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PT1302461E - Inibidores de produção de tnf-alpha - Google Patents

Inibidores de produção de tnf-alpha Download PDF

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Publication number
PT1302461E
PT1302461E PT01934447T PT01934447T PT1302461E PT 1302461 E PT1302461 E PT 1302461E PT 01934447 T PT01934447 T PT 01934447T PT 01934447 T PT01934447 T PT 01934447T PT 1302461 E PT1302461 E PT 1302461E
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Prior art keywords
tnf
production
compound
present compound
present
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PT01934447T
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English (en)
Inventor
Masakazu Ban
H Suhara
M Horiuchi
N Yamamoto
H Enomoto
H Inoue
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Santen Pharmaceutical Co Ltd
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Publication of PT1302461E publication Critical patent/PT1302461E/pt

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    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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Description

5213
DESCRIÇÃO
INIBIDORES DE PRODUÇÃO DE TNF-ALPHA
Descrição
Domínio técnico A presente invenção refere-se a inibidores de produção de TNF-a que são úteis como agentes terapêuticos para doenças auto-imunes, tais como artrite reumatóide.
Estado da Técnica 0 TNF-a (Factor de Necrose Tumoral alfa) é reconhecido como uma citocina que participa amplamente no mecanismo de biofilaxia-imune por inflamação. Sabe-se que produção prolongada e excessiva de TNF-a é um factor que origina danificação de tecido e várias doenças. Exemplos de patologias nas quais o TNF-a participa são várias patologias tais como artro-reumatismo, lúpus eritematoso sistémico (LES) , caquexia, doença infecciosa aguda, alergia, pirexia, anemia e diabetes (Yamazaki, Clinicai Immunology, 27, 1270, 1995). Também se encontra divulgado que o TNF-a desempenha um papel importante na patogénese de artrite reumatóide e na doença de Crohn, que são doenças auto-imunes (Andreas Eigler et al., Immunology Today, 18, 487, 1997).
Destes relatos, espera-se que compostos que inibam ou suprimam a produção de TNF-α sejam eficazes para o tratamento das doenças acima mencionadas, e realizaram-se vários estudos (referências acima-mencionadas: Yamazaki, 5213
Clinicai Immunology, 27, 1270, 1995, Andreas Eigler et al., Immunology Today, 18, 487, 1997). Recentemente, também foi divulgado que a metaloprotease, que é uma enzima proteolítica, participa na secreção de TNF-α e os inibidores de metaloproteases têm efeitos importantes na inibição da produção de TNF-α e semelhantes (Tradução de PCT Japonesa Publicada No. 508115/1997). As Publicações de Patente Japonesa revistas n°s. 44533/2000 e 119249/2000 divulgam compostos que têm efeitos inibidores da produção de TNF-α. Todos estes compostos são derivados da ureia que têm um átomo de enxofre nas cadeias laterais.
As patentes WO-A-99/50238 e EP-A-1103543 divulgam 1-[2-(1-adamantil)etil]-1-(2-hidroxietil)-3-(4-piridilmetil) ureia e 1-[2-(acetiltio)etil]-1-[2-(1-adamantil)etil]-3-(4-piridilmetil) ureia.
Estes dois compostos compreendem um grupo hidroxilo e grupo acetiltio em cada cadeia alquílica que são grupos funcionais bastante reactivos.
Portanto, faz sentido pesquisar compostos que têm actividades inibidoras da produção de TNF-α e sejam úteis como agentes terapêuticos para as doenças auto-imunes tais como artrite reumatóide, alergia e diabetes. Divulgação da Invenção
Os presentes inventores prepararam compostos tendo várias estruturas químicas e realizaram testes farmacológicos. Como resultado, os presentes inventores constataram que 1-[2-(1-adamantil)etil]-l-pentil-3-[3-(4-piridil)propil]ureia ou um seu sal exibe excelentes actividades inibidoras da produção de TNF-α para realizar a presente invenção. 2 5213 A presente invenção refere-se a 1-[2-(1-adamantil)etil]-l-pentil-3-[3-(4-piridil)propil]ureia ou um sal (em seguida referido por "o presente composto" desde que não hajam condições).
Este composto é representado pela fórmula seguinte.
0 presente composto é apropriado para constituir composições farmacêuticas e é um ingrediente activo de inibidores de produção de TNF-α que são úteis como agentes terapêuticos para doenças auto-imunes tais como artrite reumatóide, alergia e diabete.
Na presente invenção sais referem-se a quaisquer sais farmaceuticamente aceitáveis e são exemplificados por sais com um ácido inorgânico tais como ácido clorídrico, ácido nítrico, ácido sulfúrico ou ácido fosfórico, sais com um ácido orgânico tais como ácido acético, ácido fumárico, ácido maleico, ácido succínico ou ácido tartárico, sais com um metal alcalino ou um metal alcalino-terroso tais como sódio, potássio ou cálcio, e semelhantes. Sais de amónio quaternário dos compostos presentes também são incluídos nos sais na presente invenção. Além disso, quando existem isómeros geométricos ou isómeros ópticos nos presentes compostos, estes isómeros também estão incluídos no âmbito da 3 5213 presente invenção. Os presentes compostos podem estar na forma de hidrato e solvatos. 0 presente composto pode ser preparado através de vários processos. Um processo será descrito mais adiante nos Exemplos. 0 presente composto, que se encontra numa forma livre, pode ser convertido nos sais acima-mencionados pelo processo convencional.
Os efeitos inibidores da produção de TNF-α foram examinados para estudar a utilidade do presente composto. Serão descritos detalhes na secção de "teste Farmacológico" em baixo. Através do estudo de efeitos inibidores in vivo na libertação de TNF-α provocada por estimulação de lipopolissacáridos (LPS), o presente composto exibiu excelentes efeitos inibidores da produção de TNF-a.
Sabe-se que a produção de TNF-α está intimamente relacionada com a patogénese de doenças auto-imunes tais como artrite reumatóide, doença de Crohn e lúpus eritematoso sistémico, caquexia, doença infecciosa aguda, alergia, pirexia, anemia, diabete e semelhantes. Espera-se que os compostos que inibem a produção de TNF-α, tais como o presente composto sejam úteis para o tratamento destas diversas doenças. 0 presente composto pode ser administrado oralmente ou por via parentérica. Exemplos de formas de dosagem são comprimidos, cápsulas, grânulos, pós, injecções e semelhantes. 0 presente composto pode ser formulado em preparações pelos processos convencionais. Por exemplo, 4 5213 preparações orais tais como comprimidos, cápsulas, grânulos e pós podem ser produzidas por adição facultativa de um diluente tal como lactose, celulose cristalina, amido ou óleo vegetal; um lubrificante tal como estearato de magnésio ou talco; um ligante tal como hidroxipropilcelulose ou polivinil pirrolidona; um desintegrador tal como carboximetilcelulose de cálcio ou hidroxipropil-metilcelulose de baixa-substituição; um agente de revestimento, tal como hidroxipropilmetilcelulose, macrogol ou resina de silicone; ou um agente de formação de filme tal como filme de gelatina. A dosagem do presente composto pode ser adequadamente seleccionada de acordo com o sintoma, idade, forma de dosagem e semelhantes. No caso da preparação oral, o presente composto pode ser administrado de uma a várias vezes ao dia com uma dose diária de 0,1 a 5000 mg, de preferência 1 a 1000 mg.
Exemplos de preparações de intermediários para sintetizar o presente composto, exemplos de preparações e formulações do presente composto e resultados de teste farmacológico são mostrados em baixo. Estes exemplos não limitam o âmbito da invenção, mas pretende-se que tornem a invenção mais claramente compreensível.
[A] Preparação de Intermediários para sintetizar o presente composto
Preparação do Intermediário Exemplo 1
Cloridrato de 2-(1-Adamantil)-N-pentiletilamina (Intermediário n°. 1-1) 5 5213
Adicionou-se pentilamina (2,69 ml, 23,2 mmol), carbonato de potássio (2,14 g, 15,5 mmol) e iodeto de sódio (2,30 g, 15,3 mmol) a uma solução de 2 -(1- adamantil)etil metanossulfonato (2,07 g, 8,01 mmol) em etanol (45,8 ml), e a mistura foi submetida a refluxo durante 17 horas. A mistura reaccional foi concentrada sob pressão reduzida, e o concentrado foi diluído com clorofórmio (100 ml) . Isto foi lavado com uma solução aquosa de hidróxido de sódio 1 N (100 ml) e uma solução aquosa de cloreto de sódio saturada (100 ml) sucessivamente, e a camada orgânica foi seca sobre sulfato de magnésio. 0 solvente foi evaporado sob pressão reduzida, e o resíduo foi purificado através de cromatografia em coluna com gel de sílica. Adicionou-se uma solução 4 N de cloreto de hidrogénio em acetato de etilo (3,1 ml) a uma solução da forma livre resultando (1,52 g, 6,10 mmol) do composto do título em acetato de etilo (0,50 ml). 0 sólido precipitado foi lavado com acetato de etilo e filtrado para dar 1,33 g (60%) do composto do título.
IR(KBr): 2924, 2850, 2519, 1456 cm"1 pf: 263,0-264,5°C
Preparação de Intermediário Exemplo 2 4-(3-Aminopropil)piridina (Intermediário n°. 2-1)
Misturou-se N-[3 -(4-piridil)propil]ftalimida (67,1 g, 252 mmol) com metanol (504 ml) e hidrazina monohidrato (18,3 ml, 378 mmol), e a mistura foi submetida a refluxo durante três horas. Permitiu-se que a mistura reaccional estabilizasse, e em seguida filtrou-se uma matéria insolúvel, e o filtrado foi concentrado sob pressão reduzida. Adicionou-se clorofórmio (1 litro) e uma solução aquosa de hidróxido de sódio 4 N (500 ml) ao 6 5213 resíduo, as camadas foram separadas, e a camada orgânica foi seca sobre sulfato de sódio. A camada orgânica foi concentrada sob pressão reduzida e em seguida destilada sob pressão reduzida para dar 20,5 g (60%) do composto do título como matéria oleosa incolor. IR(puro): 3362, 2933, 1603 cm1 pe:/76,0-79,0oC/40 Pa [B] Preparação do Composto Presente
Exemplo 1 1-[2-(1-Adamantil)etil]-l-pentil-3-[3-(4-piridil)propil]ureia (Composto n°. 1-1)
Adicionou-se 1,1'-carbonildiimidazole (427 mg, 2,63 mmol) a uma solução de 4-(3-aminopropil)piridina (Intermediário n° . 2-1) (285 mg, 2,09 mmol) em tetrahidrofurano (10 ml) , e a mistura foi agitada à temperatura ambiente durante 20 minutos. Adicionou-se cloridrato de 2-(1-adamantil)-N-pentiletilamina (Intermediário n° . 1-1) (571 mg, 2,00 mmol) à mistura, e o todo foi submetido a refluxo durante uma hora. Diluiu-se a mistura reaccional com acetato de etilo (50 ml), lavou-se o todo com uma solução aquosa saturada de hidrogenocarbonato de sódio (50 ml) e um solução aquosa saturada de cloreto de sódio (50 ml) sucessivamente, e a camada orgânica foi seca sobre sulfato de magnésio. 0 solvente foi evaporado sob pressão reduzida, e o sólido precipitado foi lavado com diisopropil éter e filtrado para dar 606 mg (73%) do composto do título.
IR(KBr): 2900, 2845, 1618, 1534 cm"1 pf: 124,0-124,7°C 7 5213 [C] Formulação
Exemplos de formulação gerais de preparações orais e injecções usando o presente composto são mostrados abaixo. 1) Comprimido
Formulação 1 (em 100 mg) Presente composto 1 mg Lactose 66,4 mg Amido de milho 20mg Carboximetilcelulose de cálcio6 mg Hidroxipropilcelulose 4 mg Estearato de magnésio 0, 6 mg
Comprimidos de acordo com a formulação acima são revestidos com 2 mg/comprimido de um agente de revestimento (isto é um agente convencional de revestimento tal como hidroxipropilmetilcelulose, macrogol ou resina de silicone) para obter comprimidos revestidos desejados. (0 mesmo é aplicado a comprimidos abaixo mencionados.) Os comprimidos pretendidos podem ser obtidos alterando as quantidades do presente composto e os aditivos adequadamente. 2) Cápsula
Formulaçãol (em 150 mg)
Presente composto 5 mg
Lactose 145 mg
Podem obter-se as cápsulas pretendidas mudando a razão de mistura do presente composto para lactose adequadamente. 8 5213 3) Injecção
Formulaçãol (em 100 mg) 10-100 mg 90 mg
Presente composto Cloreto de sódio
Hidróxido de sódio Ácido clorídrico Água estéril purificada q.s. q.s. q.s.
Podem obter-se as injecções pretendidas mudando a razão de mistura do presente composto para aditivos adequadamente.
[D] Teste Farmacológico
Estudaram-se os efeitos inibidores na produção de TNF-α induzida por estimulação por lipopolissacárido (LPS) por testes in vivo de acordo com o processo de Tsuji et al. (Inflamm. res. 46 (1997) 193-198).
Como animais de teste usaram-se ratinhos fêmea (cinco por grupo), massa corporal de cerca de 200 g, cerca de oito semanas de idade. Dissolveram-se LPS de Salmonela em solução salina fisiológica para preparar uma solução de LPS (1 mg/ml). O presente composto foi dissolvido ou uniformemente suspendido numa solução de metilcelulose a 1% para dar preparação líquida da substância de teste. A solução de LPS acima-mencionada (0,5 ml/kg) foi administrada a uma pata do ratinho. Imediatamente após a administração de LPS, a preparação líquida da substância de teste (contendo 10 mg/kg) foi administrada oralmente. Duas horas após a administração de LPS, recolheu-se 9 5213 sangue da aorta abdominal e centrifugou-se a 4°C e 3000 rpm durante 10 minutos. Os níveis de TNF-α no plasma obtido foram medidos com um estojo de ELISA específico de TNF-α de ratinho. Não foi observado TNF-α no plasma quando comparado a um grupo ao qual não foi administrado LPS (controlo).
As taxas de inibição de produção de TNF-α das substâncias de teste foram determinadas pela equação seguinte.
Taxa de Inibição (%) = [(A-B)/A] x 100 A: nível de TNF-α no plasma no grupo ao qual não foi administrada substância de teste B: nível de TNF-α no plasma no grupo ao qual foi administrada substância de teste (Resultados)
Calculando as taxas de inibição de produção de TNF-a (%), o presente composto exibiu maiores taxas de inibição de produção, i.e. 92,1%.
Aplicação industrial
Os resultados do teste farmacológico mostram claramente que uma vez que o presente composto apresenta excelentes efeitos inibidores da produção de TNF-α, o 10 5213 presente composto pode ser aplicado a diversos usos médicos como agentes terapêuticos para doenças nas quais o TNF-α participa, por exemplo, doenças auto-imunes tais como artrite reumatóide, doença de Crohn, e lúpus eritematoso sistémico, caquexia, doença infecciosa aguda, alergia, pirexia, anemia, diabete e semelhantes.
Lisboa, 4 de Dezembro de 2007 11

Claims (6)

  1. 5213 REIVINDICAÇÕES 1. 1-[2-(1-adamantil)etil]-l-pentil-3-[3-(4 piridil)propil]ureia ou um sal do mesmo.
  2. 2. Composição farmacêutica que compreende o composto ou um seu sal, de acordo com a reivindicação 1, como ingrediente activo, e um aditivo farmacologicamente aceitável.
  3. 3. Agente terapêutico que inibe a produção de TNF-a, que compreende uma quantidade eficaz do composto ou um seu sal, de acordo com a reivindicação 1 como ingrediente activo e um aditivo farmacologicamente aceitável.
  4. 4. Agente terapêutico para doenças auto-imunes, que compreende o composto ou um seu sal, de acordo com a reivindicação 1, como ingrediente activo e um aditivo farmacologicamente aceitável.
  5. 5. Um anti-reumático que compreende uma quantidade eficaz do composto ou um seu sal, de acordo com a reivindicação 1, como um ingrediente activo e um aditivo farmacologicamente aceitável.
  6. 6. Agente terapêutico de acordo com a reivindicação 4, em que a doença auto-imune é artrite reumatóide, alergia ou diabetes. Lisboa, 4 de Dezembro de 2007 1
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