Patent ID: 6689881
Filing Date: 2004-02-10
Classification: A61P,C07D

Abstract:
A process for the preparation of a diazepinoindolone of formula in which:A is hydrogen, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, nitro, cyano or NR1R2; R1 and R2 are independently hydrogen or C1-C4 alkyl or form, together with the nitrogen atom to which they are bonded, a ring having 4 or 5 carbon atoms; B is hydrogen or C1-C4 alkyl; Z is CH and Z1 and Z2 are together CH or N; or Z is N and Z1 and Z2 are CH; X1 and X2 are independently hydrogen, C1-C4 alkyl, â€”(CH2)jâ€”OR3, halogen, cyano, â€”Oâ€”(C1-C6 alkyl), â€”C(&boxH;O)R4, â€”C(&boxH;O)OR5, â€”C(&boxH;O)NR6R7, or R3, R4 and R5 are independently hydrogen, C1-C6 alkyl, benzyl, phenethyl or â€”Q1â€”Q2; R6 is hydrogen or C1-C4 alkyl; R7 is hydrogen, C1-C4 alkyl, â€”CHRAâ€”C(&boxH;O)OM2 or â€”Q3â€”Q4; R8 is hydrogen, C1-C4 alkyl or â€”Q5â€”Q6; RA is a natural &agr;-amino acid residue, the carbon atom to which it is bonded being able to have either the S configuration or the R configuration; Q1 is â€”(CH2)kâ€”(CHOH)mâ€”(CH2)pâ€”; Q2 is hydroxyl, â€”Oâ€”(C1-C6 alkyl), â€”OC(&boxH;O)â€”(C1-C6 alkyl) or 4-morpholinyl; Q3 and Q5 are independently a bond, â€”CH2â€”, â€”(CH2)2â€” or â€”(CH2)3â€”; Q4 is â€”NM3M4 or 4-morpholinyl; Q6 is â€”M5 or â€”OM6; M1, M2, M3, M4, M5 and M6 are independently hydrogen or C1-C4 alkyl; j is 1, 2 or 3; k is 1, 2 or 3; m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3, with the proviso that, if m>0, then p>0; which comprises the intramolecular cyclization at a temperature not higher than 40Â° C. of a product of formula in which A, Z, Z1, Z2, B, X1 and X2 have the meaning defined above and R is C1-C4 alkyl, in the presence of a weak Lewis acid catalyst selected from scandium trifluoromethanesulphonate; aluminium trifluoromethanesulphonate; lanthanide; silicon, magnesium, tin(II), copper(II), zinc or silver trifluoromethanesulphonates; dimethoxydicyclopentadienyltitanium(IV); dicyclopentadienyltitanium(IV); bis(trifluoromethanesulphonate); iron(III), aluminium or zinc acetylacetonate; zinc diacetonate; dimthoxymagnesium; triisopropoxyaluminium; tetrabutoxytitanium(IV); tetraisopropoxytitanium(IV); trimethylboron; triethylaluminium, diethylzinc; triisobutylaluminium; tetrabutyltin(IV); triphenylboron; triphenylantimony; zinc, tin(II), antimony, titanium, scandium, indium, gallium or mercury(II) halides.