BR102019018181A2

BR102019018181A2 - ENHYZE ACETYL CHOLINESTERASE ACTIVITY INHIBITING COMPOUNDS

Info

Publication number: BR102019018181A2
Application number: BR102019018181-8A
Authority: BR
Inventors: Beatriz Fuzinato Dos Santos; Cristiane Luchese; Ethel Antunes Wilhelm; Nelson Luís De Campos Domingues
Original assignee: Universidade Federal Da Grande Dourados
Priority date: 2019-08-30
Filing date: 2019-08-30
Publication date: 2021-03-16

Abstract

compostos inibidores da atividade da enzima acetilcolinesterase, a presente invenção pertence ao campo da química orgânica, especificadamente da síntese orgânica, seu processo de obtenção envolve a síntese de uma classe de compostos inéditos derivada do núcleo btd e sua aplicação na inibição da atividade da enzima acetilcolinesterase visando novas possibilidades terapêuticas para o tratamento da doença de alzheimer, a metodologia empregada para a síntese dos compostos utilizando o catalisador pd[(l)-prolina]2 é simples, altamente eficiente e os testes biológicos de inibição da enzima acetilcolinesterase apresentaram excelentes resultados para diversos compostos, demonstrando o potencial desta classe como agente anticolinesterásico, assim, uma análise abrangente dos dados obtidos com os compostos arilsulfanil-benzotiadiazóis revela que há uma relação estrutura-atividade que pode ser útil para a pesquisa de novos agentes terapêuticos para aplicação no tratamento da doença de alzheimer.compounds that inhibit the activity of the enzyme acetylcholinesterase, the present invention belongs to the field of organic chemistry, specifically organic synthesis, its process of obtaining involves the synthesis of a class of novel compounds derived from the btd nucleus and its application in inhibiting the activity of the enzyme acetylcholinesterase aiming at new therapeutic possibilities for the treatment of alzheimer's disease, the methodology used for the synthesis of the compounds using the pd [(l) -proline] 2 catalyst is simple, highly efficient and the biological tests for inhibition of the enzyme acetylcholinesterase showed excellent results for several compounds, demonstrating the potential of this class as an anticholinesterase agent, thus, a comprehensive analysis of the data obtained with the arylsulfanyl-benzothiadiazole compounds reveals that there is a structure-activity relationship that may be useful in the search for new therapeutic agents for application in the treatment of Alzheimer's disease.

Description

ENHYZE ACETYL CHOLINESTERASE ACTIVITY INHIBITING COMPOUNDS

Field of the Invention

[1] A presente invenção pertence ao campo da química orgânica, especificamente ao ramo da síntese orgânica, e refere-se à síntese de derivados sulfurados do benzotiadiazol, bem como os ensaios in vitro desta classe de compostos como inibidores da acetilcolinesterase visando aplicação para o tratamento da doença de Alzheimer.[1] The present invention belongs to the field of organic chemistry, specifically to the branch of organic synthesis, and refers to the synthesis of sulfur derivatives of benzothiadiazole, as well as the in vitro tests of this class of compounds as inhibitors of acetylcholinesterase for application for the treatment of Alzheimer's disease.

State of the art

[2] A doença de Alzheimer é uma doença neurodegenerativa do cérebro e se caracteriza por causar problemas devastadores de memória e incapacidade do portador em realizar atividades simples do cotidiano, como se vestir ou tomar banho (Arun, K. J., Navas, A. A. & Joseph Francis P. J. Novel trends in the management of Alzheimer’s disease by using nano based materials. Madridge J. Nano Tech. 3, 98-99 (2018)). Desde que o primeiro caso da doença foi descrito em 1907 por Alois Alzheimer, muitos estudos foram feitos para revelar as suas principais causas (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer’s disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)). Atualmente, sabe-se que a doença de Alzheimer está associada ao envelhecimento, prevalecendo entre as pessoas com mais de 60 anos de idade (Santos, T. C., Gomes, T. M., Pinto, B. A. S., Camara, A. L. & Paes, A. M. A. Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer’s disease therapy. Front. Pharmacol. 9, 1192-1205 (2018)), sendo uma das principais causas de demência (Arun, K. J., Navas, A. A. & Joseph Francis P. J. Novel trends in the management of Alzheimer’s disease by using nano based materials. Madridge J. Nano Tech. 3, 98-99 (2018); Agatonovic-Kustrin, S., Kettle, C. & Morton, D. W. A molecular approach in drug development for Alzheimer’s disease. Biomed. Pharmacother. 106, 553-565 (2018)).[2] Alzheimer's disease is a neurodegenerative disease of the brain and is characterized by causing devastating memory problems and the inability of the wearer to perform simple daily activities, such as dressing or bathing (Arun, KJ, Navas, AA & Joseph Francis PJ Novel trends in the management of Alzheimer's disease by using nano based materials. Madridge J. Nano Tech. 3, 98-99 (2018)). Since the first case of the disease was described in 1907 by Alois Alzheimer, many studies have been done to reveal its main causes (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer's disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)). Currently, it is known that Alzheimer's disease is associated with aging, prevailing among people over 60 years of age (Santos, TC, Gomes, TM, Pinto, BAS, Camara, AL & Paes, AMA Naturally occurring acetylcholinesterase inhibitors and their potential use for Alzheimer's disease therapy. Front. Pharmacol. 9, 1192-1205 (2018)), being one of the main causes of dementia (Arun, KJ, Navas, AA & Joseph Francis PJ Novel trends in the management of Alzheimer's disease by using nano based materials.Madridge J. Nano Tech. 3, 98-99 (2018); Agatonovic-Kustrin, S., Kettle, C. & Morton, DW A molecular approach in drug development for Alzheimer's disease. Biomed. Pharmacother. 106, 553-565 (2018)).

[3] A demência caracteriza-se por ser uma doença neurodegenerativa progressiva que leva a um declínio gradual na função cognitiva (Agatonovic-Kustrin, S., Kettle, C. & Morton, D. W. A molecular approach in drug development for Alzheimer’s disease. Biomed. Pharmacother. 106, 553-565 (2018)). Ela está presente também nos últimos estágios da doença de Parkinson em torno de 25-30% dos casos (Aarsland, D., Zaccai, J. & Brayne, C. A systematic review of prevalence studies of dementia in Parkinson’s disease, Mov. Disord. 20, 1255-1263 (2005)). Além disso, uma pesquisa recente revelou que a doença de Alzheimer afeta aproximadamente 36 milhões de pessoas em todo o mundo, o que indica 60-80% de todos os casos de demência (Jabir, N. R., Khan, F. R. & Tabrez, S. Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer’s disease. CNS Neurosci. Ther. 24, 753-762 (2018)).[3] Dementia is characterized by being a progressive neurodegenerative disease that leads to a gradual decline in cognitive function (Agatonovic-Kustrin, S., Kettle, C. & Morton, DW A molecular approach in drug development for Alzheimer's disease. Biomed Pharmacother. 106, 553-565 (2018)). It is also present in the last stages of Parkinson's disease in around 25-30% of cases (Aarsland, D., Zaccai, J. & Brayne, C. A systematic review of prevalence studies of dementia in Parkinson's disease, Mov. Disord 20, 1255-1263 (2005)). In addition, recent research has found that Alzheimer's disease affects approximately 36 million people worldwide, indicating 60-80% of all dementia cases (Jabir, NR, Khan, FR & Tabrez, S. Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer's disease. CNS Neurosci. Ther. 24, 753-762 (2018)).

[4] A Organização Mundial de Saúde reconhece a doença de Alzheimer como prioridade global da saúde pública (Lane, C. A., Hardy, J. & Schott, J. M. Alzheimer’s disease. Eur. J. Neurol. 25, 59-70 (2018)). Estima-se que até 2050, aproximadamente 131 milhões de pessoas ao redor do mundo serão acometidas pela doença de Alzheimer (Bigueti, B. C. P., Lellis, J. Z. & Dias, J. C. R. Nutrientes essenciais na prevenção da doença de Alzheimer. Revista Ciências Nutricionais Online 2, 18-25 (2018)). No Brasil, a doença de Alzheimer já afeta 1,2 milhões de pessoas e estima-se que a cada ano 100 mil novos casos são relatados segundo a Associação Brasileira de Alzheimer (Bigueti, B. C. P., Lellis, J. Z. & Dias, J. C. R. Nutrientes essenciais na prevenção da doença de Alzheimer. Revista Ciências Nutricionais Online 2, 18-25 (2018)).[4] The World Health Organization recognizes Alzheimer's disease as a global public health priority (Lane, CA, Hardy, J. & Schott, JM Alzheimer's disease. Eur. J. Neurol. 25, 59-70 (2018)) . It is estimated that by 2050, approximately 131 million people around the world will be affected by Alzheimer's disease (Bigueti, BCP, Lellis, JZ & Dias, JCR Essential nutrients in the prevention of Alzheimer's disease. Revista Nutritional Sciences Online 2, 18 -25 (2018)). In Brazil, Alzheimer's disease already affects 1.2 million people and it is estimated that every year 100 thousand new cases are reported according to the Brazilian Alzheimer's Association (Bigueti, BCP, Lellis, JZ & Dias, JCR Essential nutrients in Prevention of Alzheimer's Disease. Nutritional Sciences Online Magazine 2, 18-25 (2018)).

[5] Todos os casos de Alzheimer podem ser divididos em dois principais grupos. O primeiro, conhecido como forma hereditária familiar, ocorre de 1 a 5% de todos os casos da doença de Alzheimer e caracteriza-se por um início precoce da doença (antes mesmos dos 50 anos) (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer’s disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)). Esse tipo está associado a mutações no gene codificador da proteína precursora amiloide e nos genes para PS1 ou PS2 - componentes do complexo γ-secretase (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer’s disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)). Já na segunda forma, denominada esporádica ou tardia, a doença de Alzheimer é caracterizada por um início tardio (geralmente após os 65 anos), atingindo uma parcela significativa da população, e a sua causa não está claramente associada a nenhum tipo de perfil de mutação (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer’s disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)).[5] All cases of Alzheimer's can be divided into two main groups. The first, known as a familial hereditary form, occurs in 1 to 5% of all cases of Alzheimer's disease and is characterized by an early onset of the disease (even before the age of 50) (Kozlov, S., Afonin, A. , Evsyukov, I. & Bondarenko, A. Alzheimer's disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)). This type is associated with mutations in the gene encoding the amyloid precursor protein and in the genes for PS1 or PS2 - components of the γ-secretase complex (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer's disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)). In the second form, called sporadic or late, Alzheimer's disease is characterized by a late onset (usually after age 65), affecting a significant portion of the population, and its cause is not clearly associated with any type of mutation profile. (Kozlov, S., Afonin, A., Evsyukov, I. & Bondarenko, A. Alzheimer's disease: as it was in the beginning. Rev. Neurosci. 28, 825-843 (2017)).

[6] As principais características da doença de Alzheimer são o depósito de peptídeos β-amiloides na superfície extracelular dos neurônios e a formação de aglomerados neurofibrilares em virtude do acúmulo intracelular da proteína Tau hiperfosforilada (Picanço, L. C. S., Ozela, P. F., Brito, M. F. B., Pinheiro, A. A., Padilha, E. C., Braga, F. S., Silva, C. H. T. P., Santos, C. B. R., Rosa, J. M. C. & Hage-Melim, L. I. S. Alzheimer's disease: a review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Curr. Med. Chem. 25, 3141-3159 (2018)). Além do mais, o déficit do neurotransmissor acetilcolina e o estresse oxidativo causado pela exacerbação da transmissão glutamatérgica também estão associados à doença de Alzheimer (Ma, L., Xiao, H., Wen, J., Liu, Z., He, Y. & Yuan, F. Possible mechanism of Vitis vinifera L. flavones on neurotransmitters, synaptic transmission and related learning and memory in Alzheimer model rats. Lipids Health Dis. 17, 152-160 (2018)).[6] The main characteristics of Alzheimer's disease are the deposition of β-amyloid peptides on the extracellular surface of neurons and the formation of neurofibrillary clusters due to the intracellular accumulation of hyperphosphorylated Tau protein (Picanço, LCS, Ozela, PF, Brito, MFB , Pinheiro, AA, Padilha, EC, Braga, FS, Silva, CHTP, Santos, CBR, Rosa, JMC & Hage-Melim, LIS Alzheimer's disease: a review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Chem. 25, 3141-3159 (2018)). Furthermore, deficit in the neurotransmitter acetylcholine and oxidative stress caused by exacerbation of glutamatergic transmission are also associated with Alzheimer's disease (Ma, L., Xiao, H., Wen, J., Liu, Z., He, Y . & Yuan, F. Possible mechanism of Vitis vinifera L. flavones on neurotransmitters, synaptic transmission and related learning and memory in Alzheimer model rats. Lipids Health Dis. 17, 152-160 (2018)).

[7] A hipótese colinérgica foi a primeira teoria a ser formulada para explicar os mecanismos fisiopatológicos da doença de Alzheimer. Esta hipótese sugere que a diminuição na síntese do neurotransmissor acetilcolina é uma das mais importantes causas do comprometimento da função cognitiva, que é o sintoma mais relevante da doença de Alzheimer (Ma, L., Xiao, H., Wen, J., Liu, Z., He, Y. & Yuan, F. Possible mechanism of Vitis vinifera L. flavones on neurotransmitters, synaptic transmission and related learning and memory in Alzheimer model rats. Lipids Health Dis. 17, 152160 (2018)).[7] The cholinergic hypothesis was the first theory to be formulated to explain the pathophysiological mechanisms of Alzheimer's disease. This hypothesis suggests that the decrease in the synthesis of the neurotransmitter acetylcholine is one of the most important causes of impaired cognitive function, which is the most relevant symptom of Alzheimer's disease (Ma, L., Xiao, H., Wen, J., Liu , Z., He, Y. & Yuan, F. Possible mechanism of Vitis vinifera L. flavones on neurotransmitters, synaptic transmission and related learning and memory in Alzheimer model rats. Lipids Health Dis. 17, 152160 (2018)).

[8] A acetilcolinesterase (AChE) é uma enzima chave que está envolvida na terminação da transmissão do impulso nervoso por meio da rápida hidrólise do neurotransmissor acetilcolina (Almeida, J. R., Figueiro, M., Almeida, W. P. & Silva, C. H. T. P. Discovery of novel dual acetylcholinesterase inhibitors with antifibrillogenic activity related to Alzheimer’s disease. Future Med. Chem. 10, 10371053 (2018)). A inativação desta enzima leva ao acúmulo de acetilcolina, o que torna os inibidores da AChE aplicáveis como medicamentos relevantes no tratamento da doença de Alzheimer (Colovic, M. B., Krsti, D. Z., Lazarevic-Pasti, T. D., Aleksandra M. Bondzic & Vesna M. Vasic. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 11, 315-335 (2013)).[8] Acetylcholinesterase (AChE) is a key enzyme that is involved in terminating nerve impulse transmission through the rapid hydrolysis of the neurotransmitter acetylcholine (Almeida, JR, Figueiro, M., Almeida, WP & Silva, CHTP Discovery of novel dual acetylcholinesterase inhibitors with antifibrillogenic activity related to Alzheimer's disease. Future Med. Chem. 10, 10371053 (2018)). Inactivation of this enzyme leads to the accumulation of acetylcholine, which makes AChE inhibitors applicable as relevant drugs in the treatment of Alzheimer's disease (Colovic, MB, Krsti, DZ, Lazarevic-Pasti, TD, Aleksandra M. Bondzic & Vesna M. Vasic. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 11, 315-335 (2013)).

[9] Os inibidores da AChE têm sido recomendados como tratamento padrão da doença de Alzheimer de acordo com o Parâmetro de Prática da Academia Americana de Neurologia (Feldman, H. H., Pirttila, T., Dartigues, J. F., Everitt, B., Baelen, B. V., Schwalen, S. & Kavanagh, S. Treatment with galantamine and time to nursing home placement in Alzheimer’s disease patients with and without cerebrovascular disease. Int. J. Geriatr. Psychiatry 24, 479-488 (2009)). Uma vez que eles inibem a enzima acetilcolinesterase de quebrar a acetilcolina, os inibidores da AChE podem ser divididos em dois grupos: o reversível e o irreversível (Colovic, M. B., Krsti, D. Z., Lazarevic-Pasti, T. D., Aleksandra M. Bondzic & Vesna M. Vasic. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 11, 315-335 (2013)). Os inibidores reversíveis, competitivos ou não competitivos, possuem principalmente aplicações terapêuticas, enquanto que os irreversíveis estão associados aos efeitos tóxicos (Colovic, M. B., Krsti, D. Z., Lazarevic-Pasti, T. D., Aleksandra M. Bondzic & Vesna M. Vasic. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 11, 315-335 (2013)).[9] AChE inhibitors have been recommended as a standard treatment of Alzheimer's disease according to the American Academy of Neurology Practice Parameter (Feldman, HH, Pirttila, T., Dartigues, JF, Everitt, B., Baelen, BV, Schwalen, S. & Kavanagh, S. Treatment with galantamine and time to nursing home placement in Alzheimer's disease patients with and without cerebrovascular disease. Int. J. Geriatr. Psychiatry 24, 479-488 (2009)). Since they inhibit the acetylcholinesterase enzyme from breaking down acetylcholine, AChE inhibitors can be divided into two groups: the reversible and the irreversible (Colovic, MB, Krsti, DZ, Lazarevic-Pasti, TD, Aleksandra M. Bondzic & Vesna M. Vasic. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 11, 315-335 (2013)). Reversible inhibitors, competitive or non-competitive, have mainly therapeutic applications, while irreversible ones are associated with toxic effects (Colovic, MB, Krsti, DZ, Lazarevic-Pasti, TD, Aleksandra M. Bondzic & Vesna M. Vasic. Acetylcholinesterase inhibitors : pharmacology and toxicology. Curr Neuropharmacol. 11, 315-335 (2013)).

[10] Apesar da ambiguidade dos médicos sobre a eficácia do uso dos inibidores da acetilcolinesterase na doença de Alzheimer, bem como a sua inconsistência e uso limitado, a gama de dados até o momento dão suporte para a prescrição dos inibidores da AChE em todos os estágios da doença (Hampel, H., Mesulam, M.-M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, G. T., Khachaturian, A. S., Vergallo, A., Cavedo, E., Snyder, P. J. & Khachaturian, Z. S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141, 1917-1933 (2018)).[10] Despite doctors' ambiguity about the effectiveness of using acetylcholinesterase inhibitors in Alzheimer's disease, as well as their inconsistency and limited use, the range of data so far supports the prescription of AChE inhibitors in all countries. stages of the disease (Hampel, H., Mesulam, M.-M., Cuello, AC, Farlow, MR, Giacobini, E., Grossberg, GT, Khachaturian, AS, Vergallo, A., Cavedo, E., Snyder, PJ & Khachaturian, ZS The cholinergic system in the pathophysiology and treatment of Alzheimer's disease.Brain 141, 1917-1933 (2018)).

[11] Embora modesto, os inibidores da AChE apresentam um efeito significativo no estado cognitivo dos pacientes com a doença de Alzheimer, bem como um efeito positivo sobre o humor e o comportamento (Grutzendler, J. & Morris, J. C. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 61, 41-52 (2001)). Além disso, os inibidores da AChE são geralmente bem tolerados e os benefícios de uso superam os custos, sendo assim, os inibidores da AChE devem ser considerados como terapia primária para os pacientes com a doença de Alzheimer (Grutzendler, J. & Morris, J. C. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 61, 41-52 (2001)).[11] Although modest, AChE inhibitors have a significant effect on the cognitive status of patients with Alzheimer's disease, as well as a positive effect on mood and behavior (Grutzendler, J. & Morris, JC Cholinesterase inhibitors for Alzheimer's disease Drugs 61, 41-52 (2001)). In addition, AChE inhibitors are generally well tolerated and the benefits of use outweigh the costs, so AChE inhibitors should be considered as primary therapy for patients with Alzheimer's disease (Grutzendler, J. & Morris, JC Cholinesterase inhibitors for Alzheimer's disease, Drugs 61, 41-52 (2001)).

[12] Ao longo dos últimos anos, grandes avanços no campo da medicina têm sido realizados para melhor compreender e tratar a doença de Alzheimer, porém a terapia atualmente empregada ainda é insatisfatória (Sereniki, A. & Vital, M. A. B. F. A doença de Alzheimer: aspectos fisiopatológicos e farmacológicos. Rev. Psiquiatr. RS. 30, 1 supl. (2008)). A realidade é que embora o tratamento realizado com os inibidores da AChE tenha demonstrado eficácia e redução na progressão da doença de Alzheimer, a maioria dos medicamentos produzem alguma melhoria em aproximadamente 30 a 40% dos pacientes portadores da doença de Alzheimer (Sereniki, A. & Vital, M. A. B. F. A doença de Alzheimer: aspectos fisiopatológicos e farmacológicos. Rev. Psiquiatr. RS. 30, 1 supl. (2008)).[12] Over the past few years, major advances in the field of medicine have been made to better understand and treat Alzheimer's disease, but the therapy currently employed is still unsatisfactory (Sereniki, A. & Vital, MABF Alzheimer's disease: pathophysiological and pharmacological aspects Rev. Psiquiatr. RS. 30, 1 supl. (2008)). The reality is that although treatment with AChE inhibitors has shown efficacy and reduced progression of Alzheimer's disease, most drugs produce some improvement in approximately 30 to 40% of patients with Alzheimer's disease (Sereniki, A. & Vital, MABF Alzheimer's disease: pathophysiological and pharmacological aspects Rev. Psiquiatr. RS. 30, 1 supl. (2008)).

[13] Os atuais medicamentos empregados no tratamento clínico da doença de Alzheimer são classificados como inibidores da AChE (o donepezil, a galantamina e a rivastigmina) e antagonista de receptor de glutamato do tipo N-metil D-aspartato (NMDA) (a memantina); todavia, essas drogas não são altamente eficazes (Yuan, C., Guo, X., Zhou, Q., Du, F., Jiang, W., Zhou, X., Liu, P., Chi, T., Ji, X., Gao, J., Chen, C., Lang, H., Xu, J., Liu, D., Yang, Y., Qiu, S., Tang, X., Chen, G. & Zou, L. OAB-14, a bexarotene derivative, improves Alzheimer’s disease-related pathologies and cognitive impairments by increasing β-amyloid clearance in APP/PS1 mice. Biochim Biophys Acta Mol Basis Dis. 1865, 161-180 (2018)). Assim, o desenvolvimento de novos medicamentos que atuem como inibidores eficientes da acetilcolinesterase é urgentemente necessário para o tratamento da doença de Alzheimer.[13] Current drugs used in the clinical treatment of Alzheimer's disease are classified as AChE inhibitors (donepezil, galantamine and rivastigmine) and N-methyl D-aspartate (NMDA) type glutamate receptor antagonist (memantine) ); however, these drugs are not highly effective (Yuan, C., Guo, X., Zhou, Q., Du, F., Jiang, W., Zhou, X., Liu, P., Chi, T., Ji , X., Gao, J., Chen, C., Lang, H., Xu, J., Liu, D., Yang, Y., Qiu, S., Tang, X., Chen, G. & Zou , L. OAB-14, a bexarotene derivative, improves Alzheimer's disease-related pathologies and cognitive impairments by increasing β-amyloid clearance in APP / PS1 mice. Biochim Biophys Acta Mol Basis Dis. 1865, 161-180 (2018)). Thus, the development of new drugs that act as efficient acetylcholinesterase inhibitors is urgently needed for the treatment of Alzheimer's disease.

[14] Nesse contexto, os sulfetos orgânicos e seus derivados constituem uma classe importante de intermediários na química orgânica devido à sua reatividade e atividade biológica e farmacológica (Thankachan, A. P., Sindhu, K. S., Krishnan, K. K. & Anilkumar, G. A. Novel and efficient zinc-catalyzed thioetherification of aryl halides. RSC Advances 5, 32675-32678 (2015)). Diversos estudos sobre a atividade dos compostos de sulfeto de arila indicam que eles possuem propriedades anti-inflamatórias e são usados no tratamento de várias doenças, como Alzheimer, Parkinson, hanseníase ou como inibidores do vírus da imunodeficiência humana (HIV) (Kabir, M. S., Lorenz, M., Van Linn, M. L., Namjoshi, O. A., Ara, S. & Cook, J. M. A very active Cu-catalytic system for the synthesis of aryl, heteroaryl, and vinyl sulfides. J. Org. Chem. 75, 3626-3643 (2010)). As metodologias usuais para a formação de ligações C-S são altamente ineficientes devido às condições de reação extremamente drásticas (Thankachan, A. P., Sindhu, K. S., Krishnan, K. K. & Anilkumar, G. A. Novel and efficient zinc-catalyzed thioetherification of aryl halides. RSC Advances 5, 32675-32678 (2015)) e, assim, a demanda de novas e eficientes metodologias para a síntese desses compostos tem emergido em síntese orgânica (Ghaderi, A. Advances in transition-metal catalyzed thioetherification reactions of aromatic compounds. Tetrahedron 72, 4758-4782 (2016)). Nesse sentido, uma forte alternativa procurada pelos pesquisadores é o design de novos catalisadores, geralmente compostos por metais de transição (Lee, C.-F., Liu, Y.-C. & Badsara, S. S. Transition-metal-catalyzed C-S bond coupling reaction. Chem. Asian J. 9, 706-722 (2014)), dentre eles, o mais emblemático é o paládio (Kosugi, M., Shimizu, T. & Migita, T. Reactions of aryl halides with thiolate anions in the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium preparation of aryl sulfides. Chem. Lett. 7, 1314 (1978); Migita, T., Shimizu, T., Asami, Y., Shiobara, J., Kato, Y. & Kosugi, M. The palladium catalyzed nucleophilic substitution of aryl halides by thiolate anions. Bull. Chem. Soc. Jpn 53, 1385-1389 (1980); Byeun, A., Baek, K., Han, M. S. & Lee, S. Palladium-catalyzed C-S bond formation by using N-amido imidazolium salts as ligands.Tetrahedron Lett. 54, 6712-6715 (2013); Iranpoor, N., Firouzabadi, H. & Rostami, A. Palladium nanoparticles supported on silica diphenylphosphinite as efficient catalyst for C-O and C-S arylation of aryl halides. Appl. Organometal. Chem. 27, 501-506 (2013)). Nas últimas décadas, houve o crescente avanço das reações de acoplamento cruzado e os catalisadores de paládio tornaram-se excelentes candidatos para a construção de ligações carbono-carbono e carbono-heteroátomo (Littke, A. F. & Fu, G. C. Palladium-catalyzed coupling reactions of aryl chlorides. Angew. Chem. Int. Ed. 41, 4176-4211 (2002)).[14] In this context, organic sulfides and their derivatives constitute an important class of intermediates in organic chemistry due to their reactivity and biological and pharmacological activity (Thankachan, AP, Sindhu, KS, Krishnan, KK & Anilkumar, GA Novel and efficient zinc -catalyzed thioetherification of aryl halides RSC Advances 5, 32675-32678 (2015)). Several studies on the activity of aryl sulfide compounds indicate that they have anti-inflammatory properties and are used in the treatment of various diseases, such as Alzheimer's, Parkinson's, leprosy or as inhibitors of the human immunodeficiency virus (HIV) (Kabir, MS, Lorenz, M., Van Linn, ML, Namjoshi, OA, Ara, S. & Cook, JM A very active Cu-catalytic system for the synthesis of aryl, heteroaryl, and vinyl sulfides. J. Org. Chem. 75, 3626 -3643 (2010)). The usual methodologies for the formation of CS bonds are highly inefficient due to the extremely drastic reaction conditions (Thankachan, AP, Sindhu, KS, Krishnan, KK & Anilkumar, GA Novel and efficient zinc-catalyzed thioetherification of aryl halides. RSC Advances 5, 32675-32678 (2015)) and, thus, the demand for new and efficient methodologies for the synthesis of these compounds has emerged in organic synthesis (Ghaderi, A. Advances in transition-metal catalyzed thioetherification reactions of aromatic compounds. Tetrahedron 72, 4758- 4782 (2016)). In this sense, a strong alternative sought by researchers is the design of new catalysts, usually composed of transition metals (Lee, C.-F., Liu, Y.-C. & Badsara, SS Transition-metal-catalyzed CS bond coupling Asian J. 9, 706-722 (2014)), among them, the most emblematic is palladium (Kosugi, M., Shimizu, T. & Migita, T. Reactions of aryl halides with thiolate anions in the presence of catalytic amounts of tetrakis (triphenylphosphine) palladium preparation of aryl sulfides.Chem. Lett. 7, 1314 (1978); Migita, T., Shimizu, T., Asami, Y., Shiobara, J., Kato, Y. & Kosugi, M. The palladium catalyzed nucleophilic substitution of aryl halides by thiolate anions. Bull. Chem. Soc. Jpn 53, 1385-1389 (1980); Byeun, A., Baek, K., Han, MS & Lee, S Palladium-catalyzed CS bond formation by using N-starch imidazolium salts as ligands.Tetrahedron Lett. 54, 6712-6715 (2013); Iranpoor, N., Firouzabadi, H. & Rostami, A. Palladium nanoparticles supported on silica d iphenylphosphinite as efficient catalyst for C-O and C-S arylation of aryl halides. Appl. Organometal. Chem. 27, 501-506 (2013)). In the last few decades, there has been an increasing advance in cross-coupling reactions and palladium catalysts have become excellent candidates for the construction of carbon-carbon and carbon-heteroatom bonds (Littke, AF & Fu, GC Palladium-catalyzed coupling reactions of aryl chlorides, Angew, Chem, Int. Ed. 41, 4176-4211 (2002)).

[15] Em relação aos compostos heterocíclicos, o benzotiadiazol (BTD) é uma importante unidade estrutural que tem recebido muita atenção nos últimos anos devido às suas diversas propriedades como fungicidas (Mataka, S., Takahashi, K., Imura, T. & Tashiro, M. Reduction of 4,7-diphenyl-1,2,5-thia(oxa)diazolo[3,4-c] pyridines affording 2,5-diphenyl- 3,4-diaminopyridines and ring closure of the diamines to fluorescent azaheterocycles. J. Heterocycl. Chem. 19, 1481-1488 (1982)), herbicidas (Gozzo, F. Systemic acquired resistance in crop protection: from nature to a chemical approach. J. Agric. Food Chem. 51, 4487-4503 (2003)), antibacteriana (Balasankar, T. , Gopalakrishnan, M. & Nagarajan S. Synthesis and antibacterial activity of some 5-(4-biphenylyl)-7-aryl[3,4-d] [1,2,3] -benzothiadiazoles. Eur. J. Med. Chem. 40, 728731 (2005)) e fotoluminescentes (Park, S. H., Roy, A., Beaupre, S., Cho, S., Coates, N., Moon, J. S., Moses, D., Leclerc, M., Lee, K. & Heeger, A. J. Bulk heterojunction solar cells with internal quantum efficiency approaching 100%. Nature Photonics 3, 297-302 (2009); Chen, J. & Cao, Y. Development of novel conjugated donor polymers for high-efficiency bulk-heterojunction photovoltaic devices. Acc. Chem. Res. 42, 1709-1718 (2009); Blouin, N., Michaud, A. & Leclerc, M. A low-bandgap poly(2,7-carbazole) derivative for use in high-performance solar cells. Adv. Mater. 19, 2295-2300 (2007); Hou, J., Chen, H.-Y., Zhang, S., Li, G. & Yang, Y. Synthesis, characterization, and photovoltaic properties of a low band gap polymer based on silole-containing polythiophenes and 2,1,3-benzothiadiazole. J. Am. Chem. Soc. 130, 16144-16145 (2008); Neto, B. A. D., Carvalho, P. H. P. R. & Correa, J. R. Benzothiadiazole derivatives as fluorescence imaging probes: beyond classical scaffolds. Acc. Chem. Res. 48, 1560-1569 (2015)). Além disso, os compostos que possuem o anel de BTD têm sido amplamente empregados com sucesso como compostos luminescentes, tais como OLEDs, células solares, cristais líquidos, corantes, células fotovoltaicas e outros (Neto, B. A. D., Lapis, A. A. M., Júnior, E. N. S. & Dupont, J. 2,1,3-benzothiadiazole and derivatives: synthesis, properties, reactions, and applications in light technology of small molecules. Eur. J. Org. Chem. 2013, 228-255 (2013); Tsao, H. N., Cho, D. M., Park, I., Hansen, M. R., Mavrinskiy, A., Yoon, D. Y., Graf, R., Pisula, W., Spiess, H. W. & Mullen, K. Ultrahigh mobility in polymer field-effect transistors by design. J. Am. Chem. Soc. 133, 2605-2612 (2011); Huang, F., Hou, L., Wu, H., Wang, X., Shen, H., Cao, W., Yang, W. & Cao, Y. High-efficiency, environment-friendly electroluminescent polymers with stable high work function metal as a cathode: green- and yellow-emitting conjugated polyfluorene polyelectrolytes and their neutral precursors. J. Am. Chem. Soc. 126, 9845-9853 (2004)). Alguns derivados de 2,1,3-benzotiadiazol também possuem propriedades biológicas de interesse, como por exemplo, a tizanidina, um relaxante muscular que atua como um agonista adrenérgico (Langis-Barsetti, S., Maris, T. & Wuest, J. D. Molecular organization of 2,1,3-benzothiadiazoles in the solid state. J. Org. Chem. 82, 5034-5045 (2017)).[15] Regarding heterocyclic compounds, benzothiadiazole (BTD) is an important structural unit that has received a lot of attention in recent years due to its diverse properties as fungicides (Mataka, S., Takahashi, K., Imura, T. & Tashiro, M. Reduction of 4,7-diphenyl-1,2,5-thia (oxa) diazolo [3,4-c] pyridines affording 2,5-diphenyl- 3,4-diaminopyridines and ring closure of the diamines to fluorescent azaheterocycles. J. Heterocycl. Chem. 19, 1481-1488 (1982)), herbicides (Gozzo, F. Systemic acquired resistance in crop protection: from nature to a chemical approach. J. Agric. Food Chem. 51, 4487- 4503 (2003)), antibacterial (Balasankar, T., Gopalakrishnan, M. & Nagarajan S. Synthesis and antibacterial activity of some 5- (4-biphenylyl) -7-aryl [3,4-d] [1,2, 3] -benzothiadiazoles. Eur. J. Med. Chem. 40, 728731 (2005)) and photoluminescent (Park, SH, Roy, A., Beaupre, S., Cho, S., Coates, N., Moon, JS , Moses, D., Leclerc, M., Lee, K. & Heeger, AJ Bulk heterojunction sola r cells with internal quantum efficiency approaching 100%. Nature Photonics 3, 297-302 (2009); Chen, J. & Cao, Y. Development of novel conjugated donor polymers for high-efficiency bulk-heterojunction photovoltaic devices. Acc. Chem. Res. 42, 1709-1718 (2009); Blouin, N., Michaud, A. & Leclerc, M. A low-bandgap poly (2,7-carbazole) derivative for use in high-performance solar cells. Adv. Mater. 19, 2295-2300 (2007); Hou, J., Chen, H.-Y., Zhang, S., Li, G. & Yang, Y. Synthesis, characterization, and photovoltaic properties of a low band gap polymer based on silole-containing polythiophenes and 2,1 , 3-benzothiadiazole. J. Am. Chem. Soc. 130, 16144-16145 (2008); Neto, B. A. D., Carvalho, P. H. P. R. & Correa, J. R. Benzothiadiazole derivatives as fluorescence imaging probes: beyond classical scaffolds. Acc. Chem. Res. 48, 1560-1569 (2015)). In addition, the compounds that have the BTD ring have been widely used successfully as luminescent compounds, such as OLEDs, solar cells, liquid crystals, dyes, photovoltaic cells and others (Neto, BAD, Lapis, AAM, Júnior, ENS & Dupont, J. 2,1,3-benzothiadiazole and derivatives: synthesis, properties, reactions, and applications in light technology of small molecules. Eur. J. Org. Chem. 2013, 228-255 (2013); Tsao, HN, Cho, DM, Park, I., Hansen, MR, Mavrinskiy, A., Yoon, DY, Graf, R., Pisula, W., Spiess, HW & Mullen, K. Ultrahigh mobility in polymer field-effect transistors by design J. Am. Chem. Soc. 133, 2605-2612 (2011); Huang, F., Hou, L., Wu, H., Wang, X., Shen, H., Cao, W., Yang, W. & Cao, Y. High-efficiency, environment-friendly electroluminescent polymers with stable high work function metal as a cathode: green- and yellow-emitting conjugated polyfluorene polyelectrolytes and their neutral precursors. J. Am. Chem. Soc. 12 6, 9845-9853 (2004)). Some 2,1,3-benzothiadiazole derivatives also have biological properties of interest, such as tizanidine, a muscle relaxant that acts as an adrenergic agonist (Langis-Barsetti, S., Maris, T. & Wuest, JD Molecular organization of 2,1,3-benzothiadiazoles in the solid state. J. Org. Chem. 82, 5034-5045 (2017)).

[16] Devido à variedade de aplicações apresentadas, várias metodologias foram descritas na literatura para a preparação de derivados do 2,1,3-benzotiadiazol (Liu, Y., Prashad, M., Repic, O. & Blacklock, T. J. Palladium-catalyzed amination with benzophenone imine as a new, safe and practical alternative to nitration for the synthesis of 7-amino-2,1,3-benzothiadiazoles. J. Heterocycl. Chem. 40, 713-716 (2003); Rao, V. R. & Reddy, M. M. M. Heterocyclic systems containing bridge head nitrogen atom: reaction of 5-mercapto-4H-imidazo[4,5-e] - [2,1,3] benzothiadiazoles and 5,6-diamino[2,1,3] benzothiazole with 3-(2-bromoacetyl)coumarins. Phosphorus Sulfur Silicon Relat. Elem. 179, 2105-2111 (2004); Neto, B. A. D., Corrêa, J. R., Carvalho, P. H. P. R., Santos, D. C. B. D., Guido, B. C., Gatto, C. C., De Oliveira, H. C. B., Fasciotti, M., Eberlin, M. N. & Júnior, E. N. S. Selective and efficient mitochondria staining with designed 2,1,3-benzothiadiazole derivatives as live cell fluorescence imaging probes. J. Braz. Chem. Soc. 23, 770-781 (2012)). No entanto, a síntese de arilsulfanil-benzo-2,1,3-tiadiazóis não tem sido muito explorada na química orgânica.[16] Due to the variety of applications presented, several methodologies have been described in the literature for the preparation of 2,1,3-benzothiadiazole derivatives (Liu, Y., Prashad, M., Repic, O. & Blacklock, TJ Palladium- catalyzed amination with benzophenone imine as a new, safe and practical alternative to nitration for the synthesis of 7-amino-2,1,3-benzothiadiazoles. J. Heterocycl. Chem. 40, 713-716 (2003); Rao, VR & Reddy, MMM Heterocyclic systems containing bridge head nitrogen atom: reaction of 5-mercapto-4H-imidazo [4,5-e] - [2,1,3] benzothiadiazoles and 5,6-diamino [2,1,3] benzothiazole with 3- (2-bromoacetyl) coumarins. Phosphorus Sulfur Silicon Report Elem. 179, 2105-2111 (2004); Neto, BAD, Corrêa, JR, Carvalho, PHPR, Santos, DCBD, Guido, BC, Gatto, CC, De Oliveira, HCB, Fasciotti, M., Eberlin, MN & Júnior, ENS Selective and efficient mitochondria staining with designed 2,1,3-benzothiadiazole derivatives as live cell fluorescence ima ging probes. J. Braz. Chem. Soc. 23, 770-781 (2012)). However, the synthesis of arylsulfanyl-benzo-2,1,3-thiadiazoles has not been widely explored in organic chemistry.

[17] Kamboj e colaboradores sintetizaram derivados de sulfanil-benzo-2,1,3-tiadiazóis via reações catalisadas por paládio e depois oxidaram os compostos em arilsulfonil-BTDs (Kukreja, G., Phukan, S., Kodam, J., More, D. M., Uravane, M. V., Palle, V. P. & Kamboj, R. K. Patent Wo2013005157 A1, (2013)).[17] Kamboj and colleagues synthesized sulfanyl-benzo-2,1,3-thiadiazole derivatives via palladium-catalyzed reactions and then oxidized the compounds to arylsulfonyl-BTDs (Kukreja, G., Phukan, S., Kodam, J., More, DM, Uravane, MV, Palle, VP & Kamboj, RK Patent Wo2013005157 A1, (2013)).

[18] Recentemente, Alves e colaboradores realizaram a síntese de arilsulfanil-benzo-2,1,3-tiadiazóis utilizando nanopartículas de cobre como catalisador (Balaguez, R. A., Ricordi, V. G., Duarte, R. C., Toldo, J. M., Santos, C. M., Schneider, P. H., Gonçalves, P. F. B., Rodembusch, F. S. & Alves, D. Bis-arylsulfenyl- and bis-arylselanyl-benzo-2,1,3-thiadiazoles: synthesis and photophysical characterization. Rsc Advances 6, 49613-49624 (2016)). Todas essas reações mencionadas acima foram realizadas por meio da reação de acoplamento cruzado C-S na posição C-4 do anel do BTD.[18] Recently, Alves and collaborators performed the synthesis of arylsulfanyl-benzo-2,1,3-thiadiazoles using copper nanoparticles as a catalyst (Balaguez, RA, Ricordi, VG, Duarte, RC, Toldo, JM, Santos, CM, Schneider, PH, Gonçalves, PFB, Rodembusch, FS & Alves, D. Bis-arylsulfenyl- and bis-arylselanyl-benzo-2,1,3-thiadiazoles: synthesis and photophysical characterization. Rsc Advances 6, 49613-49624 (2016) ). All of these reactions mentioned above were carried out by means of the cross-coupling reaction C-S at position C-4 of the BTD ring.

[19] Nosso grupo de pesquisa já descreveu alguns protocolos usando catalisadores híbridos em algumas reações, entre elas a reação de acoplamento cruzado C-S usando um catalisador de paládio reciclável sob condições de reação moderadas (Santos, B. F., Silva, C. D. G., Silva, B. A. L., Katla, R., Oliveira, A. R., Kupfer, V. L., Rinaldi, A. W. & Domingues, N. L. C. C-S cross-coupling reaction using a recyclable palladium prolinate catalyst under mild and green conditions. Chemistryselect 2, 9063- 9068 (2017)). Deste modo, aqui descrevemos uma nova metodologia, simples e eficiente para a síntese de arilsulfanil-benzo-2,1,3-tiadiazóis via funcionalização da posição C-5 do anel do BTD empregando bis-L-prolinato de paládio (II) ou Pd[(L)-prolina] 2 como catalisador. Ademais, os compostos sintetizados foram testados in vitro pela primeira vez como inibidores da acetilcolinesterase, sendo este procedimento um bom indicativo para compostos utilizados no tratamento da doença de Azheimer.[19] Our research group has already described some protocols using hybrid catalysts in some reactions, including the cross-coupling reaction CS using a recyclable palladium catalyst under moderate reaction conditions (Santos, BF, Silva, CDG, Silva, BAL, Katla, R., Oliveira, AR, Kupfer, VL, Rinaldi, AW & Domingues, NLC CS cross-coupling reaction using a recyclable palladium prolinate catalyst under mild and green conditions. Chemistryselect 2, 9063- 9068 (2017)). Thus, here we describe a new, simple and efficient methodology for the synthesis of arylsulfanyl-benzo-2,1,3-thiadiazoles via functionalization of the C-5 position of the BTD ring employing palladium (II) bis-L-prolinate or Pd [(L) -proline] 2 as a catalyst. In addition, the synthesized compounds were tested in vitro for the first time as acetylcholinesterase inhibitors, this procedure being a good indicator for compounds used in the treatment of Azheimer disease.

Purpose of the Invention

[20] A presente invenção possui a tarefa de sintetizar derivados arilsulfanil-benzo-2.1.3- tiadiazóis inéditos, utilizando o catalisador Pd[(L)-prolina] 2, cujos compostos apresentam potencial de inibir a atividade da enzima acetilcolinesterase, os quais podem ser aplicados na elaboração de medicamentos ou composição para o tratamento da doença de Alzheimer.[20] The present invention has the task of synthesizing unpublished arylsulfanyl-benzo-2.1.3-thiadiazole derivatives, using the Pd [(L) -proline] 2 catalyst, whose compounds have the potential to inhibit the activity of the enzyme acetylcholinesterase, which can be applied in the preparation of drugs or composition for the treatment of Alzheimer's disease.

Brief description of the drawings

[21] A fim de se obter uma melhor visualização dos objetivos da presente invenção, faz-se necessária a leitura deste documento, bem como a análise dos desenhos que o acompanham aos quais a referência se encontra a seguir.[21] In order to obtain a better visualization of the objectives of the present invention, it is necessary to read this document, as well as to analyze the accompanying drawings to which the reference is found below.

[22] As Figuras de 1 a 14 apresentam o Efeito dos derivados arilsulfanil-benzo-2.1.3- tiadiazóis (compostos 1 a 14, respectivamente), em diferentes concentrações (1-500μΜ), na inibição in vitro da atividade da AChE em córtex cerebral de camundongos. Os dados estão reportados como média ± erro padrão da média de 3 experimentos independentes realizados em diferentes dias. A atividade da AChE está expressa como μmol de acetiltiocolina/hora/mg de proteína. (*) denota p < 0,05 quando comparado com o grupo controle (análise de variância de uma via seguida pelo teste de Newman-Keuls).[22] Figures 1 to 14 show the effect of arylsulfanyl-benzo-2.1.3-thiadiazoles derivatives (compounds 1 to 14, respectively), in different concentrations (1-500μΜ), on the in vitro inhibition of AChE activity in cerebral cortex of mice. The data are reported as mean ± standard error of the mean of 3 independent experiments carried out on different days. AChE activity is expressed as μmol of acetylthiocholine / hour / mg of protein. (*) denotes p <0.05 when compared to the control group (one-way analysis of variance followed by the Newman-Keuls test).

[23] A Figura 15 apresenta o esquema do Procedimento geral para a síntese dos compostos arilsulfanil-benzotiadiazóis.[23] Figure 15 presents the outline of the General Procedure for the synthesis of arylsulfanyl-benzothiadiazole compounds.

Detailed description of the invention

[24] Procedimento geral para a síntese de arilsulfanil-benzo-2,1,3-tiadiazóis[24] General procedure for the synthesis of arylsulfanyl-benzo-2,1,3-thiadiazoles

[25] Método A[25] Method A

[26] 5-(feniltio)benzo[c] [1,2,5] tiadiazol (1)[26] 5- (phenylthio) benzo [c] [1,2,5] thiadiazole (1)

[27] Em um tubo de reação de 5 mL foi adicionado 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de tiofenol (82 μL) e 0,8 mmol de K2CO3 (0,110 g). A mistura foi agitada em DMF (4 mL) a 100°C em banho de óleo durante 6 h. O progresso da reação foi monitorado por CCD (eluente: EtOAc/hexano, 10:90). Após este tempo, a solução foi arrefecida até a temperatura ambiente, diluída com acetato de etila (20 mL) e lavada com água (3x 20 mL). A fase orgânica foi separada, seca com Na2SO4 anidro e concentrada sob vácuo. O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-(feniltio)benzo[c] [1,2,5] tiadiazol (R= Ph) com 85% de rendimento.[27] In a 5 mL reaction tube, 1.5 mol% of the palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0, 8 mmol of thiophenol (82 μL) and 0.8 mmol of K2CO3 (0.110 g). The mixture was stirred in DMF (4 ml) at 100 ° C in an oil bath for 6 h. The progress of the reaction was monitored by CCD (eluent: EtOAc / hexane, 10:90). After this time, the solution was cooled to room temperature, diluted with ethyl acetate (20 ml) and washed with water (3x 20 ml). The organic phase was separated, dried with anhydrous Na2SO4 and concentrated in vacuo. The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5- (phenylthio) benzo [c] [1,2,5] thiadiazole (R = Ph) in 85% yield.

[28] 5-((4-metóxifenil)tio)benzo[c] [1,2,5] tiadiazol (2)[28] 5 - ((4-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (2)

[29] Este composto foi obtido seguindo o procedimento descrito no método A.[29] This compound was obtained following the procedure described in method A.

[30] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 4-metóxitiofenol (98 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-((4-metóxifeml)tio)bemo[c] [1,2,5] tiadiazol (R=4-OMePh) com 100% de rendimento.[30] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 4-methoxyphenol (98) were used μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluant, obtaining the compound 5 - ((4-methoxyfeml) thio) bemo [c] [1,2,5] thiadiazole (R = 4-OMePh) with 100% yield.

[31] 5-(p-toliltio)benzo[c] [1,2,5] tiadiazol (3)[31] 5- (p-tolylthio) benzo [c] [1,2,5] thiadiazole (3)

[32] Este composto foi obtido seguindo o procedimento descrito no método A.[32] This compound was obtained following the procedure described in method A.

[33] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 4-metiltiofenol (0,099 g) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-(p-toliltio)benzo[c] [1,2,5] tiadiazol (R=4-MePh) com 99% de rendimento.[33] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 4-methylthiophenol (0.099) were used g) and 0.8 mmol K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5- (p-tolylthio) benzo [c] [1,2,5] thiadiazole (R = 4-MePh) with 99% income.

[34] 5-((4-flúorfenil)tio)benzo[c] [1,2,5] tiadiazol (4)[34] 5 - ((4-fluorophenyl) thio) benzo [c] [1,2,5] thiadiazole (4)

[35] Este composto foi obtido seguindo o procedimento descrito no método A.[35] This compound was obtained following the procedure described in method A.

[36] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 4- flúortiofenol (85 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-((4-flúorfenil)tio)benzo[c] [1,2,5] tiadiazol (R=4-FPh) com 86% de rendimento.[36] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 4-fluorothiophenol (85 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5 - ((4-fluorophenyl) thio) benzo [c] [1,2,5] thiadiazole (R = 4-FPh) with 86% yield.

[37] 5-((4-clorofenil)tio)benzo[c] [1,2,5] tiadiazol (5)[37] 5 - ((4-chlorophenyl) thio) benzo [c] [1,2,5] thiadiazole (5)

[38] Este composto foi obtido seguindo o procedimento descrito no método A.[38] This compound was obtained following the procedure described in method A.

[39] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 4-clorotiofenol (0,116 g) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5- ((4-clorofenil)tio)benzo[c] [1,2,5] tiadiazol (R=4-ClPh) com 80% de rendimento.[39] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 4-chlorothiophenol (0.116) were used g) and 0.8 mmol K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5- ((4-chlorophenyl) thio) benzo [c] [1,2,5] thiadiazole (R = 4-ClPh) with 80% yield.

[40] 5-((3-metóxifenil)tio)benzo[c] [1,2,5] tiadiazol (6)[40] 5 - ((3-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (6)

[41] Este composto foi obtido seguindo o procedimento descrito no método A.[41] This compound was obtained following the procedure described in method A.

[42] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 3-metóxitiofenol (98 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-((3-metóxifenil)tio)benzo[c] [1,2,5] tiadiazol (R=3-OMePh) com 95% de rendimento.[42] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 3-methoxythiophenol (98) were used μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5 - ((3-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (R = 3-OMePh) with 95% yield.

[43] 5-((2-metóxifenil)tio)benzo[c] [l,2,5] tiadiazol (7)[43] 5 - ((2-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (7)

[44] Este composto foi obtido seguindo o procedimento descrito no método A.[44] This compound was obtained following the procedure described in method A.

[45] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 2-metóxitiofenol (98 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-((2-metóxifenil)tio)benzo[c] [1,2,5] tiadiazol (R=2-OMePh) com 95% de rendimento.[45] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 2-methoxythiophenol (98) were used μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5 - ((2-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (R = 2-OMePh) with 95% yield.

[46] 5-((2-clorofenil)tio)benzo[c] [1,2,5] tiadiazol (8)[46] 5 - ((2-chlorophenyl) thio) benzo [c] [1,2,5] thiadiazole (8)

[47] Este composto foi obtido seguindo o procedimento descrito no método A.[47] This compound was obtained following the procedure described in method A.

[48] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 2-clorotiofenol (90,9 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-((2-clorofenil)tio)benzo[c] [1,2,5] tiadiazol (R=2-ClPh) com 63% de rendimento.[48] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 2-chlorothiophenol (90) were used , 9 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5 - ((2-chlorophenyl) thio) benzo [c] [1,2,5] thiadiazole (R = 2-ClPh) with 63% yield.

[49] 5-(benziltio)benzo[c] [1,2,5] tiadiazol (9)[49] 5- (benzylthio) benzo [c] [1,2,5] thiadiazole (9)

[50] Este composto foi obtido seguindo o procedimento descrito no método A.[50] This compound was obtained following the procedure described in method A.

[51] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de benzilmercaptana (93,9 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-(benziltio)benzo[c] [1,2,5] tiadiazol (R=Bn) com 82% de rendimento.[51] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of benzylmercaptan (93.9 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5- (benzylthio) benzo [c] [1,2,5] thiadiazole (R = Bn) in 82% yield.

[52] 5-(o-toliltio)benzo[c] [1,2,5] tiadiazol (10)[52] 5- (o-tolylthio) benzo [c] [1,2,5] thiadiazole (10)

[53] Este composto foi obtido seguindo o procedimento descrito no método A.[53] This compound was obtained following the procedure described in method A.

[54] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 2-metiltiofenol (93,9 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto5-(o-toliltio)benzo[c] [1,2,5] tiadiazol (R=2-MePh) com 89% de rendimento.[54] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 2-methylthiophenol (93) were used , 9 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5- (o-tolylthio) benzo [c] [1,2,5] thiadiazole (R = 2-MePh) with 89% Yield.

[55] 5-((2,4-dimetilfenil)tio)benzo[c] [1,2,5] tiadiazol (11)[55] 5 - ((2,4-dimethylphenyl) thio) benzo [c] [1,2,5] thiadiazole (11)

[56] Este composto foi obtido seguindo o procedimento descrito no método A.[56] This compound was obtained following the procedure described in method A.

[57] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5- bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 2,4-dimetiltiofenol (108 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 5-((2,4-dimetilfenil)tio)benzo[c] [1,2,5] tiadiazol (R=2,4-(CH3)2Ph) com 97% de rendimento.[57] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 2,4-dimethylthiophenol were used (108 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 5 - ((2,4-dimethylphenyl) thio) benzo [c] [1,2,5] thiadiazole (R = 2, 4- (CH3) 2Ph) with 97% yield.

[58] 4-(benzo[c] [1,2,5] tiadiazol-5-iltio)anilina (12)[58] 4- (benzo [c] [1,2,5] thiadiazol-5-ylthio) aniline (12)

[59] Este composto foi obtido seguindo o procedimento descrito no método A.[59] This compound was obtained following the procedure described in method A.

[60] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 4-aminotiofenol (83,3 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 4-(benzo[c] [1.2.5] tiadiazol-5-iltio)anilina (R=4-NH2Ph) com 91% de rendimento.[60] 1.5 mol% of the palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 4-aminothiophenol (83 , 3 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 4- (benzo [c] [1.2.5] thiadiazol-5-ylthio) aniline (R = 4-NH2Ph) with 91% income.

[61] 2-(benzo[c] [1,2,5] tiadiazol-5-iltio)anilina (13)[61] 2- (benzo [c] [1,2,5] thiadiazol-5-ylthio) aniline (13)

[62] Este composto foi obtido seguindo o procedimento descrito no método A.[62] This compound was obtained following the procedure described in method A.

[63] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 2-aminotiofenol (85,5 μL) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 2-(benzo[c] [1,2,5] tiadiazol-5-iltio)anilina (R=2-NH2Ph) com 100% de rendimento.[63] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 2-aminothiophenol (85 , 5 μL) and 0.8 mmol of K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 2- (benzo [c] [1,2,5] thiadiazol-5-ylthio) aniline (R = 2-NH2Ph) with 100% yield.

[64] 2-(benzo[c] [1,2,5] tiadiazol-5-iltio)-5-cloroanilina (14)[64] 2- (benzo [c] [1,2,5] thiadiazol-5-ylthio) -5-chloroaniline (14)

[65] Este composto foi obtido seguindo o procedimento descrito no método A.[65] This compound was obtained following the procedure described in method A.

[66] Foram utilizados 1,5% mol do catalisador de paládio (0,002 g), 0,4 mmol de 5-bromo-2,1,3-benzotiadiazol (0,086 g), 0,8 mmol de 2-amino-4-clorotiofenol (0,128 g) e 0,8 mmol de K2CO3 (0,110 g). O produto obtido foi purificado por cromatografia em coluna usando apenas hexano como o eluente, obtendo-se o composto 2-(benzo[c] [1,2,5] tiadiazol-5-iltio)-5-cloroanilina (R=2-NH2-4-ClPh) com 94% de rendimento.[66] 1.5 mol% of palladium catalyst (0.002 g), 0.4 mmol of 5-bromo-2,1,3-benzothiadiazole (0.086 g), 0.8 mmol of 2-amino-4 were used -chlorothiophenol (0.128 g) and 0.8 mmol K2CO3 (0.110 g). The product obtained was purified by column chromatography using only hexane as the eluent, obtaining the compound 2- (benzo [c] [1,2,5] thiadiazol-5-ylthio) -5-chloroaniline (R = 2- NH2-4-ClPh) with 94% yield.

[67] Procedimento geral para a avaliação da inibição in vitro da atividade da AChE pelos derivados arilsulfanil-benzo-2,1,3-tiadiazóis[67] General procedure for the evaluation of the in vitro inhibition of AChE activity by arylsulfanyl-benzo-2,1,3-thiadiazole derivatives

[68] Para validação desta invenção, preferencialmente deve-se utilizar córtex cerebral de camundongos machos Swiss.[68] To validate this invention, the cerebral cortex of male Swiss mice should preferably be used.

[69] A avaliação da inibição in vitro da atividade da AChE pelos derivados arilsulfanil-benzo-2,1,3-tiadiazóis foi determinada através do método de Ellman e colaboradores (Ellman, G. L., Courtney, K. D., Andres Jr, V. & Featherstone, R. M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7, 88-95 (1961)). Os córtex cerebrais foram homogeneizados em um tampão de sacarose 0,25 M na proporção 1/10 (peso/volume). Os homogenatos foram centrifugados a 900 xg a 4°C por 10 minutos e os sobrenadantes foram usados para o ensaio enzimático. Uma alíquota de 100 μL do sobrenadante (proteína de 2,8 mg/mL) foi incubada por 2 minutos a 25°C na presença de diferentes concentrações (1-500 μΜ) dos compostos, em um meio contendo tampão fosfato de potássio 100 mM pH 7,5. A reação enzimática foi iniciada pela adição de ácido 5,5’ -ditiobis(2-nitrobenzóico) (concentração final de 0,5mM) e iodeto de acetiltiocolina (concentração final de 0,8mM). A razão da hidrólise do iodeto de acetiltiocolina foi medida em 412 nm. Os resultados foram expressos como μmol de acetiltiocolina/h/mg de proteína. Todas as observações foram validadas por pelo menos três experimentos independentes, em duplicata.[69] The evaluation of the in vitro inhibition of AChE activity by arylsulfanyl-benzo-2,1,3-thiadiazole derivatives was determined using the method of Ellman et al. (Ellman, GL, Courtney, KD, Andres Jr, V. & Featherstone, RM A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7, 88-95 (1961)). The cerebral cortexes were homogenized in a 0.25 M sucrose buffer in a 1/10 ratio (weight / volume). The homogenates were centrifuged at 900 xg at 4 ° C for 10 minutes and the supernatants were used for the enzymatic assay. A 100 μL aliquot of the supernatant (2.8 mg / mL protein) was incubated for 2 minutes at 25 ° C in the presence of different concentrations (1-500 μΜ) of the compounds, in a medium containing 100 mM potassium phosphate buffer. pH 7.5. The enzymatic reaction was initiated by the addition of 5.5 ’-ditiobis acid (2-nitrobenzoic acid) (final concentration of 0.5 mM) and acetylthiocholine iodide (final concentration of 0.8 mM). The hydrolysis ratio of acetylthiocholine iodide was measured at 412 nm. The results were expressed as μmol of acetylthiocholine / h / mg of protein. All observations were validated by at least three independent experiments, in duplicate.

[70] Os testes de validação desta invenção mostraram que todos os derivados arilsulfanil-benzo-2,1,3-tiadiazóis acima descritos possuem capacidade de inibir in vitro a atividade da enzima AChE em córtex cerebral de camundongos (Figuras A-N). Os compostos 2, 3, 4, 5, 7 e 8 inibiram a atividade da AChE em córtex cerebral de camundongos a partir da concentração de 100 μΜ (Figuras B-E, G, H, respectivamente). Os compostos 1, 6, 9 e 11 causaram a inibição na atividade da AChE em córtex cerebral de camundongos a partir da concentração de 200 μΜ (A, F, I, K, respectivamente). Já os compostos 10, 12, 13 e 14 inibiram a atividade da enzima somente na concentração de 500 μΜ (J, L-N, respectivamente). Os resultados representados na Tabela 1 indicam que os compostos seguiram a seguinte ordem de inibição máxima: 2 > 9 > 7 = 12 > 11 > 1 > 8 > 3 > 10 > 14 > 4 = 13 > 6 > 5.[70] The validation tests of this invention showed that all the arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives described above have the ability to inhibit in vitro the activity of the AChE enzyme in the cerebral cortex of mice (Figures A-N). Compounds 2, 3, 4, 5, 7 and 8 inhibited AChE activity in the cerebral cortex of mice from the concentration of 100 μΜ (Figures B-E, G, H, respectively). Compounds 1, 6, 9 and 11 caused the inhibition of AChE activity in the cerebral cortex of mice from the concentration of 200 μΜ (A, F, I, K, respectively). Compounds 10, 12, 13 and 14, on the other hand, inhibited the enzyme activity only at the concentration of 500 μΜ (J, L-N, respectively). The results shown in Table 1 indicate that the compounds followed the following order of maximum inhibition: 2> 9> 7 = 12> 11> 1> 8> 3> 10> 14> 4 = 13> 6> 5.

[71] Tabela 1. Valores de inibição máxima dos derivados arilsulfanil-benzo-2,1,3-tiadiazóis 1-14.

[71] Table 1. Maximum inhibition values of arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives 1-14.

[72] Os derivados arilsulfanil-benzo-2,1,3-tiadiazóis da presente invenção possuem potencial terapêutico como inibidores da atividade da AChE cerebral. Deste modo, este modelo terapêutico utilizando os derivados arilsulfanil-benzo-2,1,3-tiadiazóis demonstra potencial para uma futura aplicação clínica no tratamento da doença de Alzheimer.[72] The arylsulfanyl-benzo-2,1,3-thiadiazole derivatives of the present invention have therapeutic potential as inhibitors of cerebral AChE activity. Thus, this therapeutic model using arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives demonstrates the potential for future clinical application in the treatment of Alzheimer's disease.

Claims

ENZYME ACETYL CHOLINESTERASE ACTIVITY INHIBITING COMPOUNDS, characterized by at least one of the derivatives of the arylsulfanyl-benzo-2,3-thiadiazole class with the general structural formula (I):

On what:
R is aryl groupings, such as -Ph, -4-OMePh, -4-MePh, -4-FPh, -4-ClPh, -3-OMePh, -2-OMePh, -2-ClPh, benzyl, -2- MePh, -2,4- (CH3) 2Ph, -4-NH2Ph, -2-NH2Ph and -2-NH2-4-ClPh.

COMPOUNDS INHIBITORS OF THE ACTIVITY OF THE ENZYM ACETYL CHOLINESTERASE, according to claim 1, characterized by comprising class of compounds according to the nomenclature:
5- (phenylthio) benzo [c] [1,2,5] thiadiazole (1), or,
5 - ((4-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (2), or,
5- (p-tolylthio) benzo [c] [1,2,5] thiadiazole (3), or,
5 - ((4-fluorophenyl) thio) benzo [c] [1,2,5] thiadiazole (4), or,
5 - ((4-chlorophenyl) thio) benzo [c] [1,2,5] thiadiazole (5), or,
5 - ((3-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (6), or,
5 - ((2-methoxyphenyl) thio) benzo [c] [1,2,5] thiadiazole (7), or,
5 - ((2-chlorophenyl) thio) benzo [c] [1,2,5] thiadiazole (8), or,
5- (benzylthio) benzo [c] [1,2,5] thiadiazole (9), or,
5- (o-tolylthio) benzo [c] [1,2,5] thiadiazole (10), or,
5 - ((2,4-dimethylphenyl) thio) benzo [c] [1,2,5] thiadiazole (11), or,
4- (benzo [cJ [1,2,5Jtiadiazol-5-ylthio) aniline (12), or,
2- (benzo [c] [1,2,5] thiadiazol-5-ylthio) aniline (13), or,
2- (benzo [c] [1,2,5] thiadiazol-5-ylthio) -5-chloroaniline (14).

ENZYME ACETYL CHOLINESTERASE ACTIVITY INHIBITING COMPOUNDS, according to claims 1 and 2, characterized by the presence of the Pd [(L) -proline] 2 catalyst.

Use of ENZYME ACETYL CHOLINESTERASE ACTIVITY INHIBITING COMPOUNDS, according to at least one of claims 1 to 3, characterized by being for the preparation of a medication or composition, formulation or anticholinesterase agent or similar to these to treat Alzheimer's and other actions of the enzyme acetylcholinesterase.