoxyphenyl] -3-phenylquinoxaline (5fa)

82% yield. 1H NMR (400 MHz, CDCl3) δ: 8.16 - 8.13 (m, 2H); 7.76 - 7.72 (m, 2H); 7.55 - 7.52 (m, 2H); 7.46 (d, J = 8.90 Hz, 2H); 7.37 - 7.34 (m, 3H); 6.85 (d, J = 8.90 Hz, 2H); 4.13 (t, J = 6.05 Hz, 2H); 2.78 (t, J = 6.05 Hz, 2H); 2.55 - 2.49 (m, 4H); 1.62 (quint, J = 6.05 Hz, 4H); 1.49 -1.41 (m, 2H). NMR13C (100 MHz, CDCl3) δ: 159.46; 153.43; 153.04; 141.31; 141.00; 139.42; 131.46; 131.35; 129.85; 129.75; 129.59; 129.16; 129.06; 128.74; 128.33; 114.41; 65.99; 57.83; 55.08; 25.85; 24.13. IR (vmax, dichloromethane): 3057, 2932, 1605, 1512, 1466, 1344, 1250 cm -1. MS (m / z): 409 (M +, 1), 98 (100), 96 (7), 70 (5). Anal. Elem. Shut up. paraCzyH ^ NsO: C 79.19%, H 6.65%, N 10.26%; Found: C 78.96%, H 6.91%, N 10.00%. 2- [4- (2-morpholine) ethoxyphenyl] -3-phenylquinoxaline (5fb)

Yield 60%. 1H NMR (400 MHz, CDCl3) δ: 8.17 - 8.13 (m, 2H); 7.76 - 7.69 (m, 2H); 7.55 - 7.52 (m, 2H); 7.46 (d, J = 8.75 Hz, 2H); 7.39 - 7.32 (m, 3H); 6.85 (d, J = 8.75 Hz, 2H); 4.11 (t, J = 5.65 Hz, 2H); 3.73 (t, J = 4.76 Hz, 4H); 2.79 (t, 5.65 Hz, 2H); 2.57 (t, J = 4.76 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ: 159.21; 153.24; 152.80; 141.15; 140.85; 139.27; 131.45; 131.24; 129.74; 129.62; 129.50; 129.01; 128.90; 128.60; 128.18; 114.24; 67.77; 65.72; 57.44; 53.98. IR (vmax, dichloromethane): 3059, 2922, 1637, 1607, 1250, 1117 cm -1. MS (m / z): 411 (M +, 1), 100 (100), 70 (4), 56 (8). Anal. Elem. Calc. for C26H2δN302: C 75.89%, H 6.12%, N 10.21%; Found: C 75.22%, H 5.91%, N 10.08%. Procedure for the synthesis of 2- [4- (2-piperidine) ethoxyphenyl] -3- (4-hydroxyphenyl) quinoxaline (5ka) To a solution of (5k) (1.5 mmol) in dichloromethane (20 mL) in an atmosphere of argon, a 1M solution of BBr3 in dichloromethane (12 mmol, 12 mL) was added at 0 ° C for 10 minutes. The temperature was raised to room temperature and left under stirring for 20 hours. The reaction was terminated by adding a saturated sodium bicarbonate solution (150 ml), extracted with dichloromethane (3 x 50 ml), dried with anhydrous sodium sulfate and the solvent was evaporated. A suspension was prepared containing the crude product from the previous reaction (1.95 g), acetone (15 ml), 2-chloroethylpiperidine (1.65 mmol), cesium carbonate (3.3 mmol) and potassium iodide (0.075 mmol), and left under stirring for 20 hours at 70 ° C. The solvent was evaporated under reduced pressure, water (50 ml) was added and extracted with dichloromethane (3 x 75 ml). It was dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Purification was performed by column chromatography using dichloromethane / methanol (8: 2) as the eluent and the product obtained in 60% yield.

1H NMR (400 MHz, CDCl3) δ: 8.10 - 8.07 (m, 2H); 7.70 - 7.68 (m, 2H); 7.51 - 7.43 (m, 2H); 7.32 (d, J = 8.54 Hz, 2H); 6.89 - 6.79 (m, 4H); 4.46 - 4.44 (m, 2H); 3.35 - 3.32 (m, 2H); 3.20 - 3.10 (m, 4H); 2.05 - 1.95 (m, 2H); 1.70 - 1.62 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 157.94; 157.46; 153.24; 152.76; 140.94; 139.27; 131.46; 131.36; 129.80; 129.65; 128.91; 128.80; 115.66; 114.34; 63.00; 56.49; 54.23; 23.16; 22.09. MS (m / z): 426.3 (electrospray / iontrap).

Rendimento de 90%. RMN 1H (400 MHz, CDCI3) δ : 7,98 (d, J= 9,07 Hz, 1H); 7,66 (d, J= 2,71 Hz, 1H); 7,55 (dd, J) 9,07 J2 2,71 Hz, 1H); 3,99 (s,3H);3,03 (s, 3H). RMN 13C (400 MHz, CDCI3) δ : 161,93; 156,71; 143,42; 139,86; 139,11; 129,20; 126,36; 107,08; 56,18; 39,71. 3,6-dicloro-2-(metilsulfonil)quinoxalina (6b)

Rendimento de 85%. RMN 1H (400 MHz, CDCI3) δ : 8,31 (d, J= 9,15 Hz, 1H); 7,66 (d, J= 2,24 Hz, 1H); 7,55 (dd, Ji 9,15 J2 2,24 Hz, 1H); 3,06 (s, 3H). RMN 13C (400 MHz, CDCI3) δ : 157,28; 143,16; 139,98; 139,18; 133,24; 132,69; 130,86; 127,43; 39,71. Procedimento geral para a síntese de 3-cloro-2-metilsulfonilquinoxalinas (7) Preparou-se uma solução de ácido m-cloroperbenzóico (0,25 mmol) em diclorometano (1 mL) e deixou-se sob agitação a temperatura de 0 °C. Em seguida adicionou-se lentamente, uma solução da metilsulfanilquinoxalina (3) (0,11 mmol) também em diclorometano (1 mL) e manteve-se a solução resultante sob agitação constante. Acompanhou-se a reação por cromatografia em camada fina, e verificou-se o término após 1-2 horas. Finalizou-se a reação despejando a solução em água gelada (2 mL). Lavou-se a fase orgânica com solução de bicarbonato de sódio 10% (m/V) (2 mL), água (2 mL) e solução saturada de cloreto de sódio (2 mL). Em seguida secou-se a fase orgânica com sulfato de sódio anidro e evaporou-se 0 solvente. O produto foi purificado por cromatografia em coluna, usando mistura de hexano e acetato de etila como eluente 3:2. 3-cloro-7-metoxi-2-metilsulfonilquinoxalina (7a), sintetizada conforme o artigo por Venkatesh citado acima.

Rendimento de 87%. RMN 1H (400 MHz, CDCI3) δ: 7,98 (d, J= 9,26 Hz, 1H), 7,59 (dd, J= 9,26; 2,85 Hz, 1H), 7,40 (d, J= 2,85 Hz, 1H), 4,01 (s,3H), 3,53 (s, 3H). RMN 13C (400 MHz, CDCI3) δ : 162,19; 150,00; 140,33; 139,07; 138,67; 129,23; 127,39; 106,68; 56,17; 40,27. EM (m/z): 272(M+, 63), 210 (68), 193 (90), 158 (100), 117 (50), 77 (36). 3-cloro-2-metilsulfonilquinoxalina (7b), preparada conforme o artigo por Sundaram, G. S. M.; Singh, B.; Venkatesh, C.; Ila, H.; Junjappa, H.; J. Org. Chem., 72, 5020, 2007.

Rendimento de 78%. RMN 1H (400 MHz, CDCI3) δ : 8,19 - 8,13 (m, 2H), 8,01 - 7,91 (m, 2H), 3,57 (s, 3H). RMN 13C (400 MHz, CDCI3) δ : 150,16; 142,75; 141,40; 138,25; 133,86; 131,87; 129,61; 128,51; 40,16. EM (m/z): 242(M+, 20), 180 (45), 163 (58), 102 (100), 75 (40), 51 (22). 3-cloro-6-metoxi-2-(metilsulfonil)quinoxalina (7c) preparada conforme 0 artigo por Venkatesh citado acima.

Rendimento de 99% 6-bromo-3-cloro-2-(metilsulfonil)quinoxalina (7d)

Rendimento de 91% RMN 1H (400 MHz, CDCI3) δ : 8,31 (d,J 1,95 Hz, 1H); 8,03 (d.J 8,90 Hz, 1H); 8,00 (dd, J1 8,90 e J2 1,95 Hz, 1H); 3,55 (s, 3H). RMN 13C (100 MHz, CDCI3) δ : 150,42; 143,07; 142,62; 137,00; 135,65; 130,91; 130,62; 128,75; 40,17. 3-cloro-6-fluoro-2-(metilsulfonil)quinoxalina (7e), preparada conforme artigo por Sundaram, G. S. M.; Singh, B.; Venkatesh, C.; Ila, H.; Junjappa, H.; J. Org. Chem., 72, 5020, 2007.

Rendimento de 88% Síntese do 3-Fenil-2-metilsulfonil-7-metoxiquinoxalina (8a) Preparou-se uma solução de ácido m-cloroperbenzóico (0,25 mmol) em diclorometano (1 mL) e deixou-se sob agitação a temperatura de 0 °C. Em seguida adicionou-se lentamente, uma solução da 3-fenil-2-metilsulfanil-7- metoxiquinoxalina (4a) (0,11 mmol) também em diclorometano (1 mL) e manteve-se a solução resultante sob agitação constante. Acompanhou-se a reação por cromatografia em camada fina, e verificou-se o término após 1-2 horas. Finalizou-se a reação despejando a solução em água gelada (2 mL). Lavou-se a fase orgânica com solução de bicarbonato de sódio 10% (m/v) (2 mL), água (2 mL) e solução saturada de cloreto de sódio (2 mL). Em seguida secou-se a fase orgânica com sulfato de sódio anidro e evaporou-se o solvente. O produto foi purificado por cromatografia em coluna, usando mistura de hexano e acetato de etila como eluente 1:1.

Rendimento de 72%. RMN1H (400 MHz, CDCI3) δ : 8,10 (d, J 9,14 Hz, 1H); 7,87 - 7,85 (m, 2H); 7,58 (d, J1 9,14 J2 2,83 Hz, 1H); 7,54 - 7,53 (m, 3H); 7,41 (d, J 2,83 Hz, 1H); 4,02 (s, 3H), 3,43 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 161,95; 152,13; 148,79; 140,41; 139,08; 136,51; 130,31; 130,21; 129,83; 129,73; 126,74; 106,19; 56,12; 40,72. EM (m/z) :314 (M+, 28), 235 (100), 192 (19), 77 (30). As 3-cloro-2-metilsulfonilquinoxalinas (7) foram utilizadas como material de partida em uma sequência de duas reações de substituição nucleofílicas que forneceram 3-cloro-2-aminoquinoxalinas (9) e 2,3-diaminoquinoxalinas (10) (Vide Figura 12, que ilustra 0 Esquema 7). Procedimento geral para a síntese de 3-cloro-2-amino-quinoxalinas (9) Preparou-se uma solução de 3-cloro-7-metoxi-2-metilsulfonilquinoxalina (7a) (1mmol), butilamina ou benzilamina, em dimetilformamida (2 mL), e deixou- se sob agitação na temperatura de 25°C por 6 horas. Finalizou-se a reação adicionando diclorometano (20 mL) e lavou-se com H2O (2 x 20 mL) e solução saturada de NaCI (20 mL). Secou-se a fase orgânica com sulfato de sódio anidro e evaporou-se o solvente. Os produtos foram purificados por coluna cromatográfica usando mistura de hexano/acetato de etila 1:1 como eluente. 3-cloro-7-metoxi-2-butilaminoquinoxalina (9a), preparada conforme o artigo por Venkatesh citado acima.

Rendimento de 75%. 3-cloro-7-metoxi-2-benzilaminoquinoxalina (9b), preparada conforme o mesmo artigo por Venkatesh citado acima.

Rendimento de 81%. Síntese de 2,3-diaminoquinoxalinas (10) Síntese de 2,3-dialquilamino-quinoxalinas Preparou-se uma solução de 2-cloro-3-amino-quinoxalina (9a) ou (9b) (1mmol) em butilamina (1mL) em um tubo selado e deixou-se sob agitação na temperatura de 100 °C por 20h. Evaporou-se a butilamina e purificou-se o produto por coluna cromatográfica usando mistura de hexano/acetato de etila 2:1 como eluente. 2,3-dibutilamino-6-metoxiquinoxalina (10a)

Rendimento de 98%. RMN1H (400 MHz, CDCI3) δ : 7,57 (d, J 9,22 Hz, 1H); 7,11 (d, J 2,94 Hz, 1H); 6,96 (dd, J1 9,22 J2 2,94 Hz, 1H); 3,88 (s, 3H); 3,55 - 3,48 (m, 4H); 1,67 - 1,59 (m, 4H); 1,48 - 1,38 (m, 4H); 0,97 - 0,93 (m, 6H). RMN13C (100 MHZ, CDCI3) δ : 157,11; 145,02; 143,32; 137,99; 131,67; 126,32; 114,75; 106,23; 55,66; 41,64; 41,51; 31,50; 31,44; 20,39; 13,91. EM (m/z) :302 (M+, 80);259 (78); 246 (38); 229 (53);203 (100); 147 (22). 3-benzilamino-2-butilamino-6-metoxiquinoxalina (10b), preparada conforme 0 procedimento descrito por Venkatesh conforme citado acima.

Rendimento de 82%.Figure 9, Scheme 4 illustrates how the methoxyls of the quinoxaline (5f) and (5k) were deprotected and O-alkylated providing the derivatives of piperidine (5fa) and (5ka) and morpholine (5fb). In order to investigate the influence on the biological activity of methylsulfoxyl and methylsulfonyl groups present in quinoxalins, 3-chloro-2-methylsulfanylquinoxaline (3) were subjected to oxidation reactions leading to a series of 3-chloro-2-methylsulfoxylquinoxaline compounds (6) and 3-chloro-2-methylsulfonylquinoxaline (7) (See Figure 10, which illustrates Scheme 5). General procedure for the synthesis of methylsulfoxyquinoxaline (6) A solution of m-chloroperbenzoic acid (0.11 mmol) in dichloromethane (1 ml) was prepared and left under stirring at 0 ° C. Then, a solution of methylsulfanylquinoxaline (3) (0.11 mmol) also in dichloromethane (1 ml) was added slowly and the resulting solution was kept under constant stirring. The reaction was monitored by thin layer chromatography, and the completion was verified after 1-2 hours. The reaction was terminated by pouring the solution into ice water (2 mL). The organic phase was washed with 10% sodium bicarbonate solution (m / V) (2 ml), water (2 ml) and saturated sodium chloride solution (2 ml). Then the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated. The product was purified by column chromatography, using a mixture of hexane and ethyl acetate as eluent 2: 1. 3-chloro-7-methoxy-2- (methylsulfonyl) quinoxaline (6a)

Yield 90%. 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J = 9.07 Hz, 1H); 7.66 (d, J = 2.71 Hz, 1H); 7.55 (dd, J) 9.07 J2 2.71 Hz, 1H); 3.99 (s, 3H); 3.03 (s, 3H). 13C NMR (400 MHz, CDCl3) δ: 161.93; 156.71; 143.42; 139.86; 139.11; 129.20; 126.36; 107.08; 56.18; 39.71. 3,6-dichloro-2- (methylsulfonyl) quinoxaline (6b)

Yield 85%. 1H NMR (400 MHz, CDCl3) δ: 8.31 (d, J = 9.15 Hz, 1H); 7.66 (d, J = 2.24 Hz, 1H); 7.55 (dd, Ji 9.15 J2 2.24 Hz, 1H); 3.06 (s, 3H). 13C NMR (400 MHz, CDCl3) δ: 157.28; 143.16; 139.98; 139.18; 133.24; 132.69; 130.86; 127.43; 39.71. General procedure for the synthesis of 3-chloro-2-methylsulfonylquinoxaline (7) A solution of m-chloroperbenzoic acid (0.25 mmol) in dichloromethane (1 ml) was prepared and left under stirring at 0 ° C . Then, a solution of methylsulfanylquinoxaline (3) (0.11 mmol) also in dichloromethane (1 ml) was added slowly and the resulting solution was kept under constant stirring. The reaction was monitored by thin layer chromatography, and the completion was verified after 1-2 hours. The reaction was terminated by pouring the solution into ice water (2 mL). The organic phase was washed with 10% sodium bicarbonate solution (m / V) (2 ml), water (2 ml) and saturated sodium chloride solution (2 ml). Then the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated. The product was purified by column chromatography, using a mixture of hexane and ethyl acetate as eluent 3: 2. 3-chloro-7-methoxy-2-methylsulfonylquinoxaline (7a), synthesized according to the article by Venkatesh cited above.

87% yield. 1H NMR (400 MHz, CDCI3) δ: 7.98 (d, J = 9.26 Hz, 1H), 7.59 (dd, J = 9.26; 2.85 Hz, 1H), 7.40 ( d, J = 2.85 Hz, 1H), 4.01 (s, 3H), 3.53 (s, 3H). 13C NMR (400 MHz, CDCl3) δ: 162.19; 150.00; 140.33; 139.07; 138.67; 129.23; 127.39; 106.68; 56.17; 40.27. MS (m / z): 272 (M +, 63), 210 (68), 193 (90), 158 (100), 117 (50), 77 (36). 3-chloro-2-methylsulfonylquinoxaline (7b), prepared according to the article by Sundaram, GSM; Singh, B .; Venkatesh, C .; Ila, H .; Junjappa, H .; J. Org. Chem., 72, 5020, 2007.

78% yield. 1H NMR (400 MHz, CDCl3) δ: 8.19 - 8.13 (m, 2H), 8.01 - 7.91 (m, 2H), 3.57 (s, 3H). 13C NMR (400 MHz, CDCl3) δ: 150.16; 142.75; 141.40; 138.25; 133.86; 131.87; 129.61; 128.51; 40.16. MS (m / z): 242 (M +, 20), 180 (45), 163 (58), 102 (100), 75 (40), 51 (22). 3-chloro-6-methoxy-2- (methylsulfonyl) quinoxaline (7c) prepared according to the article by Venkatesh cited above.

Yield 99% 6-bromo-3-chloro-2- (methylsulfonyl) quinoxaline (7d)

Yield 91% 1H NMR (400 MHz, CDCl3) δ: 8.31 (d, J 1.95 Hz, 1H); 8.03 (dJ 8.90 Hz, 1H); 8.00 (dd, J1 8.90 and J2 1.95 Hz, 1H); 3.55 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 150.42; 143.07; 142.62; 137.00; 135.65; 130.91; 130.62; 128.75; 40.17. 3-chloro-6-fluoro-2- (methylsulfonyl) quinoxaline (7e), prepared according to the article by Sundaram, GSM; Singh, B .; Venkatesh, C .; Ila, H .; Junjappa, H .; J. Org. Chem., 72, 5020, 2007.

88% yield Synthesis of 3-Phenyl-2-methylsulfonyl-7-methoxyquinoxaline (8a) A solution of m-chloroperbenzoic acid (0.25 mmol) in dichloromethane (1 mL) was prepared and left under stirring at temperature 0 ° C. Then a solution of 3-phenyl-2-methylsulfanyl-7-methoxyquinoxaline (4a) (0.11 mmol) also in dichloromethane (1 ml) was added slowly and the resulting solution was kept under constant stirring. The reaction was monitored by thin layer chromatography, and the completion was verified after 1-2 hours. The reaction was terminated by pouring the solution into ice water (2 mL). The organic phase was washed with 10% (w / v) sodium bicarbonate solution (2 ml), water (2 ml) and saturated sodium chloride solution (2 ml). Then the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated. The product was purified by column chromatography, using a mixture of hexane and ethyl acetate as eluent 1: 1.

72% yield. 1 H NMR (400 MHz, CDCl 3) δ: 8.10 (d, J 9.14 Hz, 1H); 7.87 - 7.85 (m, 2H); 7.58 (d, J1 9.14 J2 2.83 Hz, 1H); 7.54 - 7.53 (m, 3H); 7.41 (d, J 2.83 Hz, 1H); 4.02 (s, 3H), 3.43 (s, 3H). 13 C NMR (100 MHz, CDCl 3) δ: 161.95; 152.13; 148.79; 140.41; 139.08; 136.51; 130.31; 130.21; 129.83; 129.73; 126.74; 106.19; 56.12; 40.72. MS (m / z): 314 (M +, 28), 235 (100), 192 (19), 77 (30). The 3-chloro-2-methylsulfonylquinoxaline (7) were used as starting material in a sequence of two nucleophilic substitution reactions that provided 3-chloro-2-aminoquinoxaline (9) and 2,3-diaminoquinoxaline (10) (See Figure 12, which illustrates Scheme 7). General procedure for the synthesis of 3-chloro-2-amino-quinoxaline (9) A solution of 3-chloro-7-methoxy-2-methylsulfonylquinoxaline (7a) (1mmol), butylamine or benzylamine was prepared in dimethylformamide (2 ml), and left under stirring at 25 ° C for 6 hours. The reaction was terminated by adding dichloromethane (20 ml) and washed with H2O (2 x 20 ml) and saturated NaCl solution (20 ml). The organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated. The products were purified by column chromatography using a 1: 1 hexane / ethyl acetate mixture as eluent. 3-chloro-7-methoxy-2-butylaminoquinoxaline (9a), prepared according to the article by Venkatesh cited above.

75% yield. 3-chloro-7-methoxy-2-benzylaminoquinoxaline (9b), prepared according to the same article by Venkatesh cited above.

Yield 81%. Synthesis of 2,3-diaminoquinoxaline (10) Synthesis of 2,3-dialkylaminoquinoxaline A solution of 2-chloro-3-amino-quinoxaline (9a) or (9b) (1mmol) in butylamine (1mL) was prepared in a sealed tube and allowed to stir at 100 ° C for 20h. Butylamine was evaporated and the product was purified by chromatographic column using a 2: 1 hexane / ethyl acetate mixture as eluent. 2,3-dibutylamino-6-methoxyquinoxaline (10a)

98% yield. 1 H NMR (400 MHz, CDCl 3) δ: 7.57 (d, J 9.22 Hz, 1H); 7.11 (d, J 2.94 Hz, 1H); 6.96 (dd, J1 9.22 J2 2.94 Hz, 1H); 3.88 (s, 3H); 3.55 - 3.48 (m, 4H); 1.67 - 1.59 (m, 4H); 1.48 - 1.38 (m, 4H); 0.97 - 0.93 (m, 6H). 13 C NMR (100 MHZ, CDCl 3) δ: 157.11; 145.02; 143.32; 137.99; 131.67; 126.32; 114.75; 106.23; 55.66; 41.64; 41.51; 31.50; 31.44; 20.39; 13.91. MS (m / z): 302 (M +, 80); 259 (78); 246 (38); 229 (53); 203 (100); 147 (22). 3-benzylamino-2-butylamino-6-methoxyquinoxaline (10b), prepared according to the procedure described by Venkatesh as mentioned above.

82% yield.

Synthesis of 2,3-dianilino-6-methoxyquinoxaline (10c), prepared according to the article by Beckert, R. et al; Pharmazie, 52, 638, 1997.

A mixture of 3-chloro-2-methylsulfanyl-7-methoxyquininoxaline (3a) (Immol) and aniline (1 ml) was prepared in a reaction tube in the microwave reactor. The mixture was irradiated at 130 ° C for 30 minutes.

Rendimento de 93%.The product was purified by column chromatography, using a 2: 1 hexane / acetate mixture as the eluent.

93% yield.

1 H NMR (400 MHz, CDCl 3) δ: 7.90 - 6.45 (m, 13H); 3.81 (s, 3H). MS (m / z): 342 (M +, 80); 341 (100); 298 (12); 224 (20); 77 (31).

A series of 3-amino-2-methylsulfanylquinoxalins (11) is synthesized using 3-chloroquinoxalins (3) as starting material in nucleophilic substitution reactions (see Figure 13, Scheme 8).

General procedure for the synthesis of 3-amino-2 * methylsulfanyl-quinoxalins (11)

A mixture of 3-chloro-2-methylsulfanylquinoxaline (3) (1 mmol) and amine (1 mL) was prepared in a reaction tube in the microwave reactor, 5 The mixture was irradiated at 130 ° C for 30 minutes.

10 Rendimento de 82% RMN1H (400 MHz, CDCI3) δ : 7,68 (d, J 8,93 Hz, 1H); 7,20 (d, J 2,82 Hz, 1H); 7,15 (dd, J1 8,93 J2 2,82 Hz, 1H); 3,90 (s, 3H); 3,00 (s, 6H); 2,63 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 158,46; 153,45; 152,27; 140,14; 133,71; 127,98; 119,42; 106,25; 55,59; 41,58; 13,35. 15 EM (m/z) :249 (M+, 39);234 (100); 219 (20); 117(21). 3-butilamino-2-metilsulfanil-7-metoxiquinoxalina (11b), preparada conforme o artigo por Venkatesh citado acima.

20 Rendimento de 67% 3-(2-hidroxietanolamina)-2-metilsulfanil-7-metoxiquinoxalina (11c)

Rendimento de 44%. 25 RMN1H (400 MHz, CDCI3) δ : 7,54 (d, J 8,87 Hz, 1H); 7,19-7,11 (m, 2H); 3,91 - 3,85 (m, 5H); 3,75 - 3,70 (m, 2H); 2,72 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 157,11; 148,32; 146,99; 138,25; 133,37; 126,34; 119,44; 106,90; 63,56; 55,59; 45,27; 12,79. EM (m/z) :265 (M+, 80);247 (38); 234 (95); 221 (100); 159 (49). 30 3-butilamino-2-metilsulfanilquinoxalina (11 d)

Rendimento de 85%. RMN1H (400 MHz, CDCI3) δ : 7,77 (dd, J1 8,36 J2 1,49 Hz, 1H); 7,68 (dd, J1 8,36 J2 1,49 Hz, 1H); 7,47 - 7,43 (m, 1H); 7,34 - 7,30 (m, 1H); 3,62 - 3,57 (m, 2H); 2,73 (s, 3H), 1,73 - 1,65 (m, 2H); 1,47 (sext, J 7,71 Hz, 2H); 0,99 (t, J 7,71 5 Hz, 3H). RMN13C (100 MHz, CDCI3) δ : 146,71; 139,71; 137,29; 128,99; 127,96; 127,09; 125,97; 124,13; 41,20; 31,42; 20,27; 13,93; 12,73. EM (m/z) :247 (M+, 50);232 (51); 200 (68); 191 (100); 129 (45). 3-(2-hidroxietanolamina)-2-metilsulfanilquinoxalina (He), preparada conforme a publicação alemã DE1117586.

15 3-cicloexilamino-2-metilsulfanil-7-metoxiquinoxalina (11f)

Rendimento de 90%. 20 RMN1H (400 MHz, CDCI3) δ : 7,58 (d, J 8,91 Hz, 1H); 7,18 (d, J 2,93 Hz, 1H); 7,12 (dd, J1 8,91 J2 2,93 Hz, 1H); 4,13 - 4,06 (m, 1H); 3,90 (s, 3H); 2,72 (s, 3H), 2,15 - 2,09 (m, 2H); 1,80 - 1,73 (m, 2H); 1,79 - 1,62 (m, 3H); 1,53 - 1,43 (m, 2H); 1,33-1,24 (m, 3H). 25 RMN13C (100 MHz, CDCI3) δ : 156,61; 147,31; 146,73; 137,84; 134,77; 126,85; 119,09; 106,85; 55,59; 49,46; 33,05; 25,89; 24,88; 12,75. EM (m/z) :303 (M+, 48);288 (20); 221 (100); 188 (43); 55 (14). 3-butilamino-2-metilsulfanil-6-metoxiquinoxalina (11 g)

Rendimento de 92% RMN1H (400 MHz, CDCI3) δ : 7,66 (d, J 8,88 Hz, 1H); 7,06 (d, J 2,74 Hz, 1H); 6,97 (dd, J1 8,88 J2 2,74 Hz, 1H); 3,90 (s, 3H); 3,60 - 3,56 (m, 2H); 2,71 (s, 3H), 35 1,72 - 1,67 (m, 2H); 1,47 (sext, J 7,69 Hz, 2H); 0,99 (t, J 7,69 Hz, 3H). RMN13C (100 MHz, CDCI3) δ : 159,63; 149,46; 143,37; 141,08; 132,82; 128,09; 115,43; 105,50; 55,59; 41,20; 31,43; 20,30; 13,94; 12,83. EM (m/z) :277 (M+, 85);230 (84); 221 (100); 188 (90). 3-(2-hidroxietanolamina)-2-metilsulfanil-6-metoxiquinoxalina (11 h)

Rendimento de 80% RMN1H (400 MHz, CDCI3) δ : 7,67 (d, J 9,72 Hz, 1H); 7,01 - 6,98 (m, 2H); 3,92 - 3,87 (m, 5H); 3,77 - 3,73 (m, 2H); 2,71 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 159,82; 149,81; 143,54; 139,81; 133,09; 128,14; 116,11; 105,00; 63,61; 55,63; 45,30; 12,93. 3-cicloexilamino-2-metilsulfanil-6-metoxiquinoxalina (11 i)

Rendimento de 94% RMN1H (400 MHz, CDCI3) δ : 7,65 (d, J 8,75 Hz, 1H); 7,05 (d, J 2,40 Hz, 1H); 6,96 (dd, J1 8,75 J2 2,40 Hz, 1H); 4,15 - 4,12 (m, 1H); 3,90 (s, 3H); 2,70 (s, 3H), 2,15 - 2,10 (m, 2H); 1,80 - 1,64 (m, 3H); 1,53 - 1,43 (m, 2H); 1,34 - 1,26 (m, 3H). RMN13C (100 MHz, CDCI3) δ : 159,58; 148,64; 143,37; 141,14; 132,73; 128,05; 115,30; 105,48; 55,56; 49,42; 32,99; 25,86; 24,88; 12,86. EM (m/z) :303 (M+, 35);288 (22); 221 (100); 188 (56); 55 (18). 3-isobutilamino-2-metilsulfanil-6-metoxiquinoxalina (11j)

Rendimento de 89% RMN1H (400 MHz, CDCI3) δ : 7,66 (d, J 9,05 Hz, 1H); 7,06 (d, J 2,76 Hz, 1H); 6,96 (dd, J1 9,05 J2 2,76 Hz, 1H); 3,90 (s, 3H); 3,43 - 3,40 (m, 2H); 2,71 (s, 3H), 2,06 - 1,96 (m, 1H); 1,03 (d, J 6,65 Hz, 6H). RMN13C (100 MHz, CDCI3) δ : 159,63; 149,55; 143,39; 141,07; 132,84; 128,08; 115,42; 105,50; 55,59; 48,82; 28,12; 20,40; 12,83. EM (m/z) :277 (M+, 40);262 (18); 234 (55); 221 (100); 188 (50). 3-isopentilamino-2-metilsulfanil-6-metoxiquinoxalina (11 k)

Rendimento de 82% RMN1H (400 MHz, CDCI3) δ : 7,66 (d, J 8,90 Hz, 1H); 7,07 (d, J 2,85 Hz, 1H); 6,97 (dd, J1 8,90 J2 2,85 Hz, 1H); 3,90 (s, 3H); 3,62 - 3,57 (m, 2H); 2,70 (s, 3H), 1,81-1,69 (m, 1H); 1,63 - 1,58 (m, 2H); 0,99 (d, J 6,48 Hz, 6H). RMN13C (100 MHz, CDCI3) δ : 159,63; 149,43; 143,37; 141,10; 132,82; 128,09; 115,42; 105,53; 55,59; 39,77; 38,31; 26,07; 22,65; 12,81. EM (m/z) :291 (M+, 50);244 (30); 235 (35); 220 (100); 188 (52). 6-bromo-3-butilamino-2-metilsulfanilquinoxalina (111)

Rendimento de 65% RMN1H (400 MHz, CDCI3) δ : 7,83 (d, J 2,17 Hz, 1H); 7,60 (d, J 8,67 Hz, 1H); 7,38 (dd, J1 8,67 J2 2,17 Hz, 1H); 3,59-3,54 (m, 2H); 2,71 (s, 3H), 1,71 - 1,64 (m, 2H); 1,45 (sext, J 7,53 Hz, 2H); 0,98 (t, J 7,53 Hz, 3H). EM (m/z) :327 (M+2, 40); 325 (M+, 38);312 (48); 310 (45); 269 (100); 238 (45). 6-bromo-3-(2-hidroxietanolamina)-2-metilsulfanilquinoxalina (11 m)

Rendimento de 46% RMN 13C (100 MHz, DMSO-d6) δ : 149,11; 147,67; 140,29; 135,12; 128,46; 127,29; 126,59; 120,33; 58,87; 43,37; 12,30. 3-isobutilamino-2-metilsulfanil-7-metoxiquinoxalina (11 n)

Rendimento de 92% RMN1H (400 MHz, CDCI3) δ : 7,59 (d, J 8,84 Hz, 1H); 7,20 (d, J 2,94 Hz, 1H); 7,12 (dd, J1 8,84 J2 2,94 Hz, 1H); 3,89 (s, 3H); 3,41 - 3,48 (m, 2H); 2,73 (s, 3H), 2,04 - 1,95 (m, 1H); 1,02 (d, J 6,78 Hz, 6H). RMN13C (100 MHz, CDCI3) δ : 148,21; 146,77; 137,97; 134,71; 130,91; 126,87; 119,14; 106,89; 55,60; 48,90; 28,11; 20,42; 12,72. EM (m/z) :277 (M+, 47);262 (15); 234 (78); 221 (100); 188 (30). 6-cloro-3-butilamino-2-metilsulfanilquinoxalina (11o)

Rendimento de 92%. RMN1H (400 MHz, CDCI3) δ : 7,69 - 7,66 (m, 2H); 7,26 (dd, J1 7, 11 J2 2,42 Hz, 1H); 3,60 - 3,55 (m, 2H); 2,72 (s, 3H), 1,72 - 1,65 (m, 2H); 1,46 (sext, J 7,50 Hz, 2H); 0,99 (t, J 7,50 Hz, 3H). RMN13C (100 MHz, CDCI3) δ : 149,30; 147,05; 140,39; 135,74; 133,23; 128,11; 125,17; 124,62; 41,19; 31,33; 20,24; 13,88; 12,72. EM (m/z) :281 (M+, 53);266 (60); 234 (70); 225 (100); 192 (40). 3-cicloexilamino-2-metilsulfanil-6-cloroquinoxalina (11 p)

Rendimento de 90%. RMN1H (400 MHz, CDCI3) δ : 7,67 - 7,65 (m, 2H); 7,24 (dd, J1 8,69 J2 2,40 Hz, 1H); 4,16-4,07 (m, 1H); 2,71 (s, 3H), 2,13-2,09 (m, 2H); 1,80 - 1,65 (m, 3H); 1,53 - 1,43 (m, 2H); 1,34 - 1,23 (m, 3H). RMN13C (100 MHz, CDCI3) δ : 148,49; 147,06; 140,45; 135,66; 133,19; 128,09; 125,16; 124,50; 49,63; 32,87; 25,82; 24,85; 12,78. EM (m/z) :307 (M+, 28);292 (18); 225 (100); 192 (30); 55 (25). Os grupos metilsulfanil das quinoxalinas 11 são posteriormente oxidados para sulfona e sulfóxido nas quinoxalinas 12 e 13 respectivamente (Vide Figura 14, Esquema 9). Procedimento geral para a síntese de 3-amino-2-metilsulfonilquinoxalinas (12) Preparou-se uma solução de ácido m-cloroperbenzóico (0,25 mmol) em diclorometano (1 mL) e deixou-se sob agitação a temperatura de 0 °C. Em seguida adicionou-se lentamente, uma solução de 3-amino-2- metilsulfanilquinoxalina (11) (0,11 mmol) também em diclorometano (1 mL) e manteve-se a solução resultante sob agitação constante. Acompanhou-se a reação por cromatografia em camada fina, e verificou-se o término após 1-2 horas. Finalizou-se a reação despejando a solução em água gelada (2 mL). Lavou-se a fase orgânica com solução de bicarbonato de sódio 10% (m/V) (2 mL), água (2 mL) e solução saturada de cloreto de sódio (2 mL). Em seguida secou-se a fase orgânica com sulfato de sódio anidro e evaporou-se 0 solvente. O produto foi purificado por cromatografia em coluna, usando mistura de hexano e acetato de etila como eluente 2:1. 3-dimetilamino-2-metilsulfonil-7-metoxiquinoxalina (12a)

Rendimento de 15% RMN1H (400 MHz, CDCI3) δ : 7,69 (d, J 9,23 Hz, 1H); 7,38 (dd, J1 9,23 J2 2,91 Hz, 1H); 7,19 (d, J 2,91 Hz, 1H); 3,93 (s, 3H); 3,42 (s, 3H); 3,26 (s, 6H). RMN13C (100 MHz, CDCh) δ : 158,26; 149,71; 144,21; 138,37; 138,28; 127,55; 125,77; 106,33; 55,76; 42,01; 41,95. EM (m/z) :281 (M+, 72);252 (28); 202 (70); 159 (100); 219 (20); 117 (47). 3-butilamino-2-metilsulfonil-7-metoxiquinoxalina (12b)

Rendimento de 63% RMN1H (400 MHz, CDCI3) δ : 7,63 (d, J 9,26 Hz, 1H); 7,36 (dd, J1 9,26 J2 2,90 Hz, 1H); 7,20 (d, J 2,90 Hz, 1H); 3,90 (s, 3H); 3,58 - 3,53 (m, 2H); 3,38 (s, 3H), 1,72 -1,65 (m, 2H); 1,47 (sext, J 7,35 Hz, 2H); 0,98 (t, J 7,35 Hz, 3H). RMN13C (100 MHz, CDCI3) δ : 157,44; 147,42; 140,22; 140,10; 135,55; 127,24; 125,96; 107,09; 55,70; 40,81; 40,66; 31,14; 20,26; 13,85. EM (m/z) :309 (M+, 42);266 (100); 230 (62); 159 (90); 147 (30). 3-(2-hidroxietanolamina)-2-metilsulfonil-7-metoxiquinoxalina (12c)

Rendimento de 95% RMN1H (400 MHz, CDCI3) δ : 7,61 - 7,59 (m, 1H); 7,39 - 7,36 (m, 1H); 7,12 - 7,08 (m, 1H); 3,95 - 3,88 (m, 5H); 3,80 - 3,75 (m, 2H); 3,41 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 157,81; 140,68; 138,98; 135,95; 133,34; 126,82; 126,32; 107,09; 62,78; 55,70; 44,35; 40,59. 3-butilamino-2-metilsulfonilquinoxalina (12d)

Rendimento de 98% RMN1H (400 MHz, CDCI3) δ : 7,87 - 7,84 (m,1 H); 7,73 - 7,65 (m, 2H); 7,43 - 7,39 (m, 1H); 3,62 - 3,57 (m, 2H); 3,42 (s, 3H), 1,74 - 1,66 (m, 2H); 1,47 (sext, J 7,68 Hz, 2H); 0,98 (t, J 7,68 Hz, 3H). RMN13C (100 MHz, CDCI3) δ : 148,08; 144,06; 141,07; 134,62; 132,89; 129,50; 126,32; 125,31; 40,82; 40,48; 31,02; 20,24; 13,85. EM (m/z) :279 (M+, 30);236 (100); 200 (75); 129 (95); 102 (48). 3-(2-hidroxietanolamina)-2-metilsulfonilquinoxalina (12e)

Rendimento de 91% RMN1H (400 MHz, CDCI3) δ : 7,90 - 7,86 (m, 1H); 7,71 - 7,69 (m, 2H); 7,48 - 7,44 (m, 1H); 3,94 - 3,92 (m, 2H); 3,83 - 3,79 (m, 2H); 3,45 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 143,06; 141,51; 139,94; 133,29; 130,12; 129,53; 125,97; 125,93; 62,72; 44,41; 40,46. EM (m/z) :267 (M+, 35);236 (100); 129 (100); 102 (47). 3-cicloexilamino-2-metilsulfonil-7-metoxiquinoxalina (12f)

Rendimento de 65% RMN1H (400 MHz, CDCI3) δ : 7,61 (d, J 9,37 Hz, 1H); 7,35 (dd, J1 9,37 J2 2,86 Hz, 1H); 7,18 (d, J 2,86 Hz, 1H); 4,14 - 4,08 (m, 1H); 3,89 (s, 3H); 3,38 (s, 3H), 2,10-2,05 (m, 2H); 1,80 -1,62 (m, 4H); 1,50 - 1,32 (m, 4H). RMN13C (100 MHz, CDCI3) δ : 157,34; 146,68; 140,16; 140,04; 135,46; 127,21; 125,93; 107,03; 106,85; 55,70; 49,11; 40,72; 32,50; 25,80; 24,66. EM (m/z) :335 (M+, 50);278 (68); 253 (100); 174 (32); 55 (20). 3-butilamino-2-metilsulfonil-6-metoxiquinoxalina (12g)

Rendimento de 71% RMN1H (400 MHz, CDCI3) δ : 7,73 (d, J 9,03 Hz, 1H); 7,05 (dd, J1 9,03 J2 2,86 Hz, 1H); 7,02 (d, J 2,86 Hz, 1H); 3,95 (s, 3H); 3,60 - 3,56 (m, 2H); 3,38 (s, 3H), 1,73 - 1,68 (m, 2H); 1,48 (sext, J 7,85 Hz, 2H); 1,00 (t, J 7,85 Hz, 3H). RMN13C (100 MHZ, CDCI3) δ : 163,58; 148,61; 146,20; 137,67; 130,61; 130,41; 118,52; 104,38; 55,83; 40,79; 40,77; 31,08; 20,26; 13,87. EM (m/z) :309 (M+, 32);266 (99); 230 (80); 159 (100); 147 (28); 77 (37). 3-(2-hidroxietanolamina)-2-metilsulfonil-6-metoxiquinoxalina (12h)

Rendimento de 77% RMN1H (400 MHz, CDCI3) δ : 7,74 (d, J 9,02 Hz, 1H); 7,08 (dd, J1 9,02 J2 2,61 Hz, 1H); 6,97 (d, J 2,61 Hz, 1H); 3,94 - 3,90 (m, 5H); 3,80 - 3,76 (m, 2H); 3,39 (s, 3H). RMN13C (100 MHz, CDCI3) δ : 163,91; 149,03; 145,29; 137,91; 130,80; 130,67; 5 119,16; 104,04; 63,90; 55,94; 44,42; 40,78. 3-cicloexilamino-2-metilsulfonil-6-metoxiquinoxalina (12i)

10 Rendimento de 80% RMN1H (400 MHz, CDCI3) δ : 7,70 (d, J 9,08 Hz, 1H); 7,03 (dd, J1 9,08 J2 2,71 Hz, 1H); 6,99 (d, J 2,71 Hz, 1H); 4,18-4,11 (m, 1H); 3,95 (s, 3H); 3,36 (s, 3H), 2,10 - 2,05 (m, 2H); 1,80 - 1,75 (m, 2H); 1,67 - 1,64 (m, 2H); 1,52 - 1,28 (m, 4H). 15 RMN13C (100 MHz, CDCI3) δ : 163,55; 147,89; 146,31; 137,51; 130,59; 122,99; 118,44; 104,34; 55,81; 49,09; 40,86; 32,45; 25,77; 24,65. EM (m/z) :335 (M+, 37);278 (62); 253 (100); 174 (38); 162 (40). 3-isobutilamino-2-metilsulfonil-6-metoxiquinoxalina (12j)

Rendimento de 62% RMN1H (400 MHz, CDCI3) δ : 7,72 (d, J 9,08 Hz, 1H); 7,04 (dd, J1 9,08 J2 2,72 Hz, 1H); 7,00 (d, J 2,76 Hz, 1H); 3,94 (s, 3H); 3,43 - 3,40 (m, 2H); 3,37 (s, 3H), 25 2,07 - 1,97 (m, 1H); 1,04 (d, J 6,59 Hz, 6H). RMN13C (100 MHz, CDCI3) δ : 163,61; 148,78; 146,20; 137,64; 130,62; 130,46; 118,55; 104,37; 55,84; 48,43; 40,81; 27,94; 20,40. EM (m/z) :209 (M+, 18);266 (100); 253 (60); 159 (68). 30 3-isopentilamino-2-metilsulfonil-6-metoxiquinoxalina (12k)

Rendimento de 78% RMN1H (400 MHz, CDCI3) δ : 7,72 (d, J 8,89 Hz, 1H); 7,04 (dd, J1 8,89 J2 2,65 35 Hz, 1H); 7,01 (d, J 2,65 Hz, 1H); 3,95 (s, 3H); 3,61 - 3,56 (m, 2H); 3,37 (s, 3H), 1,81-1,71 (m, 1H); 1,63 - 1,58 (m, 2H); 0,98 (d, J 6,81 Hz, 6H). RMN13C (100 MHz, CDCI3) δ : 163,61; 148,61; 146,25; 137,64; 130,64; 130,43; 118,55; 104,40; 55,84; 40,80; 39,32; 37,93; 26,00; 22,57. EM (m/z) :323 (M+, 15);267 (100); 159 (62); 77 (12). 6-bromo-3-butilamino-2-metilsulfonilquinoxalina (12I)

Rendimento de 80% RMN1H (400 MHz, CDCI3) δ : 7,89 (d, J 2,04 Hz, 1H); 7,69 (d, J 9,02 Hz, 1H); 7,48 (dd, J1 9,02 J2 2,04 Hz, 1H); 3,59- 3,54 (m, 2H); 3,41 (s, 3H), 1,72 - 1,65 (m, 2H); 1,46 (sext, J 7,56 Hz, 2H); 0,98 (t, J 7,56 Hz, 3H). RMN13C (100 MHz, CDCI3) δ : 148,34; 144,68; 141,32; 133,26; 130,55; 128,87; 128,77; 127,51; 40,90; 40,47; 30,91; 20,22; 13,83. EM (m/z) :359 (M+2, 20); 357 (M+, 18);316 (100); 314 (97); 280 (80); 278 (84); 209 (80); 207 (78). 6-bromo-3-(2-hidroxietanolamina)-2-metilsulfonilquinoxalina (12m)

Rendimento de 95% RMN1H (400 MHz, CDCI3) δ : 7,88 (d, J 2,04 Hz, 1H); 7,72 (d, J 8,56 Hz, 1H); 7,52 (dd, J1 8,56 J2 2,04 Hz, 1H); 3,93 - 3,91 (m, 2H); 3,81 - 3,77 (m, 2H); 3,43 (s, 3H). RMN 13C (100 MHz, DMSO-d6) δ : 143,84; 133,54; 130,58; 130,16; 129,78; 129,46; 128,51; 127,91; 62,14; 44,11; 40,45. 3-isobutilamino-2-metilsulfonil-7-metoxiquinoxalina (12n)

Rendimento de 79% RMN1H (400 MHz, CDCI3) δ : 7,62 (d, J 9,41 Hz, 1H); 7,36 (dd, J1 9,41 J2 2,84 Hz, 1H); 7,20 (d, J 2,84 Hz, 1H); 3,90 (s, 3H); 3,42 - 3,38 (m, 5H); 2,06 - 1,96 (m, 1H); 1,03 (d, J 6,65 Hz, 6H). RMN13C (100 MHz, CDCI3) δ : 157,44; 147,56; 140,19; 129,84; 127,23; 126,01; 111,47; 107,07; 55,72; 48,51; 40,69; 27,94; 20,40. EM (m/z) :309 (M+, 23);266 (100); 253 (43); 176 (22); 159 (65). 6-cloro-3-butilamino-2-metilsulfonilquinoxalina (12o)

Rendimento de 75% RMN1H (400 MHz, CDCI3) δ : 7,77 (d, J 8,96 Hz, 1H); 7,71 (d, J 2,24 Hz, 1H); 7,35 (dd, J1 8,96 J2 2,24 Hz, 1H); 3,60 - 3,55 (m, 2H); 3,41 (s, 3H), 1,73 - 1,65 (m, 2H); 1,46 (sext, J 7,85 Hz, 2H); 0,98 (t, J 7,85 Hz, 3H). EM (m/z) :313 (M+, 23);270 (100); 234 (78); 163 (82); 136 (31). 3-cicloexilamino-2-metilsulfonil-6-cloroquinoxalina (12p)

Rendimento de 82% RMN1H (400 MHz, CDCI3) δ : 7,76 (d, J 8,79 Hz, 1H); 7,70 (d, J 1,96 Hz, 1H); 7,33 (dd, J1 8,79 J2 1,96 Hz, 1H); 4,15-4,11 (m, 1H); 3,40 (s, 3H), 2,09-2,05 (m, 2H); 1,80 - 1,75 (m, 2H); 1,49 - 1,25 (m, 6H). RMN13C (100 MHz, CDCI3) δ ; 147,64; 141,08; 138,93; 135,82; 132,97; 130,49; 126,15; 125,37; 49,39; 40,54; 32,25; 25,71; 24,59. EM (m/z) :339 (M+, 65);282 (98); 257 (100); 178 (55); 55 (53). Procedimento geral para a síntese de 3-amino-2-metilsulfoxilquinoxalinas (13) Preparou-se uma solução de ácido m-cloroperbenzóico (0,11 mmol) em diclorometano (1 mL) e deixou-se sob agitação a temperatura de 0 °C. Em seguida adicionou-se lentamente, uma solução da metilsulfanilquinoxalina (11) (0,11 mmol) também em diclorometano (1 mL) e manteve-se a solução resultante sob agitação constante. Acompanhou-se a reação por cromatografia em camada fina, e verificou-se o término após 1-2 horas. Finalizou-se a reação despejando a solução em água gelada (2 mL). Lavou-se a fase orgânica com solução de bicarbonato de sódio 10% (m/V) (2 mL), água (2 mL) e solução saturada de cloreto de sódio (2 mL). Em seguida secou-se a fase orgânica com sulfato de sódio anidro e evaporou-se 0 solvente. O produto foi purificado por cromatografia em coluna, usando mistura de hexano e acetato de etila 2:1 como eluente. cicloexil-2-metilsulfoxil-7-metoxiquinoxalina (13a)

Rendimento de 54% RMN1H (400 MHz, CDCI3) δ : 7,59 (d, J 8,92 Hz, 1H); 7,28 (dd, J1 8,92 J2 2,98 Hz, 1H); 7,12 (d, J 2,98 Hz, 1H); 4,13-4,09 (m, 1H); 3,88 (s, 3H); 3,01 (s, 3H); 2,10 - 2,05 (m, 2H); 1,78 - 1,74 (m, 2H); 1,48 -1,24 (m, 6H). RMN13C (100 MHz, CDCh) δ : 156,90; 149,64; 145,81; 138,24; 136,07; 127,12; 123,87; 107,08; 55,64; 48,61; 39,09; 32,72; 32,34; 25,88; 24,70. EM (m/z) :319 (M+, 23);302 (100); 147 (23); 55 (30). 3-cicloexil-6-cloro-2-metilsulfoxilquinoxalina (13b)

Rendimento de 87% RMN1H (400 MHz, CDCI3) δ : 7,96 - 7,94 (m, 1H); 7,66 - 7,64 (m, 1H); 7,29 - 7,25 (m, 1H); 4,16 - 4,07 (m, 1H); 3,02 (s, 3H); 2,08 - 2,05 (m, 2H); 1,78 - 1,74 (m, 2H); 1,52 - 1,26 (m, 6H). RMN13C (100 MHz, CDCh) δ : 150,77; 146,59; 143,19; 137,31; 133,85; 129,84; 125,31; 125,25; 48,81; 39,45; 32,43; 32,12; 25,77; 24,61. EM (m/z) :323 (M+, 12);306 (100); 178 (38); 55 (65). Utilizando como reagente a 3-fenil-2-metilsulfanil-7-metoxiquinoxalina (4a), anteriormente preparada, sintetizou-se a 3-fenil-2-metilsulfonil-7- metoxiquinoxalina (8a), empregada em reações de substituição sob irradiação de microondas para produzir as 3-aril-2-aminoquinoxalinas (14) (Vide Figura 11, que ilustra 0 Esquema 6). Procedimento geral para a síntese de 3-aril-2-aminoquinoxalinas (14) Preparou-se uma mistura de 3-fenil-2-metilsulfonil-7-metoxiquinoxalina (8a) (1mmol) e amina (1 mL) em um tubo para reações no reator de micro- ondas. Irradiou-se a mistura na temperatura de 130 °C por 30 minutos. Purificou-se o produto por coluna cromatográfica, usando mistura de hexano/acetato 2:1 como eluente. 2-butilamino-3-fenil-7-metoxiquinoxalina (14a), preparada conforme o artigo por Venkatesh citado acima.

Rendimento de 79% 2-(2-hidroxietanamina)-3-fenil-7-metoxiquinoxalina (14b)

Rendimento de 82%. RMN1H (400 MHz, CDCI3) δ : 7,79 (d, J 9,61 Hz, 1H); 7,69 - 7,66 (m, 2H); 7,56 - 7,49 (m, 3H); 7,06 - 7,03 (m, 2H); 3,92 (s, 3H); 3,88 - 3,86 (m, 2H); 3,70 - 3,67 (m, 2H). RMN13C (100 MHz, CDCI3) δ : 161,23; 150,99; 143,90; 142,00; 136,64; 132,75; 129,89; 129,59; 129,38; 128,47; 116,85; 104,55; 63,86; 55,72; 45,32. 2-(2-piperidiniletilamina)-3-fenil-7-metoxiquinoxalina (14c)

Rendimento de 86%. RMN1H (400 MHz, CDCI3) δ : 7,78 (d, J 9,06 Hz, 1H); 7,72 - 7,70 (m, 2H); 7,56 - 7,45 (m, 3H); 7,09 (d, J 2,88 Hz, 1H); 7,00 (dd, J1 9,06 J2 2,88 Hz, 1H); 3,93 (s, 3H); 3,60 -3,56 (m, 2H); 2,57 (t, J 6,19 Hz, 2H); 2,42 - 2,34 (m, 4H); 1,49 - 1,41 (m , 6H). RMN13C (100 MHz, CDCI3) δ : 161,19; 150,85; 148,10; 144,12; 137,37; 132,68; 130,16; 129,65; 129,59; 128,73; 116,37; 105,40; 55,93; 41,37; 31,69; 20,61; 14,19. EM (m/z) :111 (52);98 (100).The product was purified by column chromatography, using a 2: 1 hexane / acetate mixture as the eluent. 3-dimethylamino-2-methylsulfanyl-7-methoxyquinoxaline (11a)

10 Yield 82% NMR1H (400 MHz, CDCl3) δ: 7.68 (d, J 8.93 Hz, 1H); 7.20 (d, J 2.82 Hz, 1H); 7.15 (dd, J1 8.93 J2 2.82 Hz, 1H); 3.90 (s, 3H); 3.00 (s, 6H); 2.63 (s, 3H). NMR13C (100 MHz, CDCl3) δ: 158.46; 153.45; 152.27; 140.14; 133.71; 127.98; 119.42; 106.25; 55.59; 41.58; 13.35. 15 MS (m / z): 249 (M +, 39); 234 (100); 219 (20); 117 (21). 3-butylamino-2-methylsulfanyl-7-methoxyquinoxaline (11b), prepared according to the article by Venkatesh cited above.

20 67% yield 3- (2-hydroxyethanolamine) -2-methylsulfanyl-7-methoxyquinoxaline (11c)

Yield 44%. 25 1 H NMR (400 MHz, CDCl 3) δ: 7.54 (d, J 8.87 Hz, 1H); 7.19-7.11 (m, 2H); 3.91 - 3.85 (m, 5H); 3.75 - 3.70 (m, 2H); 2.72 (s, 3H). 13 C NMR (100 MHz, CDCl 3) δ: 157.11; 148.32; 146.99; 138.25; 133.37; 126.34; 119.44; 106.90; 63.56; 55.59; 45.27; 12.79. MS (m / z): 265 (M +, 80); 247 (38); 234 (95); 221 (100); 159 (49). 30 3-butylamino-2-methylsulfanylquinoxaline (11 d)

Yield 85%. 1 H NMR (400 MHz, CDCl 3) δ: 7.77 (dd, J1 8.36 J2 1.49 Hz, 1H); 7.68 (dd, J1 8.36 J2 1.49 Hz, 1H); 7.47 - 7.43 (m, 1H); 7.34 - 7.30 (m, 1H); 3.62 - 3.57 (m, 2H); 2.73 (s, 3H), 1.73 - 1.65 (m, 2H); 1.47 (sext, J 7.71 Hz, 2H); 0.99 (t, J 7.71 5 Hz, 3H). NMR13C (100 MHz, CDCl3) δ: 146.71; 139.71; 137.29; 128.99; 127.96; 127.09; 125.97; 124.13; 41.20; 31.42; 20.27; 13.93; 12.73. MS (m / z): 247 (M +, 50); 232 (51); 200 (68); 191 (100); 129 (45). 3- (2-hydroxyethanolamine) -2-methylsulfanylquinoxaline (He), prepared according to the German publication DE1117586.

15 3-cyclohexylamino-2-methylsulfanyl-7-methoxyquininoxaline (11f)

Yield 90%. 20 1 H NMR (400 MHz, CDCl 3) δ: 7.58 (d, J 8.91 Hz, 1H); 7.18 (d, J 2.93 Hz, 1H); 7.12 (dd, J1 8.91 J2 2.93 Hz, 1H); 4.13 - 4.06 (m, 1H); 3.90 (s, 3H); 2.72 (s, 3H), 2.15 - 2.09 (m, 2H); 1.80 - 1.73 (m, 2H); 1.79 - 1.62 (m, 3H); 1.53 - 1.43 (m, 2H); 1.33-1.24 (m, 3H). 25 NMR13C (100 MHz, CDCl3) δ: 156.61; 147.31; 146.73; 137.84; 134.77; 126.85; 119.09; 106.85; 55.59; 49.46; 33.05; 25.89; 24.88; 12.75. MS (m / z): 303 (M +, 48); 288 (20); 221 (100); 188 (43); 55 (14). 3-butylamino-2-methylsulfanyl-6-methoxyquinoxaline (11 g)

Yield 92% NMR1H (400 MHz, CDCl3) δ: 7.66 (d, J 8.88 Hz, 1H); 7.06 (d, J 2.74 Hz, 1H); 6.97 (dd, J1 8.88 J2 2.74 Hz, 1H); 3.90 (s, 3H); 3.60 - 3.56 (m, 2H); 2.71 (s, 3H), 35 1.72 - 1.67 (m, 2H); 1.47 (sext, J 7.69 Hz, 2H); 0.99 (t, J 7.69 Hz, 3H). 13 C NMR (100 MHz, CDCl 3) δ: 159.63; 149.46; 143.37; 141.08; 132.82; 128.09; 115.43; 105.50; 55.59; 41.20; 31.43; 20.30; 13.94; 12.83. MS (m / z): 277 (M +, 85); 230 (84); 221 (100); 188 (90). 3- (2-hydroxyethanolamine) -2-methylsulfanyl-6-methoxyquinoxaline (11 h)

Yield 80% NMR1H (400 MHz, CDCl3) δ: 7.67 (d, J 9.72 Hz, 1H); 7.01 - 6.98 (m, 2H); 3.92 - 3.87 (m, 5H); 3.77 - 3.73 (m, 2H); 2.71 (s, 3H). NMR13C (100 MHz, CDCl3) δ: 159.82; 149.81; 143.54; 139.81; 133.09; 128.14; 116.11; 105.00; 63.61; 55.63; 45.30; 12.93. 3-cyclohexylamino-2-methylsulfanyl-6-methoxyquinoxaline (11 i)

Yield 94% NMR1H (400 MHz, CDCl3) δ: 7.65 (d, J 8.75 Hz, 1H); 7.05 (d, J 2.40 Hz, 1H); 6.96 (dd, J1 8.75 J2 2.40 Hz, 1H); 4.15 - 4.12 (m, 1H); 3.90 (s, 3H); 2.70 (s, 3H), 2.15 - 2.10 (m, 2H); 1.80 - 1.64 (m, 3H); 1.53 - 1.43 (m, 2H); 1.34 - 1.26 (m, 3H). NMR13C (100 MHz, CDCl3) δ: 159.58; 148.64; 143.37; 141.14; 132.73; 128.05; 115.30; 105.48; 55.56; 49.42; 32.99; 25.86; 24.88; 12.86. MS (m / z): 303 (M +, 35); 288 (22); 221 (100); 188 (56); 55 (18). 3-isobutylamino-2-methylsulfanyl-6-methoxyquinoxaline (11j)

Yield 89% NMR1H (400 MHz, CDCl3) δ: 7.66 (d, J 9.05 Hz, 1H); 7.06 (d, J 2.76 Hz, 1H); 6.96 (dd, J1 9.05 J2 2.76 Hz, 1H); 3.90 (s, 3H); 3.43 - 3.40 (m, 2H); 2.71 (s, 3H), 2.06 - 1.96 (m, 1H); 1.03 (d, J 6.65 Hz, 6H). 13 C NMR (100 MHz, CDCl 3) δ: 159.63; 149.55; 143.39; 141.07; 132.84; 128.08; 115.42; 105.50; 55.59; 48.82; 28.12; 20.40; 12.83. MS (m / z): 277 (M +, 40); 262 (18); 234 (55); 221 (100); 188 (50). 3-isopentylamino-2-methylsulfanyl-6-methoxyquinoxaline (11 k)

Yield 82% NMR1H (400 MHz, CDCl3) δ: 7.66 (d, J 8.90 Hz, 1H); 7.07 (d, J 2.85 Hz, 1H); 6.97 (dd, J1 8.90 J2 2.85 Hz, 1H); 3.90 (s, 3H); 3.62 - 3.57 (m, 2H); 2.70 (s, 3H), 1.81 - 1.69 (m, 1H); 1.63 - 1.58 (m, 2H); 0.99 (d, J 6.48 Hz, 6H). 13 C NMR (100 MHz, CDCl 3) δ: 159.63; 149.43; 143.37; 141.10; 132.82; 128.09; 115.42; 105.53; 55.59; 39.77; 38.31; 26.07; 22.65; 12.81. MS (m / z): 291 (M +, 50); 244 (30); 235 (35); 220 (100); 188 (52). 6-bromo-3-butylamino-2-methylsulfanylquinoxaline (111)

Yield 65% NMR1H (400 MHz, CDCl3) δ: 7.83 (d, J 2.17 Hz, 1H); 7.60 (d, J 8.67 Hz, 1H); 7.38 (dd, J1 8.67 J2 2.17 Hz, 1H); 3.59-3.54 (m, 2H); 2.71 (s, 3H), 1.71 - 1.64 (m, 2H); 1.45 (sext, J 7.53 Hz, 2H); 0.98 (t, J 7.53 Hz, 3H). MS (m / z): 327 (M + 2.40); 325 (M +, 38); 312 (48); 310 (45); 269 (100); 238 (45). 6-bromo-3- (2-hydroxyethanolamine) -2-methylsulfanylquinoxaline (11 m)

Yield 46% 13C NMR (100 MHz, DMSO-d6) δ: 149.11; 147.67; 140.29; 135.12; 128.46; 127.29; 126.59; 120.33; 58.87; 43.37; 12.30. 3-isobutylamino-2-methylsulfanyl-7-methoxyquininoxaline (11 n)

Yield 92% NMR1H (400 MHz, CDCl3) δ: 7.59 (d, J 8.84 Hz, 1H); 7.20 (d, J 2.94 Hz, 1H); 7.12 (dd, J1 8.84 J2 2.94 Hz, 1H); 3.89 (s, 3H); 3.41 - 3.48 (m, 2H); 2.73 (s, 3H), 2.04 - 1.95 (m, 1H); 1.02 (d, J 6.78 Hz, 6H). NMR13C (100 MHz, CDCl3) δ: 148.21; 146.77; 137.97; 134.71; 130.91; 126.87; 119.14; 106.89; 55.60; 48.90; 28.11; 20.42; 12.72. MS (m / z): 277 (M +, 47); 262 (15); 234 (78); 221 (100); 188 (30). 6-chloro-3-butylamino-2-methylsulfanylquinoxaline (11o)

Yield 92%. 1 H NMR (400 MHz, CDCl 3) δ: 7.69 - 7.66 (m, 2H); 7.26 (dd, J1 7, 11 J2 2.42 Hz, 1H); 3.60 - 3.55 (m, 2H); 2.72 (s, 3H), 1.72 - 1.65 (m, 2H); 1.46 (sext, J 7.50 Hz, 2H); 0.99 (t, J 7.50 Hz, 3H). NMR13C (100 MHz, CDCl3) δ: 149.30; 147.05; 140.39; 135.74; 133.23; 128.11; 125.17; 124.62; 41.19; 31.33; 20.24; 13.88; 12.72. MS (m / z): 281 (M +, 53); 266 (60); 234 (70); 225 (100); 192 (40). 3-cyclohexylamino-2-methylsulfanyl-6-chloroquinoxaline (11 p)

Yield 90%. 1 H NMR (400 MHz, CDCl 3) δ: 7.67 - 7.65 (m, 2H); 7.24 (dd, J1 8.69 J2 2.40 Hz, 1H); 4.16-4.07 (m, 1H); 2.71 (s, 3H), 2.13-2.09 (m, 2H); 1.80 - 1.65 (m, 3H); 1.53 - 1.43 (m, 2H); 1.34 - 1.23 (m, 3H). NMR13C (100 MHz, CDCl3) δ: 148.49; 147.06; 140.45; 135.66; 133.19; 128.09; 125.16; 124.50; 49.63; 32.87; 25.82; 24.85; 12.78. MS (m / z): 307 (M +, 28); 292 (18); 225 (100); 192 (30); 55 (25). The methylsulfanyl groups of quinoxaline 11 are subsequently oxidized to sulfone and sulfoxide in quinoxaline 12 and 13 respectively (See Figure 14, Scheme 9). General procedure for the synthesis of 3-amino-2-methylsulfonylquinoxaline (12) A solution of m-chloroperbenzoic acid (0.25 mmol) in dichloromethane (1 mL) was prepared and left under stirring at 0 ° C . Then a solution of 3-amino-2-methylsulfanylquinoxaline (11) (0.11 mmol) also in dichloromethane (1 ml) was added slowly and the resulting solution was kept under constant stirring. The reaction was monitored by thin layer chromatography, and the completion was verified after 1-2 hours. The reaction was terminated by pouring the solution into ice water (2 mL). The organic phase was washed with 10% sodium bicarbonate solution (m / V) (2 ml), water (2 ml) and saturated sodium chloride solution (2 ml). Then the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated. The product was purified by column chromatography, using a mixture of hexane and ethyl acetate as eluent 2: 1. 3-dimethylamino-2-methylsulfonyl-7-methoxyquinoxaline (12a)

Yield 15% NMR1H (400 MHz, CDCl3) δ: 7.69 (d, J 9.23 Hz, 1H); 7.38 (dd, J1 9.23 J2 2.91 Hz, 1H); 7.19 (d, J 2.91 Hz, 1H); 3.93 (s, 3H); 3.42 (s, 3H); 3.26 (s, 6H). NMR13C (100 MHz, CDCh) δ: 158.26; 149.71; 144.21; 138.37; 138.28; 127.55; 125.77; 106.33; 55.76; 42.01; 41.95. MS (m / z): 281 (M +, 72); 252 (28); 202 (70); 159 (100); 219 (20); 117 (47). 3-butylamino-2-methylsulfonyl-7-methoxyquinoxaline (12b)

Yield 63% NMR1H (400 MHz, CDCl3) δ: 7.63 (d, J 9.26 Hz, 1H); 7.36 (dd, J1 9.26 J2 2.90 Hz, 1H); 7.20 (d, J 2.90 Hz, 1H); 3.90 (s, 3H); 3.58 - 3.53 (m, 2H); 3.38 (s, 3H), 1.72 -1.65 (m, 2H); 1.47 (sext, J 7.35 Hz, 2H); 0.98 (t, J 7.35 Hz, 3H). NMR13C (100 MHz, CDCl3) δ: 157.44; 147.42; 140.22; 140.10; 135.55; 127.24; 125.96; 107.09; 55.70; 40.81; 40.66; 31.14; 20.26; 13.85. MS (m / z): 309 (M +, 42); 266 (100); 230 (62); 159 (90); 147 (30). 3- (2-hydroxyethanolamine) -2-methylsulfonyl-7-methoxyquinoxaline (12c)

Yield 95% NMR1H (400 MHz, CDCl3) δ: 7.61 - 7.59 (m, 1H); 7.39 - 7.36 (m, 1H); 7.12 - 7.08 (m, 1H); 3.95 - 3.88 (m, 5H); 3.80 - 3.75 (m, 2H); 3.41 (s, 3H). NMR13C (100 MHz, CDCl3) δ: 157.81; 140.68; 138.98; 135.95; 133.34; 126.82; 126.32; 107.09; 62.78; 55.70; 44.35; 40.59. 3-butylamino-2-methylsulfonylquinoxaline (12d)

Yield 98% NMR1H (400 MHz, CDCl3) δ: 7.87 - 7.84 (m, 1 H); 7.73 - 7.65 (m, 2H); 7.43 - 7.39 (m, 1H); 3.62 - 3.57 (m, 2H); 3.42 (s, 3H), 1.74 - 1.66 (m, 2H); 1.47 (sext, J 7.68 Hz, 2H); 0.98 (t, J 7.68 Hz, 3H). NMR13C (100 MHz, CDCl3) δ: 148.08; 144.06; 141.07; 134.62; 132.89; 129.50; 126.32; 125.31; 40.82; 40.48; 31.02; 20.24; 13.85. MS (m / z): 279 (M +, 30); 236 (100); 200 (75); 129 (95); 102 (48). 3- (2-hydroxyethanolamine) -2-methylsulfonylquinoxaline (12e)

Yield 91% NMR1H (400 MHz, CDCl3) δ: 7.90 - 7.86 (m, 1H); 7.71 - 7.69 (m, 2H); 7.48 - 7.44 (m, 1H); 3.94 - 3.92 (m, 2H); 3.83 - 3.79 (m, 2H); 3.45 (s, 3H). NMR13C (100 MHz, CDCl3) δ: 143.06; 141.51; 139.94; 133.29; 130.12; 129.53; 125.97; 125.93; 62.72; 44.41; 40.46. MS (m / z): 267 (M +, 35); 236 (100); 129 (100); 102 (47). 3-cyclohexylamino-2-methylsulfonyl-7-methoxyquinoxaline (12f)

Yield 65% NMR1H (400 MHz, CDCl3) δ: 7.61 (d, J 9.37 Hz, 1H); 7.35 (dd, J1 9.37 J2 2.86 Hz, 1H); 7.18 (d, J 2.86 Hz, 1H); 4.14 - 4.08 (m, 1H); 3.89 (s, 3H); 3.38 (s, 3H), 2.10-2.05 (m, 2H); 1.80 -1.62 (m, 4H); 1.50 - 1.32 (m, 4H). NMR13C (100 MHz, CDCl3) δ: 157.34; 146.68; 140.16; 140.04; 135.46; 127.21; 125.93; 107.03; 106.85; 55.70; 49.11; 40.72; 32.50; 25.80; 24.66. MS (m / z): 335 (M +, 50); 278 (68); 253 (100); 174 (32); 55 (20). 3-butylamino-2-methylsulfonyl-6-methoxyquinoxaline (12g)

Yield 71% NMR1H (400 MHz, CDCl3) δ: 7.73 (d, J 9.03 Hz, 1H); 7.05 (dd, J1 9.03 J2 2.86 Hz, 1H); 7.02 (d, J 2.86 Hz, 1H); 3.95 (s, 3H); 3.60 - 3.56 (m, 2H); 3.38 (s, 3H), 1.73 - 1.68 (m, 2H); 1.48 (sext, J 7.85 Hz, 2H); 1.00 (t, J 7.85 Hz, 3H). NMR13C (100 MHZ, CDCl3) δ: 163.58; 148.61; 146.20; 137.67; 130.61; 130.41; 118.52; 104.38; 55.83; 40.79; 40.77; 31.08; 20.26; 13.87. MS (m / z): 309 (M +, 32); 266 (99); 230 (80); 159 (100); 147 (28); 77 (37). 3- (2-hydroxyethanolamine) -2-methylsulfonyl-6-methoxyquinoxaline (12h)

Yield 77% NMR1H (400 MHz, CDCl3) δ: 7.74 (d, J 9.02 Hz, 1H); 7.08 (dd, J1 9.02 J2 2.61 Hz, 1H); 6.97 (d, J 2.61 Hz, 1H); 3.94 - 3.90 (m, 5H); 3.80 - 3.76 (m, 2H); 3.39 (s, 3H). NMR13C (100 MHz, CDCl3) δ: 163.91; 149.03; 145.29; 137.91; 130.80; 130.67; 5 119.16; 104.04; 63.90; 55.94; 44.42; 40.78. 3-cyclohexylamino-2-methylsulfonyl-6-methoxyquinoxaline (12i)

10 Yield 80% NMR1H (400 MHz, CDCl3) δ: 7.70 (d, J 9.08 Hz, 1H); 7.03 (dd, J1 9.08 J2 2.71 Hz, 1H); 6.99 (d, J 2.71 Hz, 1H); 4.18-4.11 (m, 1H); 3.95 (s, 3H); 3.36 (s, 3H), 2.10 - 2.05 (m, 2H); 1.80 - 1.75 (m, 2H); 1.67 - 1.64 (m, 2H); 1.52 - 1.28 (m, 4H). 15 NMR13C (100 MHz, CDCl3) δ: 163.55; 147.89; 146.31; 137.51; 130.59; 122.99; 118.44; 104.34; 55.81; 49.09; 40.86; 32.45; 25.77; 24.65. MS (m / z): 335 (M +, 37); 278 (62); 253 (100); 174 (38); 162 (40). 3-isobutylamino-2-methylsulfonyl-6-methoxyquininoxaline (12j)

Yield 62% NMR1H (400 MHz, CDCl3) δ: 7.72 (d, J 9.08 Hz, 1H); 7.04 (dd, J1 9.08 J2 2.72 Hz, 1H); 7.00 (d, J 2.76 Hz, 1H); 3.94 (s, 3H); 3.43 - 3.40 (m, 2H); 3.37 (s, 3H), 25 2.07 - 1.97 (m, 1H); 1.04 (d, J 6.59 Hz, 6H). NMR13C (100 MHz, CDCl3) δ: 163.61; 148.78; 146.20; 137.64; 130.62; 130.46; 118.55; 104.37; 55.84; 48.43; 40.81; 27.94; 20.40. MS (m / z): 209 (M +, 18); 266 (100); 253 (60); 159 (68). 30 3-isopentylamino-2-methylsulfonyl-6-methoxyquinoxaline (12k)

Yield 78% NMR1H (400 MHz, CDCl3) δ: 7.72 (d, J 8.89 Hz, 1H); 7.04 (dd, J1 8.89 J2 2.65 35 Hz, 1H); 7.01 (d, J 2.65 Hz, 1H); 3.95 (s, 3H); 3.61 - 3.56 (m, 2H); 3.37 (s, 3H), 1.81 to 1.71 (m, 1H); 1.63 - 1.58 (m, 2H); 0.98 (d, J 6.81 Hz, 6H). NMR13C (100 MHz, CDCl3) δ: 163.61; 148.61; 146.25; 137.64; 130.64; 130.43; 118.55; 104.40; 55.84; 40.80; 39.32; 37.93; 26.00; 22.57. MS (m / z): 323 (M +, 15); 267 (100); 159 (62); 77 (12). 6-bromo-3-butylamino-2-methylsulfonylquinoxaline (12I)

Yield 80% NMR1H (400 MHz, CDCl3) δ: 7.89 (d, J 2.04 Hz, 1H); 7.69 (d, J 9.02 Hz, 1H); 7.48 (dd, J1 9.02 J2 2.04 Hz, 1H); 3.59 - 3.54 (m, 2H); 3.41 (s, 3H), 1.72 - 1.65 (m, 2H); 1.46 (sext, J 7.56 Hz, 2H); 0.98 (t, J 7.56 Hz, 3H). NMR13C (100 MHz, CDCl3) δ: 148.34; 144.68; 141.32; 133.26; 130.55; 128.87; 128.77; 127.51; 40.90; 40.47; 30.91; 20.22; 13.83. MS (m / z): 359 (M + 2.20); 357 (M +, 18); 316 (100); 314 (97); 280 (80); 278 (84); 209 (80); 207 (78). 6-bromo-3- (2-hydroxyethanolamine) -2-methylsulfonylquinoxaline (12m)

Yield 95% NMR1H (400 MHz, CDCl3) δ: 7.88 (d, J 2.04 Hz, 1H); 7.72 (d, J 8.56 Hz, 1H); 7.52 (dd, J1 8.56 J2 2.04 Hz, 1H); 3.93 - 3.91 (m, 2H); 3.81 - 3.77 (m, 2H); 3.43 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 143.84; 133.54; 130.58; 130.16; 129.78; 129.46; 128.51; 127.91; 62.14; 44.11; 40.45. 3-isobutylamino-2-methylsulfonyl-7-methoxyquinoxaline (12n)

Yield 79% NMR1H (400 MHz, CDCl3) δ: 7.62 (d, J 9.41 Hz, 1H); 7.36 (dd, J1 9.41 J2 2.84 Hz, 1H); 7.20 (d, J 2.84 Hz, 1H); 3.90 (s, 3H); 3.42 - 3.38 (m, 5H); 2.06 - 1.96 (m, 1H); 1.03 (d, J 6.65 Hz, 6H). NMR13C (100 MHz, CDCl3) δ: 157.44; 147.56; 140.19; 129.84; 127.23; 126.01; 111.47; 107.07; 55.72; 48.51; 40.69; 27.94; 20.40. MS (m / z): 309 (M +, 23); 266 (100); 253 (43); 176 (22); 159 (65). 6-chloro-3-butylamino-2-methylsulfonylquinoxaline (12o)

Yield 75% NMR1H (400 MHz, CDCl3) δ: 7.77 (d, J 8.96 Hz, 1H); 7.71 (d, J 2.24 Hz, 1H); 7.35 (dd, J1 8.96 J2 2.24 Hz, 1H); 3.60 - 3.55 (m, 2H); 3.41 (s, 3H), 1.73 - 1.65 (m, 2H); 1.46 (sext, J 7.85 Hz, 2H); 0.98 (t, J 7.85 Hz, 3H). MS (m / z): 313 (M +, 23); 270 (100); 234 (78); 163 (82); 136 (31). 3-cyclohexylamino-2-methylsulfonyl-6-chloroquinoxaline (12p)

Yield 82% NMR1H (400 MHz, CDCl3) δ: 7.76 (d, J 8.79 Hz, 1H); 7.70 (d, J 1.96 Hz, 1H); 7.33 (dd, J1 8.79 J2 1.96 Hz, 1H); 4.15-4.11 (m, 1H); 3.40 (s, 3H), 2.09-2.05 (m, 2H); 1.80 - 1.75 (m, 2H); 1.49 - 1.25 (m, 6H). NMR13C (100 MHz, CDCl3) δ; 147.64; 141.08; 138.93; 135.82; 132.97; 130.49; 126.15; 125.37; 49.39; 40.54; 32.25; 25.71; 24.59. MS (m / z): 339 (M +, 65); 282 (98); 257 (100); 178 (55); 55 (53). General procedure for the synthesis of 3-amino-2-methylsulfoxyquinoxaline (13) A solution of m-chloroperbenzoic acid (0.11 mmol) in dichloromethane (1 ml) was prepared and left under stirring at 0 ° C . Then a solution of methylsulfanylquinoxaline (11) (0.11 mmol) also in dichloromethane (1 ml) was added slowly and the resulting solution was kept under constant stirring. The reaction was monitored by thin layer chromatography, and the completion was verified after 1-2 hours. The reaction was terminated by pouring the solution into ice water (2 mL). The organic phase was washed with 10% sodium bicarbonate solution (m / V) (2 ml), water (2 ml) and saturated sodium chloride solution (2 ml). Then the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated. The product was purified by column chromatography, using a mixture of hexane and ethyl acetate 2: 1 as eluent. cyclohexyl-2-methylsulfoxyl-7-methoxyquinoxaline (13a)

Yield 54% NMR1H (400 MHz, CDCl3) δ: 7.59 (d, J 8.92 Hz, 1H); 7.28 (dd, J1 8.92 J2 2.98 Hz, 1H); 7.12 (d, J 2.98 Hz, 1H); 4.13-4.09 (m, 1H); 3.88 (s, 3H); 3.01 (s, 3H); 2.10 - 2.05 (m, 2H); 1.78 - 1.74 (m, 2H); 1.48 -1.24 (m, 6H). NMR13C (100 MHz, CDCh) δ: 156.90; 149.64; 145.81; 138.24; 136.07; 127.12; 123.87; 107.08; 55.64; 48.61; 39.09; 32.72; 32.34; 25.88; 24.70. MS (m / z): 319 (M +, 23); 302 (100); 147 (23); 55 (30). 3-cyclohexyl-6-chloro-2-methylsulfoxyquinoxaline (13b)

Yield 87% NMR1H (400 MHz, CDCl3) δ: 7.96 - 7.94 (m, 1H); 7.66 - 7.64 (m, 1H); 7.29 - 7.25 (m, 1H); 4.16 - 4.07 (m, 1H); 3.02 (s, 3H); 2.08 - 2.05 (m, 2H); 1.78 - 1.74 (m, 2H); 1.52 - 1.26 (m, 6H). NMR13C (100 MHz, CDCh) δ: 150.77; 146.59; 143.19; 137.31; 133.85; 129.84; 125.31; 125.25; 48.81; 39.45; 32.43; 32.12; 25.77; 24.61. MS (m / z): 323 (M +, 12); 306 (100); 178 (38); 55 (65). Using 3-phenyl-2-methylsulfanyl-7-methoxyquinoxaline (4a), previously prepared, 3-phenyl-2-methylsulfonyl-7-methoxyquinoxaline (8a), used in substitution reactions under microwave irradiation, was synthesized to produce the 3-aryl-2-aminoquinoxaline (14) (See Figure 11, which illustrates Scheme 6). General procedure for the synthesis of 3-aryl-2-aminoquinoxaline (14) A mixture of 3-phenyl-2-methylsulfonyl-7-methoxyquininoxaline (8a) (1mmol) and amine (1 mL) was prepared in a reaction tube in the microwave reactor. The mixture was irradiated at 130 ° C for 30 minutes. The product was purified by column chromatography, using a 2: 1 hexane / acetate mixture as the eluent. 2-butylamino-3-phenyl-7-methoxyquinoxaline (14a), prepared according to the article by Venkatesh cited above.

79% Yield 2- (2-hydroxyethanamine) -3-phenyl-7-methoxyquinoxaline (14b)

82% yield. 1 H NMR (400 MHz, CDCl 3) δ: 7.79 (d, J 9.61 Hz, 1H); 7.69 - 7.66 (m, 2H); 7.56 - 7.49 (m, 3H); 7.06 - 7.03 (m, 2H); 3.92 (s, 3H); 3.88 - 3.86 (m, 2H); 3.70 - 3.67 (m, 2H). NMR13C (100 MHz, CDCl3) δ: 161.23; 150.99; 143.90; 142.00; 136.64; 132.75; 129.89; 129.59; 129.38; 128.47; 116.85; 104.55; 63.86; 55.72; 45.32. 2- (2-piperidinylethylamine) -3-phenyl-7-methoxyquinoxaline (14c)

86% yield. 1 H NMR (400 MHz, CDCl 3) δ: 7.78 (d, J 9.06 Hz, 1H); 7.72 - 7.70 (m, 2H); 7.56 - 7.45 (m, 3H); 7.09 (d, J 2.88 Hz, 1H); 7.00 (dd, J1 9.06 J2 2.88 Hz, 1H); 3.93 (s, 3H); 3.60 -3.56 (m, 2H); 2.57 (t, J 6.19 Hz, 2H); 2.42 - 2.34 (m, 4H); 1.49 - 1.41 (m, 6H). 13 C NMR (100 MHz, CDCl 3) δ: 161.19; 150.85; 148.10; 144.12; 137.37; 132.68; 130.16; 129.65; 129.59; 128.73; 116.37; 105.40; 55.93; 41.37; 31.69; 20.61; 14,19. MS (m / z): 111 (52); 98 (100).

Preparation of stock solutions of compounds Stock solutions of synthesized substances and reference drugs (benzonidazole - Central Medicines Laboratory - UFPE; amphotericin B - Cristália Produtos Químicos Farmacêuticos Ltda.) Were prepared aseptically in dimethylsulfoxide (DMSO - Sigma Chemical Co, St Louis , MO, USA) and diluted in an appropriate culture medium, so that the final concentration of DMSO does not exceed 1% in the experiments. In vitro tests Parasite culture process In all biological experiments, epimastigote forms of Trypanosoma cruzi cepa Y and promastigotes forms of Leishmania amazonensis strain WHOM / BR / 75 / JOSEFA were used. Epimastigote forms were cultured at 28 ° C by weekly transfers in liver infusion and tryptose medium (LIT - “liver infusion tryptose”), supplemented with 10% fetal bovine serum (SFB) (Gibco Invitrogen Corporation, New York, USA) . Promastigote forms were grown at 28 ° C, by transfers in Warren medium (Brain and heart infusion), supplemented with 10% SFB. Trypomastigote forms were obtained by infection of cells of the LLCMK2 lineage, in Dulbecco's modified Eagle's medium (DMEM, Gibco Invitrogen Corporation, NewYork, USA), pH 7.6, supplemented with 10% SFB and 50 mg / mL gentamicin, at the rate of 10 trypomastigotes per cell counted in a Neubauer chamber and kept at 37 ° C in a humid greenhouse, with a controlled atmosphere of 5%. Cell culture process Macaca mulatta kidney epithelial cells (LLCMK2) were cultured in DMEM medium, supplemented with 10% SFB at 37 ° C in a humid greenhouse, with a controlled atmosphere of 5% CO2. Macrophages J774-A1, were grown in RPMI 1640 medium (Sigma, St Louis, MO, USA), supplemented with 10% SFB at 37 ° C in a humid greenhouse, with a controlled atmosphere of 5% CO2. Plastic bottles with screw caps and a CO2 inlet device were used for cultivation.

The biological tests were performed against the promastigote and intracellular amastigote of L. amazonensis and the epimastigote, trypomastigote and intracellular amastigote of T. cruzi. The compounds shown in the present invention showed different levels of effectiveness against both protozoa.

Evaluation of in vitro antiproliferative activity against T. cruzi epimastigotes

To determine the antiproliferative activity of the quinoxaline derivatives, epimastigote forms in exponential growth phase (96 h) were resuspended in LIT medium, supplemented with 10% SFB. Then, 900 μL parasite suspension (1.0 x 106 parasites / mL) was added in 24-well plates and incubated at 28 ° C for 96 h, in the presence of 100 μL of LIT medium containing or not different concentrations of the substances synthesized (0.05 μM to 100 μM). Cell growth was evaluated by counting the parasites in a Neubauer chamber under an optical microscope. The antiproliferative effect was expressed through the percentage of growth inhibition in relation to the control. The inhibitory concentration of 50% of the protozoa (IC50) was calculated by linear regression analysis of the dose-response curve. Benzonidazole was used as a reference substance. All tests were performed in duplicate on three different occasions.

Evaluation of antiproliferative activity in vitro against L. amazonensis promastigotes

To determine the antiproliferative activity of the quinoxaline derivatives, promastigote forms in exponential growth phase (48 h) were resuspended in Warren's medium, supplemented with 10% SFB. Then, 900 μL parasite suspension (1.0 x 106 parasites / mL) was added in 24-well plates and incubated at 25 ° C for 72 h, in the presence of 100 μL of Warren's medium containing or not different concentrations of the substances synthesized (0.05 μM to 100 μM). Cell growth was evaluated by counting the parasites in a Neubauer chamber under an optical microscope. The antiproliferative effect was expressed through the percentage of growth inhibition in relation to the control. The inhibitory concentration of 50% of the protozoa (IC50) was calculated by linear regression analysis of the dose-response curve. Amphotericin B was used as a reference substance. All tests were performed in duplicate on three different occasions.

Cytotoxicity assay on LLCMK2 cells and J774-A1 macrophages by the MTT reduction method

The cytotoxic effect of quinoxaline derivatives was evaluated by the MTT reduction method (3- [4,5-dimethyl-thiazol-2-yl] -2,5-diphenyl-tetrazolium bromide (Amresco, Solon, Ohio, USA) Initially, an inoculum containing LLCMK2 cells (2.5 x 105 cells / ml) in DMEM medium or J774-A1 macrophages (5.0 x 105 cells / ml) in RPMI 1640 medium plus 10% SFB were obtained from of 72 h cultures, then 100 μL of this suspension was deposited in 96-well plates and incubated for 24 h at 37 ° C with 5% CO2 tension to form a cell monolayer. on the monolayer, different concentrations of the synthesized substances diluted in appropriate culture medium for each cell (1 to 1000 μM). After the 96 h incubation period for LLCMK2 cells and 48 h for macrophages, the medium was carefully removed and replaced by MTT dye (5.9 mM in 0.01 M PBS (buffered saline - pH 7.2)) and the cells were again incubated s for another 4 h in the same conditions already described and protected from light. Then, for the solubilization of the formed formazan crystals, DMSO was added. The plates were shaken for 5 min and the reading performed in an ELISA reader (Bio-Tek FL-600 Microplate Fluorescence Reader), at an optical density (DO) of 492 nm.

The cytotoxic concentration for 50% cells (CC5o) was determined as the concentration capable of reducing 50% of the optical density of the treated cells compared to the control, according to the formula below. The CC5θ was calculated by linear regression analysis of the dose-response curve.

Cell cytotoxicity (%) = 100- ((DO tto x 100) / DO cc)

Where, DO tto is the optical density of the treated cells and DO cc is the optical density of the control of untreated cells. All trials were performed in triplicate on three different occasions.

Evaluation of trypanocidal activity in vitro against T. cruzi trypomastigote

Trypomastigote forms obtained from LLCMK2 cell culture infection were extracted at the parasitic peak and resuspended at a concentration of 1.0 x 107 parasites / mL in DMEM medium. Then, the parasite suspension was added in a 96-well plate and incubated for 24 h at 37 ° C, in the presence or absence of different concentrations of the synthesized substances of greatest interest (0.1 μM to 100 μM). The results were expressed through the observation of motility, which determines the viability of the parasites (Pizzi-Brener method). 5 μL aliquots of each sample were taken and immediately observed under an optical microscope (BRENER et al., 1962). The effective concentration for 50% of the protozoa (EC50) was calculated by linear regression analysis of the dose-response curve. Benzonidazole was used as a reference substance. All tests were performed in duplicate on three different occasions.

Evaluation of in vitro activity against intracellular forms of T. cruzi

To assess the effect against intracellular amastigote forms of T. cruzi, a suspension of LLCMK2 cells (2.5 x 105 cells / mL) in DMEM medium supplemented with 10% SFB was dispensed over round glass coverslips arranged in 24-mm plates. wells and incubated at 37 ° C with 5% CO2 tension for 24 h to obtain the cell monolayer on the coverslips. After this period, the cell monolayer was incubated for 24 h in the presence of trypomastigote forms, with an inoculum of 1.0 x 107 parasites / mL in DMEM medium. After the interaction between LLCMK2 cells and the parasites, different concentrations of the synthesized substances of greatest interest were added (0.1 μM to 100 μM). The plate was again incubated at 37 ° C with a 5% CO2 tension for 96 h.

After this period, the coverslips were fixed with methanol, stained with Giemsa and prepared permanently on slides with Entellan® (Merck). The survival rate (number of infected cells / average of amastigotes per cell) was measured by counting 200 cells under an optical microscope. Benzonidazole was used as a reference substance. All tests were performed three times in duplicate, on different occasions.

Evaluation of in vitro activity against intracellular amastigote forms of L. amazonensis

To evaluate the effect against intracellular amastigote forms of L amazonensis, a suspension of macrophages (5 x 105 cells / mL) in RPMI medium supplemented with 10% SFB was dispensed on round glass coverslips arranged in 24-well plates and incubated at 37 ° C with 5% CO2 tension for 2 h for cell adhesion on coverslips. After this period, the cell monolayer was incubated for 6 h in the presence of metacyclic promastigote forms, with an inoculum of 3.5 x 107 parasites / mL in RPMI medium. After the interaction between macrophages and parasites, different concentrations of the synthesized substances of greatest interest were added (0.1 μM to 100 μM). The plate was again incubated at 34 ° C with a tension of 5% CO2 for 48 h.

After this period, the coverslips were fixed with methanol, stained with Giemsa and prepared permanently on slides with Entellan® (Merck). The survival rate (number of infected cells / average of amastigotes per cell) was measured by counting 200 cells under an optical microscope. Amphotericin B was used as a reference substance. All tests were performed three times in duplicate, on different occasions.

Evaluation of the combinatorial activity of benzonidazole and the substance 3-chloro-7-methoxy-2-methylsulfonylquinoxaline (7a)

To assess the combinatorial activity of the substance (7a) and benzonidazole, the drug combination method proposed by Chou, T. C .; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55, 1984.

For this, the experiments of activity in epimastigotes, trypomastigotes and LLCMK2 cells, were carried out as described and outlined above, however at least five serial concentrations (dilution factor 2) of each of the drugs alone or in multiple combinations were used.

The data obtained were analyzed by calculating the Combination Index (CI), according to the equation:

IC = [Combined benzonidazole IC50 / Isolated benzonidazole ICso] + [Combined 7 th IC50 / Isolated 7 th IC50]

Where, the numerators represent the combined concentration of each compound that inhibited 50% of cell growth and the denominators correspond to the concentration of each isolated drug that exhibited this same effect.

The results obtained were classified according to the CI, values greater than, less than or equal to one were considered as synergistic, antagonistic or additive interaction between drugs, respectively.

All tests were performed three times in duplicate, on different occasions.

The biological tests were performed against the promastigote form of L. amazonensis and the epimastigote, trypomastigote and intracellular amastigote form of T. cruzi.

The compounds shown in the present invention showed different levels of effectiveness against both protozoa.

Following are the tests performed and the results obtained.

Antiparasitic activity of 1,1-dimethylsulfanyl-2-nitroethene

Composto μM Atividade antiparasitária de nitroetenos A/,S-acetais Derivados de nitroetenos /V,S-acetais foram sintetizados a partir do composto 1. Os compostos sintetizados apresentaram baixos níveis de atividade frente às formas promastigota de L. amazonensis e epimastigota T. cruzi (Tabela 2). Dentro desta classe, a presença dos anéis benzenamina e 2- [nitroetenil]-benzenamina nos compostos (2b) e (2k), respectivamente, bem como a presença de cloro e flúor nos anéis causaram um aumento na atividade biológica com valores de IC5o inferiores a 25 μM para ambos os protozoários (formas promastigota e epimastigota) em relação aos demais compostos. Já a presença do grupo amina no composto 2n foi o responsável pela atividade moderada frente à forma promastigota de L amazonensis e epimastigota e 5 tripomastigota de T. cruzi. Sendo, portanto, o único composto com atividade inferior a 50 μM frente à forma tripomastigota. TABELA 2

3.3. Atividade antiparasitária de 3-cloro-2-metilsulfanilquinoxalinas A partir de nitroetenos A/,S-acetais uma série de 3-cloro-2- metilsulfanilquinoxalinas foram sintetizadas. A avaliação destes compostos frente à L. amazonensis e ao 7". cruzi revelou um aumento nos níveis de 15 atividade em relação aos derivados de nitroetenos A/,S-acetais, mostrando-se mais ativos frente aos protozoários do que para as células mamíferas (Tabela 3). Na busca por compostos com baixos níveis de toxicidade frente às células hospedeiras, a 3-cloro-7-metoxi-2-metilsulfanilquinoxalina (3a) se 5 destaca, uma vez que demonstrou ser 19,3 vezes mais seletiva para o T. cruzi, além do composto 3,6-dicloro-2-metilsulfanilquinoxalina (3e) que demonstrou ser 22,1 e 16,1 vezes mais seletivo para a L. amazonensis e para o T. cruzi, respectivamente. TABELA 3

Atividade antiparasitária de 3-aril-2-metilsulfanilquinoxalinas Partindo do composto (3a) obteve-se as 3-aril-2-metilsulfanilquinoxalinas. Os compostos sintetizados (4a) e (4b) não apresentaram atividade frente à 15 forma promastigota de L. amazonenses e as formas epimastigota e tripomastigota de T. cruzi (Tabela 4). 20 TABELA 4

IS: índice de seletividade (CC5o/IC5o ou EC50); IC: Concentração inibitória; CC: Concentração citotóxica; EC: concentração efetiva; ND: não determinado; NT: não testado Atividade antiparasitária de quinoxalinas 2,3-diarilsubstituídas Por meio de uma série de reações químicas de acoplamento e condensação obteve-se as quinoxalinas 2,3-diarilsubstituídas. Os compostos sintetizados pertencentes a este grupo apresentaram uma melhora na atividade biológica frente à L amazonensis e ao T. cruzi em relação aos derivados de quinoxalinas já descritos (Tabela 5).The compound 1,1-dimethylsulfanyl-2-nitroethene (1) showed satisfactory results only against the promastigote and epimastigote form of L. amazonensis and T. cruzi, respectively, as listed in Table 1 below. TABLE 1

ΜM compound Antiparasitic activity of nitroethenes A /, S-acetals Nitroethene derivatives / V, S-acetals were synthesized from compound 1. The synthesized compounds showed low levels of activity against the promastigote forms of L. amazonensis and epimastigote T. cruzi (Table 2). Within this class, the presence of benzenamine and 2- [nitroetenyl] -benzenamine rings in compounds (2b) and (2k), respectively, as well as the presence of chlorine and fluorine in the rings caused an increase in biological activity with lower IC50 values. at 25 μM for both protozoa (promastigote and epimastigote forms) in relation to the other compounds. The presence of the amine group in compound 2n was responsible for the moderate activity against the promastigote form of L amazonensis and epimastigote and 5 T. cruzi trypomastigote. Therefore, it is the only compound with activity below 50 μM compared to the trypomastigote form. TABLE 2

3.3. Antiparasitic activity of 3-chloro-2-methylsulfanylquinoxalines From nitroethenes A /, S-acetals a series of 3-chloro-2-methylsulfanylquinoxalines were synthesized. The evaluation of these compounds against L. amazonensis and 7 ". Cruzi revealed an increase in activity levels in relation to nitroethene derivatives A /, S-acetals, showing to be more active against protozoa than for mammalian cells (Table 3) In the search for compounds with low levels of toxicity against host cells, 3-chloro-7-methoxy-2-methylsulfanylquinoxaline (3a) stands out, since it has shown to be 19.3 times more selective for T. cruzi, in addition to the compound 3,6-dichloro-2-methylsulfanylquinoxaline (3e), which proved to be 22.1 and 16.1 times more selective for L. amazonensis and T. cruzi, respectively.

Antiparasitic activity of 3-aryl-2-methylsulfanylquinoxaline Starting from compound (3a) 3-aryl-2-methylsulfanylquinoxaline was obtained. The synthesized compounds (4a) and (4b) did not show activity against the L. amazonenses promastigote and T. cruzi epimastigote and trypomastigote forms (Table 4). 20 TABLE 4

IS: selectivity index (CC5o / IC5o or EC50); CI: Inhibitory concentration; CC: Cytotoxic concentration; EC: effective concentration; ND: not determined; NT: not tested Antiparasitic activity of 2,3-diaryl substituted quinoxalins Through a series of chemical reactions of coupling and condensation, 2,3-diaryl substituted quinoxalins were obtained. The synthesized compounds belonging to this group showed an improvement in biological activity against L amazonensis and T. cruzi in relation to the quinoxaline derivatives already described (Table 5).

Among them, in (5k) the presence of 4-methoxyphenyl rings in position 2 and 3 of the pyrazine ring proved to be responsible for the activity in the promastigote and epimastigote forms. Its low level of toxicity against host cells revealed selectivity rates of 19.7 against L. amazonensis and 9.0 against T. cruzi. Structural changes in 5k gave rise to compound (5ka) (2- [4- (2-piperidine) ethoxyphenyl] -3- (4-hydroxyphenyl) quinoxaline), which showed an increase in activity (IC50 5.7 ± 0, 4 μM) against the promastigote form of L. amazonensis. However, greater toxicity was observed in relation to the host cell when compared to its precursor (5k), thus causing a reduction in the selectivity index to 8.2. When both compounds were evaluated against the trypomastigote form, an absence of activity was observed with EC5o values above 50 μM.

In 6,7-dichloro-2,3-diphenylquinoxaline (5i) the presence of chlorine molecules in the benzene ring and the phenyl ring in positions 2 and 3 in the pyrazine ring, were responsible for the high activity against the promastigote form (IC50 5 , 3 ± 0.7 μM), as well as the low levels of toxicity, which is 38.5 times more selective for the protozoan than for the host cell. Like compounds (5k) and (5ka), compound 5i also showed no activity against the trypomastigote form of T. cruzi.

Assays using the compound 2- (4-methoxyphenyl) -3-phenylquinoxaline (5f) revealed activity against both protozoa (IC5o <21.5 μM). From this, compounds (5fa) and (5fb) were synthesized. Such structural changes led to an important increase in activity, especially in relation to the promastigote form of L. amazonensis with IC50 values of 1.9 ± 0.2 μM and 6.2 ± 0.6 pM, respectively, resulting in a selectivity index from 29.6 to 0 compound (5fa) and from 8.7 to (5fb).

Atividade antiparasitária de metilsulfoxilquinoxalinas 5 A partir de uma solução contendo metilsulfanilquinoxalina (3), obtiveram- se as metilsulfoxilquinoxalinas (6a e 6b).In contrast to the other compounds in the 2,3-diaryl substituted quinoxaline group, the substance (5fa) was the only one that showed activity against the trypomastigote form of T. cruzi, with an EC50 value of 20.3 ± 2.3 pM accompanied by a selectivity index of 1.8. TABLE 5

Methylsulfoxylquinoxaline antiparasitic activity 5 From a solution containing methylsulfanylquinoxaline (3), methylsulfoxyquinoxaline (6a and 6b) were obtained.

Tests performed against the epimastigote form of T. cruzi revealed high activity with IC5QO values, 5 ± 0.1 μM for (6a) and 0.1 ± 0.0 μM for (6b). IO Tests performed against the promastigote form of L. amazonensis revealed high activity with IC 50 values 0.8 ± 0.2 pM for (6a) and 0.1 ± 0.0 pM for (6b).

It appears that the increase in activity is directly linked to the addition of the methyl sulfoxyl radical at position 2 of the pyrazine ring. When evaluating its activity against the trypomastigote form of T. cruzi, high activity is observed with EC5o values below 4.2 μM, however, such compounds showed low selectivity indexes in relation to this evolutionary form. TABLE 6

Antiparasitic activity of 3-chloro-2-methylsulfonylquinoxalines Through reactions also carried out from a solution of methylsulfanylquinoxaline, 3-chloro-2-methylsulfonylquinoxaline compounds were synthesized (Table 7). The evaluation of the antiproliferative activity of these compounds against the promastigote form of L amazonensis and epimastigote of T. cruzi revealed high activity with IC5o values below 3.1 μM, in addition to a high activity against the trypomastigote form of T. cruzi, which presented EC50 values below 9.8 μM. Despite the cytotoxicity observed against host cells, high selectivity rates were obtained, especially in compounds (7a), (7b), (7d) and (7e). TABLE 7

Atividade antiparasitária de 3-cloro-2-amino-quinoxalinasAntiparasitic activity of 3-phenyl-2-methylsulfonyl-7-methoxyquinoxaline The oxidation reactions of the compound 3-phenyl-2-methylsulfanyl-7-methoxyquininoxine (4a) gave rise to the compound 3-phenyl-2-methylsulfonyl-7-methoxyquininoxaline ( 8a). This showed IC50 values of 24.7 ± 2.3 μM against the promastigote form of L. amazonensis and 28.4 ± 1.9 μM against the epimastigote form with a reduction in its activity compared to the trypomastigote form of T. cruz / (Table 8). TABLE 8

Antiparasitic activity of 3-chloro-2-amino-quinoxalins

The synthesis of the 3-chloro-2-amino-quinoxaline compounds (9a, 9b and 9c) took place from reactions using the compound 3-chloro-7-methoxy-2-methylsulfonylquinoxaline (7a). All compounds showed activity against the promastigote form of L. amazonensis and epimastigote form of T. cruzi (Table 9). It can be noted that the compound (9b) was slightly more active than the compound (9a), with IC50 values of 24.5 ± 1.7 μM in front of the promastigote and 15.9 ± 1.6 μM in front to the epimastigote form, being up to 22 times more selective for the protozoan than for the host cell. However, when evaluating against the trypomastigote form of T. cruzi, this class of compounds showed no activity. TABLE 9

2,3-diaminoquinoxaline antiparasitic activity The 2,3-diaminoquinoxaline derivatives were obtained through two different synthetic routes, the compounds (10a) and (10b) being obtained from a solution of 3-chloro-2-aminoquinoxaline (9a or 9b) and an amine as the compound (10c) from a mixture of 3-chloro-2-methylsulfanyl-7-methoxyquinoxaline (3a) and aniline. Differently from the other classes, the compounds were considered more active against the promastigote form of L. amazonensis with IC 50 values between 6.5 and 20.9 μM, than for the epimastigote and trypomastigote form of T. cruzi, which varied between 29.4 and 45.6 μM and between 37.9 and> 50 μM, respectively (Table 10). TABLE 10

Antiparasitic activity of 3-amino-2-methylsulfanyl-quinoxaline From a solution containing methylsulfanylquinoxaline (3), 3-amino-2-methylsulfanylquinoxaline can also be obtained. This series is composed of 16 derivatives, which showed different levels of activity among them against L. amazonensis and T. cruzi (Table 11). However, despite the large number of compounds obtained and evaluated, it was not possible to obtain high rates of selectivity. The best selectivity index was obtained by the compound 3-cyclohexylamino-2-methylsulfanyl-7-methoxyquininoxaline (11f) against the epimastigote form of T. cruzi, which was 8.5 times more selective for the protozoan than for the host cell . TABLE 11

Antiparasitic activity of 3-amino-2-methylsulfonylquinoxaline 5 Another important class of synthesized compounds was obtained through the oxidation reaction of 3-amino-2-methylsulfanylquinoxaline (11). This series of 3-amino-2-methylsulfonylquinoxaline derivatives totaled 16 compounds, which showed great variation in biological activity against the protozoa L. amazonensis and T. cruzi (Table 12). 10 Among the compounds evaluated, the derivatives (12b) (3-butylamino-2-methylsulfonyl-7-methoxyquininoxaline), (12c) (3- (2-hydroxyethanolamine) -2-methylsulfonyl-7-methoxyquininoxaline) and (12f) ( 3-cyclohexylamino-2-methylsulfonyl-7-methoxyquininoxaline) have the same substituents, with the exception of the amine group at position 2 in the pyrazine ring. The similarities between the compounds (12c) and (12f) were also seen in relation to the biological activity against the promastigote forms of L. amazonensis and epimastigote of T. cruzi (IC5o between 2.2 and 2.9 μM). Despite the different levels of toxicity presented by these compounds, there was no significant variation in the selectivity indexes that varied between 13.3 and 25.2. Both compounds showed a reduction in activity when evaluated against the trypomastigote form of T. cruzi.

Similar activity in relation to the promastigote and epimastigote and trypomastigote forms was observed for the compound (12b), 0 which presented IC 50 values of 2.5 ± 0.3 μM, 3.6 ± 0.3 μM and EC50 of 39, 2 ± 1.8 μM, respectively. However, it can be seen that the presence of the butylamino group in the compound (12b) caused an important reduction in toxicity towards the host cells in relation to the other compounds, with compound 12b being 108.5 and 10 times more selective for the epimastigote and trypomastiogta form of T. cruzi, respectively.

It can be seen that the presence of the bromine molecule at position 6 of the benzene ring of compounds (121) and (12m) caused a significant increase in activity in relation to the other compounds belonging to this group. When evaluated against the promastigote and epimastigote forms, we observed IC50 values that varied between 0.8 and 2.3 μM and EC50 values of 5.6 ± 0.5 μM for the compound (121) and 8.2 ± 2 , 7 μM against the trypomastigote form. The best selectivity index between these two compounds for L. amazonensis was 40.3 presented by the compound (12m). However, compared to T. cruzi, the best selectivity indexes were seen by the compound (121), which was 43.7 and 17.8 times more selective for the epimastigote and trypomastigote forms of T. cruzi.

Another compound belonging to this group that drew attention was (12o), which proved to be 0 active, as well as, the most selective against both protozoa. A small variation in activity was obtained in relation to the promastigote and epimastigote forms with IC 50 of 1.4 ± 0.3 μM and 2.3 ± 0.1 μM, in addition to excellent selectivity rates of 50.6 and 93.4, respectively. In contrast to the trypomastigote form, a slight reduction in activity with an EC50 of 9.0 ± 1.8 μM was observed, 23.8 times more selective for this evolutionary form.

The compound (12p) showed similar activity in relation to all 5 evolutionary forms of both protozoa with IC50 of 2.2 ± 0.1 μM, 2.0 ± 0.0 pM and 3.9 ± 1.4 pM against the promastigote form of L. amazonensis and the epimastigote and trypomastigote forms of T. cruzi, respectively. TABLE 12

Antiparasitic activity of 3-amino-2-methylsulfoxylquinoxalins The synthesis of the quinoxaline derivatives, 3-amino-2-methylsulfoxylquinoxalines occurred from the oxidation of methylsulfanylquinoxalines (11). This class of compounds showed high activity against both protozoa, especially the compound 3-cyclohexyl-2-methylsulfoxyl-7-methoxyquininoxaline (13a) against the epimastigote form of T. cruzi (Table 13), however, it was the compound (13b), the most active compared to the trypomastigote form with EC50 of 6.3 ± 1.4 μM, with a selectivity index of 6.2 for this evolutionary form. The high activity combined with its moderate toxicity shows that the compounds (13a) and (13b) are approximately 72.8 and 21.8 times more selective for T. cruzi compared to the epimastigote form and 8.0 and 33.8 times more selective for L. amazonensis than for the host cell, respectively. TABLE 13

Antiparasitic activity of 2-aryl-3-aminoquinoxalines From a mixture of 3-phenyl-2-methylsulfonyl-7-methoxyquinoxaline (8a) and amine, 3-aryl-2-aminoquinoxaline derivatives were obtained, which showed changes only in position 2 of the pyrazine ring. The evaluation of the biological activity of these compounds against the promastigote form of L amazonensis and the epimastigote and trypomastigote forms of T. cruzi revealed moderate activity, accompanied by low rates of selectivity (Table 14). TABLE 14

In vitro trypanocidal activity of 2,3-disubstituted quinoxaline derivatives against epimastigote, trypomastigote and intracellular amastigote of T. cruzi

Among the compounds evaluated in the present invention against the epimastigote and trypomastigote form, those that presented high selectivity indexes were selected for the evaluation against the intracellular amastigote form of T. cruzi (Table 18).

In the viability test of trypomastigote forms, the 3-chloro-2-methylsulfonylquinoxaline derivatives (7a and 7b) were the most active with EC5O values of 7.1 and 6.4 μM, respectively. Although they showed high activity, the selectivity index of the compound (7a) was only 1.5, whereas the compound (7b) proved to be 7.3 times more selective.

Compound (13a) showed an EC50 of 25.4 μM, accompanied by a low toxicity index, demonstrating to be 7.1 times more selective for the protozoan than for the host cell.

However, the best selectivity indexes were observed for compounds (121) and (12p), which were 17.8 and 19.6 times more selective for this evolutionary form, respectively. Despite the moderate activity against the protozoan, another interesting selectivity index (IS = 10) in relation to the trypomastigote form was observed by the compound (12b).

Intracellular amastigote forms of T. cruzi have been shown to be more sensitive to quinoxaline derivatives than trypomastigote forms.

When the parasites were treated with compounds (5k), (7a), (12b) and (13a), a reduction in the number of intracellular amastigotes was observed, with compound (7a) being the most active with an IC50 value of 2 , 6 μM.

However, the other compounds (7b), (9b), (12c), (12f) and (121) 5 showed low antiproliferative activity compared to the intracellular amastigote.

Among the compounds evaluated against the intracellular amastigote form, the compounds (5k), (12b) and (13a), in addition to being active at low concentrations, with IC50 values of 8.6 to 14.3 μM, were also the most selective, with IO indexes greater than 19.5, the compound (5k) being 38.4 times more selective for the protozoan than for the host cells. Table 18

In vitro activity of 2,3-disubstituted quinoxaline derivatives against the promastigote and intracellular amastigote forms of L. amazonensis

Based on the results of biological activity for the promastigote form of L amazonensis presented, the compounds with the best selectivity index were selected to evaluate the activity against the intracellular amastigotes of L. amazonensis (Table 19).

The biological activity against the promastigote form of L. amazonensis was more pronounced in the derivatives of methylsulfoxylquinoxaline (6a) and 3-chloro-2-methylsulfonylquinoxaline (7d) and (7e) with IC50 of 0.1 pM, 0.2 μM and 0 , 2 pM, respectively, resulting in a selectivity index of 107.6 for compound (6a), 71.8 for compound (7d) and 66.0 for compound (7e), when compared to its cytotoxicity. In addition, the 2,3-diaryl substituted quinoxaline derivatives, represented by (5fa) and (5i) stand out with IC50 of 1 pM and 5.3 pM and selectivity index of 29.6 and 38.5 respectively.

The evaluation of the activity in L amazonensis intracellular amastigotes demonstrated that 2,3-diaryl substituted quinoxaline derivatives (5fa, 5i and 5k), methylsulfoxylquinoxaline derivatives (6a and 6b), 3-chloro-2-methylsulfonylquinoxaline derivatives (7d and 7e), 3-chloro-7-methoxy-2-benzylaminoquinoxaline (9b), 3-amino-2-methylsulfonylquinoxaline derivatives (12b, 12c, 12f) and compound (13a) showed promising biological activity with IC50 below 25 uM preliminary tests.

For the compound (5fa, 5i and 5k) the IC50 was equal to 10.4 pM, 16.3 pM and 19.3 pM, respectively, resulting in a selectivity index of 5.4, 12.5 and 30.6 consequently for the respective compounds.

When the activity of the compound 3,6-dichloro-2- (methylsulfonyl) quinoxaline (6b) is evaluated, a high activity is observed with an IC50 of 1.5 pM, which is 9 times more selective for the protozoan than for the host cell. .

The compound 3-chloro-7-methoxy-2-benzylaminoquinoxaline (9b) showed an IC50 of 25 pM and a selectivity index of 5.3.

For compounds (12c) and (13a), the IC5o is 17.3 μM and 7.3 μM, respectively and the selectivity index equal to 2.2 for (12c) and 2.8 for (13a). Thus, the 2,3-diaryl substituted quinoxaline derivatives (5i) and (5k) proved to be more active because they have a higher selectivity index for L. amazonensis intracellular amastigote than for the host cell. TABLE 19

Anti-Trypanosoma activity, mechanism of action and combinatorial effect with benzonidazole of the substance 3-chloro-7-methoxy-2-methylsulfonylquinoxaline (7a)

The substance (7a) showed wide trypanocidal activity against all evolutionary forms of the protozoan T. cruzi. The activity was greater against the replicative forms of the protozoan, with an IC50 of 2.6 μM against intracellular amastigotes and 1.1 μM against epimastigotes. This compound also showed activity against the trypomastigote form (EC50 of 7.1 μM), however a severe reduction in this activity was observed when the experiment was conducted in the presence of 20% blood of Swiss mice (EC50 of 109.5 μM) . This inhibition is particularly related to the cellular fraction of the blood, since in the same experiment conducted in the presence of plasma from Swiss mice, no significant reduction in activity was observed (EC50 of 13.5 pM).

As for the toxicity parameters, the drug was hemolytic for less than 3% of human erythrocytes in the highest concentration tested (1000 pM), this cytotoxic for 50% of epithelial cells (LLCMK2) in the concentration of 23.3 pM.

When analyzed in combination, benzonidazole and the compound (7a) showed synergistic activity against epimastigotes (CI: 0.69) and trypomastigotes (CI: 0.66), in addition to antagonistic interaction when the drugs were tested in LLCMK2 cells (Cl: 1 , 04). These results from the drug combination assay demonstrated an increase in activity against protozoa, in addition to reduced toxicity against mammalian cells, when both drugs are used together.

Ultrastructural and functional data were obtained in order to evaluate the mechanism of action of the compound (7a) against T. cruzi, for this purpose epimastigote forms of the protozoan treated for 24 h were used as a model. Results of scanning electron microscopy (SEM), transmission electron microscopy (MET) and flow cytometry indicated a reduction in cell volume and preservation of the plasma membrane integrity of protozoa submitted to treatment with this compound. However, the cytoplasm of the treated cells was altered, with the presence of autophagosomes, membrane figures and profiles of endoplasmic reticulum surrounding other organelles, especially the reservoirs. Taken together, these characteristics strongly indicate a programmed cell death process with autophagic involvement.

Claims (25)

1. Compounds derived from quinoxaline, characterized by being in accordance with the formula

where R1 is selected from the group consisting of Cl, Phenyl, or NHR, where R is selected from the group consisting of Me, Et, nBu, iBu, Cyclohexyl, Phenyl, CH2CH2OH; R2 is selected from the group consisting of Phenyl, SMe, SOMe, SO2Me, NHR where R is selected from the group consisting of Me, Et, nBu, iBu, Cyclohexyl, Phenyl, CH2CH2OH; R3 is selected from the group consisting of H, F, Cl, Br, OMe; and R4 is selected from the group consisting of H, OMe, Cl; Since, when R1 and R2 are both phenyl, R3 and R4 are not simultaneously H; Since, when R1 is NHCH3 and R2 is SMe, R3 and R4 are not simultaneously H; Since, when R1 is NHC2H5 and R2 is SMe, R3 and R4 are not simultaneously H; Since, when R1 or R2 are Cl or SMe, R3 or R4 are not H, OMe, Cl, or F; Since, when R1 or R2 are SO2Me or NHR, where R is an alkyl group, R3 and R4 are not H, OMe, Cl, or F; Since, when R2 and R3 are both OMe, R1 and R4 are not simultaneously H; Since, when R2 is OMe and R3 is H, R1 and R4 are not simultaneously H. Pharmaceutical composition prepared on the basis of the compound of formula according to claim 1, characterized in that it comprises the compound 3-chloro-7-methoxy-2-methylsulfanylquinoxaline (3a), active for Trypanosoma cruzi, and an acceptable vehicle from the point of pharmacist view. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3,6-dichloro-2-methylsulfanylquinoxaline (3e) selective against Leishmania amazonensis and Trypanosoma cruzi, and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 6,7-dichloro-2,3-diphenylquinoxaline (5i), selective against Leishmania amazonensis, and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 2,3-di- (4-methoxyphenyl) -quinoxaline (5k), selective against Leishmania amazonensis and Trypanosoma cruzi, and an acceptable vehicle from the point of pharmacist view. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 2- [4- (2-piperidine) ethoxyphenyl] -3-phenylquinoxaline (5fa) selective against Leishmania amazonensis and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 2- [4- (2-morpholine) ethoxyphenyl] -3-phenylquinoxaline (5fb), selective against Leishmania amazonensis and Trypanosoma cruzi, and an acceptable vehicle from a pharmaceutical point of view. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-chloro-7-methoxy-2- (methylsulfonyl) quinoxaline (6a), selective against Leishmania amazonensis and Trypanosoma cruzi and an acceptable vehicle from the point of pharmacist view. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3,6-dichloro-2- (methylsulfonyl) quinoxaline (6b) selective against Leishmania amazonensis and Trypanosoma cruzi and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-chloro-7-methoxy-2-methylsulfonylquinoxaline (7a), selective against Leishmania amazonensis and Trypanosoma cruzi and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises an effective proportion of the compound 3-chloro-2-methylsulfonylquinoxaline (7b) selective against Leishmania amazonensis and Trypanosoma cruzi and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 6-bromo-3-chloro-2- (methylsulfonyl) quinoxaline (7d) selective against Leishmania amazonensis and Trypanosoma cruzi and an acceptable vehicle from the point of view pharmaceutical. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-chloro-6-fluoro-2- (methylsulfonyl) quinoxaline (7e), selective against Leishmania amazonensis and Trypanosoma cruzi and an acceptable vehicle from the point of pharmacist view. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-butylamino-2-methylsulfonyl-7-methoxyquininoxine (12b) selective against Leishmania amazonensis and Trypanosoma cruzi and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3- (2-hydroxyethanolamine) -2-methylsulfonyl-7-methoxyquinoxaline (12c) selective against Leishmania amazonensis and Trypanosoma cruzi and an acceptable vehicle from the point of view pharmacist view. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-butylamino-2-methylsulfonylquinoxaline (12d), selective against Leishmania amazonensis, and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 3, characterized in that it comprises the compound 3- (2-hydroxyethanolamine) -2-methylsulfonylquinoxaline (12e), selective against Leishmania amazonensis, and a pharmaceutically acceptable vehicle. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-cyclohexylamino-2-methylsulfonyl-7-methoxyquininoxaline (12f), selective against Leishmania amazonensis and Trypanosoma cruzi, and a pharmaceutically acceptable vehicle . 19. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 6-bromo-3-butylamino-2-methylsulfonylquinoxaline (12l), selective against Leishmania amazonensis and Trypanosoma cruzi, and a pharmaceutically acceptable vehicle . Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 6-bromo-3- (2-hydroxyethanolamine) -2-methylsulfonylquinoxaline (12m), selective against Leishmania amazonensis, and a pharmaceutically acceptable vehicle . 21. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-isobutylamino-2-methylsulfonyl-7-methoxyquininoxaline (12n), selective against Leishmania amazonensis and Trypanosoma cruzi, and a pharmaceutically acceptable vehicle . 22. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-cyclohexylamino-2-methylsulfonyl-6-chloroquinoxaline (12p), selective against Leishmania amazonensis and Trypanosoma cruzi, and a pharmaceutically acceptable vehicle . Pharmaceutical composition according to claim 2, characterized in that it comprises the cyclohexyl-2-methylsulfoxyl-7-methoxyquinoxaline compound (13a) selective against Trypanosoma cruzi, and a pharmaceutically acceptable vehicle. 24. Pharmaceutical composition according to claim 2, characterized in that it comprises the compound 3-cyclohexyl-6-chloro-2-methylsulfoxylquinoxaline (13b), selective against Leishmania amazonensis and Trypanosoma cruzi, and a pharmaceutically acceptable vehicle . 25. Use of the pharmaceutical compositions according to claims 2 to 24, characterized in that it is for preparing a medicament to treat conditions caused by Leishmania amazonensis and Trypanosoma cruzi.

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