BRPI0804764A2 - alpha-glycosity inhibitors, pharmaceutical compositions comprising them and process for their preparation - Google Patents
alpha-glycosity inhibitors, pharmaceutical compositions comprising them and process for their preparation Download PDFInfo
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- BRPI0804764A2 BRPI0804764A2 BRPI0804764A BRPI0804764A2 BR PI0804764 A2 BRPI0804764 A2 BR PI0804764A2 BR PI0804764 A BRPI0804764 A BR PI0804764A BR PI0804764 A2 BRPI0804764 A2 BR PI0804764A2
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
INIBIDORES DA ALFA-GLICOSIDADES, COMPOSIçõES FARMACêUTICAS COMPREENDENDO OS MESMOS E PROCESSO PARA SUA PREPARAçãO. A presente invenção situa-se no campo dos compostos triazólicos inibidores de <244>-gIicosidades. Especificamente, os compostos triazólicos da presente invenção são compostos do grupo dos <244>-D-ribo, <244>-D-xilo e <244>-D-arabno-triazólicos que apresentam atividade inibitória das enzimas c- glicosidases, e a composições farmacêuticas com atividades antiviral, antiproliferativa, antimicrobiana, antiobesidade, imunoestimulantes, antiag regantes píaq uetários e/ou antidiabéticos. A presente invenção também é relacionada a processos para o preparo destes compostos.ALPHA-GLYCOSITIES INHIBITORS, PHARMACEUTICAL COMPOSITIONS UNDERSTANDING THE SAME AND PROCESS FOR PREPARING THEM. The present invention is in the field of triazole inhibitors of? -Glycosities. Specifically, the triazole compounds of the present invention are compounds of the group of β-D-ribo, β-D-xyl and β-D-arabno-triazoles which exhibit c-glycosidase enzyme inhibitory activity, and the pharmaceutical compositions with antiviral, antiproliferative, antimicrobial, anti-obesity, immunostimulant, anti-inflammatory and / or antidiabetic irrigating activities. The present invention also relates to processes for the preparation of these compounds.
Description
Relatório Descritivo de Patente de InvençãoPatent Invention Descriptive Report
Inibidores da Alfa-Glicosidades, Composições FarmacêuticasCompreendendo os mesmos e Processo para Sua PreparaçãoAlpha-Glucosity Inhibitors, Pharmaceutical CompositionsUnderstanding Them and Process for Their Preparation
Campo da InvençãoField of the Invention
A presente invenção situa-se no campo dos compostos triazólicosinibidores de a-glicosidades. Especificamente, os compostos triazólicos dapresente invenção são compostos do grupo dos a-D-ribo, a-D-xilo e a-D-arabino-triazólicos que apresentam atividade inibitória das enzimas a-glicosidases, e a composições farmacêuticas com atividades antiviral,antiproliferativa, antimicrobiana, antiobesidade, imunoestimulantes,antiagregantes plaquetários e/ou antidiabéticos.The present invention is in the field of triazolic α-glucosinhibitor compounds. Specifically, the triazole compounds of the present invention are compounds of the group of αD-ribo, αD-xyl and αD-arabinothiazoles which exhibit inhibitory activity of α-glycosidase enzymes, and pharmaceutical compositions having antiviral, antiproliferative, antimicrobial, anti-obesity, immunostimulant activities. , antiplatelet and / or antidiabetic agents.
A presente invenção também é relacionada a processos para o preparodestes compostos.The present invention also relates to processes for preparing these compounds.
Antecedentes da InvençãoBackground of the Invention
Milhões de pessoas no mundo continuam a morrer de doenças quepodem ser prevenidas e tratadas. Tratamentos inadequados ou mesmoinexistentes, para diversas doenças infecciosas e parasitárias vêm vitimandoum número elevado de pessoas principalmente em países emdesenvolvimento. Milhares de vidas são perdidas, ou duramente prejudicadasdevido a estas doenças, que prejudicam o bem-estar social e excluem umaparcela importante de indivíduos de suas atividades sociais e produtivas. Comoexemplo de doenças que acometem grande número de pessoas em todomundo podemos citar o diabetes, o câncer e as doenças de origem viral.Millions of people around the world continue to die from diseases that can be prevented and treated. Inadequate or even non-existent treatments for various infectious and parasitic diseases come victimizing a large number of people, especially in developing countries. Thousands of lives are lost, or severely harmed due to these diseases, which undermine social welfare and exclude an important portion of individuals from their social and productive activities. As an example of diseases that affect large numbers of people around the world, we can mention diabetes, cancer and diseases of viral origin.
A ligação glicosídica é uma ligação química covalente que une doisaçúcares simples por meio de um átomo de oxigênio. Muitos polissacarídeossão formados por monossacarídeos ligados pelas ligações alfa e betaglicosídica.The glycosidic bond is a covalent chemical bond that joins single sugars by means of an oxygen atom. Many polysaccharides are formed by monosaccharides linked by alpha and beta-glycosidic bonds.
Durante o processo da digestão estas ligações são hidrolisadas porenzimas glicosídicas específicas liberando as unidades de carboidratos comonutrientes (Dwek 1996). Por exemplo, as enzimas amilases são produzidas nosistema digestivo para quebrar as ligações alfa glicosídicas do amido.During the digestion process these bonds are hydrolyzed by specific glycosidic enzymes releasing the comonutrient carbohydrate units (Dwek 1996). For example, amylase enzymes are produced in the digestive system to break starch alpha glycosidic bonds.
Adicionalmente, as enzimas glicosidases estão envolvidas em processosbiológicos importantes, tais como a digestão intestinal e o catabolismolisossomal dos glicoconjugados. Inibidores das glicosidases são também úteiscomo, anti-virais (Courageot et al 2000; Van den Broek 1997), no tratamento demetástases de câncer (Gross et al 1995), como agentes antiproliferativos ecomo agentes antidiabéticos.In addition, glycosidase enzymes are involved in important biological processes such as intestinal digestion and glycoconjugate catabolismolysis. Glycosidase inhibitors are also useful as antivirals (Courageot et al 2000; Van den Broek 1997) in the treatment of cancer metastases (Gross et al 1995) as antiproliferative agents and antidiabetic agents.
A inibição das a-glicosidases situadas nos finos vasos no intestino curtocontrola o aumento rápido da glicose no sangue após uma refeição (Tattersall1993). Os inibidores suprimem ou retardam o metabolismo da glicose nosangue humano e animal. Conseqüentemente, são eficazes em melhorar ascondições hiperglicêmicas assim como as várias doenças induzidas pelahiperglicemia tal como a obesidade e a diabetes.Inhibition of α-glycosidases in the thin vessels in the intestine shortens the rapid increase in blood glucose after a meal (Tattersall1993). Inhibitors suppress or retard human and animal blood glucose metabolism. Therefore, they are effective in improving hyperglycemic conditions as well as various diseases induced by hyperglycemia such as obesity and diabetes.
Além disso, as glicosidases são encontradas igualmente envolvidas natransformação de células normais em células cancerosas, na invasão e namigração da célula tumoral. Igualmente observou-se que os níveis deglicosidases do soro são elevados em muitos pacientes com tumores diferentese provavelmente estão envolvidos na degradação da matriz extracelular nainvasão da célula tumoral (Bernacki et al 1985). Portanto, o uso de inibidoresde glicosidases para a prevenção de anomalias durante o processoglicoproteico e a inibição das glicosidades catabólicas está sendo levado acabo ativamente como a estratégia terapêutica para o câncer. (Watson et al 2001).In addition, glycosidases are also found to be involved in normal cell transformation into cancer cells, in tumor cell invasion and naming. Serum deglucosidase levels have also been observed to be elevated in many patients with different tumors and are likely to be involved in the degradation of extracellular matrix in tumor cell invasion (Bernacki et al 1985). Therefore, the use of glycosidase inhibitors for the prevention of abnormalities during process glycoprotein and the inhibition of catabolic glucosides is being actively pursued as the therapeutic strategy for cancer. (Watson et al 2001).
Muitos vírus animais contêm um envelope exterior, o qual é composto deuma ou mais glicoproteínas virais. Estas glicoproteínas são freqüentementeproteínas essenciais que são exigidas no ciclo de vida viral, ou no conjunto dovírus e na secreção e/ou na infectividade. Assim, inibidores que processam a-glicosidases foram mostrados na diminuição de infectividade em uma largaescala de vírus humanos patogênicos. (Mehta et al 1998; Watson et al 2001).Similarmente, os inibidores de a-glicosidases foram também utilizadosna restauração da resposta imune de animais experimentaisimunocomprometidos. (Kayakiri et al 1991).Many animal viruses contain an outer envelope, which is composed of one or more viral glycoproteins. These glycoproteins are often essential proteins that are required in the viral life cycle, or in the whole virus, and in secretion and / or infectivity. Thus, inhibitors that process α-glycosidases have been shown to decrease infectivity in a wide range of pathogenic human viruses. (Mehta et al 1998; Watson et al 2001). Similarly, α-glycosidase inhibitors were also used in restoring the immune response of immunocompromised experimental animals. (Kayakiri et al 1991).
Os inibidores de a-glicosidases são também extensivamente estudadoscomo imunoestimulantes. (Inoue et al 2004). Muitos organismos possueminibidores endógenos que controlam a atividade das glicosidases e dasglicosiltransferases. A Nojirimicina e a Deoxinojirimicina, isolados do caldo decarne cultivado da espécie dos estreptomicetos, são dois inibidores clássicosde glicosidase nos estágios avançados dos processos glicoproteicos. ANojirimicina foi o primeiro mimetizador natural da glicose com um átomo denitrogênio no lugar do oxigênio do anel que é um inibidor potente para a-e (3-glicosidases provenientes de diversas fontes. Desde a descoberta destassubstâncias, diversos outros compostos inibidores de glicosidase foramisolados de plantas e de microorganismos. (Asano 2003; James et al 1989).Α-Glycosidase inhibitors are also extensively studied as immunostimulants. (Inoue et al 2004). Many organisms have endogenous inhibitors that control the activity of glycosidases and glucosyltransferases. Nojirimycin and Deoxinojirimycin, isolated from cultured broth of the streptomycetes species, are two classic glycosidase inhibitors in the advanced stages of glycoprotein processes. Ojirimycin was the first natural glucose mimetic with a denitrogen atom in place of ring oxygen which is a potent inhibitor for α (3-glycosidases from various sources. Since the discovery of these substances, several other plant-isolated glycosidase-inhibiting compounds have been isolated). microorganisms (Asano 2003; James et al 1989).
Os inibidores digestivos de a-glicosidases podem ser utilizadosterapêuticamente para o tratamento de doenças metabólicas tal como odiabetes mellitus. Estes agentes antidiabéticos agem inibindo algumas a-glicosidases pancreáticas e intestinais, que regulam a absorção doscarboidratos. A busca por inibidores de a-glicosidases conduziu à descobertada acarbose (Glucobay®, Precose), isolado de bactérias do tipo Actinoplanesda classe SE 50, como um potente inibidor de sucrase. Este composto inibe asucrase intestinal do porco com um valor de IC50 de 0.5 uM (Schmidt et al1977). Após muitas investigações clínicas ele foi introduzido no mercado, em1990, para o tratamento do diabetes.Digestive inhibitors of α-glycosidases may be used therapeutically for the treatment of metabolic diseases such as odiabetes mellitus. These antidiabetic agents act by inhibiting some pancreatic and intestinal α-glycosidases, which regulate the absorption of carbohydrates. The search for α-glycosidase inhibitors led to the discovery of acarbose (Glucobay®, Precose), isolated from SE 50 class Actinoplanes bacteria, as a potent sucrase inhibitor. This compound inhibits pig intestinal asucrase with an IC 50 value of 0.5 µM (Schmidt et al1977). After many clinical investigations it was introduced in the market in 1990 for the treatment of diabetes.
Os compostos que possuem aza-heterociclos de cinco membros atuamcomo miméticos de açúcares e, conseqüentemente, são inibidores poderososda glicosidase. Deve-se ressaltar que as estruturas destes compostosCompounds having five-membered azaheterocycles act as sugar mimetics and, consequently, are powerful inhibitors of glycosidase. It should be noted that the structures of these compounds
R = OH, NojirimicinaR = OH, Nojirimycin
R = H, Deoxinojirimicinaheterocíclicos variam em função do heteroátomo presente no anel, a saber:pirróis-, imidazóis- (Tschamber et al 2003; Granier et al 1997), triazóis- (Krulleet al 1997; Périon et al 2005; Rossi et al 2005; Tatsuta et al 1996; Castro et al2007; Sabesan 2005), e glico-tetrazóis (Davis et al 1999; Davis et al 1999). Assuas atividades inibidoras frente às glicosidases dependem da natureza e daorientação dos grupos funcionais no anel heterocíclico, assim como osfragmentos glico-conjugados nestes anéis.R = H, Heterocyclic deoxinojirimycin vary depending on ring heteroatom, namely: pyrroles-, imidazoles- (Tschamber et al 2003; Granier et al 1997), triazoles- (Krulleet al 1997; Périon et al 2005; Rossi et al 2005 ; Tatsuta et al 1996; Castro et al 2007; Sabesan 2005), and glycetetrazoles (Davis et al 1999; Davis et al 1999). Their inhibitory activities against glycosidases depend on the nature and orientation of the functional groups on the heterocyclic ring, as well as the glyco-conjugated fragments on these rings.
A literatura patentária apontou alguns documentos relevantes, porémque não comprometem a patenteabilidade da presente invenção, descritos aseguir. O documento US 2005/0124563 relata uma série de compostosinibidores de a-glicosidases que compreendem dois açúcares unidos entre sipor um grupo triazólico. A presente invenção difere deste documento por nãocompreender dois açúcares unidos por um grupamento triazólico, mas simsomente um grupo sacarídico.The patent literature has pointed to some relevant documents, however, which do not compromise the patentability of the present invention, described below. US 2005/0124563 discloses a series of α-glycosidase inhibitor compounds comprising two sugars joined between sipor a triazole group. The present invention differs from this document in that it does not comprise two sugars joined by a triazole group, but only one saccharide group.
O documento WO 2006/096769 relata um método de tratar infecçõesvirais, especificamente, infecções causadas por flavivírus, como por exemplo, ovírus da hepatite C que consiste na administração de um inibidor das a-glicosidases de membrana e pelo menos, um agente terapêutico.WO 2006/096769 discloses a method of treating viral infections, specifically, infections caused by flaviviruses, such as hepatitis C ovirus consisting of the administration of a membrane α-glycosidase inhibitor and at least one therapeutic agent.
Especificamente, os inibidores das a-glicosidases relatados neste documentoincluem quaisquer imino-açúcares, inibidores das a-glicosidases do retículoendoplasmático, inibidores das a-glicosidases de membrana, miglitol, análogose derivados, acarbose, análogos e derivados.Specifically, the α-glycosidase inhibitors reported herein include any imino sugars, reticuloendoplasmic α-glycosidase inhibitors, membrane α-glycosidase inhibitors, miglitol, derived analogues, acarbose, analogs and derivatives.
O documento WO 1991/18915 relata compostos inibidores das a-glicosidases especificamente para o tratamento de diabetes, obesidade edoenças associadas a retrovírus.WO 1991/18915 reports α-glycosidase inhibitor compounds specifically for the treatment of diabetes, obesity and retrovirus-associated diseases.
O documento US 5,091,418 relata inibidores das a-glicosidases, apradimicina. Especificamente, a pradimicina descrita neste documento é obtidaa partir de uma bactéria, a Actinomadura verrucososoora subsp. neohibiscaUS 5,091,418 reports α-glycosidase inhibitors, apradimycin. Specifically, the pradimycin described herein is obtained from a bacterium, Actinomadura verrucososoora subsp. neohibisca
O documento US 2001/0034356 relata um método de tratamento dadiabetes e doenças associadas em mamíferos que compreende aadministração de um sensibilizador de insulina e um inibidor das a-glicosidasesanti-hiperglicêmico. Especificamente, o inibidor das a-glicosidases sãocompostos derivados de tiazolinedionas.US 2001/0034356 discloses a method of treating dadiabetes and associated diseases in mammals comprising administering an insulin sensitizer and an α-glucosidase-hyperglycemic inhibitor. Specifically, the α-glycosidase inhibitor are thiazolinedione derivative compounds.
O documento EP 1 690 519 relata inibidores das a-glicosidasesprovenientes de um extrato vegetal, o extrato de Nelumbonaceae Nelumbo.Especificamente, o extrato vegetal deste documento é utilizado para tratar ouprevenir a diabetes.EP 1,690,519 discloses α-glycosidase inhibitors from a plant extract, the Nelumbonaceae Nelumbo extract. Specifically, the plant extract in this document is used to treat or prevent diabetes.
A presente invenção difere destes documentos, pelos compostosinibidores das a-glicosidases serem compostos escolhidos do grupo quecompreende os triazóis, mais especificamente, os compostos a-D-glico-triazólicos.The present invention differs from these documents in that Î ± -glycosidase inhibitor compounds are compounds selected from the group comprising triazoles, more specifically, Î ± -G-triazole compounds.
Não há, em toda extensão da literatura química especializada, seja emrevistas, jornais, anais, livros, enciclopédias, ou em patentes, nenhuma citaçãopara o uso das substâncias dos grupos I a III atuando na inibição de enzimasa-glicosidases, com potencial utilização farmacêutica, em especial para otratamento diabetes mellitus e outras enfermidades relacionadas à absorção decarboidratos. Portanto, não foi encontrado na literatura nenhum documento queantecipe ou sequer sugira as particularidades da presente invenção.Objeto da InvençãoTo the fullest extent of the specialized chemical literature, whether in journals, journals, annals, books, encyclopedias, or in patents, there are no citations for the use of group I to III substances acting in the inhibition of enzyme glycosidases with potential pharmaceutical use, especially for the treatment of diabetes mellitus and other diseases related to absorption of carbohydrates. Therefore, no document has been found in the literature that would have a suggestion or even suggest the particularities of the present invention.
É objeto da presente invenção compostos inibidores das enzimas a-glicosidases apresentando estruturas de acordo com as fórmulas gerais (I), (II)e/ou (III):An object of the present invention is Î ± -glycosidase enzyme inhibiting compounds having structures according to the general formulas (I), (II) and / or (III):
<formula>formula see original document page 6</formula><formula>formula see original document page 7</formula><formula> formula see original document page 6 </formula> <formula> formula see original document page 7 </formula>
onde R1, R2, R3, R4 e R5 são, independentemente, escolhidos do grupo quecompreende H, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-C10-alcoxilas, C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10tioalcoxicarbonilas, anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicoscom 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n éescolhido entre 0 a 7 e onde o heteroátomo é escolhido do grupo quecompreende N, S e/ou O; onde tais anéis podem ser opcionalmentesubstituídos; S03X onde X é escolhido do grupo que compreende H, Na, Li, K,C1-C10 alquil, aril, heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CNe mistura dos mesmos; derivados de ésteres carboxílicos C02R onde R éescolhido do grupo que compreende H, C1-C10 alquil; anéis carbocíclicos e/ouheterocíclicos fundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas,hidroxiaminas e mistura dos mesmos; bem como seus sais, suas formasestereoisoméricas, solvatos e/ou hidratos.where R 1, R 2, R 3, R 4 and R 5 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is selected from the group comprising N, S and / or O; where such rings may optionally be substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CNe mixture thereof; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyamines and mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates.
É também objeto da presente invenção um processo de produção dosinibidores de oc-glicosidases compreendendo as etapas de:It is also the object of the present invention a process for producing oc-glycosidase inhibitors comprising the steps of:
a) formação de acetonídeos de fórmula geral (IV) e/ou (V):(a) formation of acetonides of formula (IV) and / or (V):
<formula>formula see original document page 7</formula><formula> formula see original document page 7 </formula>
onde:Rl R2 e R3 são, independentemente, escolhidos do grupo quecompreende H, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-C10-alcoxilas, C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10tioalcoxicarbonilas, anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicoscom 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n éescolhido entre 0 a 7 e onde o heteroátomo é escolhido do grupo quecompreende N, S e/ou O; onde tais anéis podem ser opcionalmentesubstituídos; S03X onde X é escolhido do grupo que compreende H, Na, Li, K,C1-C10 alquil, aril, heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CNe mistura dos mesmos; derivados de ésteres carboxílicos C02R onde R éescolhido do grupo que compreende H, C1-C10 alquil; anéis carbocíclicos e/ouheterocíclicos fundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas,hidroxiaminas e mistura dos mesmos; bem como seus sais, suas formasestereoisoméricas, solvatos e/ou hidratos;wherein: R 1 R 2 and R 3 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is selected from the group comprising N, S and / or O; where such rings may optionally be substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CNe mixture thereof; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyamines and mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates;
b) mesilação e/ou tosilação dos acetonídeos;b) mesylation and / or tosylation of acetonides;
c) substituição nucleofílica com azida de sódio;c) nucleophilic substitution with sodium azide;
d) reação com alcinos de fórmula geral (VII) na presença de cobre.d) reaction with alkynes of formula (VII) in the presence of copper.
R4 = R5 (VII)R4 = R5 (VII)
onde R4 e R5 são, independentemente, escolhidos do grupo que compreendeH, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-C10-alcoxilas,C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10 tioalcoxicarbonilas,anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- comoespaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicos com 3 a 7membros compreendendo -(CH2)n- como espaçadores onde n é escolhidoentre 0 a 7 e onde o heteroátomo é escolhido do grupo que compreende N, Se/ou O; onde tais anéis podem ser opcionalmente substituídos; S03X onde X éescolhido do grupo que compreende H, Na, Li, K, C1-C10 alquil, aril,heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CN e mistura dosmesmos; derivados de ésteres carboxílicos C02R onde R é escolhido do grupoque compreende H, C1-C10 alquil; anéis carbocíclicos e/ou heterocíclicosfundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas, hidroxiaminase mistura dos mesmos; bem como seus sais, suas formas estereoisoméricas,solvatos e/ou hidratos; ewherein R 4 and R 5 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is selected from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is chosen from the group comprising N, Se / or O; wherein such rings may be optionally substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CN and mixture of the same; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyminase mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates; and
e) opcionalmente compreender uma etapa de hidrólise dos acetonídeos.e) optionally comprising an acetonide hydrolysis step.
É um objeto da presente invenção uma composição farmacêuticacompreendendo:An object of the present invention is a pharmaceutical composition comprising:
a) pelo menos um inibidor de a-glicosidases de acordo com asfórmulas gerais (I), (II) e/ou (III):(a) at least one α-glycosidase inhibitor according to the general formulas (I), (II) and / or (III):
<formula>formula see original document page 9</formula><formula> formula see original document page 9 </formula>
onde R1, R2, R3, R4 e R5 são, independentemente, escolhidos do grupo quecompreende H, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-C10-alcoxilas, C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10tioalcoxicarbonilas, anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicoscom 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n éescolhido entre 0 a 7 e onde o heteroátomo é escolhido do grupo quecompreende N, S e/ou O; onde tais anéis podem ser opcionalmentesubstituídos; S03X onde X é escolhido do grupo que compreende H, Na, Li, K,C1-C10 alquil, aril, heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CNe mistura dos mesmos; derivados de ésteres carboxílicos C02R onde R éescolhido do grupo que compreende H, C1-C10 alquil; anéis carbocíclicos e/ouheterocíclicos fundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas,hidroxiaminas e mistura dos mesmos; bem como seus sais, suas formasestereoisoméricas, solvatos e/ou hidratos.where R 1, R 2, R 3, R 4 and R 5 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is selected from the group comprising N, S and / or O; where such rings may optionally be substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CNe mixture thereof; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyamines and mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates.
b) um veículo farmaceuticamente aceitável.b) a pharmaceutically acceptable carrier.
É também objeto da presente invenção, o uso destascomposições farmacêuticas em seres humanos bem como em animais.It is also an object of the present invention to use these pharmaceutical compositions in humans as well as animals.
Estes e outros objetos da invenção serão melhor compreendidos à luzda descrição detalhada e das reivindicações em anexo.These and other objects of the invention will be better understood in light of the detailed description and the appended claims.
Descrição Detalhada da InvençãoDetailed Description of the Invention
Os exemplos descritos a seguir não tem a intenção de limitar a invenção,mas apenas de exemplificar uma das formas de realizá-las dentre as váriaspossíveis.The following examples are not intended to limit the invention, but merely to exemplify one of several embodiments.
Para efeitos desta invenção, por "composições farmacêuticas" entende-se toda e qualquer composição que contenha um princípio ativo, com finsprofiláticos, paliativos e/ou curativos, atuando de forma a manter e/ou restaurara homeostase, podendo ser administrada de forma tópica, parenteral, enterale/ou intratecal.For the purposes of this invention, "pharmaceutical compositions" means any composition that contains an active principle, for prophylactic, palliative and / or curative purposes, acting to maintain and / or restore homeostasis and may be administered topically, parenteral, enteral and / or intrathecal.
A expressão "farmaceuticamente aceitável" é empregada aqui para sereferir a compostos, materiais, composições, e/ou forma de dosagem que são,dentro do âmbito da medicina, apropriados para uso em contato com os tecidosde humanos e animais sem toxicidade excessiva, irritação, resposta alérgica,ou outro problema ou complicação, proporcional com uma relação razoável debenefício/risco.The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage form which are, within the scope of medicine, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.
A composição da presente invenção pode ser administrada em forma dedosagem oral, como tabletes, cápsulas (cada qual inclui a liberação sustentadaou formulações com tempo de liberação) pílulas, pós, granulados, elixires,tinturas, suspensões, xaropes, e emulsões. Eles podem ser administradossozinhos, mas geralmente serão administrados com um veículo farmacêuticoselecionado na base de rota de administração escolhida e da práticafarmacêutica padrão.The composition of the present invention may be administered in oral fingering form, such as tablets, capsules (each including sustained release or time release formulations) pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the route of administration chosen and standard pharmaceutical practice.
Dos objetos desenvolvidos iniciaremos a descrição detalhada a partirdos compostos inibidores das cc-glicosidases.From the developed objects we will start the detailed description from the cc-glycosidase inhibitor compounds.
Os inibidores das cc-glicosidases da presente invenção são compostospertencentes à família de compostos que possuem as fórmulas (I), (II) e/ou (III):The α-glycosidase inhibitors of the present invention are compounds belonging to the family of compounds having the formulas (I), (II) and / or (III):
<formula>formula see original document page 11</formula><formula> formula see original document page 11 </formula>
onde R1, R2, R3, R4 e R5 são, independentemente, escolhidos do grupo quecompreende H, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-C10-alcoxilas, C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10tioalcoxicarbonilas, anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicoscom 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n éescolhido entre 0 a 7 e onde o heteroatomo é escolhido do grupo quecompreende N, S e/ou O; onde tais anéis podem ser opcionalmentesubstituídos; S03X onde X é escolhido do grupo que compreende H, Na, Li, K,C1-C10 alquil, aril, heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CNe mistura dos mesmos; derivados de ésteres carboxílicos C02R onde R éescolhido do grupo que compreende H, C1-C10 alquil; anéis carbocíclicos e/ouheterocíclicos fundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas,hidroxiaminas e mistura dos mesmos; bem como seus sais, suas formasestereoisoméricas, solvatos e/ou hidratos.where R 1, R 2, R 3, R 4 and R 5 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is selected from the group comprising N, S and / or O; where such rings may optionally be substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CNe mixture thereof; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyamines and mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates.
Os compostos preferenciais da presente invenção incluem os compostosde fórmula geral (I):Preferred compounds of the present invention include compounds of general formula (I):
Onde R1 é um grupo metoxi, R2 é metil, R3 é metil, R4 é hidrogênio, R5é escolhido dentre fenil, 1-ciclohexenil, 1-hidroxi-ciclohexanil, fenoxi-metil,tetrahidropiran-2-iloximetil, carboxila esterificada, 2-propan-2-ol e/ou alquilcloro.Where R1 is a methoxy group, R2 is methyl, R3 is methyl, R4 is hydrogen, R5 is chosen from phenyl, 1-cyclohexenyl, 1-hydroxy-cyclohexanyl, phenoxymethyl, tetrahydropyran-2-yloxymethyl, esterified carboxyl, 2-propan -2-ol and / or alkylchlorine.
Os compostos preferenciais da presente invenção são também oscompostos de fórmula geral (II):Preferred compounds of the present invention are also compounds of formula (II):
onde R2 é metil, R3 é metil, R4 é hidrogênio, R5 é fenil, 1-ciclohexenile/ou metan-1-ol.where R2 is methyl, R3 is methyl, R4 is hydrogen, R5 is phenyl, 1-cyclohexenyl or methan-1-ol.
Os compostos preferenciais da presente invenção são também oscompostos de fórmula geral (III):Preferred compounds of the present invention are also compounds of general formula (III):
<formula>formula see original document page 12</formula>onde R4 é hidrogênio e R5 é escolhido dentre fenil, 1-ciclohexenil, 1-hidroxi-ciclohexanil e/ou fenóxi-metil.<formula> formula see original document page 12 </formula> where R4 is hydrogen and R5 is chosen from phenyl, 1-cyclohexenyl, 1-hydroxy-cyclohexanyl and / or phenoxymethyl.
Os inibidores das a-glicosidases podem ser obtidos pelo processo deprodução descrito a seguir.Α-Glycosidase inhibitors may be obtained by the production process described below.
Os 1,2,3-triazóis podem ser sintetizados por diversas rotas sintéticasclássicas ou modernas. Pode-se citar como uma das metodologias maisrecentes a cicloadição 1,3-dipolar, que é bastante empregada na síntese dederivados 1,2,3-triazólicos (SIVAKUMAR, 2004; HOTHA, 2005; THIBAULT,2006; OPPILLIART, 2007; YADAV, 2008). As referidas cicloadições 1,3-dipolares entre azidas e alcinos, de modo geral ocorrem rapidamente, sendoum dos métodos mais versáteis para preparação de 1,2,3-triazóis.1,2,3-triazoles can be synthesized by a variety of classical or modern synthetic routes. One of the most recent methodologies can be cited 1,3-dipolar cycloaddition, which is widely used in the synthesis of 1,2,3-triazole derivatives (SIVAKUMAR, 2004; HOTHA, 2005; THIBAULT, 2006; OPPILLIART, 2007; YADAV, 2008). Said 1,3-dipolar cycloadditiones between azides and alkynes generally occur rapidly, as one of the most versatile methods for preparing 1,2,3-triazoles.
A obtenção dos 1,2,3-triazóis glicoconjugados foi realizada pelametodologia desenvolvida recentemente por Sharpless e colaboradores, queutiliza a reação de cicloadição 1,3-dipolar catalisada por Cu(l) tambémconhecida como "Click Chemistry". O cobre utilizado como catalisador além deaumentar a velocidade da reação, controla integralmente suaregiosseletividade levando somente ao produto 1,4 (KOLB, 2001).The glycoconjugate 1,2,3-triazole was obtained by a methodology developed recently by Sharpless et al., Which uses the Cu (1) catalyzed 1,3-dipolar cyclic reaction also known as "Click Chemistry". Copper used as a catalyst in addition to increasing the reaction rate, fully controls its selectivity leading only to the product 1,4 (KOLB, 2001).
A rota que foi estabelecida para este estudo pode ser descrita de acordocom o esquema abaixo:The route that was established for this study can be described according to the scheme below:
<formula>formula see original document page 13</formula><formula> formula see original document page 13 </formula>
Assim como observado por Sharpless, a velocidade e rendimentos reacionaisMsCI, Acetato de etila .As observed by Sharpless, the speed and reaction yieldsMsCI, Ethyl acetate.
<formula>formula see original document page 13</formula>são muito superiores comparando com o método tradicional, com rendimentosmaiores que 80% e 100% de regiosseletividade.<formula> formula see original document page 13 </formula> are far superior compared to the traditional method, with yields greater than 80% and 100% regioselectivity.
A síntese dos glicoconjugados é realizada através de um processocompreendendo as seguintes etapas:The synthesis of glycoconjugates is performed by a process comprising the following steps:
a) formação de acetonídeos de fórmula geral (IV), (V) e/ou (VI):(a) formation of acetonides of formula (IV), (V) and / or (VI):
<formula>formula see original document page 14</formula><formula> formula see original document page 14 </formula>
onde:Where:
R1, R2 e R3 são, independentemente, escolhidos do grupo quecompreende H, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-ClO-alcoxilas, C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10tioalcoxicarbonilas, anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicoscom 3 a 7 membros compreendendo -(CH2)n- como espaçadores onde n éescolhido entre 0 a 7 e onde o heteroátomo é escolhido do grupo quecompreende N, S e/ou O; onde tais anéis podem ser opcionalmentesubstituídos; S03X onde X é escolhido do grupo que compreende H, Na, Li, K,C1-C10 alquil, aril, heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CNe mistura dos mesmos; derivados de ésteres carboxílicos C02R onde R éescolhido do grupo que compreende H, C1-C10 alquil; anéis carbocíclicos e/ouheterocíclicos fundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas,hidroxiaminas e mistura dos mesmos; bem como seus sais, suas formasestereoisoméricas, solvatos e/ou hidratos;R 1, R 2 and R 3 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is selected from the group comprising N, S and / or O; where such rings may optionally be substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CNe mixture thereof; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyamines and mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates;
b) mesilação e/ou tosilação dos acetonídeos;b) mesylation and / or tosylation of acetonides;
c) substituição nucleofílica com azida de sódio;c) nucleophilic substitution with sodium azide;
d) reação com alcinos de fórmula geral (VII) na presença de cobre.onde R4 e R5 são, independentemente, escolhidos do grupo que compreendeH, OH, N02, NH2, CN, C1-C10 alquilas, C2-C10 alquenilas; C1-C10-alcoxilas,C1-C10 tioalcoxilas, C1-C10-alcoxicarbonilas; C1-C10 tioalcoxicarbonilas,anéis carbocíclicos com 3 a 7 membros compreendendo -(CH2)n- comoespaçadores onde n é escolhido entre 0 a 7; anéis heterocíclicos com 3 a 7membros compreendendo -(CH2)n- como espaçadores onde n é escolhidoentre 0 a 7 e onde o heteroátomo é escolhido do grupo que compreende N, Se/ou O; onde tais anéis podem ser opcionalmente substituídos; S03X onde X éescolhido do grupo que compreende H, Na, Li, K, C1-C10 alquil, aril,heterociclos, aminas; alquilaminas; alcoxilas; N02; NH2; CN e mistura dosmesmos; derivados de ésteres carboxílicos C02R onde R é escolhido do grupoque compreende H, C1-C10 alquil; anéis carbocíclicos e/ou heterocíclicosfundidos a anéis aromáticos e/ou triazólicos; iminas, hidrazonas, hidroxiaminase mistura dos mesmos; bem como seus sais, suas formas estereoisoméricas,solvatos e/ou hidratos;d) reaction with alkynes of formula (VII) in the presence of copper wherein R 4 and R 5 are independently selected from the group comprising H, OH, NO 2, NH 2, CN, C 1 -C 10 alkyl, C 2 -C 10 alkenyl; C1-C10-alkoxy, C1-C10 thioalkoxy, C1-C10-alkoxycarbonyls; C 1 -C 10 thioalkoxycarbonyls, 3- to 7-membered carbocyclic rings comprising - (CH 2) n- as spacers where n is selected from 0 to 7; 3- to 7-membered heterocyclic rings comprising - (CH 2) n- as spacers where n is chosen from 0 to 7 and where the heteroatom is chosen from the group comprising N, Se / or O; wherein such rings may be optionally substituted; SO3 where X is selected from the group comprising H, Na, Li, K, C1 -C10 alkyl, aryl, heterocycles, amines; alkylamines; alkoxyls; NO2; NH2; CN and mixture of the same; carboxylic ester derivatives of CO 2 R where R is selected from the group comprising H, C 1 -C 10 alkyl; carbocyclic and / or heterocyclic rings fused to aromatic and / or triazole rings; imines, hydrazones, hydroxyminase mixtures thereof; as well as their salts, stereoisomeric forms, solvates and / or hydrates;
e) opcionalmente compreender uma etapa de hidrólise dos acetonídeos.e) optionally comprising an acetonide hydrolysis step.
Em conformidade com a rota sintética proposta neste trabalho,inicialmente foram sintetizado todos os intermediários necessários à obtençãodos azido carboidratos. Para tal, inicialmente, preparou-se os acetonídeos doscarboidratos. A etapa seguinte foi realizada visando à obtenção de umreagente que apresentasse um melhor grupo abandonador no carbono C5, alvodas reações subseqüentes, obtendo-se o derivado tosilado ou mesilado.In accordance with the synthetic route proposed in this work, initially all the intermediates necessary to obtain the carbohydrate azide were synthesized. To do this, initially, the carbohydrate acetonides were prepared. The next step was performed to obtain a reagent that presented a better leaving group on carbon C5, and subsequent reactions, obtaining the tosylated or mesylated derivative.
O intermediários tosilados ou mesilados foram utilizados na etapaseguinte de substituição nucleofílica com azida de sódio, sob refluxo à 120°Cem DMF por 12 horas. Após retirada do DMF, dissolução do resíduo comclorofórmio, lavagem com água, secagem e evaporação do solvente obteve-seos produtos na forma de um líquido amarelo com rendimento na faixa de 90-95% sem necessidade de prévia purificação para a realização dos triazóisdesejados.Para obtenção dos derivados triazólicos, resumidamente, uma soluçãodo derivado azido com o alcino teminal foi tratada com sulfato de cobrepentaidratado (5 mol%) e ascorbato de sódio (15 mol%), este último que foiadicionado lentamente. A mistura foi agitada durante um intervalo de temporeacional que variou entre 4-6 hrs dependendo dos substratos iniciais. Oproduto desejado foi isolado por extração e purificado por cromatografiaquando necessário.The tosylated or mesylated intermediates were used in the next step nucleophilic sodium azide substitution under reflux at 120 ° C DMF for 12 hours. After removal of the DMF, dissolution of the residue with chloroform, washing with water, drying and evaporation of the solvent, the products were obtained as a yellow liquid in the 90-95% yield without prior purification for the desired triazoles. To obtain the triazole derivatives, briefly, a solution of the azide derivative with the terminal alkyne was treated with copperpentahydrate sulfate (5 mol%) and sodium ascorbate (15 mol%), the latter slowly added. The mixture was stirred for a time interval ranging from 4-6 hrs depending on initial substrates. The desired product was isolated by extraction and purified by chromatography when necessary.
Em especial, a razão acetonídeos.alcinos está entre 1:6 a 1:10(mol/mol), preferencialmente 1:8.In particular, the acetonide.alkine ratio is between 1: 6 to 1:10 (mol / mol), preferably 1: 8.
A composição farmacêutica da presente invenção é uma composiçãoque compreende:The pharmaceutical composition of the present invention is a composition comprising:
a) pelo menos um inibidor da a-glicosidase;a) at least one α-glycosidase inhibitor;
b) um veículo farmaceuticamente aceitável.b) a pharmaceutically acceptable carrier.
Especificamente o inibidor da a-glicosidase é um inibidor escolhido dogrupo que compreende os compostos descritos no item acima "Inibidores de a-glicosidases".Specifically the α-glycosidase inhibitor is a chosen inhibitor of the group comprising the compounds described in the above item “α-glycosidase inhibitors”.
O veículo farmaceuticamente aceitável é um veículo escolhido do grupoque compreende os veículos aceitáveis para composições orais, endovenosas,dentre outros possíveis e podem compreender excipientes como o amido,açúcar, talco, manteiga de cacau, glicerina, óleos vegetais, dentre outrospossíveis bem como a mistura dos mesmos e soluções aquosas tais comoágua pra injeção, solução salina (NaCI 0,9%), solução de glicose 5%, soluçãoglicofisiológica (glicose 5% e NaCI 0,9%) dentre outras possíveis bem como amistura das mesmas.The pharmaceutically acceptable carrier is a carrier selected from the group which comprises acceptable carriers for oral, intravenous, among other possible compositions and may comprise excipients such as starch, sugar, talc, cocoa butter, glycerin, vegetable oils, among others, as well as the mixture. aqueous solutions such as water for injection, saline solution (NaCl 0.9%), glucose solution 5%, glycophysiological solution (glucose 5% and NaCl 0.9%) and other possible mixtures.
A composição farmacêutica da presente invenção apresenta atividadeinibitória contra as enzimas a-glicosidases sendo indicada à inibição daatividade antiviral de vírus tais como o vírus da dengue, o vírus HIV, dentreoutros possíveis, inibição da atividade antiproliferativa de células neoplásicas,atividade antimicrobiana, atividade redutora da glicemia, atividadeantiobesidade, imunoestimulantes, antiagregantes plaquetários eantidiabéticos, doenças associadas à intolerância à glicose, Doença de Pompedentre outras.The pharmaceutical composition of the present invention has inhibitory activity against α-glycosidase enzymes and is indicated for inhibition of antiviral activity of viruses such as dengue virus, HIV virus, among others, inhibition of neoplastic cell antiproliferative activity, antimicrobial activity, antimicrobial activity. blood glucose, anthiobesity activity, immunostimulants, antidiabetic platelet antiaggregants, glucose intolerant diseases, Pomped's Disease and others.
Exemplo 1. Síntede dos InibidoresExample 1. Inhibitor Synthesis
A uma solução contendo 7 mmols de alcinos terminais, 0,83 mmols dederivados azido carboidratos em diclorometano (0,7 mL) e água (0,7 ml_) foramadicionados 9,3 mg (0,04 mmols) de sulfato de cobre pentahidratado e 22 mg(0,11 rnols) de ascorbato de sódio. A solução resultante foi deixada sobagitação por um período de 4 - 6 horas à temperatura ambiente. Após estetempo, a mistura foi diluída com 5 mL de diclorometano e 5 mL de água. Asfases orgânicas foram separadas, secas com sulfato de sódio e concentradas àpressão reduzida. Os derivados 1,2,3-triazólicos foram obtidos como sólidosvariando sua coloração de amarelo claro à branco com rendimentos variandode 75 - 98%.To a solution containing 7 mmoles of terminal alkynes, 0.83 mmoles of carbohydrate-azide derivatives in dichloromethane (0.7 mL) and water (0.7 mL_) were added 9.3 mg (0.04 mmols) of pentahydrate copper sulfate and 22 mg (0.11 mmol) of sodium ascorbate. The resulting solution was allowed to stir for a period of 4-6 hours at room temperature. After this time, the mixture was diluted with 5 mL dichloromethane and 5 mL water. The organic phases were separated, dried over sodium sulfate and concentrated under reduced pressure. 1,2,3-Triazolic derivatives were obtained as solids varying their color from light yellow to white with yields ranging from 75 - 98%.
Exemplo2. Ensaios inibidores das enzimas a-glicosidasesExample2. Α-Glycosidase Enzyme Inhibitor Assays
Alguns exemplos de substâncias testadas das classes I a III estãomostrados na Tabela 1, onde se podem observar os efeitos inibitórios (Inibição(%) dos glico-triazóis pleiteados na presente invenção, frente a enzima a-glicosidase obtida a partir de leveduras comparando com a atividade daacarbose.Some examples of tested substances of classes I to III are shown in Table 1, where the inhibitory effects (Inhibition (%) of the glycothiazoles claimed in the present invention can be observed against the enzyme a-glycosidase obtained from yeasts compared to daacarbose activity.
2.1. Detalhes do Procedimento Experimental dos Testes Bioquímicos2.1. Details of Experimental Procedure of Biochemical Tests
Brevemente, uma solução contendo a enzima a-glucosidase foiincubada com soluções das substâncias dissolvidas em DMSO em diferentesconcentrações. Após isso foi adicionado um reativo (qual reativo?), que sofredegradação pela enzima e ao se degradar gera um composto colorido o qualpode ser dosado por espectrofotometria. A intensidade da cor formada éproporcional à atividade da a-glucosidase na solução. A inibição da cor,comparada com a de um controle contendo o diluente utilizado (DMSO) éproporcional à inibição da enzima. Desta forma, foi calculada a porcentagem deinibição da enzima na concentração de 0,5 mmol/L dos glico-triazóis I a III. Oresultado deste ensaio está mostrado na Tabela 1.Tabela 1: Efeito inibitório (%) dos glico-triazóis (0,5 mmol/L) frente à enzima o>glicosidase obtida a partir de leveduras.Briefly, a solution containing the α-glucosidase enzyme was incubated with solutions of the substances dissolved in DMSO at different concentrations. After that a reactive (which reactive?) Was added, which undergoes degradation by the enzyme and when degraded generates a colored compound which can be dosed by spectrophotometry. The intensity of the color formed is proportional to the activity of α-glucosidase in the solution. Color inhibition compared to a control containing the diluent used (DMSO) is proportional to enzyme inhibition. Thus, the percentage of inhibition of the enzyme at the concentration of 0.5 mmol / L of glyc triazoles I to III was calculated. The result of this assay is shown in Table 1. Table 1: Inhibitory effect (%) of glyco-triazoles (0.5 mmol / L) against the enzyme> glycosidase obtained from yeast.
<table>table see original document page 18</column></row><table><table>table see original document page 19</column></row><table><table>table see original document page 20</column></row><table><table> table see original document page 18 </column> </row> <table> <table> table see original document page 19 </column> </row> <table> <table> table see original document page 20 < / column> </row> <table>
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105237595A (en) * | 2015-11-13 | 2016-01-13 | 武汉工程大学 | N2-glycosyl-substituted 1,2,3-triazole compound and synthesis method and application thereof |
| CN106046087A (en) * | 2016-06-13 | 2016-10-26 | 武汉工程大学 | 1,5-Disubstituted 1,2,3-triazole glycoconjugate and its derivatives |
| CN106083959A (en) * | 2016-06-13 | 2016-11-09 | 武汉工程大学 | 1,4(‑NO2),5‑trisubstituted 1,2,3‑triazole sugar conjugates and their derivatives |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237595A (en) * | 2015-11-13 | 2016-01-13 | 武汉工程大学 | N2-glycosyl-substituted 1,2,3-triazole compound and synthesis method and application thereof |
| CN106046087A (en) * | 2016-06-13 | 2016-10-26 | 武汉工程大学 | 1,5-Disubstituted 1,2,3-triazole glycoconjugate and its derivatives |
| CN106083959A (en) * | 2016-06-13 | 2016-11-09 | 武汉工程大学 | 1,4(‑NO2),5‑trisubstituted 1,2,3‑triazole sugar conjugates and their derivatives |
| CN106046087B (en) * | 2016-06-13 | 2019-05-03 | 武汉工程大学 | 1,5-Disubstituted 1,2,3-triazole glycoconjugates and their derivatives |
| CN106083959B (en) * | 2016-06-13 | 2019-05-28 | 武汉工程大学 | 1,4(-NO2),5-trisubstituted 1,2,3-triazole glycoconjugate and its derivatives |
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