Patent ID: 6277880
Filing Date: 2001-08-21
Classification: A61K,A61P,B82Y,C07C,C07D

Abstract:
A pharmaceutical composition comprising as prodrug ingredient a compound of Formula I ##STR51##or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable diluent or carrier, wherein:R.sup.1 and R.sup.2 each independently is I, Br, Cl, OSO.sub.2 Me, wherein Me is meithyl, and OSO.sub.2 phenyl, wherein phenyl is substituted with 1 or 2 substituents in the 2 and/or 4 positions independently selected from C.sub.1-4 alkyl, halogen, --CN or --NO.sub.2 ;R.sup.1a and R.sup.2a each independently is hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl;R.sup.3 and R.sup.4 each independently is hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl;R.sup.5a, R.sup.5b, R.sup.5c and R.sup.5d each independently is hydrogen, C.sub.1-4 alkyl, optionally comprising one double bond or one triple bond, C.sub.1-4 alkoxy, halogen, cyano, --NH.sub.2, --CONR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 are as defined below, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2 or C.sub.2-5 alkanoyl; orR.sup.5a and R.sup.5b together isa) C.sub.4 alkylene, optionally having one double bond;b) C.sub.3 alkylene; orc) --CH.dbd.CH--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 --CH.dbd.CH--, each optionally substituted with 1, 2, 3 or 4 substituents, said substituents each independently selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, cyano, nitro, C.sub.2-5 alkanoyl and --CONR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 are as defined below;X is O or NH;Y is O;Z is --V--W where V is --CH.sub.2 --T-- in which T is --CH.sub.2 --, --O--, --S--, --(SO)-- or --(SO.sub.2)--, provided that when V has sulphur or oxygen as its second atom W is other than --COOH, and said group V optionally further carrics one or two substituents Q.sup.1 and Q.sup.2 on a carbon,wherein Q.sup.1 and Q.sup.2 each independently is C.sub.1-4 alkyl or halogen or, when Q.sup.1 and Q.sup.2 are bonded to adjacent carbon atoms, Q.sup.1 and Q.sup.2 together optionally are a C.sub.3 -C.sub.4 alkylene radical, optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C.sub.1-4 alkyl and halogen; andW is:(1) --COOH;(2) --(C.dbd.O)--O--R.sup.6, wherein R.sup.6 is a C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or aryl group, wherein aryl is phenyl;(3) --(C.dbd.O)--NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 each independently is hydrogen or a C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, aryl, heteroaryl linked to N via a carbon atom, or C.sub.7-9 aralkyl group, whereinaryl is phenyl;heteroaryl is a 5 or 6 membered ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and sulphur; andthe aryl moiety per se, the heteroaryl moiety and the aryl moiety of the aralkyl group are optionally substituted on carbon with 1-4 substituents selected from the group consisting of --COOH, --OH, --NH.sub.2, --CH.sub.2 --NH.sub.2, --(CH.sub.2).sub.1-4 -COOH, tetrazol-5-yl and --SO.sub.3 H, and the alkyl moiety optionally carries a methyl group;(4) --SO.sub.2 NHR.sup.9 wherein R.sup.9 is as defined above for R.sup.7, or, additionally, --CF.sub.3, --CH.sub.2 CF.sub.3 or aryl as defined above;(5) SO.sub.3 R.sup.10 in which R.sup.10 is H, C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl;(6) PO.sub.3 R.sup.10 R.sup.10, wherein the R.sup.10 radicals, which are the same or different, and are as defined in 5 above;(7) a tetrazol-5-yl group;(8) --CONH--SO.sub.2 R.sup.11 in which R.sup.11 is(a) C.sub.3-7 cycloalkyl;(b) C.sub.1-6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl as defined in 8c below, C.sup.1-4.sup.- alkyl, CF.sub.3 or halogen; or(c) perfluoro-C.sub.1-6 alkyl;wherein aryl is phenyl or phenyl having 1-5 substituents, wherein the substituents are selected from the group consisting of halogen, --NO.sub.2, --CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, --NH.sub.2, --NHCOCH.sub.3, --CONH.sub.2, --OCH.sub.2 COOH, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --NHCOOC.sub.1-4 alkyl, --OH, --COOH, --CN and --COOC.sub.1-4 alkyl; or(9) --M-Het, wherein M is S, SO or SO.sub.2, and Het is a 5 or 6 membered heterocyclic aromatic ring linked to M via a carbon atom of the aromatic ring, said aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N and S, said aromatic ring optionally being substituted on carbon atoms of the ring with 1, 2, 3 or 4 substituents selected from the group consisting of --OH, --SH, --CN, --CF.sub.3, --NH.sub.2 and halogen.