NMI-377
Chemical Name: 2-[2-(2,6-Dichlorophenylamino)phenyl]acetic acid 3-[N-methyl-N-[1-(nitrososulfanyl)cyclohexylmethyl]amino]propyl ester
项目整合开发状态: Preclinical
项目研究机构: NitroMed (Originator)
合成路线:Treatment of cyclohexanecarboxaldehyde (I) with sulfur monochloride produced the dimeric disulfide (II).After condensation of (II) with 3-amino-1-propanol (III),reduction with NaBH4 afforded diamine (IV).Subsequent N-methylation of (IV) to give (VI) was achieved by condensation with formaldehyde,followed by NaBH4 reduction of the resulting oxazine (V).Reductive cleavage of the disulfide group of (VI) using LiAlH4 provided thiol (VII).Optionally,nitrosation of the sulfhydryl group of (VII) by means of tert-butyl nitrite gave rise to the nitrosothio derivative (VIII).Further coupling of this compound with diclofenac (IX) in the presence of DCC and DMAP furnished the title ester.Alternatively,the title compound was prepared by esterification of mercapto alcohol (VII) with diclofenac,followed by S-nitrosation of the resulting ester (X).
📌 参考资料/链接：
参考文献标题:NMI-377,a nitric oxide-donating diclofenac derivative with gastroprotective properties
文献作者:Bandarage,U.K.; et al.
参考来源:217th ACS Natl Meet (March 21 1999,Anaheim) 1999,Abst MEDI 81
📄 详细内容
合成路线:Treatment of cyclohexanecarboxaldehyde (I) with sulfur monochloride produced the dimeric disulfide (II).After condensation of (II) with 3-amino-1-propanol (III),reduction with NaBH4 afforded diamine (IV).Subsequent N-methylation of (IV) to give (VI) was achieved by condensation with formaldehyde,followed by NaBH4 reduction of the resulting oxazine (V).Reductive cleavage of the disulfide group of (VI) using LiAlH4 provided thiol (VII).Optionally,nitrosation of the sulfhydryl group of (VII) by means of tert-butyl nitrite gave rise to the nitrosothio derivative (VIII).Further coupling of this compound with diclofenac (IX) in the presence of DCC and DMAP furnished the title ester.Alternatively,the title compound was prepared by esterification of mercapto alcohol (VII) with diclofenac,followed by S-nitrosation of the resulting ester (X).
参考文献标题:Nitrosothiol esters of diclofonecac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs
文献作者:Bandarage,U.K.; Chen,L.; Fang,X.; Garvey,D.S.; Glavin,A.; Janero,D.R.; Letts,L.G.; Mercer,G.J.; Saha,J.K.; Schroeder,J.D.; Shumway,M.J.; Tam,S.W.
参考来源:J Med Chem 2000,43(21),4005