BR102015032954A2 - PROCESS OF PRODUCTION OF DIFFERENTIAL DISSELLANTS OF AMPHETAMINE AND MIXED COMPOUNDS OF ENZYME GLUTATIONA PEROXIDASE (GPX) - Google Patents
PROCESS OF PRODUCTION OF DIFFERENTIAL DISSELLANTS OF AMPHETAMINE AND MIXED COMPOUNDS OF ENZYME GLUTATIONA PEROXIDASE (GPX) Download PDFInfo
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Abstract
processo de produção de disselenetos derivados da anfetamina e compostos miméticos da enzima glutationa peroxidase (gpx) para a síntese de disselenetos derivados da anfetamina além de descrever o disseleneto representado pela fórmula(i) como mimético da enzima glutationa peroxidase (gpx), e os disselenetos sintetizados possuem uma estrutura que poderá fornecer fármacos com diferentes aplicações.process of producing amphetamine-derived diselenides and glutathione peroxidase (gpx) mimetic compounds for the synthesis of amphetamine-derived diselenides as well as describing the diselenide represented by formula (i) as glutathione peroxidase (gpx) mimetic, and the diselenides The synthesized products have a structure that can provide drugs with different applications.
Description
PROCESSO DE PRODUÇÃO DE DISSELENETOS DERIVADOS DA ANFETAMINA E COMPOSTOS MIMÉTICOS DA ENZIMA GLUTATIONA PEROXIDASE (GPX) [001] A presente invenção está relacionada ao processo de produção de disselenobis-amidas derivados da anfetamina ((±)-1-fenilpropan-2-amina) de fórmula geral (I). <0- [002] Adicionalmente, a presente invenção descreve composições farmacêuticas antioxidantes compreendendo os disselenetos derivados da anfetamina.[001] The present invention relates to the process of producing amphetamine-derived ((±) -1-phenylpropan-2-amine) diselenobis-amides derived from the amphetamine-derived disinfectants and mimetic compounds of the enzyme Glutathione Peroxide (GPX). of general formula (I). Additionally, the present invention describes antioxidant pharmaceutical compositions comprising the amphetamine-derived diselenides.
[003] Antecedentes da Invenção [004] Durante as últimas décadas, os compostos orgânicos de selênio vêm atraindo considerável atenção devido à descoberta de selenoproteínas, inicialmente encontradas em bactérias (Andreese.Jr; Ljungdah.Lg J Bacteriol 1973, 116, 867-873.) e posteriormente em mamíferos (Forstrom, J. W., et ai. Biochemistry-Us 1978,17,2639-2644.). Tais proteínas estão envolvidas em uma série de processos fisiológicos, como no sistema antioxidante, na produção do hormônio da tireóide, no sistema imunológico e reprodutor, dentre outros. Uma das descobertas mais expressivas demonstrou que o selênio desempenha papel fundamental na atividade da enzima glutationa peroxidase (GPx), a qual protege o organismo do estresse oxidativo, inerente ao metabolismo do oxigênio.(Alberto , E. E., et al. J Brazil Chem Soc 2010, 21,2032-2041.) [005] Dessa forma, a concepção e síntese de moléculas biologicamente relevantes contendo selênio constituem uma importante e promissora área de pesquisa para empresas farmacêuticas. Sendo assim, pequenas moléculas orgânicas de selênio têm se apresentado como potentes miméticos da glutationa peroxidase (pedido de patente internacional WO 2004/047925 A2), devido sua capacidade redox de transferência de elétrons entre espécies de calcogênios (II) e (IV). Nesse contexto, os disselenetos orgânicos têm recebido destaque por atuarem como miméticos da enzima GPx.(Back, T. G.; Moussa, Z. J Am Chem Soc 2002, 124, 12104-12105.) Dentre eles, podemos destacar alguns disselenetos descritos na literatura com pronunciada atividade GPx, como os disselenetos derivados de amidas secundárias e terciárias ( Bhabak , K. P.; Mugesh, G. Chem-Asian J 2009, 4, 974-983).Background of the Invention During the last decades, organic selenium compounds have attracted considerable attention due to the discovery of selenoproteins, initially found in bacteria (Andreese.Jr; Ljungdah.Lg J Bacteriol 1973, 116, 867-873 .) and later in mammals (Forstrom, JW, et al. Biochemistry-Us 1978,17,2639-2644.). Such proteins are involved in a series of physiological processes, such as the antioxidant system, the production of thyroid hormone, the immune and reproductive system, among others. One of the most significant findings has shown that selenium plays a key role in the activity of the enzyme glutathione peroxidase (GPx), which protects the body from oxidative stress inherent in oxygen metabolism. (Alberto, EE, et al. J Brazil Chem Soc 2010 , 21,2032-2041.) [005] Thus, the design and synthesis of biologically relevant selenium-containing molecules is an important and promising area of research for pharmaceutical companies. Thus, small organic selenium molecules have been presented as potent glutathione peroxidase mimetics (International Patent Application WO 2004/047925 A2), due to their redox electron transfer ability between species of calcogen (II) and (IV). In this context, organic diselenides have been highlighted for acting as GPx enzyme mimetics. (Back, TG; Moussa, Z. J Am Chem Soc 2002, 124, 12104-12105.) Among them, we can highlight some diselenides described in the literature with GPx activity, such as diselenides derived from secondary and tertiary amides (Bhabak, KP; Mugesh, G. Chem-Asian J 2009, 4, 974-983).
[006] Por outro lado, anfetaminas e seus derivados recebem destaque pelo seu grande potencial estimulante do sistema nervoso central (pedido internacional de patente WO 2006/121552). A classe das feniletilaminas interfere no sistema nervoso periférico e é capaz de induzir a liberação de noradrenalína, atuando assim, como potente vasoconstritor. Somado a isso, essas aminas são importantes intermediários na síntese de compostos com interesse farmacológico (Prestes, A D., et al. Mol Cell Biochem 2012, 365, 85- 92.). Além disso, derivados de anfetaminas tem apresentado relevância medicinal no tratamento de déficit de atenção, na terapia da narcolepsia e em curto prazo em pacientes com depressão intolerantes aos antidepressivos tricíclicos (Ciement, B., et a/. Chem Res Toxicol 2000, 13, 1037-1045).On the other hand, amphetamines and their derivatives are highlighted for their great central nervous system stimulating potential (International Patent Application WO 2006/121552). The phenylethylamine class interferes with the peripheral nervous system and is capable of inducing noradrenaline release, thus acting as a potent vasoconstrictor. In addition, these amines are important intermediates in the synthesis of compounds of pharmacological interest (Prestes, A. D., et al. Mol Cell Biochem 2012, 365, 85-92). In addition, amphetamine derivatives have been of medicinal relevance in the treatment of attention deficit, narcolepsy and short-term therapy in tricyclic antidepressant intolerant depression patients (Ciement, B., et al. Chem Res Toxicol 2000, 13, 1037-1045).
[007] No entanto, na literatura não são encontrados relatos quanto à síntese de compostos derivados da anfetamina contendo o átomo de selênio.However, there are no reports in the literature regarding the synthesis of selenium atom-containing amphetamine-derived compounds.
[008] Dessa forma, tendo em vista o potencial valor farmacêutico e bioquímica do composto da fórmula I, a presente invenção apresenta a síntese de compostos disseleneto derivado da anfetamina, assim como seu processo de produção e composições farmacêuticas antioxidantes compreendendo tais compostos.Thus, in view of the potential pharmaceutical and biochemical value of the compound of formula I, the present invention provides the synthesis of amphetamine-derived diselenide compounds as well as their production process and antioxidant pharmaceutical compositions comprising such compounds.
[009] Do que se depreende a literatura pesquisada, não foram encontrados documentos referentes à síntese e aplicação de disselenetos derivados da anfetamina, assim como não foram encontrados documentos antecipando ou sugerindo os ensinamentos da presente invenção.From the researched literature, no documents were found regarding the synthesis and application of amphetamine-derived diselenides, as well as no documents anticipating or suggesting the teachings of the present invention.
[0010] Sumário da Invenção [0011] O objetivo da presente invenção é proporcionar novos compostos disselenetos derivados da anfetamina de fórmulas (II), (III) e (IV). Adicionalmente também são descritas composições farmacêuticas antioxidantes compreendendo tais compostos.Summary of the Invention The object of the present invention is to provide novel amphetamine-derived diselenide compounds of formulas (II), (III) and (IV). Additionally, antioxidant pharmaceutical compositions comprising such compounds are also described.
FÓRWU-Λ lí I FÓRMULA flj FÓRMULA m [0012] Dessa forma, para obtenção dos compostos planejados, os disselenetos de ácidos carboxflicos alifáticos e aromático são convertidos nas respectivas amidas pela condensação com a anfetamina a temperatura ambiente utilizando reagentes de acoplamento, tais como, 4-(Dimetilamino)piridina (DMAP) e hidrocloreto de N-(2-Dimetilaminopropii)-N'-etilcarbodiimida (EDC) em diclorometano.Thus, to obtain the planned compounds, aliphatic and aromatic carboxylic acid diselenides are converted to their respective amides by condensation with amphetamine at room temperature using coupling reagents such as, 4- (Dimethylamino) pyridine (DMAP) and N- (2-Dimethylaminopropii) -N'-ethylcarbodiimide hydrochloride (EDC) in dichloromethane.
[0013] Dentre os agentes de acoplamento utilizados no acoplamento dos disselenetos de ácidos carboxílicos (alifáticos e aromáticos) pode-se citar, sem implicar qualquer limitação, DCC/DMAP, DIC/DMAP, EDC/DMAP, EDC/HOBt, DIC/HOBt, HATU/HOAt, PyBroP/DIPEA, BOP/DMAP. Preferencialmente o acoplamento é realizado com EDC/DMAP.Among the coupling agents used in the coupling of carboxylic acid diselenates (aliphatic and aromatic) can be mentioned, without any limitation, DCC / DMAP, DIC / DMAP, EDC / DMAP, EDC / HOBt, DIC / HOBt , HATU / HOAt, PyBroP / DIPEA, BOP / DMAP. Preferably the coupling is performed with EDC / DMAP.
[0014] É também um objeto da presente invenção uma composição farmacêutica caracterizada por compreender os compostos das fórmulas II, III e IV: ftt e por ser utilizada na fabricação de medicamento com ação antioxidante. Adicionalmente, é objeto da presente invenção demonstrar o uso dos compostos de fórmulas II, III e IV como mimético da enzima glutationa peroxidase (GPx).It is also an object of the present invention a pharmaceutical composition to comprise the compounds of formulas II, III and IV: ftt and to be used in the manufacture of an antioxidant-acting medicament. Additionally, it is an object of the present invention to demonstrate the use of the compounds of formulas II, III and IV as glutathione peroxidase (GPx) mimetic.
[0015] Estes e outros objetos da invenção serão imediatamente valorizados pelos versados na arte e pelas empresas com interesses no segmento, e serão descritos em detalhes suficientes para sua reprodução na descrição a seguir.[0015] These and other objects of the invention will be immediately appreciated by those skilled in the art and companies having an interest in the segment, and will be described in sufficient detail for their reproduction in the following description.
[0016] Na FIGURA 1 representa a preparação das diselenobis-amidas alifáticas derivadas da anfetamina.FIGURE 1 depicts the preparation of amphetamine-derived aliphatic diselenobis-amides.
[0017] Na FIGURA 2 representa a preparação das diselenobis-amidas aromáticas derivadas da anfetamina.FIGURE 2 depicts the preparation of amphetamine-derived aromatic diselenobis-amides.
[0018] A invenção é relacionada à síntese de diselenobis-amidas derivadas da anfetamina da fórmula geral (I), e especificamente das fórmulas (II), (III) e (IV).The invention relates to the synthesis of amphetamine-derived diselenobisamides of the general formula (I), and specifically of the formulas (II), (III) and (IV).
[0019] Os compostos da fórmula (I) obtidos desta maneira são especialmente úteis para o tratamento de algumas doenças em humanos, particularmente no tratamento de doenças causadas por dano celular devido à formação aumentada de espécies reativas de oxigênio como danos hepáticos, infarto do miocárdio, infecções, psoríase ou danos por radiação, câncer, Parkinson, e problemas inflamatórios. Podem ser usados, também, como estimulante do sistema nervoso central, sendo úteis em doenças relacionadas.The compounds of formula (I) obtained in this manner are especially useful for the treatment of some diseases in humans, particularly in the treatment of diseases caused by cell damage due to the increased formation of reactive oxygen species such as liver damage, myocardial infarction. , infections, psoriasis or radiation damage, cancer, Parkinson's, and inflammatory problems. They can also be used as a central nervous system stimulant and are useful in related diseases.
[0020] Os exemplos aqui mostrados têm o intuito somente de exemplificar uma das inúmeras maneiras de se realizar a invenção, contudo, sem limitar o escopo da mesma. A síntese dos compostosda invenção está baseada em um procedimento de duas etapas.The examples shown herein are intended solely to exemplify one of the numerous ways of carrying out the invention, however, without limiting the scope thereof. The synthesis of the compounds of the invention is based on a two step procedure.
[0021] Na primeira etapa, os bromo-ácidos alifáticos são convertidos nos seus disselenetos correspondentes, assim como o disseleneto do ácido aromático é convertido a partir do ácido antranílico. Na segunda etapa, os disselenetos dos ácidos alifáticos e aromáticos sintetizados são convertidos nas respectivas diselenobis-amidas derivadas da anfetamina através de um processo eficiente e econômico. A síntese é conduzida em um balão de duas bocas e sob atmosfera de argônio, e a reação inicia-se pela adição de 0,25 mmol do disseleneto do ácido carboxílico desejado, 2 ml de CH2CI2, 0,28 mmol da anfetamina e 0,05 mmol de 4-dimetil aminopiridina (DMAP). Resfria-se o sistema reacional à < 5 °C e adiciona-se 0,28mmol trietilamina e 0,28mmol de hidrocloreto de N-(2-Dimetilaminopropii) - Ν'-etilcarbodiimida (EDC) e deixa-se voltar à temperatura ambiente e agita-se por 24 horas. Ao final da reação, dilui-se com CH2CI2 e lava-se com solução de 0,5 N HCI (1 x 10 mL ), 1% NaOH (1 x 10 ml) e NaCI_saturado (1x10 ml). Retira-se a água com MgS04, filtra-se e remove-se o solvente a vácuo.In the first step, aliphatic bromo acids are converted to their corresponding diselenides, just as aromatic acid diselenide is converted from anthranilic acid. In the second step, the synthesized aliphatic and aromatic diselenides are converted to their amphetamine-derived diselenobis-amides through an efficient and economical process. The synthesis is conducted in a two-necked flask under argon atmosphere, and the reaction begins by the addition of 0.25 mmol of the desired carboxylic acid diselenide, 2 mL of CH 2 Cl 2, 0.28 mmol of amphetamine and 0, 5 mmol 4-dimethyl aminopyridine (DMAP). The reaction system is cooled to <5 ° C and 0.28mmol triethylamine and 0.28mmol N- (2-Dimethylaminopropii) --'-ethylcarbodiimide hydrochloride (EDC) are added and allowed to return to room temperature and Stir for 24 hours. At the end of the reaction, dilute with CH 2 Cl 2 and wash with 0.5 N HCl solution (1 x 10 mL), 1% NaOH (1 x 10 mL) and saturated NaCl (1 x 10 mL). Remove water with MgSO4, filter and remove solvent in vacuo.
[0022] Purifica-se por coluna cromatográfica com sílica gel e utiliza-se uma mistura de acetato de etila:hexano para obter os disselenetos derivados de anfetaminas em bons rendimentos.Purify by silica gel column chromatography and use a mixture of ethyl acetate: hexane to obtain amphetamine-derived diselenides in good yields.
[0023] O disseleneto derivado da anfetamina (IV) mostra-se um eficiente mimético da glutationa peroxidase (GPx) pois desempenha excelente atividade catalítica na redução do H2O2 na água, utilizando o tiofenol como cofator. O disseleneto (IV) reduz a concentração de tiol para metade do seu valor (T50) em apenas 16,81 min com apenas 5 mol % de catalisador, sendo aproximadamente 9 vezes mais ativo que o conhecido mimético da GPx, ebselen, o qual apresenta T50 =154,26 min. m [0024] Dados espectrais e analíticos para o composto de fórmula (II): Rendimento: 79%. Óleo amarelo escuro; 1H NMR (CDCb, 400 MHz) δ = 7.29-7.19 (m, 10H), 7.06 (d, J = 8 Hz, 2H), 4.24-4.17 (m, 2H), 3.55-3.47 (m, 4H), 2.98-2.87 (m, 2H) ,2.74-2.67 (m, 2H), 1.15 (d, J =4 Hz, 6H); 13C NMR (CDCb, 100 MHz), δ =169.40, 138.12, 129.28, 128.28, 126.33, 47.20, 42.50, 29.60, 20.08.Amphetamine (IV) derived diselenide is an efficient glutathione peroxidase (GPx) mimetic as it performs excellent catalytic activity in reducing H2O2 in water, using thiophenol as cofactor. Diselenide (IV) reduces the thiol concentration to half its value (T50) by only 16.81 min with only 5 mol% catalyst, being approximately 9 times more active than the known GPx mimetic ebselen, which presents T50 = 154.26 min. m Spectral and analytical data for the compound of formula (II): Yield: 79%. Dark yellow oil; 1H NMR (CDCl3, 400 MHz) δ = 7.29-7.19 (m, 10H), 7.06 (d, J = 8 Hz, 2H), 4.24-4.17 (m, 2H), 3.55-3.47 (m, 4H), 2.98 -2.87 (m, 2H), 2.74-2.67 (m, 2H), 1.15 (d, J = 4 Hz, 6H); 13 C NMR (CDCb, 100 MHz), δ = 169.40, 138.12, 129.28, 128.28, 126.33, 47.20, 42.50, 29.60, 20.08.
[0025] Espectrometria de Massas de Alta Resolução calculado para C22H28N2C>2Se2 [M+ ]: 513.0558, encontrado 513.0558.High Resolution Mass Spectrometry calculated for C22H28N2C> 2Se2 [M +]: 513,0558, found 513,0558.
[0026] Dados espectrais e analíticos para 0 composto de fórmula (III): Rendimento: 83%. Sólido amarelo claro (ponto de fusão :95 -96 °C); 1H NMR (CDCb, 400 MHz) δ = 7.30-7.17 (m, 10H}, 6.03 (d, J =4Hz, 2H), 4.32-4 .21 (m, 2H), 3.09 (t,J =4Hz, 4H), 2.86 (dd, J1= 12Hz, J2= 4Hz, 2H), 2.71 (dd, J1= 16Hz, J2= 8Hz, 2H), 2.59-2.56 (m, 4H) , 1.13 (d,J =8Hz, 6H); 13C NMR (CDCb, 100 MHz), δ =170.57, 137.94, 129.34, 128.32, 126.37, 46.30, 42.40,37.43, 24.47 , 19.97. Espectrometria de Massas de Alta Resolução calculado para C24H32N202Se2 [M+]: 541.0871, encontrado 541.0885.Spectral and analytical data for the compound of formula (III): Yield: 83%. Light yellow solid (mp 95-96 ° C); 1H NMR (CDCl3, 400 MHz) δ = 7.30-7.17 (m, 10H}, 6.03 (d, J = 4Hz, 2H), 4.32-4 .21 (m, 2H), 3.09 (t, J = 4Hz, 4H ), 2.86 (dd, J1 = 12Hz, J2 = 4Hz, 2H), 2.71 (dd, J1 = 16Hz, J2 = 8Hz, 2H), 2.59-2.56 (m, 4H), 1.13 (d, J = 8Hz, 6H 13 C NMR (CDCb, 100 MHz), δ = 170.57, 137.94, 129.34, 128.32, 126.37, 46.30, 42.40,37.43, 24.47, 19.97. High Resolution Mass Spectrometry calculated for C24H32N202Se2 [M +]: 541.0871, found 541.0885 .
[0027] Dados espectrais e analíticos para o composto de fórmula (IV): Rendimento: 55%. Sólido branco (ponto de fusão :200 - 201 °C);. 1H NMR (CDCLs, 400 MHz) δ = 7.87 (d, J = 8 Hz, 2H), 7.35-7.17 (m, 16H), 5.99 (d, J = 4 Hz, 2H), 4.55-4.48 (m, 2H), 2.99 (dd, J1= 12Hz, J2= 4Hz, 2H), 2.91 (dd, i= 12Hz, J2= 8 Hz, 2H) , 1.27 (d, J =8Hz, 6H): 13C NMR (CDCLs, 100 MHz) δ = 167.47, 137.59,131.66, 129.58, 128.48, 126.61, 126.38, 126.02, 46.76, 42.25 , 19.95. Espectrometria de Massas de Alta Resolução calculado para CsaHsaNaOaSea [M+]: 637.0873, encontrado 637.0879.Spectral and analytical data for the compound of formula (IV): Yield: 55%. White solid (melting point: 200 - 201 ° C); 1H NMR (CDCl3, 400 MHz) δ = 7.87 (d, J = 8 Hz, 2H), 7.35-7.17 (m, 16H), 5.99 (d, J = 4 Hz, 2H), 4.55-4.48 (m, 2H ), 2.99 (dd, J1 = 12Hz, J2 = 4Hz, 2H), 2.91 (dd, i = 12Hz, J2 = 8Hz, 2H), 1.27 (d, J = 8Hz, 6H): 13 C NMR (CDCLs, 100 MHz) δ = 167.47, 137.59,131.66, 129.58, 128.48, 126.61, 126.38, 126.02, 46.76, 42.25, 19.95. High Resolution Mass Spectrometry calculated for CsaHsaNaOaSea [M +]: 637.0873, found 637.0879.
[0028] O incremento catalítico do composto (IV) mostra o grande potencial antioxidante desse composto, de modo que o estresse oxidativo está associado com doenças, tais como: Alzheimer, Parkinson, câncer e hipertensão arterial.The catalytic increase of compound (IV) shows the great antioxidant potential of this compound, so that oxidative stress is associated with diseases such as Alzheimer's, Parkinson's, cancer and high blood pressure.
[0029] Os versados na arte valorizarão os conhecimentos aqui apresentados e poderão reproduzir a invenção nas modalidades apresentadas e em outras variantes, abrangidos no escopo das reivindicações anexas.Those skilled in the art will enhance the knowledge presented herein and may reproduce the invention in the embodiments disclosed and in other embodiments within the scope of the appended claims.
REIVINDICAÇÕES
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