Patent ID: 6362336
Filing Date: 2002-03-26
Classification: A61P,C07D

Abstract:
A process for the preparation of a quinazoline derivative of formula I, or a salt thereof: wherein:Y1 represents â€”Oâ€”, â€”Sâ€”, â€”CH2â€”, â€”SOâ€”, â€”SO2â€”, â€”NR5COâ€”,â€”CONR6â€”, â€”SO2NR7â€”, â€”NR8SO2â€”or  â€”NR9â€”, wherein R5, R6, R7, R8 and R9 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or NR10R11, wherein R10 and R11, which may be the same or different, each represents hydrogen or C1-3alkyl; R2 represents hydrogen, hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro; m is an integer from 1 to 5; R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R4 is selected from one of the following eight groups: 1) X1, wherein X1 represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from 0, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, amino, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4aminoalkyl, C1-4alkylamino, C1-4hydroxyalkoxy, carboxy, cyano, â€”CONR12R13 and â€”NR14COR15, wherein R12, R13, R14 and R15, which may be the same or different, each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl; 2) C1-5alkylX1, wherein X1 is as defined hereinbefore; 3) C2-5alkenylX1, wherein X1 is as defined hereinbefore; 4) C2-5alkynylX1, wherein X1 is as defined hereinbefore; 5) C1-5alkylY2X1, wherein Y2 represents â€”Oâ€”, â€”Sâ€”, â€”SOâ€”, â€”SO2â€”, â€”OCOâ€”, â€”NR16COâ€”, CONR17â€”, â€”SO2NR18â€”, â€”NR19SO2â€” or â€”NR20â€”, wherein R16, R17, R18, R19 and R20 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl, and X1 is as defined hereinbefore; 6) C2-5alkenylY3X1, wherein Y3 represents â€”Oâ€”, â€”Sâ€”, â€”SOâ€”, â€”SO2â€”, â€”OCOâ€”, â€”NR21COâ€”, â€”CONR22â€”, â€”SO2NR23â€”, â€”NR24SO2â€” or â€”NR25â€”, wherein R21, R22, R23, R24, and R25 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and X1 is as defined hereinbefore; 7) C2-5alkynylY4X1, wherein Y4 represents â€”Oâ€”, â€”Sâ€”, â€”SOâ€”, â€”SO2â€”, â€”OCOâ€”, â€”NR26COâ€”, â€”CONR27â€”, â€”SO2NR28â€”, â€”NR29SO2â€” or â€”NR30â€”, wherein R26, R27, R28, R29 and R30 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl, and X1 is as defined hereinbefore; and 8) C1-3alkylY5C1-3alkylX1, wherein Y5 represents â€”Oâ€”, â€”Sâ€”, â€”SOâ€”, â€”SO2â€”, â€”NR31COâ€”, â€”CONR32â€”, â€”SO2NR33â€”, â€”NR34SO2â€” or â€”NR35â€”, wherein R31, R32, R33, R34 R35 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl, and X1 is as defined hereinbefore; Z represents â€”NHâ€”, â€”Oâ€”, â€”Sâ€”, or â€”CH2â€”; with the proviso that where R4 is selected from one of the groups 1), 2), and 5) above and X1 is unsubstituted phenyl or substituted phenyl with 1 to 2 substituents selected from halogeno, C1-4alkyl and C1-4alkoxy, then m is an integer from 3 to 5 and/or Z is â€”Oâ€”, Sâ€”, or â€”CH2â€”; which process comprises:(a) the reaction of a compound of the formula III: â€ƒwherein R1, R2, R4 and Y1 are as defined above and L1 is a displaceable group, with a compound of the formula IV: â€ƒwherein Z, R3 and m are as defined above, whereby to obtain compounds of the formula I and salts thereof; (b) for the preparation of compounds of formula I and salts thereof in which the group of formula IIb: â€ƒrepresents a phenyl group carrying one or more hydroxy groups, the deprotection of a compound of formula V: â€ƒwherein Y1, m, R1, R2, R3, R4 and Z are as defined above, P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that mâˆ’p1 is equal to the number of R3 substituents which are not protected hydroxy; (c) for the preparation of those compounds of formula I and salts thereof wherein the substituent Y1 is â€”Oâ€”, â€”Sâ€” or â€”NR9â€”, the reaction, of a compound of the formula VI: â€ƒwherein m, Y1, R1, R2, R3 and Z are as defined above, with a compound of formula VII: R4â€”L1â€ƒâ€ƒ(VII) â€ƒwherein R4 and L1 are as defined above; (d) the reaction of a compound of the formula VIII: â€ƒwherein R1, R2, R3, Z, L1 and m are as defined above, with a compound of the formula IX: R4â€”Y1â€”Hâ€ƒâ€ƒ(IX) â€ƒwherein R4 and Y1 are as defined above; (e) for the preparation of compounds of formula I and salts thereof wherein R4 is C1-5alkylX2, wherein X2 is selected from one of the following three groups: 1) X1 as defined above; 2) Y7X1, wherein Y1 represents â€”Oâ€”, â€”Sâ€”, â€”SO2â€”, â€”NR47COâ€”, â€”NR48SO2â€” or â€”NR49â€” (wherein R47, R48 and R49 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and X1 as defined above; and 3) Y8C1-5alkylY5X1 wherein Y8 represents â€”Oâ€”, â€”Sâ€”, â€”SO2â€”, â€”NR50COâ€”, â€”NR51SO2â€” or â€”NR52â€” (wherein R50, R51 and R52 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and Y5 and X1 are as defined above; â€ƒthe reaction of a compound of the formula X: â€ƒwherein Y1, R1, R2, R3, Z, L1 and m are as defined above, and R53 is C1-5alkyl, with a compound of the formula XI: X2â€”Hâ€ƒâ€ƒ(XI) â€ƒwherein X2 is as defined above, to give a compound of the formula I; (f) for the preparation of those compounds of formula I and salts thereof, wherein the substituent R1 is represented by NR10R11 (where one or both of R10 and R11 are C1-3alkyl), the reaction of compounds of formula I wherein the substituent R1 is an amino group with an alkylating agent; (g) for the preparation of those compounds of formula I and salts thereof wherein one or more of the substituents R1, R2 or R3 is an amino group, the reduction of a corresponding compound of formula I wherein the substituent(s) at the corresponding position(s) of the quinazoline and/or phenyl ring is/are a nitro group(s); and when a pharmaceutically acceptable salt of a quinazoline derivative of formula I is required, reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt.