Patent ID: 6323208
Filing Date: 2001-11-27
Classification: A61P,C07D

Abstract:
An atropisomer of the formula ##STR15##wherein either each of V, X, Y and Z is carbon or one of them is nitrogen and each of the others is carbon;each of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is hydrogen, halogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, cyano, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylthio or --C.dbd.O)--O--(C.sub.1 -C.sub.6)alkyl, with the proviso that: (a) R.sup.1 can not be the same as R.sup.5 when each of V, X and Z is carbon; (b) at least one of R.sup.1 and R.sup.5 must be other than hydrogen; and (c) when V, X, Y or Z is nitrogen, then R.sup.5, R.sup.4, R.sup.3 or R.sup.2, respectively, is absent;ring A' is a fused 5 membered heteroaromatic ring which, taken together with the carbon atoms common to both rings of the bicyclic system, has the formula ##STR16##wherein one of the ring atoms ""F"", ""G"" and ""J"" is sulfur and each of the others is carbon;wherein said fused heteroaromatic ring optionally may be independently substituted on any of the carbon atoms with hydrogen, (C.sub.1 -C.sub.6)alkyl, halogen, trifluoromethyl, amino-(CH.sub.2).sub.n, (C.sub.1 -C.sub.6)alkylamino-(CH.sub.2).sub.n --, di(C.sub.1 -C.sub.6)alkyl-amino-(CH.sub.2).sub.n --, (C.sub.1 -C.sub.6)alkoxy, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-O--(C.sub.1 -C.sub.6)alkyl-, --CN, (C.sub.1 -C.sub.6)alkyl-CO--O--(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkyl-O--CO--O--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO--O--, hydroxy, --NO.sub.2, R.sup.15 --C(.dbd.O)--, R.sup.15 --O--C(.dbd.O)--, di(C.sub.1 -C.sub.6)alkyl-N--C(.dbd.O)--, (C.sub.3 -C.sub.7)cycloalkyl, or R.sup.15 --NH--C(.dbd.O)--, or phenyl optionally substituted with halo, (C.sub.1 -C.sub.6)alkyl, --CN, or --CF.sub.3 ;R.sup.6 is phenyl of the formula Ph.sup.1 or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula ##STR17##wherein ""N"" is nitrogen; wherein each of said ring positions ""K"", ""L"" and ""M"" is carbon or nitrogen, with the proviso that only one of ""K"", ""L"" or ""M"" is nitrogen;wherein said five membered heterocycle has the formula ##STR18##wherein each of said ring positions ""P,"" ""Q"" and ""T"" is carbon, nitrogen, oxygen or sulfur; with the proviso that only one of ""P,"" ""Q"" or ""T"" can be oxygen or sulfur and at least one of ""P,"" ""Q"" or ""T"" must be a heteroatom;wherein said Ph.sup.1 is a group of the formula ##STR19##wherein each R.sup.15 is, independently, hydrogen or (C.sub.1 -C.sub.6)alkyl;each of R.sup.9, R.sup.10 and R.sup.11 is hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted with one to three halogen atoms, halo, CF.sub.3, (C.sub.1 -C.sub.6)alkoxy optionally substituted with one to three halogen atoms, (C.sub.1 -C.sub.6)alkylthio, R.sup.16 O--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-NH--(CH.sub.2).sub.p --, di(C.sub.1 -C.sub.6)alkyl-N--(CH.sub.2).sub.p --, (C.sub.3 -C.sub.7)cycloalkyl-NH--(CH.sub.2).sub.p --, H.sub.2 N--(C.dbd.O)--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-HN--(C.dbd.O)--(CH.sub.2).sub.p --, di(C.sub.1 -C.sub.6)alkyl-N--(C.dbd.O)--(CH.sub.2).sub.p --, (C.sub.3 -C.sub.7)cycloalkyl-NH--(C.dbd.O)--(CH.sub.2).sub.p --, R.sup.16 O--(C.dbd.O)--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--O--(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-O--(O.dbd.C)--O--(C.sub.1 -C.sub.6)-alkyl-, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--O--, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--NH--(CH.sub.2).sub.p --, H(O.dbd.C)--NH--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--N--[(C.sub.1 -C.sub.6)alkyl](CH.sub.2).sub.p --, H(O.dbd.C)--N--[(C.sub.1 -C.sub.6)alkyl](CH.sub.2).sub.p --, hydroxy, H--C(.dbd.O)--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-C(.dbd.O)--, (C.sub.1 -C.sub.6)alkyl-O--C(.dbd.O)--, R.sup.15 --(CH.sub.2).sub.p --O--C(.dbd.O)--, amino-(CH.sub.2).sub.p --, hydroxy-(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-O--(C.sub.1 -C.sub.6)alkyl- or cyano;each of R.sup.7, R.sup.12 and R.sup.13 is hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted with one to three halogen atoms, halogen, CF.sub.3, (C.sub.1 -C.sub.6)alkoxy optionally substituted with one to three halogen atoms, (C.sub.1 -C.sub.6)alkylthio, R.sup.16 O--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-NH--(CH.sub.2).sub.p --, di(C.sub.1 -C.sub.6)alkyl-N--(CH.sub.2).sub.p --, (C.sub.3 -C.sub.7)cycloalkyl-NH--(CH.sub.2).sub.p --, H.sub.2 N--(C.dbd.O)--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-HN--(C.dbd.O)--(CH.sub.2).sub.p --, di(C.sub.1 -C.sub.6)alkyl-N--(C.dbd.O)--(CH.sub.2).sub.p --, (C.sub.3 -C.sub.7)cycloalkyl-NH--(C.dbd.O)--(CH.sub.2).sub.p --, R.sup.16 O--(C.dbd.O)--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--O--(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-O--(O.dbd.C)--O--(C.sub.1 -C.sub.6)-alkyl-, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--O--, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--NH--(CH.sub.2).sub.p --, H(O.dbd.C)--NH--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-(O.dbd.C)--N--[(C.sub.1 -C.sub.6)alkyl](CH.sub.2).sub.p, H(O.dbd.C)--N--[(C.sub.1 -C.sub.6)alkyl](CH.sub.2).sub.p --, hydroxy, H--C(.dbd.O)--(CH.sub.2).sub.p --, (C.sub.1 -C.sub.6)alkyl-C(.dbd.O)--, (C.sub.1 -C.sub.6)alkyl-O--C(.dbd.O)--, R.sup.15 --(CH.sub.2).sub.p --O--C(.dbd.O)--, amino-(CH.sub.2).sub.p --, hydroxy-(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-O--(C.sub.1 -C.sub.6)alkyl-, --CHO or cyano;each R.sup.14 is, hydrogen, halogen, cyano or trifluoromethyl,each R.sup.16 is, hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-(C.dbd.O)--, (C.sub.1 -C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.1 -C.sub.6)alkyl-NH--(C.dbd.O)--, or di(C.sub.1 -C.sub.6)alkyl-N--(C.dbd.O)--;each R.sup.8 is hydrogen, cyano, (C.sub.1 -C.sub.6)alkyl, halogen, trifluoromethyl, --CHO or (C.sub.1 -C.sub.6)alkoxy;n is an integer from zero to 3; andp is an integer from zero to 3;with the proviso that when R.sup.11 is hydrogen, one of R.sup.13 and R.sup.14 is other than hydrogen;and with the proviso that when ""G"" is sulfur, R.sup.6 is not said 6-membered heterocycle;or a pharmaceutically-acceptable salt of such an atropisomer.