Patent ID: 6358952
Filing Date: 2002-03-19
Classification: A61K,A61P

Abstract:
A method of reducing toxicity associated with the administration of a therapeutically effective amount of a non-competitive thymidylate synthase inhibitor to a mammal, comprising: administering to said mammal a folate derivative selected from folic acid, 5-formyltetrahydrofolate, or 5-methyltetrahydrofolate in an amount effective to reduce said toxicity without blocking therapeutic effect of the non-competitive thymidylate synthase inhibitor, whereinthe non-competitive thymidylate synthase inhibitor is a benzoquinazoline derivative of formula (I) â€ƒor a salt thereof, wherein the dotted line represents a single or double bond, R1 is C1-4 alkyl or amino optionally substituted by a C1-4 alkyl, C1-5 alkanoyl or benzyl group; R2, R3, R4 and R5 are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O)nR8 wherein n is the integer 0, 1 or 2 and R8 is halo or is C1-4 alkyl or a group NR9R10 wherein R9 and R10 are both hydrogen, a group NR11R12 wherein R11 and R12 are the same or different and each is hydrogen or C1-4 alkyl, a group OR13 wherein R13 is hydrogen or C1-4 alkyl optionally substituted by halo, a C1-4 aliphatic group optionally substituted by a group OR14 or NR14R15 where R14 and R15 are the same or different and each is hydrogen or C1-4 alkyl; or two of R2 to R5 are linked together to form a benzo group, or one of R2 to R5 is a group â€”Xâ€”Yâ€”R16 wherein X is CH2, NR17, CO or S(O)m and m is 0, 1 or 2 and R17 is hydrogen or a C1-4 aliphatic group and Y is CH2, NR17â€²,O, or S(O)mâ€² wherein mâ€² is 0,1 or 2 and R17â€² is hydrogen or a C1-4 aliphatic group provided that X and Y are only the same when each is CH2, or â€”Xâ€”Yâ€” is a group â€”Oâ€”, â€”NR17â€”, â€”CH&boxH;CHâ€” or â€”N&boxH;Nâ€” wherein R17 is as hereinbefore defined, R16 is a C1-4 aliphatic group or a 5- or 6-membered aromatic ring optionally substituted by a group R18 at a position at least one carbon atom removed from that linked to Y, the 5- or 6-membered ring being optionally further substituted by a halo atom; and R18 is halo, C1-4 alkoxy, nitro, nitrile, C1-4 alkyl optionally substituted by halo, halo or a group COR19 wherein R19 is hydroxy, C1-4 alkoxy or C1-6 alkyl optionally substituted by one or two carboxyl groups or C1-12 esters thereof or R19 is a group NR20R21 wherein R20 and R21 are the same or different and each is hydrogen or C1-4 alkyl optionally substituted by hydroxy or R19 is an amino acid group or an ester thereof in which the first nitrogen atom of the amino acid group may be linked to the 5- or 6-membered aromatic ring to form a further 5- or 6-membered heterocyclic ring or R19 is an C2-3 alkylene group linked to the 5- or 6-membered aromatic ring to form a further 5- or 6-membered ring; R6 and R7 are the same or different and each is hydrogen, C1-4 alkyl optionally substituted by hydroxy or C1-4 alkoxy, or methyl substituted by bromo, or together form a benzo group; provided that at least one of R2 to R7 is other than hydrogen and that R4 is not methoxy when R1 is hydroxy or methyl.