BRPI1004176A2 - Functionalized aryl and / or heteroaryl urea compounds; synthesis process of these compounds; pharmaceutical composition containing such compounds and uses - Google Patents
Functionalized aryl and / or heteroaryl urea compounds; synthesis process of these compounds; pharmaceutical composition containing such compounds and uses Download PDFInfo
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/80—Acids; Esters in position 3
Abstract
Compostos aril e/ou hetero aril uréias funcionalizados; processo de síntese desses compostos; composição farmacêutica contendo tais compostos e usos. A presente invenção refere-se a compostos aril e/ou heteroaril uréias funcionalizados de fórmula geral (i) e (ii), assim como seus sais e/ou solvatos e polimorfos capazes de atuar na inibição de proteínas quinases da família mapk e, ainda, na modulação das citocinas como tnf e il1<225>. Além disso, a invenção descreve um processo sintético para tais compostos, o preparo de uma composição farmacêutica que será utilizada na produção de medicamentos para o tratamento ou prevenção de distúrbios associados à dor aguda ou crônica, bem como no tratamento de doenças de natureza inflamatórias, sendo esta inflamação aguda ou crônica.Functionalized aryl and / or heteroaryl urea compounds; synthesis process of these compounds; pharmaceutical composition containing such compounds and uses. The present invention relates to functionalized aryl and / or heteroaryl urea compounds of general formula (i) and (ii), as well as their salts and / or solvates and polymorphs capable of inhibiting mapk family protein kinases and furthermore , in the modulation of cytokines as tnf and il1 <225>. Furthermore, the invention describes a synthetic process for such compounds, the preparation of a pharmaceutical composition which will be used in the manufacture of medicaments for the treatment or prevention of disorders associated with acute or chronic pain, as well as for the treatment of inflammatory diseases. this being acute or chronic inflammation.
Description
Relatório Descritivo COMPOSTOS ARIL E/OU HETERO ARIL URÉIAS FUNCIONALIZADOS; PROCESSO DE SÍNTESE DESSES COMPOSTOS; COMPOSIÇÃO FARMACÊUTICA CONTENDO TAIS COMPOSTOS E USOSDescription Report ARIL AND / OR HETERO ARIL COMPOUNDS FUNCTIONALIZED UREAS; SUMMARY PROCESS OF THESE COMPOUNDS; PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS AND USES
Campo da Invenção A presente invenção está relacionada a derivados aril e/ou heteroaril uréias funcionalizadas e congêneres de fórmula geral (I) e (II), mais particularmente, relífciona-se a derivados 2-(3-cicloexilureido)~4,5-dimetoxibenzoato de etila (LASSBio- 1494) , 6-(3-cicloexilureido)-l,3~benzodioxola-5-carboxilato de metila (LASSBio- 1495) , 2-(3-cicloexilureido)-benzoato de etila (LASSBio-1496), 2-(3-cicloexilureido)-piridina-3-carboxilato de metila (LASSBio-1497) e seus solvatos e polimorfos, bem como a um processo para sua preparação, composições farmacêuticas contendo os mesmos, e a seu emprego como agente terapêutico para o tratamento de doenças de origem inflamatória e da dor aguda e/ou crônica e/ou neuropática.FIELD OF THE INVENTION The present invention relates to functionalized and similar aryl and / or heteroaryl urea derivatives of general formula (I) and (II), more particularly to 2- (3-cyclohexylurido)-4,5-derivatives. ethyl dimethoxybenzoate (LASSBio-1494), methyl 6- (3-cyclohexylureido) -1,3-benzodioxola-5-carboxylate (LASSBio-1495), ethyl 2- (3-cyclohexylureido) -benzoate (LASSBio-1496) Methyl 2- (3-cyclohexylurido) -pyridine-3-carboxylate (LASSBio-1497) and its solvates and polymorphs, as well as to a process for their preparation, pharmaceutical compositions containing them, and their use as a therapeutic agent for the treatment of inflammatory diseases and acute and / or chronic and / or neuropathic pain.
Antecedentes da Invenção A proteína quinase ativada por mitógeno p38 (MAPK p38) é uma serína-treonina quinase ativada por fatores de estresse e estímulos inflamatórios [Zhang, J.; Shen, B.; Lin, A. TRENDS in Pharmacological Sciences, 2006, 28, 286]; está envolvida na biossíntese de citocinas proinflamatórias, como TNF-α e IL-Ιβ em níveis de transdução e tradução, Diversos membros da família das proteínas quinases já foram identificados até o momento. Estas enzimas catalisam a reação de fosforilação de diferentes substratos, desempenhando funções primordiais em praticamente todas as etapas da vida celular.Background of the Invention The p38 mitogen-activated protein kinase (MAPK p38) is a serine-threonine kinase activated by stress factors and inflammatory stimuli [Zhang, J .; Shen, B .; Lin, A. TRENDS in Pharmacological Sciences, 2006, 28, 286]; is involved in the biosynthesis of proinflammatory cytokines such as TNF-α and IL-Ιβ at transduction and translation levels. Several members of the protein kinases family have been identified so far. These enzymes catalyze the phosphorylation reaction of different substrates, performing primary functions at virtually every stage of cell life.
Atualmente são conhecidos quatro membros da família das MAPK-p38 designados pelas letras α, β, γ e δ. Essas isoformas diferem quanto à distribuição tecidual, ativação de outras quinases e fosforilação de substratos [Lee, J. C. et aí., Nature, 1994, 372, 739], O grau de homologia da p38a em relação a ρ38β, ρ38γ e ρ38δ é de 75, 62, e 64%, respectivamente. Embora a expressão da p38a e das cinases relacionadas possa variar, essa enzima é predominantemente expressa em células envolvidas com a resposta inflamatória e imunomoduladora do organismo [Lee, J. C. et ah, Nature, 1994, 372, 739], justificando seu papel central no desenvolvimento de patologias de origem inflamatória. A maioria dos compostos descritos como capazes de inibir a MAPK p38 exercem seu mecanismo de ação através da inibição competitiva com o ATP, entretanto, embora menos numerosos, inibidores alostéricos da MAPK p38 são conhecidos e alguns exemplos são ilustrados às fls 3/13 a seguir. [Montalban, A. G. et ai, Bioorganic and Medicinal Chemtstry Letters, 2008,18, 1772]. A constatação de que a MAPK p38 desempenhava papel chave nos processos inflamatórios, associada à demonstração dos efeitos benéficos dos inibidores de p-38 em modelos animais de inflamação e dor, tornam a MAPK p38 um atraente alvo para a intervenção terapêutica visando o tratamento de diferentes doenças de origem inflamatória aguda e/ou crônica e para o controle da dor inflamatória e neuropática [Coulthard, L. R. et al., Trends in Molecular Medicine, 2009, 15, 369].There are currently four known members of the MAPK-p38 family designated by the letters α, β, γ and δ. These isoforms differ in tissue distribution, activation of other kinases, and substrate phosphorylation [Lee, JC et al., Nature, 1994, 372, 739]. The degree of homology of p38a with respect to ρ38β, ρ38γ, and ρ38δ is 75 , 62, and 64%, respectively. Although the expression of p38a and related kinases may vary, this enzyme is predominantly expressed in cells involved with the organism's inflammatory and immunomodulatory response [Lee, JC et ah, Nature, 1994, 372, 739], justifying its central role in the development. of pathologies of inflammatory origin. Most compounds described as capable of inhibiting p38 MAPK exert their mechanism of action through competitive inhibition of ATP, however, although less numerous, allosteric inhibitors of p38 MAPK are known and some examples are illustrated on pages 3/13 below. . [Montalban, A. G. et al., Bioorganic and Medicinal Chemistry Letters, 2008, 18, 1772]. The fact that p38 MAPK played a key role in inflammatory processes, coupled with demonstration of the beneficial effects of p-38 inhibitors in animal models of inflammation and pain, make p38 MAPK an attractive target for therapeutic intervention to treat different diseases of acute and / or chronic inflammatory origin and for the control of inflammatory and neuropathic pain [Coulthard, LR et al., Trends in Molecular Medicine, 2009, 15, 369].
Sumário da Invenção É objeto da presente invenção os compostos aril e/ou hetero aril ureias funcionalizados de fórmula geral (I) e (II), assim como seus sais e/ou solvatos e/ou polimorfos, capazes de inibirem em animais mamíferos humano.s e não humanos as proteínas quinases pertencentes a família das MAPK.Summary of the Invention The object of the present invention is the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), as well as their salts and / or solvates and / or polymorphs, capable of inhibiting human mammalian animals. if not human the protein kinases belonging to the MAPK family.
Ainda é objeto da presente invenção os compostos aril e/ou hetero aril ureias funcionalizadas de fórmula geral (I) e (II), assim como seus sais e/ou solvatos e/ou polimorfos capazes de modular a expressão e/ou inibição de citocinas, particularmente, TNF e IL1 β em animais mamíferos humanos e não humanos. O terceiro objeto da presente invenção refere-se ao processo de síntese doè-compostos aril e/ou hetero aril ureias funcionalizados fórmula geral (I) e (II), assim como seus derivados, seus possíveis sais e/ou solvatos e/ou polimorfos capazes de inibirem a proteínas quinases da família da MAPK. O quarto objeto da presente invenção refere-se a uma composição farmacêutica que contém os compostos aril e/ou hetero aril ureias funcionalizados de fórmula geral (I) e (II), e/ou seus sais e solvatos e/ou polimorfos, capazes de inibirem as proteínas quinases da família MAPK. O quinto objeto da presente invenção refere-se ao uso da composição farmacêutica, contendo os compostos aril e/ou hetero aril ureias e/ou seus sais, solvatos e/ou polimorfos capazes de inibir as proteínas quinases da família MAPK, no tratamento de processos ou doenças relacionadas com a regulação das proteínas quinases da família MAPK em animais mamíferos humanos e não humanos. O sexto objeto da presente invenção refere-se ao uso da composição farmacêutica para a produção de um medicamento contendo os compostos aril é!é>>' hetero aril ureias e/ou seus sais, solvatos e/ou polimorfos, capazes de modular a expressão e/ou produção de TNF e IL1 β e/ou inibir as proteínas quinases da família MAPK, no tratamento de doenças inflamatórias aguda e/ou crônica em animais mamíferos humanos e não humanos. O sétimo objeto da presente invenção refere-se ao uso da composição farmacêutica para a produção de um medicamento contendo os compostos aril e/ou hetel*o aril ureias e/ou seus sais, solvatos e/ou polimorfos, capazes de modular a expressão e/ou produção de TNF e ÍLl β e/ou inibir as proteínas quinases da família MAPK, no tratamento de distúrbios relacionados à dor aguda e/ou crônica e/ou neuropática em animais mamíferos humanos e não humanos.Further object of the present invention are the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), as well as their salts and / or solvates and / or polymorphs capable of modulating cytokine expression and / or inhibition. particularly TNF and IL1 β in human and non-human mammalian animals. The third object of the present invention relates to the process of synthesizing functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), as well as their derivatives, their possible salts and / or solvates and / or polymorphs. capable of inhibiting the protein kinases of the MAPK family. The fourth object of the present invention relates to a pharmaceutical composition containing the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvates and / or polymorphs, capable of inhibit the MAPK family protein kinases. The fifth object of the present invention relates to the use of the pharmaceutical composition containing the aryl and / or heteroaryl urea compounds and / or their salts, solvates and / or polymorphs capable of inhibiting the MAPK family protein kinases in the treatment of processes. or diseases related to the regulation of MAPK family protein kinases in human and non-human mammalian animals. The sixth object of the present invention relates to the use of the pharmaceutical composition for the manufacture of a medicament containing the aryl and heteroaryl urea compounds and / or their salts, solvates and / or polymorphs capable of modulating the expression. and / or production of TNF and IL1 β and / or inhibit MAPK family protein kinases in the treatment of acute and / or chronic inflammatory diseases in human and non-human mammalian animals. The seventh object of the present invention relates to the use of the pharmaceutical composition for the manufacture of a medicament containing the aryl and / or hetero aryl urea compounds and / or their salts, solvates and / or polymorphs capable of modulating the expression and / or production of TNF and ILI β and / or inhibit MAPK family protein kinases in the treatment of acute and / or chronic and / or neuropathic pain-related disorders in human and non-human mammalian animals.
Descrição das Figuras Figura 1- A figura I mostra o efeito de LASSBio-1494, LASSBio-1495, LASSBio-1496 e LASSBio-1497, comparado ao efeito dos padrões LASSBio-998 e SB203580, sobre a expressão gênica de TNF (A) e na secreção de TNF (B) por células THP-1 estimuladas com LPS. P < 0.05 em relação ao veículo.Description of the Figures Figure 1- Figure I shows the effect of LASSBio-1494, LASSBio-1495, LASSBio-1496, and LASSBio-1497, compared to the effect of LASSBio-998 and SB203580 standards on gene expression of TNF (A) and TNF (B) secretion by LPS-stimulated THP-1 cells. P <0.05 relative to the vehicle.
Figura 2- A figura 5 mostra o efeito de LASSBio-1494, LASSBio-1495, LASSBio-1496 e LASSBio-1497, comparado ao efeito dos padrões LASSBio-998 e SB203580, no modelo de viabilidade celular em macrófagos humanos, utilizando o teste do MTT.Figure 2- Figure 5 shows the effect of LASSBio-1494, LASSBio-1495, LASSBio-1496 and LASSBio-1497, compared to the effect of LASSBio-998 and SB203580 standards on the cell viability model in human macrophages using the MTT.
Figura 3- A figura 3 mostra o efeito de LASSBio-1494, LASSBio-1495, LASSBio-1496 e LASSBio-1497, comparado ao efeito dos padrões LASSBio-998 e SB203580, sobre a expressão gênica de IL-Ιβ (A) e na secreção de IL-Ιβ em células THP-1 estimuladas com LPS. P < 0.05 em relação ao veículo.Figure 3- Figure 3 shows the effect of LASSBio-1494, LASSBio-1495, LASSBio-1496 and LASSBio-1497 compared to the effect of LASSBio-998 and SB203580 standards on IL-β (A) gene expression and IL-Ιβ secretion in LPS-stimulated THP-1 cells. P <0.05 relative to the vehicle.
Figura 4- A figura 4 mostra o efeito de LASSBio-1494, LASSBio-1495, LASSBiq-1;49A e LASSBio-1497, comparado ao efeito dos padrões LASSBio-998 e SB203580, sobre aTnibição da fosforilação da MAPK p38 através de ensaio de Western Blotting.Figure 4- Figure 4 shows the effect of LASSBio-1494, LASSBio-1495, LASSBiq-1; 49A and LASSBio-1497 compared to the effect of LASSBio-998 and SB203580 standards on MAPK p38 phosphorylation inhibition assay. Western blotting.
Figura 5- A figura 5 mostra o efeito anti-hipernociceptivo temporal de LASSBio-1494, LASSBio-1495, LASSBio-1496 e LASSBio-1497, comparado ao efeito dos padrões LASSBio-998 e SB203580, no modelo de hipernocicepção térmica induzida por capsaicina (A) e (B). N de 8-10 animais, dose = 100 μιηοΙ/Kg, via oral, *P <0,05 comparados ao veículo.Figure 5- Figure 5 shows the temporal antihypernociceptive effect of LASSBio-1494, LASSBio-1495, LASSBio-1496, and LASSBio-1497 compared to the effect of LASSBio-998 and SB203580 standards on the capsaicin-induced thermal hypernociception model ( A) and (B). N of 8-10 animals, dose = 100 μιηοΙ / kg, orally, * P <0.05 compared to vehicle.
Descrição detalhada t A produção e secreção de mediadores liberados nos processos e doenças inflamatórias sâo dependentes da cascata de sinalização intracelular regulada pelas proteínas quinases e fosfatases. As quinases são responsáveis pela fosforilação de proteínas nas células, tendo o ATP como substrato, enquanto as fosfatases regulam esta fosforilação. Nos últimos anos as quinases tornaram-se o alvo farmacológico mais estudado pelas indústrias farmacêuticas na busca por inibidores destas proteínas para o tratamento de doenças inflamatórias crônicas.Detailed Description The production and secretion of mediators released in inflammatory processes and diseases are dependent on the intracellular signaling cascade regulated by protein kinases and phosphatases. Kinases are responsible for protein phosphorylation in cells, with ATP as a substrate, while phosphatases regulate this phosphorylation. In recent years kinases have become the most studied pharmacological target by pharmaceutical companies in search of inhibitors of these proteins for the treatment of chronic inflammatory diseases.
Os compostos aril e/ou hetero aril ureias funcionali/.ados de fórmula geral (I) e (II), assim como seus sais e solvatos e/ou polimorfos que são objeto desta invenção, são capaz.es de inibir as proteínas quinases, sendo mais preciso as da família MAPK tais como as proteínas quinases reguladas extracelularmente (ERKs), proteínas quinases da junção-C N-terminal (JNKs) proteínas quinases ativadas por estresse (MAPK p38) e a ERK5 (também conhecida como BMK1), sendo mais preferencialmente, ainda, para a presente invenção, a inibição da proteína quinase MAPKp-38 e suas isoformas. A inibição das MAPK p-38 pelos compostos se prevalece pelo fato dos mesmos ligarem-se a um sítio diferente do ATP, conhecido como sítio alostérico. Após essa ligação as MAPK p-38 diminuem sua afinidade pelo seu substrato natural, o ATP, assim interrompendo a cascata de ativação e transcrição de citocinas proinflamatórias envolvidas em processos e doenças inflamatórias, onde, tanto para o composto de fórmula geral (I) e (II) R. pode ser qualquer grupo cicloalcanos de 3 a 7 átomos de carbono, grupo alquila de 1 a 7 átomos de carbono, arila e heteroarila; sendo que tais radicais podem ainda ser opcionalmente substituídos, insaturados e/ou ramificados. Sendo preferencialmente para R um grupo OH, OCH3, OC2H5, OCH(CH3)2, OC(CH3)3, NH2, NHCH3, NHC2H5, NHCH(CH3), NC(CH3)3, N(C2I:I5)2, N(CH3)2, NI-1NH2; onde Y pode ser C, CH, N, NH; onde Y1 pode ser C, CH, N, NH; onde RI qualquer grupo cicloalcanos de 3 a 7 átomos de carbono, grupo alquila de 1 a 7 átomos de carbono, arila e heteroarila; sendo que tais radicais podem ainda ser opcionalmente substituídos, insaturados e/ou ramificados.Sendo preferencialmente para este radical RI um grupo cicloeptila, cicloexila, ciclopentila, ciclobutila, ciclopropila. Alquil linear, alquil ramificado, aril e heteroaril.The functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), as well as their salts and solvates and / or polymorphs which are the object of this invention, are capable of inhibiting protein kinases, MAPK family such as extracellularly regulated protein kinases (ERKs), N-terminal C-junction protein kinases (JNKs), stress-activated protein kinases (MAPK p38) and ERK5 (also known as BMK1). even more preferably for the present invention, inhibition of MAPKp-38 protein kinase and its isoforms. Inhibition of p-38 MAPK by the compounds is prevalent because they bind to a different site than ATP, known as the allosteric site. Following this binding, p-38 MAPKs decrease their affinity for their natural substrate, ATP, thus disrupting the activation and transcription cascade of proinflammatory cytokines involved in inflammatory processes and diseases, where for both the compound of formula (I) and (II) R. may be any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. Preferably R is OH, OCH3, OC2H5, OCH (CH3) 2, OC (CH3) 3, NH2, NHCH3, NHC2H5, NHCH (CH3), NC (CH3) 3, N (C2I: I5) 2, N (CH 3) 2, NI-1NH 2; where Y may be C, CH, N, NH; where Y1 may be C, CH, N, NH; where R1 is any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. Preferably for this radical R 1 is a cycloeptyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl group. Linear alkyl, branched alkyl, aryl and heteroaryl.
Somente para o composto de fórmula geral (I), onde X pode ser H, O, OH, OCH3, N, NH, NH2; onde XI pode ser H, O, OH, OCH3, CH2, N, NH, NH2; onde n pode ser 0, CH2, CH, C2H4.Only for the compound of formula (I), where X may be H, O, OH, OCH 3, N, NH, NH 2; where XI may be H, O, OH, OCH 3, CH 2, N, NH, NH 2; where n may be 0, CH 2, CH, C 2 H 4.
Os compostos de fórmula geral (I) e (II), assim como seis sais e/ou solvatos e/ou polimorfos, além de atuarem na inibição das proteínas quinases da famlia MAPK, são capazes de modular a expressão das citocinas proinflamatórias TNF e IL1 β .Essa modulação é estabelecida devido a esses compostos competirem pelo sítio de ligação das citocinas. Quando os compostos (I) e (II) ligam-se ao sitio desencadeiam uma; resposta antagonista às das citocinas proinflamatorias citadas anteriormente. DessfeV forma, esses compostos ao ligarem-se a este sitio promovem a paralização da cascata de ativação que seria gerada pelas citocinas proinflamatórias.The compounds of formula (I) and (II), as well as six salts and / or solvates and / or polymorphs, in addition to inhibiting MAPK family protein kinases, are able to modulate the expression of TNF and IL1 proinflammatory cytokines β .This modulation is established because these compounds compete for the cytokine binding site. When compounds (I) and (II) bind to the site they trigger one; antagonist response to the pro-inflammatory cytokines mentioned above. Thus, by binding to this site such compounds promote the paralysis of the activation cascade that would be generated by the proinflammatory cytokines.
Os compostos de formula geral (I) e (II) onde, tanto para o composto de fórmula geral (I) e (II) R pode ser pode ser qualquer grupo cicloalcanos de 3 a 7 átomos de carbono, grupo alquila de 1 a 7 átomos de carbono, arila e heteroarila; sendo que tais radicais podem ainda ser opcionalmente substituídos, insaturados e/ou ramificados. Sendo preferencialmente para R um grupo OH, OCH3, OC2H5, OCH(CH3)2, OC(CH3)3, NH2, NHCH3, NHC2H5, NHCH(CH3), NC(CH3)3, N(C2H5)2, N(CH3)2, NHNH2; onde Y pode ser C, CH, N, NH; onde Y1 pode ser C, CH, N, NH; onde RI qualquer grupo cicloalcanos de 3 a 7 átomos de carbono, grupo alquila de 1 a 7 átomos de carbono, arila e heteroarila; sendo que tais radicais podem ainda ser opcionalmente substituídos, insaturados e/ou ramificados. Sendo preferencialmente para este radical RI um grupo cicloeptila, cicloexila, ciclopentila, ciclobutila, ciclopropila. Alquil linear, alquil ramificado, aril e heteroaril. Somente para o composto de fórmula geral (I), onde X pode ser H, O, OH, OCH3, N, NH, NH2; onde XI pode ser H, O, OH, OCH3, CH2, N, NH, NH2; onde n pode ser 0, CH2, CH, C2H4. O processo de síntese dos compostos de fórmula geral (I) e (II) compreende a formação de um intermediário carbamato funcionalizado, obtido pela reação entre unia amina funcionalizada e jonitrofenil-cloroformato. O processo de síntese do composto de fórmula geral (I) e (II) são divididos nas seguintes etapas: Etapa (a)- Condensação da amina de fórmula molecular (III) e/ou fórmula molecular (IV) ao p-nilrotenil-cloroformato, para obtenção do carbamato de fórmula geral (V) e/ou fórmula geral (VI) Etapa (b) - Adição nucleofílica, seguida de eliminação, de aminas funcionalizadas (NH2R1) ao intermediário carbamato de fórmula geral V e/ou VI, O que difere no processo de síntese do composto fórmula geral (I) para composto de fórmula geral (II) está relacionado com a amina precursora. No caso da síntese do composto fórmula geral (I), a amina precursora é a de fórmula geral (III), no caso do composto de fórmula geral (II) a amina precursora é a de fórmula geral (IV). As demais etapas do processo são idênticas para os 2 compostos, sendo respeitado o número de etapas , todas as concentrações, todos os solventes envolvidos, todos os método de separação e purificação, assim como as temperaturas e pressões. A etapa (a) ocorre pela adição nucleofílica da amina de fórmula geral (III), para síntese do composto de fórmula geral (I), ou a amina de fórmula geral (IV) para a formação do composto de fórmula geral (II). onde os radical R pode ser OH, OCH3, OC2H5, OCH(CH3)2, OC(CH3)3, NH2, NHCH3, NHC2H5, NHCH(CH3)2, NHC(CH3)3, N(C2H5)2, N(CH3)2; onde Y pode ser C, 0; onde Y1 pode ser N, CH, NH; onde X pode ser H, O, OH, OCH3, CH2, N, NH, NH2; e onde XI Kode ser H, O, OH, OCH3, CH2, N, NH, NH2 , com o />-nitrofenil-cloroformato, em meio de clorofórmio. A reação inicia com a adição de 0,2 a 2 mmol da amina escolhida, sendo preferencialmente de 0,5 a 1,0 mmol da amina precursora em um balão contendo clorofórmio e p-nitrofenil-cloroformato. A mistura é mantida a temperatura ambiente sob processo de agitação magnética por até 24 horas. A etapa é finalizada com a formação de um composto, o carbamato de fórmula geral V e/ou VI. A purificação do carbamato intermediário é realizada pela recristalização em solvente orgânico como etanol, propanol, hexano, propanona, sendo preferencialmente o hexano, sendo mais preferencialmente ainda o n-hexano. A etapa (b) baseia-se no tratamento do intermediário carbonato funcionalizado de fórmula geral (V) e/ou fórmula geral (VI) com uma amina funcionalizada (NH2Ri), para obtenção da aril e/ou hetero aril ureias funcionalizadas de fórmula geral (I) e (II), os quais são purificados por recristalização utilizando um solvente orgânico ou em mistura de solvente orgânico-água, este solvente orgânico pode ser etanol, propanol, isopropanol, isobutanol, acetona, acetato, diclorometano, sendo preferencialmente o etanol, sendo mais preferencialmente ainda a mistura etanol/água na proporção de 1:1.The compounds of formula (I) and (II) where, for both the compound of formula (I) and (II) R may be may be any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. Preferably R is OH, OCH 3, OC 2 H 5, OCH (CH 3) 2, OC (CH 3) 3, NH 2, NHCH 3, NHC 2 H 5, NHCH (CH 3), NC (CH 3) 3, N (C 2 H 5) 2, N (CH 3 ) 2, NHNH 2; where Y may be C, CH, N, NH; where Y1 may be C, CH, N, NH; where R1 is any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. Preferably for this radical R1 is a cycloeptyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl group. Linear alkyl, branched alkyl, aryl and heteroaryl. Only for the compound of formula (I), where X may be H, O, OH, OCH 3, N, NH, NH 2; where XI may be H, O, OH, OCH 3, CH 2, N, NH, NH 2; where n may be 0, CH 2, CH, C 2 H 4. The synthesis process of the compounds of formula (I) and (II) comprises the formation of a functionalized carbamate intermediate obtained by the reaction between a functionalized amine and jonitrophenyl chloroformate. The synthesis process of the compound of formula (I) and (II) is divided into the following steps: Step (a) - Condensation of the amine of molecular formula (III) and / or molecular formula (IV) to p-nylrotenyl chloroformate to obtain carbamate of formula (V) and / or formula (VI) Step (b) - Nucleophilic addition followed by removal of functionalized amines (NH2R1) to carbamate intermediate of formula V and / or VI which differs in the synthesis process from compound (I) to compound (II) is related to the precursor amine. In the case of the synthesis of the compound (I), the precursor amine is of the formula (III), in the case of the compound of formula (II) the precursor amine is of the formula (IV). The other process steps are identical for both compounds, respecting the number of steps, all concentrations, all solvents involved, all separation and purification methods, as well as temperatures and pressures. Step (a) occurs by nucleophilic addition of the amine of formula (III) for synthesis of the compound of formula (I) or the amine of formula (IV) to form the compound of formula (II). where the radicals R may be OH, OCH 3, OC 2 H 5, OCH (CH 3) 2, OC (CH 3) 3, NH 2, NHCH 3, NHC 2 H 5, NHCH (CH 3) 2, NHC (CH 3) 3, N (C 2 H 5) 2, N ( CH3) 2; where Y may be C, 0; where Y1 may be N, CH, NH; where X may be H, O, OH, OCH 3, CH 2, N, NH, NH 2; and where XI can be H, O, OH, OCH 3, CH 2, N, NH, NH 2 with the nitrophenyl chloroformate in chloroform medium. The reaction begins with the addition of 0.2 to 2 mmol of the chosen amine, preferably 0.5 to 1.0 mmol of the precursor amine in a flask containing chloroform and p-nitrophenyl chloroformate. The mixture is kept at room temperature under magnetic stirring for up to 24 hours. The step is completed with the formation of a compound, the carbamate of formula V and / or VI. Purification of the intermediate carbamate is accomplished by recrystallization from organic solvent such as ethanol, propanol, hexane, propanone, preferably hexane, most preferably n-hexane. Step (b) is based on treating the functionalized carbonate intermediate of formula (V) and / or formula (VI) with a functionalized amine (NH 2 Ri) to obtain the functionalized aryl and / or heteroaryl ureas of formula (I) and (II), which are purified by recrystallization using an organic solvent or in an organic solvent-water mixture, this organic solvent may be ethanol, propanol, isopropanol, isobutanol, acetone, acetate, dichloromethane, preferably ethanol. most preferably the ethanol / water mixture being 1: 1.
Sendo este intermediário carbonato funcionalizado, preparado na etapa anteríbr íat. apresenta fórmula geral V e/ou VI os sadical R pode ser OH, OCH3, OC2H5, OCH(CH3)2, OC(CH3)3, NH2, NHCH3, NHCaHs, NHCH(CH3)2, NHC(CH3)b, N(C2H5)2, N(CH3)2; onde Y pode ser C, 0; onde Y1 pode ser N, CH, NH; onde W pode ser N, CI I, NH; onde X pode ser H, O, OH, OCH3, CH2, N, NH, NH2; e onde XI pode ser H, O, OH, OCII3, CH2, N, NH, NH2. A amina funcionali/.ada possui fórmula geral (NH2-R1), onde o radical R| pode ser qualquer grupo cicloalcanos de 3 a 7 átomos de carbono, grupo alquila de 1 a 7 átomos de carbono, arila e heteroarila; sendo que tais radicais podem ainda ser opcionalmente substituídos, insaturados e/ou ramificados. O quarto objeto da invenção consiste numa composição farmacêutica contendo isoladamente ou em associações os compostos aril e/ou hetero aril ureias funcionalizados de fórmula geral (I) e/ou (II), e/ou seus sais e solvatos e/ou polimorfos, na inibição das proteínas quinases da família MAPK, preferencialmente a MAPK p38 e suas isoformas ρ38α, ρ38β, ρ38γ e ρ38δ, em mamíferos humanos e não humanos. Para tal formulação aceitamos, além dos compostos ditos acima, outras substâncias farmaceuticamente não ativas como adjuvantes, excipientes, dispersantes, antioxidantes, emolientes, edulcorantes, flavorizantes, conservantes, além de outras substâncias farmaceuticamente não ativas já conhecidas por um técnico na arte. O nosso quinto objeto é uma composição farmacêutica contendo isoladamente ou em associações os compostos aril e/ou hetero aril ureias funcionalizados de fórmula geral (I) e (II), e/ou seus sais e solvatos e/ou porlimorfos, para a modulação da expressão das leucinas proinflamatórias TNF e ILip em animais mamíferos humanos e não humanos. Outras substâncias farmaceuticamente não ativas já conhecidas no estado da arte estão incluídas nesta composição, sendo preferencialmente adjuvantes, excipientes, dispersantes, antioxidantes, emolientes, edulcorantes, flavorizantes, conservantes. A concentração dos compostos encontrada nestas composições são todas aquelas farmaceuticamente aceitáveis para os mesmo, podendo variar de 0,026 mmol a 2,6 mmol, sendo preferencialmente, 0,078 mmol a 0,78 mmol. O nosso sexto objeto descreve o uso da composição farmacêutica contendo isoladamente ou em associações os compostos aril e/ou hetero aril uréias funcionalizados de formula geral (I) e (II), e/ou seus sais e solvados e/ou polimorfos, para produção de um medicamento utilizado no tratamento e/ou prevenção de doenças inflamatórias agudas e/ou crônica associados com a inibição das proteínas quinases da família MAPK e na modulação da expressão das leucinas proinflamatórias TNF e IL1 β, em animais mamíferos humanos e não humanos, O último objeto desta invenção está relacionado com o uso de uma composição farmacêutica contendo isoladamente ou em associações os compostos aril e/ou hetero aril uréias funcionalizados de fórmula geral (I) e (II), e/ou seus sais e solvatos e/ou polimorfos, para a produção de um medicamento utilizado no tratamento e/ou prevenção de distúrbios relacionados à dor aguda e/ou crônica e/ou neuropática em animais mamíferos humanos e não humanos. Esses compostos são capazes de modular a expressão e/ou produção de TNF e ΕΕΙβ e/ou inibir as proteínas quinases da família ΜΑΡΚ.Since this carbonate intermediate is functionalized, prepared in the anteribride stage. R 2 is OH, OCH 3, OC 2 H 5, OCH (CH 3) 2, OC (CH 3) 3, NH 2, NHCH 3, NHCaHs, NHCH (CH 3) 2, NHC (CH 3) b, N (C 2 H 5) 2, N (CH 3) 2; where Y may be C, 0; where Y1 may be N, CH, NH; where W may be N, CI I, NH; where X may be H, O, OH, OCH 3, CH 2, N, NH, NH 2; and where XI may be H, O, OH, OCII 3, CH 2, N, NH, NH 2. The functional amine has the general formula (NH 2 -R 1), where the radical R 1 | may be any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. The fourth object of the invention is a pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and / or (II), and / or their salts and solvates and / or polymorphs. inhibition of MAPK family protein kinases, preferably MAPK p38 and its isoforms ρ38α, ρ38β, ρ38γ and ρ38δ, in human and non-human mammals. For such formulation we accept, in addition to the above compounds, other non-active pharmaceutical substances as adjuvants, excipients, dispersants, antioxidants, emollients, sweeteners, flavorants, preservatives, in addition to other non-active substances already known to one skilled in the art. Our fifth object is a pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvates and / or porphorphs, for the modulation of expression of TNF and ILip proinflammatory leucines in human and non-human mammalian animals. Other non-active pharmaceutically active substances already known in the art are included in this composition, preferably being adjuvants, excipients, dispersants, antioxidants, emollients, sweeteners, flavorants, preservatives. The concentration of compounds found in these compositions are all those pharmaceutically acceptable for them, and may range from 0.026 mmol to 2.6 mmol, preferably 0.078 mmol to 0.78 mmol. Our sixth object describes the use of the pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvents and / or polymorphs, for production. of a medicament for the treatment and / or prevention of acute and / or chronic inflammatory diseases associated with inhibition of MAPK family protein kinases and modulation of TNF and IL1 β proinflammatory leucine expression in human and non-human mammalian animals, O The last object of this invention relates to the use of a pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvates and / or polymorphs. for the manufacture of a medicament for the treatment and / or prevention of acute and / or chronic and / or neuropathic pain-related disorders in human mammalian animals. and not humans. These compounds are capable of modulating the expression and / or production of TNF and ΕΕΙβ and / or inhibit the qu family protein kinases.
Tais distúrbios e doenças ditas anteriormente incluem as diferentes formas de artrite, preferencialmente a artrite reumatoide, osteoartrite, Lúpus, psoríase, doença de Crohn, asma, COPD, melanoma, doença de Alzheimer, mal de Parkinson. Além da dor aguda e/ou crônica, incluindo a dor neuropática, associada aos distúrbios citados e/ou a qualquer manifestação álgica (i.e. dolorosa) dependente da participação das MAPKs, preferencialmente a MAPK p38, e/ou de citocinas proinflamatórias, particularmente ΙΡΙβ e TNFa. * Os medicamentos ditos anteriormente podem ser encontrados em diversas formas farmacêuticas descritas no estado da arte, entretanto, sendo preferencialmente as formas farmacêuticas de uso através da via oral. Mais preferencialmente, ainda, para esta invenção, as formas farmacêuticas de uso por via oral são comprimidos, pastilhas, cápsulas, drágeas, pílulas, xaropes, suspensão, emulsão e soluções, incluindo-se as formas farmacêuticas orais de liberação prolongada, lenta ou sustentada.Such disorders and diseases mentioned above include the different forms of arthritis, preferably rheumatoid arthritis, osteoarthritis, lupus, psoriasis, Crohn's disease, asthma, COPD, melanoma, Alzheimer's disease, Parkinson's disease. In addition to acute and / or chronic pain, including neuropathic pain, associated with the aforementioned disorders and / or any pain (ie painful) manifestation dependent on the participation of MAPKs, preferably p38 MAPK, and / or proinflammatory cytokines, particularly ΙΡΙβ and TNFα. * The foregoing medicaments may be found in various pharmaceutical forms described in the state of the art, however, preferably being pharmaceutical forms of oral use. Most preferably, for this invention, the oral dosage forms are tablets, lozenges, capsules, pills, pills, syrups, suspension, emulsion and solutions, including the slow, sustained or prolonged release oral dosage forms. .
Claims (17)
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PCT/BR2011/000389 WO2012054996A1 (en) | 2010-10-25 | 2011-10-25 | Functionalized aryl and/or heteroaryl urea compounds; a method for synthesizing same; a pharmaceutical composition containing such compounds and uses thereof |
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JPS63502903A (en) * | 1986-03-28 | 1988-10-27 | ジヤヌス・フアルマチエウテイシ・エスアールエル | Method for synthesizing compounds with therapeutic anti-ulcer activity |
WO1996025157A1 (en) * | 1995-02-17 | 1996-08-22 | Smithkline Beecham Corporation | Il-8 receptor antagonists |
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US6093742A (en) * | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
WO2000041698A1 (en) * | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS |
CA2374737C (en) * | 1999-07-09 | 2008-02-12 | Boehringer Ingelheim Pharmaceuticals, Inc. | Novel process for synthesis of heteroaryl-substituted urea compounds |
US7053070B2 (en) * | 2000-01-25 | 2006-05-30 | Warner-Lambert Company | Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors |
DE10252650A1 (en) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | New 1,4-disubstituted cyclohexylamine derivatives, are opioid receptor like-receptor 1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain |
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