PD-189659, CI-1044-药物合成数据库

【药物名称】PD-189659, CI-1044

化学结构式(Chemical Structure):

参考文献No.	34633
标题:	Diazepino-indoles as phosphodiesterase IV inhibitors
作者:	Pascal, Y.; Jacobelli, H.; Calvet, A.; Payne, A.; Dahl, S.G. (Institut de Recherche Jouveinal)
来源:	EP 0828742; US 5972927; WO 9736905

合成路线图解说明: Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.

参考文献No.	599896
标题:	Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent, selective phosphodiesterase type 4 inhibitors
作者:	Burnouf, C.; Auclair, E.; Avenel, N.; Bertin, B.; Bigot, C.; Calvet, A.; Chan, K.; Durand, C.; Fasquelle, V.; Feru, F.; Gilbertsen, R.B.; Jacobelli, H.; Kebsi, A.; Lallier, E.; Maignel, J.; Martin, B.; Milano, S.; Ouagued, M.; Pascal, Y.; et al.
来源:	J Med Chem 2000,43(25),4850

合成路线图解说明: Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.