Patent ID: 6319915
Filing Date: 2001-11-20
Classification: A61K

Abstract:
A method of treating cancer sensitive to compounds of the following formula, in mammals in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a compound of the formula: ##STR11##or a pharmaceutically acceptable salt, or hydrate thereof, wherein:R.sup.1 is a group having an acidic proton, particularly --CO.sub.2 H, --CONHSO.sub.2 R.sup.8, --CONR.sup.8 (CH.sub.2)CO.sub.2 H, --SO.sub.2 H, --PO.sub.3 H.sub.2, ##STR12##R.sup.2 is H or R.sup.1, or R.sup.1 and R.sup.2 together with the phenyl ring form ##STR13##R.sup.3 and R.sup.4 are independently selected from hydrogen, (C.sub.1 -C.sub.10)alkyl, phenyl, and a 4 to 10 membred hetrocyclic group or R.sup.3 and R.sup.4 taken together with the two carbons to which they are attached form phenyl, which is optionally substituted by one or more R.sup.5 groups;R.sup.5 is thienyl, pyridyl, furyl, or pyrimidyl, halogen, (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.6)alkoxy, optionally substituted with from one to three fluorine atoms, (C.sub.3 -C.sub.10) aryl, phenyl, --(CH.sub.2).sub.t phenyl, --(CH.sub.2).sub.t -(4 to 10 membered heterocyclic group), nitro, cyano, amino, --NH(C.sub.1 -C.sub.6)alkyl, --N((C.sub.1 -C.sub.8)alkyl).sub.2, --S(C.sub.1 -C.sub.8)alkyl, --SO(C.sub.1 -C.sub.8)alkyl, --C(O)(C.sub.1 -C.sub.8)alkyl, --CO(O)(C.sub.1 -C.sub.8)alkyl, wherein said phenyl, aryl or heterocycle moiety may be optionally substituted with one or two substituents independently selected from halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, nitro, cyano, amino and trifluoromethyl;W is OH or NR.sup.6 R.sup.7 ;R.sup.6 and R.sup.7 are independently selected from H, (C.sub.1 -C.sub.8)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, or R.sup.6 and R.sup.7 taken together form a six-membered saturated ring containing 5 carbon atoms and one nitrogen atom, one or more of said carbon atoms being optionally substituted with one or more substituents independently selected from (C.sub.1 -C.sub.3)alkyl;R.sup.8 is H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, --(CH.sub.2).sub.t (C.sub.6 -C.sub.10 aryl), or --(CH.sub.2).sub.t (4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally including 1 or 2 hetero moieties selected from O, S and --N(R.sup.6)-- with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R.sup.8 groups being optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms in said 4 to 10 membered heterocyclic group of R.sup.8 being optionally substituted by an oxo (.dbd.O) moiety; the --(CH.sub.2).sub.t -- moieties of R.sup.8 optionally including a carbon-carbon double or triple bond when t is an integer from two to five; R.sup.8 groups being optionally substituted by one to five R.sup.9 groups;R.sup.9 is each independently selected from C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --OR.sup.10, --C(O)R.sup.11, --C(O)OR.sup.10, --NR.sup.11 C(O)OR.sup.10, --OC(O)R.sup.10, --NR.sup.11 SO.sub.2 R.sup.10, --SO.sub.2 NR.sup.10 OR.sup.11, --NR.sup.11 C(O)R.sup.10, --C(O)NR.sup.10 R.sup.11, --NR.sup.10 R.sup.11, --S(O).sub.j R.sup.12, --SO.sub.3 H, --NR.sup.10 (CR.sup.11 R.sup.12).sub.t OR.sup.11, --(CH.sub.2).sub.t (C.sub.6 -C.sub.10 aryl), --SO.sub.2 (CH.sub.2).sub.t (C.sub.6 -C.sub.10 aryl), --S(CH.sub.2).sub.t (C.sub.6 -C.sub.10 aryl), --O(CH.sub.2).sub.t (C.sub.6 -C.sub.10 aryl), --(CH.sub.2).sub.t (4 to 10 membered heterocyclic group), and --(CR.sup.11 R.sup.12).sub.m OR.sup.11, said alkyl group optionally containing one or two hetero moieties selected from O, S and --N(R.sup.8)-- with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; aryl and heterocyclic moieties of R.sup.9 being optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms of the heterocyclic moieties of R.sup.9 being optionally substituted by an oxo (.dbd.O) moiety; and the alkyl, aryl and heterocyclic moieties of R.sup.9 groups being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --NR.sup.11 SO.sub.2 R.sup.10, --SO.sub.2 NR.sup.10 R.sup.11, --C(O)R.sup.10, --C(O)OR.sup.10, --OC(O)R.sup.10, --NR.sup.11 C(O)R.sup.10, --C(O)NR.sup.10 R.sup.11, --NR.sup.10 R.sup.11, --(CR.sup.11 R.sup.12).sub.m OR.sup.11, --OR.sup.10 and R.sup.10 ;R.sup.10 is each independently selected from H, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.t (C.sub.6 -C.sub.10 aryl), and --(CH.sub.2).sub.t (4 to 10 membered heterocyclic), said alkyl group optionally including one or two hetero moieties selected from O, S and --N(R.sup.6)-- with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R.sup.10 groups being optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4 to 10 membered heterocyclic group; the foregoing moieties of R.sup.10, with the exception of H, being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --C(O)R.sup.11, --C(O)OR.sup.11, --CO(O)R.sup.11, --NR.sup.11 C(O)R.sup.12, --C(O)NR.sup.11 R.sup.12, --NR.sup.11 R.sup.12, hydroxy, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy;R.sup.11 and R.sup.12 are each independently H or C.sub.1 -C.sub.6 alkyl;X, Y and Z are each independently selected from O, S, CH, CHR.sup.13, SO, SO.sub.2 and NR.sup.13 ;R.sup.13 is H, (C.sub.3 -C.sub.8)cycloalkyl, phenyl, (C.sub.7 -C.sub.8)phenylalkyl, or a 4 to 11 membered heterocyclic group optionally substituted with one or more substituents selected from halogen, hydroxy, (C.sub.1 -C.sup.8)alkyl and (C.sub.1 -C.sub.8)alkoxy;m is an integer ranging from one to five;t is an integer ranging from zero to five; andj is an integer ranging from zero to two.