BRPI0815331B1 - Composição farmacêutica compreendendo um derivado de benzeno glucopiranosila substituída,bem como seu uso - Google Patents
Composição farmacêutica compreendendo um derivado de benzeno glucopiranosila substituída,bem como seu uso Download PDFInfo
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- BRPI0815331B1 BRPI0815331B1 BRPI0815331-0A BRPI0815331A BRPI0815331B1 BR PI0815331 B1 BRPI0815331 B1 BR PI0815331B1 BR PI0815331 A BRPI0815331 A BR PI0815331A BR PI0815331 B1 BRPI0815331 B1 BR PI0815331B1
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- ILTRPILDWNCOMQ-UHFFFAOYSA-N CC#CC[n]1c(N(CCC2)CC2N)nc(N(C)C(N2Cc3nc(cccc4)c4cn3)=O)c1C2=O Chemical compound CC#CC[n]1c(N(CCC2)CC2N)nc(N(C)C(N2Cc3nc(cccc4)c4cn3)=O)c1C2=O ILTRPILDWNCOMQ-UHFFFAOYSA-N 0.000 description 1
- ZSBOMTDTBDDKMP-UHFFFAOYSA-N CN(C(C=C(N1Cc2ccccc2C#N)N(CCC2)CC2N)=O)C1=O Chemical compound CN(C(C=C(N1Cc2ccccc2C#N)N(CCC2)CC2N)=O)C1=O ZSBOMTDTBDDKMP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
- - para prevenir, reduzir a evolução, retardar, ou tratar um distúrbio metabólico;
- - para melhorar o controle glicêmico e/ou reduzir a glicose plasmática de jejum, a glicose plasmática pós-prandial e/ou a hemoglobina glicosilada HbA1c;
- - para prevenir, reduzir, retardar ou reverter a evolução de tolerância à glicose prejudicada, glicose sanguínea de jejum prejudicada, resistência à insulina e/ou da síndrome metabólica associada ao diabetes melito tipo 2;
- - para prevenir, reduzir a evolução, retardar ou tratar de uma condição ou distúrbio selecionado do grupo que consiste em complicações do diabetes melito;
- - para reduzir o peso corporal ou prevenir o aumento do peso corporal ou facilitar a redução do peso corporal;
- - para prevenir ou tratar a degeneração das células beta pancreáticas e/ou melhorar e/ou restaurar a funcionalidade das células beta pancreáticas e/ou restaurar a funcionalidade da secreção de insulina pancreática;
- - para prevenir, reduzir, retardar ou tratar doenças ou condições atribuídas a uma acumulação anormal de gordura hepática;
- - manter e/ou melhorar a sensibilidade à insulina e/ou para tratar ou prevenir a hiperinsulinemia e/ou resistência à insulina,
- (1) Wright, E.M. (2001) Am. J. Renal Physiol. 280, F10-F18;
- (2) Wright, E.M. et al. (2004) Pflugers Arch. 447(5):510-8;
- (3) You, G. et al. (1995) J. Biol. Chem. 270 (49) 29365-29371;
- (4) Pajor AM, Wright EM (1992) J Biol. Chem. 267(6):3557-3560;
- (5) Zhou, L. et al. (2003) J. Cell. Biochem. 90:339-346;
- (6) Diez-Sampedro, A. et al. (2003) Proc. Natl. Acad. Sci. USA 100(20), 11753-11758;
- (7) Tabatabai, N.M. (2003) Kidney Int. 64, 1320-1330;
- (8) Curtis, R.A.J. (2003) US Patent Appl. 2003/0054453;
- (9) Bruss,M. & Bonisch,H. (2001) Cloning and functional characterization of a new human sugar transporter in kidney (Genbank Acc. No. AJ305237);
- (10) Rossetti, L. Et al. (987) J. Clin. Invest. 79, 1510-1515;
- (11) Gouvea, W.L. (1989) Kidney Int. 35(4):1041-1048.
- sitagliptina (MK-0431) que tem a fórmula estrutural A abaixo é (3R)-3-amino-1-[3-(trifluormetil)-5,6,7,8-tetra-hidro-5H-[1,2,4]triazol[4,3-a]pirazin-7-il]-4-(2,4,5-trifluorfenil)butan-1-ona, também conhecida como (2R)-4-oxo-4-[3-(trifluormetil)-5,6-di-hidro[1,2,4]triazol[4,3-a]pirazin-7(8H)-il]-1-(2,4,5-trifluorfenil)butan-2-amina,Em uma modalidade, a sitagliptina está na forma de seu sal de di-hidrogenofosfato, isto é, fosfato de sitagliptina. Em uma outra modalidade, o fosfato de sitagliptina está na forma de um anidrato ou mono-hidrato cristalino. Uma classe desta modalidade refere-se ao mono-hidrato de fosfato de sitagliptina. A base livre da sitagliptina e sais farmaceuticamente aceitáveis da mesma estão descritos na Patente US N° 6.699.871 e no Exemplo 7 do documento WO 03/004498. O mono-hidrato de fosfato de sitagliptina cristalino está descrito no documento WO 2005/003135 e no documento WO 2007/050485. Para detalhes, por exemplo sobre um processo para produzir ou formular este composto ou um sal do mesmo, é feito portanto referência a esses documentos. Uma formulação de comprimido para a sitagliptina encontra-se comercialmente disponível sob o nome comercial Januvia®.
Para detalhes, por exemplo sobre um processo para produzir ou formular este composto ou um sal do mesmo, é feito portanto referência a esses documentos. Uma formulação de comprimido para vildagliptina está comercialmente disponível sob o nome comercial Galvus®.
Esses compostos e métodos para sua preparação estão descritos no documento WO 03/037327. O sal de mesilato do primeiro composto assim como polimorfos cristalinos do mesmo estão descritos no documento WO 2006/100181. O sal de fumarato do último composto assim como polimorfos cristalinos do mesmo estão descritos no documento WO 2007/071576. Esses compostos podem ser formulados como uma composição farmacêutica da maneira descrita no documento WO 2007/017423. Para detalhes, por exemplo sobre um processo para produzir, formular ou usar esses compostos ou um sal dos mesmos, é feito portanto referência a esses documentos.
Este composto e métodos para sua preparação estão descritos nos documentos WO 2005/116014 e US 7291618. Para detalhes, por e-xemplo sobre o processo de fabricação, formulação e uso deste composto ou um sal do mesmo, é feito portanto referência a esses documentos.
glucopiranosila substituída de fórmula (I)onde R1 representa Cl, metila ou ciano; R2 representa H, metila, metóxi ou hidróxi e R3 representa etila, ciclopropila, etinila, etóxi, (R)-tetra-hidrofuran-3-ilóxi ou (S)-tetra-hidrofuran-3-ilóxi,seja, em uma primeira modalidade (modalidade A), em combinação com
um inibidor de DPP IV de fórmula (I)ou de fórmula (II) ou de fórmula (III) ou de fórmula (IV) onde R1 representa ([1,5]naftiridin-2-il)metila, (quinazolin-2-il)metila, (quinoxalin-6-il)metila, (4-metil-quinazolin-2-il)metila, 2-ciano-benzila, (3-ciano-quinolin-2-il)metila, (3-ciano-piridin-2-il)metila, (4-metil-pirimidin-2-il)metila, ou (4,6-dimetil-pirimidin-2-il)metil e R2 representa 3-(R)-amino-piperidin-1-ila, (2-amino-2-metil-propil)-metilamino ou (2-(S)-amino-propil)-metilamino, ou seu sal farmaceuticamente aceitável;
(2S)-1-{[2-(5-Metil-2-fenil-oxazol-4-il)-etilamino]-acetil}-pirrolidina-2-carbonitrila, (2S)-1-{[1,1,-Dimetil-3-(4-piridin-3-il-imidazol-1-il)-propilamino]-acetil}-pirrolidina-2-carbonitrila,
(S)-1-((2S,3S,11 bS)-2-Amino-9,10-dimetóxi-1,3,4,7,11 b-hexa-hidro-2H-pirido[2,1-a]isoquinolin-3-il)-4-fluormetil-pirrolidin-2-ona,
(3,3-Difluorpirrolidin-1-il)-((2S,4S)-4-(4-(pirimidin-2-il)piperazin-1-il)pirrolidin-2-il)metanona,
(1((3S,4S)-4-amino-1-(4-(3,3-difluorpirrolidin-1-il)-1,3,5-triazin-2-il)pirrolidin-3-il)-5,5-difluorpiperidin-2-ona,
(2S,4S)-1 -{2-[(3S,1 R)-3-(1 H-1,2,4-Triazol-1 -ilmetil)ciclopentilamino]-acetil}-4-fluorpirrolidina-2-carbonitrila, e
(R)-2-[6-(3-Amino-piperidin-1-il)-3-metil-2,4-dioxo-3,4-di-hidro-2H-pirimidin-1-ilmetil]-4-flúor-benzonitriia,
ou um sal farmaceuticamente aceitável das mesmas.
- - prevenir, reduzir a evolução, retardar ou tratar um distúrbio metabólico selecionado do grupo que consiste em diabetes melito tipo 1, diabetes melito tipo 2, tolerância à glicose prejudicada (IGT), glicose sanguínea de jejum prejudicada (IFG), hiperglicemia, hiperglicemia pós-prandial, excesso de peso, obesidade e síndrome metabólica; ou
- - melhorar o controle glicêmico e/ou reduzir a glicose plasmática de jejum, a glicose plasmática pós-prandial e/ou a hemoglobina glicosilada HbA1c; ou
- - prevenir, reduzir, retardar ou reverter a evolução de tolerância à glicose prejudicada (IGT), glicose sanguínea de jejum prejudicada (IFG), resistência à insulina e/ou da síndrome metabólica associada ao diabetes melito tipo 2; ou
- - prevenir, reduzir a evolução, retardar ou tratar uma condição ou distúrbio selecionado do grupo que consiste em complicações do diabetes melito tais como cataratas e doenças microvasculares e macrovascula-res, tais como nefropatia, retinopatia, neuropatia, isquemia tecidual, arteriosclerose, infarto do miocárdio, acidente vascular cerebral e doença arterial oclusiva periférica; ou
- - reduzir o peso corporal ou prevenir o aumento do peso corporal ou facilitar a redução do peso corporal; ou
- - prevenir, reduzir, retardar ou tratar a degeneração das células beta pancreáticas e/ou a diminuição da funcionalidade das células beta pancreáticas e/ou melhorar e/ou restaurar a funcionalidade das células beta pancreáticas e/ou restaurar a funcionalidade da secreção de insulina pancreática; ou
- - prevenir, reduzir, retardar ou tratar doenças ou condições a-tribuídas a uma acumulação anormal de gordura hepática; ou
- - manter e/ou melhorar a sensibilidade à insulina e/ou tratar ou prevenir a hiperinsulinemia e/ou resistência à insulina;
- - prevenir, reduzir a evolução, retardar ou tratar um distúrbio metabólico selecionado do grupo que consiste em diabetes melito tipo 1, diabetes melito tipo 2, tolerância à glicose prejudicada (IGT), glicose sanguínea de jejum prejudicada (IFG), hiperglicemia, hiperglicemia pós-prandial, excesso de peso, obesidade e síndrome metabólica; ou
- - melhorar o controle glicêmico e/ou reduzir a glicose plasmática de jejum, a glicose plasmática pós-prandial e/ou a hemoglobina glicosilada HbA1c; ou
- - prevenir, reduzir, retardar ou reverter a evolução de tolerância à glicose prejudicada (IGT), glicose sanguínea de jejum prejudicada (IFG), resistência à insulina e/ou da síndrome metabólica associada ao dia-betes melito tipo 2; ou
- - prevenir, reduzir a evolução, retardar ou tratar uma condição ou distúrbio selecionado do grupo que consiste em complicações do diabetes melito tais como cataratas e doenças microvasculares e macrovasculares, tais como nefropatia, retinopatia, neuropatia, isquemia tecidual, arteriosclerose, infarto do miocárdio, acidente vascular cerebral e doença arterial oclusiva periférica; ou
- - reduzir o peso corporal ou prevenir o aumento do peso corporal ou facilitar a redução do peso corporal; ou
- - prevenir, reduzir, retardar ou tratar a degeneração das células beta pancreáticas e/ou a diminuição da funcionalidade das células beta pancreáticas e/ou melhorar e/ou restaurar a funcionalidade das células beta pancreáticas e/ou restaurar a funcionalidade da secreção de insulina pancreática; ou
- - prevenir, reduzir, retardar ou tratar doenças ou condições a-tribuídas a uma acumulação anormal de gordura hepática; ou
- - manter e/ou melhorar a sensibilidade à insulina e/ou tratar ou prevenir a hiperinsulinemia e/ou resistência à insulina;
HOMA-IR = [insulina sérica de jejum (μU/mL)] x [glicose plasmática de jejum (mmol/L)/22,5]
- 1. obesidade abdominal, definida como circunferência da cintura > 40 polegadas ou 102 cm em homens, e > 35 polegadas ou 94 cm em mulheres; ou com respeito à etnia japonesa ou pacientes japoneses, definida como circunferência da cintura > 85 cm em homens e > 90 cm em mulheres;
- 2. triglicerídeos: = 150 mg/dL
- 3. colesterol HDL < 40 mg/dL em homens
- 4. pressão sanguínea > 130/85 mm Hg (SBP > 130 ou DBP > 85)
- 5. glicose sanguínea de jejum = 110 mg/dL
De preferência R1 representa cloro ou ciano; em particular cloro.
De preferência R2 representa H.
De preferência R3 representa etila, ciclopropila, etinila, (R)-tetra-hidrofuran-3-ilóxi ou (S)-tetra-hidrofuran-3-i\óxi. Ainda mais preferivelmente R3 representa ciclopropila, etinila, (R)-tetra-hidrofuran-3-ilóxi ou (S)-tetra-hidrofuran-3-ilóxi.
- (1) 6-(4-Etilbenzil)-4-(β-D-glucopiranos-1-il)-2-metóxi-benzonitrila
- (2) 2-(4-Etilbenzil)-4-(β-D-glucopiranos-1-il)-5-metóxi-benzonitrila
- (3) 1 -Ciano-2-(4-etilbenzil)-4-(β-D-glucopiranos-1 -il)-5-metil-benzeno
- (4) 2-(4-Etilbenzil)-4-(β-D-glucopiranos-1-il)-5-hidróxi-benzonitrila
- (5) 2-(4-Etilbenzil)-4-(β-D-glucopiranos-1 -il)-benzonitrila
- (6) 2-(4-Ciclopropil-benzil)-4-(β -D-glucopiranos-1 -il)-benzonitrila
- (7) 1 -cloro-4-(β-D-glucopiranos-1 -il)-2-(4-etinil-benzil)-benzeno
- (8) 1 -cloro-4-(β-D-glucopiranos-1 -il)-2-[4-((R)-tetra-hidrofuran-3-ilóxl)-benzil]-benzeno
- (9) 1 -cloro-4-(β-D-glucopiranos-1 -il)-2-[4-{(S)-tetra-hidrofuran-3-ilóxl)-benzil]-benzeno
- (10) 1-Metil-2-[4-(R)-tetra-hidrofuran-3-ilóxi)-benzil]-4-(3-D-glucopiranos-1-il)-benzeno
- (11) 1-Metil-2-[4-(S)-tetra-hidrofuran-3-ilóxi)-benzil]-4-(β-D-glucopiranos-1-il)-benzeno
(A): 1 -[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8-(3-(R)-amino-piperidin-1-il)-xantina (conforme WO 2004/018468, exemplo 2(142)):(B): 1 -[([1,5]naftiridin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8-((R)- 3-amino-piperidin-1-il)-xantina (conforme WO 2004/018468, exemplo 2(252)): (C):1-[(quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1 -il)-xantina (conforme WO 2004/018468, exemplo 2(80)): (D): 2-((R)-3-amino-piperidin-1 -il)-3-(but-2-inil)-5-(4-metil- quinazolin-2-ilmetil)-3,5-di-hidro-imidazo[4,5-d]piridazin-4-ona (conforme WO 2004/050658, exemplo 136): (E): 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8- [(2-amino-2-metil-propil)-metilamino]-xantina (conforme WO 2006/029769, exemplo 2(1)): (F): 1 -[(3-ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8-((R)-3-amino-piperidin-1-il)-xantina (conforme WO 2005/085246, exemplo 1(30)): (G): 1 -(2-ciano-benzil)-3-metil-7-(2-butin-1 -il)-8-((R)-3-amino- piperidin-1-il)-xantina (conforme WO 2005/085246, exemplo 1(39)): (H): 1 -[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8- [(S)-(2-amino-propil)-metilamino]-xantina (conforme WO 2006/029769, e-xemplo 2(4)): (I): 1 -[(3-ciano-piridin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8-((R)-3-amino-piperidin-1-il)-xantina (conforme WO 2005/085246, exemplo 1(52)): (J): 1 -[(4-metil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8-((R)-3-amino-piperidin-1-il)-xantina (conforme WO 2005/085246, exemplo 1(81)): (K): 1-[(4,6-dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)- 8-((R)-3-amino-piperidin-1-il)-xantina (conforme WO 2005/085246, exemplo 1(82)): (L): 1 -[(quinoxalin-6-il)metil]-3-metil-7-(2-butin-1 -il)-8-((R)-3-amino-piperidin-1-il)-xantina (conforme WO 2005/085246, exemplo 1(83)):
Tabela 1
- (a) uma concentração de glicose sanguínea de jejum ou de glicose sérica maior que 110 mg/dL, em particular maior que 125 mg/dL;
- (b) um nível de glicose plasmática pós-prandial maior ou igual a 140 mg/dL;
- (c) um valor de HbA1c maior ou igual a 6,5 %, em particular maior ou igual a 8,0 %.
- - resistência à insulina,
- - hiperinsulinemia,
- - pré-diabetes,
- - diabetes melito tipo 2, em particular diabetes melito tipo 2tardio,
- - diabetes melito tipo 1.
- (a) obesidade (incluindo obesidade classe I, II e/ou III), obesidade visceral e/ou obesidade abdominal,
- (b) nível sanguíneo de triglicerídeos ≥150 mg/dL,
- (c) nível sanguíneo de colesterol HDL < 40 mg/dL em mulheres e < 50 mg/dL em homens,
- (d) uma pressão sanguínea sistólica >130 mm Hg e uma pressão sanguínea diastólica ≥ 85 mm Hg,
- (e) um nível de glicose sanguínea de jejum ≥110 mg/dL.
- (a) um primeiro recipiente contendo uma forma de dosagem compreendendo o derivado de benzeno glucopiranosila substituída e pelo menos um veículo farmaceuticamente aceitável, e
- (b) um segundo recipiente contendo uma forma de dosagem compreendendo o inibidor de DPP IV e pelo menos um veículo farmaceuticamente aceitável.
as composições farmacêuticas e os métodos de acordo com esta invenção podem ser testados em animais geneticamente hiperinsulinêmi-cos ou diabéticos como camundongos db/db, camundongos ob/ob, ratos Zucker obesos (fa/fa) ou ratos Zucker obesos diabéticos (ZDF). Além disso, eles podem ser testados em animais com diabetes induzido experimentalmente como ratos HanWistar ou Sprague Dawley pré-tratados com estreptozotocina.
fBu ter-butil
dba dibenzilidenoacetona
DMF dimetilformamida
DMSOdimetil sulfóxido
NMP N-metil-2-pirrolidona
THF tetra-hidrofurano
Preparação dos compostos de partida:
Exemplo I
Rendimento: 27,2 g (96% da teoria)
Espectro de massa (ESI-): m/z = 339/341 (Br) [M-H]-
O composto a seguir pode ser obtido de maneira análoga ao Exemplo I:
(1) (2-Bromo-5-iodo-4-metóxi-fenil)-(4-etil-fenil)-metanonaEspectro de massa (ESI+): m/z = 445/447 (Br) [M+H]+
O material de partida, (2-bromo-4-metóxi-fenil)-(4-etil-fenil)-metanona, é preparado da maneira descrita nos Exemplos II e III.
Exemplo II
Rendimento: 30,8 g (97% da teoria)
Espectro de massa (ESI+): m/z = 415/417 (Br) [M+H]+
Os compostos a seguir podem ser obtidos de maneira análoga ao Exemplo II:
(1) (2-Bromo-5-iodo-4-metil-fenil)-(4-etil-fenil)-metanonaEspectro de massa (ESI+): m/z = 429/431 (Br) [M+H]+ (2) (2-Bromo-4-flúor-fenil)-(4-etil-fenil)-metanona Espectro de massa (ESI+): m/z = 307/309 (Br) [M+H]+
Exemplo III
Rendimento: 33,7 g (75% da teoria)
Espectro de massa (ESI+): m/z = 319/321 (Br) [M+H]+
Exemplo IV
Rendimento: 21 g (68% da teoria)
Espectro de massa (ESI+): m/z = 418/420 (Br) [M+NH4]+
Os compostos a seguir podem ser obtidos de maneira análoga ao Exemplo IV:
(1) 4-Bromo-5-(4-etilbenzil)-1 -iodo-2-metil-benzenoEspectro de massa (ESI+): m/z = 432/434 (Br) [M+NH4]+ (2) 4-Bromo-5-(4-etilbenzil)-1 -iodo-2-metóxi-benzenoEspectro de massa (ESI+): m/z = 448/450 (Br) [M+NH4]+
Exemplo V
Rendimento: 10,0 g (58% da teoria)
Espectro de massa (ESI+): m/z = 330/332 (Br) [M+H]+
Exemplo VI
Rendimento: 41,0 g (82% da teoria)
Exemplo VIl
Rendimento: 38,0 g (79% da teoria)
Exemplo VIII
Rendimento: 7,8 g (93% da teoria)
Os compostos a seguir podem ser obtidos de maneira análoga ao Exemplo VIII:
(1) 1 -Bromo-2-(4-etilbenzil)-4-(1 -metóxi-D-glucopiranos-1 -il)-benzenoEspectro de massa (ESI-): m/z = 511/513 (Br) [M+HCOO]-
(2) 1 -Bromo-2-(4-etilbenzil)-4-(1 -metóxi-D-glucopiranos-1 -il)-5-metil-benzeno
(3) 1 -Bromo-2-(4-etilbenzil)-4-(1 -metóxi-D-glucopiranos-1 -il)-5-metóxi-benzenoExemplo IX
Rendimento: 0,5 g (7% da teoria)
Exemplo X
Rendimento: 6,78 g (60% da teoria)
Espectro de massa (ESI+): m/z = 610/612 (Br) [M+NH4]+
Os compostos a seguir podem ser obtidos de maneira análoga ao Exemplo X:
(1) 1 -Bromo-2-(4-etilbenzil)-4-(2,3,4,6-tetra-O-acetil-β-D-glucopiranos-1 -il)-benzenoEspectro de massa (ESI+): m/z = 622/624 [M+NH4]+
(2) 1-Bromo-2-(4-etilbenzil)-4-(2,3,4,6-tetra-O-acetil-β-D-glucopiranos-1-il)-5-metóxi-benzenoEspectro de massa (ESI+): m/z = 652/654 (Br) [M+NH4]+
(3) 6-(4-Etilbenzil)-4-(2,3,4,6-tetra-O-acetil-β-D-glucopiranos-1-il)-2-metóxi-benzonitrilaEspectro de massa (ESI+): m/z = 599 [M+NH4]+
A redução é conduzida em 6-(4-etilbenzil)-4-(1-metóxi-D-glucopiranos-1-il)-2-metóxi-benzonitrila por analogia com o procedimento descrito acima.
(4) 1 -Bromo-2-(4-etilbenzil)-4-(β-D-glucopiranos-1 -il)-5-metil-benzenoEspectro de massa (ESI+): m/z = 468/470 (Br) [M+NH4]+
Este composto é isolado com os grupos hidroxila livres depois de terminada a redução de acordo com o procedimento descrito acima.
Exemplo XI
Rendimento: 4,10 g (84% da teoria)
Espectro de massa (ESI+): m/z = 557 [M+NH4]+
Alternativamente, o composto também pode ser obtido empregando-se os procedimentos descritos nos Exemplos XII e 3
Exemplo XII
Rendimento: 1,1 g (75% da teoria)
Espectro de massa (ESI+): m/z = 583 [M+NH4]+
Este composto também pode ser preparado usando-se os procedimentos descritos para os Exemplos XI e 3.
Exemplo XIII
Rendimento: 0,52 g (75% da teoria)
Espectro de massa (ESI+): m/z = 543/545 (Br) [M+NH4]+
Exemplo XIV
Rendimento: 2,92 g (60% da teoria)
Espectro de massa (ESI-): m/z = 207 (Cl) [M+HCOO]-
Preparação dos compostos finais:
Exemplo (1): 6-(4-Etilbenzil)-4-(β-D-glucopiranos-1-il)-2-metóxi-benzonitrila
Rendimento: 65 mg (57% da teoria)
Espectro de massa (ESI+): m/z = 431 [M+NH4]+
O composto a seguir é obtido de maneira análoga ao Exemplo1:
Exemplo (2): 2-(4-Etilbenzil)-4-(β-D-glucopiranos-1 -il)-5-metóxi-benzonitrilaEspectro de massa (ESI+): m/z = 431 [M+NH4]+
Exemplo (3): 1 -Ciano-2-(4-etilbenzil)-4-(β-D-glucopiranos-1 -il)-5-metil-benzeno
Rendimento: 0,30 g (85% da teoria)
Espectro de massa (ESI+): m/z = 415 [M+NH4]+
Exemplo (4): 2-(4-Etilbenzil)-4-(β-D-qlucopiranos-1-il)-5-hidróxi-benzonitrila
Rendimento: 0,25 g (46 % da teoria)
Espectro de massa (ESI+): m/z = 398 [M-H]"
Exemplo (5): 2-(4-Etilbenzil)-4-(β-D-glucopiranos-1-il)-benzoni-trila
Rendimento: 0,51 g (81% da teoria)
Espectro de massa (ESI+): m/z = 401 [M+NH4]+
Exemplo (6): 2-(4-Ciclopropil-benzil)-4-(β-D-glucopiranos-1-il)- benzonitrila
Rendimento: 0,91 g (76% da teoria)
Espectro de massa (ESI+): m/z = 413 [M+NH4]+
Exemplo (7): 1 -cloro-4-(β-D-glucopiranos-1 -il)-2-(4-etinil-benzil)- benzenoO composto (7) pode ser vantajosamente preparado de acordo com o exemplo 12 descrito no documento WO 2005/092877.
Exemplo 1: ampola seca contendo 75 mg de substância ativa por 10 ml Composição:
Substância ativa 75,0 mg
Manitol 50,0 mg
água para injeção ad 10,0 ml
Preparação:
A substância ativa e manitol são dissolvidos em água. Depois de acondicionada, a solução é liofilizada. Para produzir uma solução pronta para uso, o produto é dissolvido em água para injeção.
Substância ativa 35,0 mg
Manitol 100,0 mg
água para injeção ad 2,0 ml
Preparação:
A substância ativa e manitol são dissolvidos em água. Depois de acondicionada, a solução é liofilizada.
Para produzir uma solução pronta para uso, o produto é dissolvido em água para injeção.
Composição:Preparação:
(1), (2) e (3) são misturados e granulados com uma solução aquosa de (4). (5) é adicionado ao material granulado seco. A partir desta mistura são prensados comprimidos biplanares, facetados em ambos os lados e com um entalhe em um lado.
Diâmetro dos comprimidos: 9 mm.
Preparação: (1), (2) e (3) são misturados e granulados com uma solução aquosa de (4). (5) é adicionado ao material granulado seco. A partir desta mistura são prensados comprimidos biplanares, facetados em ambos os lados e com um entalhe em um lado.
Diâmetro dos comprimidos: 12 mm.
Composição:Preparação:
(1) é triturado com (3). Esta trituração é adicionada à mistura de (2) e (4) com agitação vigorosa. Esta mistura em pó é acondicionada em cápsulas de gelatina de tamanho 3 em uma máquina de encher cápsulas.
Claims (10)
- Composição farmacêutica, caracterizada pelo fato que compreende o derivado de benzeno glicopiranosil-substituído 1-cloro-4-(β-D-glucopiranos-1-il)-2-[4-((S)-tetra-hidrofuran-3-ilóxi)-benzil]-benzeno em combinação com um inibidor de DPP IV 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1 -il)-8-(3-(R)-amino-piperidin-1 -il)-xantina, ou sal farmaceuticamente aceitável do mesmo.
- Composição farmacêutica de acordo com a reivindicação 1, caracterizada pelo fato de que a composição é adequada para uso combinado ou simultâneo ou sequencial de derivado de benzeno glicopiranosil-substituído e de inibidor DPP IV.
- Composição farmacêutica de acordo com a reivindicação 1 ou 2, caracterizada pelo fato de que o derivado de benzeno glicopiranosil-substituído e o inibidor de DPP IV estão presentes em forma de dosagem única.
- Composição farmacêutica de acordo com qualquer uma das reivindicações 1 a 3, caracterizada pelo fato de que o derivado de benzeno glicopiranosil-substituído e o inibidor de DPP IV estão presentes em uma forma de dosagem separada.
- Composição farmacêutica, de acordo com uma das reivindicações 1 a 4, caracterizada pelo fato de que compreende uma quantidade de 5 a 50 mg do derivado de benzeno glicopiranosil-substituído.
- Composição farmacêutica, de acordo com a reivindicação 5, caracterizada pelo fato de que compreende uma quantidade de 5 mg, 10 mg, 15 mg, 20 mg, 25 mg ou 50 mg do derivado de benzeno glicopiranosil-substituído.
- Composição farmacêutica, de acordo com uma das reivindicações 1 a 6, caracterizada pelo fato de que compreende uma quantidade de 0,5 a 10 mg do inibidor de DPP IV.
- Composição farmacêutica, de acordo com a reivindicação 7, caracterizada pelo fato de que compreende uma quantidade de 1 mg, 2,5 mg ou 5 mg do inibidor DPP IV.
- Composição farmacêutica, de acordo com qualquer uma das reivindicações 1 a 4, caracterizada pelo fato de que compreende uma
quantidade de 5 a 50 mg do derivado de benzeno glicopiranosil-substituído e uma quantidade de 0,5 a 10 mg do inibidor de DPP IV. - Composição farmacêutica, de acordo com qualquer uma das reivindicações 1 a 9, caracterizada pelo fato de que a composição farmacêutica é formulada para administração oral na forma sólida.
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