Patent FR-2778406-A1 (FR)
Title: Alpha-cetoamides for treating viral infections especially hepatitis C, hepatitis G and human GB
Inventor: HURST DAVID NIGEL
IPC: A61K31/16
Filed: 1999-05-04
Abstract: alpha -Cetoamide derivatives (I) are new.- DETAILED DESCRIPTION - alpha -Cetoamide derivatives of formula (I) and their salts are new.- R1 = lower alkyl (optionally substituted by halo, cyano, (lower alkyl)-thio-, aryl-(lower alkyl)-thio-, aryl or heteroaryl), lower alkenyl or lower alkynyl; - R2 = lower alkyl (optionally substituted by OH, carboxy, aryl, aminocarbonyl, lower cycloalkyl, aryl-(lower alkoxy)-aryl or heteroaryl); - R3, R6, R9 = H or lower alkyl; - R2 + R3 = di- or trimethylene (optionally substituted by OH); - R4 = lower alkyl (optionally substituted by OH, lower cycloalkyl, carboxy, aryl, aryl-(lower alkoxy)-aryl, aryl-(lower alkoxy), aryl-(lower alkoxy)-carbonyl, (lower alkyl)-thio, cyano-(lower alkyl)-thio, aryl-(lower alkyl)-thio, heteroaryl, arylsulfonylguanidino, acetamidothio, (lower alkyl)-carbonylamino or formamido), lower alkenyl, aryl or lower cycloalkyl; - R5 = lower alkyl (optionally substituted by OH, (lower alkyl)-thio, aryl, aryl-(lower alkyl)-thio, cyano-(lower alkyl)-thio, lower cycloalkyl, aryl-(lower alkoxy)-carbonyl, aryl-(lower alkoxy)-aryl, arylsulfonylguanidino, aryl-(lower alkoxy), heteroaryl or formamido), aryl or lower cycloalkyl; - R7 = H, lower alkyl (optionally substituted by carboxy, OH, aryl, lower cycloalkyl, heteroaryl, nitroguanidino, aryl-(lower alkoxy), aryl-(lower alkyl)-thio, aryl-(lower alkoxy)-carbonyl, arylsulfonylguanidino, acetamidothio, (lower alkyl)-sulfonyl, heteroaryl, aryl-(lower alkoxy)-aryl, aryl-(lower alkoxy)-heteroaryl, (lower alkyl)-carbonyloxy, (lower alkyl)-carbonylamino, aryl-(lower alkyl)-heteroaryl, (lower alkenyl)-oxycarbonyl, (lower alkyl)-thio or formamido), lower cycloalkyl or aryl; - R8 = R2, lower cycloalkyl, lower alkyl (substituted by mercapto, (lower alkyl)-sulfonyl, aryl-(lower alkoxy), arylheteroaryl, nitroguanidino, acetamidothio, arylsulfonylguanidino, aryl-(lower alkoxy)-(loweralkyl)-heteroaryl, (lower alkyl)-sulfinyl, (lower alkyl)-aminocarbonyl, (lower alkyl)-thio, formamido) or aryl; - R10 = R11-C(O)- or (lower alkyl)-sulfonyl; - R11 = lower alkyl (optionally substituted by carboxy, aryl, heteroaryl, arylaminocarbonyl, heteroarylthio, heteroarylcarbonyl, lower alkoxy, arylcarbonyl, (lower alkoxy)-(lower alkoxy)-(lower alkoxy), arylcarbonylamino, (lower alkyl)-carbonyloxy, aryloxy, di(lower alkyl)-amino, aryl-(lower alkoxy)-carbonyl amino, heterocyclyl, (lower alkyl)-thio, (lower alkoxy)-carbonyl, di(lower alkyl)-aminocarbonyl, halo, (lower alkyl)-carbonylamino, lower cycloalkyl, arylsulfonylarylaminocarbonyloxy, (lower alkyl)-sulfonyl, (lower alkyl)-carbonyl, hydroxyhalo or di(lower alkyl)-phosphinyl), lower alkoxy (substituted by arylcarbonyl or aryl), heteroaryl, hydroxyfluorenyl, heterocyclyl, lower alkynyl, lower cycloalkyl, lower alkenyl (optionally substituted by (lower alkyl)-carbonylamino, aryl) or lower cycloalkenyl; and - R12, R13 = H, lower alkyl, aryl (optionally substituted by aryl, diaryl, lower cycloalkyl, (lower alkyl)-aminocarbonyl or (lower alkyl)-thio), heteroaryl, lower alkoxy or OH.- INDEPENDENT CLAIMS are also included for: - (1) the preparation of (I); - (2) the addition salt of an amine with an acid, of formula (II); - (3) the alpha -hydroxyamide of formula (IV); and - (4) a medicament comprising (I).- ACTIVITY - Virucide; hepatotropic; antiinflammatroy. Details of the activity of (I) are described in WO9822496. 3 (RS)-((N-(N-(N-(N-(N-(3-carboxypropionyl)-L- alpha -asparyl)-L- alpha -glutamyl)-2-methyl-L-phenylalanyl)-3-methyl-L-valyl)-L-leucyl)amino) -5,5,5-trifluoro-N-(1(S)-2-naphthyl)ethyl)-2-oxovaleramide (Ia) has an IC50 of 0.004 micro mol/l.- MECHANISM OF ACTION - Inhibitors of viral protease