Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones

A compound of Formula I

• wherein X is CZ where Z is H, C.sub.1 -C.sub.5 alkyl, amino (-NH.sub.2) or a halogen atom;
• Y is -(CH.sub.2).sub.n -(4-morpholine) optionally substituted with one or two members selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo or trifluoromethyl;
• R.sub.5, R.sub.6, R.sub.7 and R.sub.8, being the same or different, are selected from the group consisting of hydrogen, C.sub.1 -C.sub.8 alkyl, -(CH.sub.2).sub.n phenyl, -(CH.sub.2).sub.n naphthyl, -(CH.sub.2).sub.n pyridinyl, -(CH.sub.2).sub.q NR.sub.9 R.sub.10, -CH.dbd.CH-phenyl, -CH.sub.2 -CH.dbd.CH.sub.2, -CH.dbd.CH-CH.sub.3, -CH.dbd.CH.sub.2, -O-CH.sub.2 -CH.dbd.CH.sub.2, -C.ident.C-phenyl, -O(CH.sub.2).sub.p (N-methylpiperdin-3-yl), -O-(CH.sub.2).sub.p NR.sub.9 R.sub.10,-O-(CH.sub.2).sub.p -4-(C.sub.1 -C.sub.4 alkyl)-1-piperazine, -O-(CH.sub.2).sub.p (1-piperidinyl), -O-(CH.sub.2).sub.p (1-pyrrolidinyl), -O-(CH.sub.2).sub.2 -4-methyl-1-piperazine, -O-CH.sub.2 CH(OCH.sub.3).sub.2, -O-(CH.sub.2).sub.p OR.sub.15, -O-(CH.sub.2).sub.p -O-(CH.sub.2).sub.p -OR.sub.15, -O-(CH.sub.2).sub.p -S-R.sub.15, -O-(CH.sub.2).sub.p -O-(CH.sub.2).sub.p NR.sub.9 R.sub.10,-O-(CH.sub.2).sub.p -S-(CH.sub.2).sub.p NR.sub.9 R.sub.10, -O-(CH.sub.2).sub.p -S-(CH.sub.2).sub.p -OR.sub.15, -O-(CH.sub.2).sub.p -S(O)-R.sub.15, -O-(CH.sub.2).sub.p -S(O.sub.2)-R.sub.15, -O-(CH.sub.2).sub.p -S(O)-(CH.sub.2).sub.p NR.sub.9 R.sub.10,-O-(CH.sub.2).sub.p -S(O)-(CH.sub.2).sub.p -OR.sub.15, -O-(CH.sub.2).sub.p -S(O.sub.2) -(CH.sub.2).sub.p NR.sub.9 R.sub.10,-O-(CH.sub.2).sub.p -S(O.sub.2)-(CH.sub.2).sub.p -OR.sub.15, -O-(CH.sub.2).sub.p -›4-›(CH.sub.2).sub.p OR.sub.15 !-1-piperazine!, -O-(CH.sub.2).sub.p -›4-(CH)(phenyl).sub.2 -1-piperazine!, -O-(CH.sub.2).sub.p -›4-(CH.sub.2).sub.q phenyl-1-piperazine !, -O-(CH.sub.2).sub.p -›4-(CH.sub.2).sub.q pyridinyl-1-piperazine!, -O-(CH.sub.2).sub.p -›4-(NR.sub.9 R.sub.10 substituted pyridinyl)-1-piperazine!, -O-(CH.sub.2).sub.p -(OH substituted 1-piperidine, -O-(CH.sub.2).sub.p -1-pyrrolidin-2-one, -(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.n R.sub.9, -(CH.sub.2).sub.n C(O)O-(CH.sub.2).sub.p R.sub.9, -(CH.sub.)n C(O)O-(CH.sub.2).sub.p NR.sub.9 R.sub.10, -(CH.sub.2).sub.n C(O)(CH.sub.2).sub.n NR.sub.9 R.sub.10, NO.sub.2, -O-(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.p R.sub.9, -O-(CH.sub.2).sub.n C(O)O-(CH.sub.2).sub.p R.sub.9, -O-(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.n NR.sub.9 R.sub.10,-NR.sub.9 R.sub.10,-N(R.sub.9)(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.n R.sub.10,-N(R.sub.9)-(CH.sub.2).sub.n C(O)O-(CH.sub.2).sub.n R.sub.10,N(R.sub.9)(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.n NR.sub.9 R.sub.10,-O-(CH.sub.2).sub.n phenyl, -O-(CH.sub.2).sub.n pyridine, -O(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.n pyridine, -O-(CH.sub.2).sub.n C(O)O-(CH.sub.2).sub.n pyridine, -O(CH.sub.2).sub.n C(O)-N(R.sub.9)(CH.sub.2).sub.n pyridine, -O-(CH.sub.2).sub.n quinoxalinyl, -O-(CH.sub.2).sub.n quinolinyl, -O-(CH.sub.2).sub.n pyrazinyl, -O-(CH.sub.2).sub.n naphthyl, -O-(CH.sub.2).sub.n C(O)-(CH.sub.2).sub.n naphthyl, -O-(CH.sub.2).sub.n C(O)O-(CH.sub.2).sub.n naphthyl, -O-(CH.sub.2).sub.n C(O)NR.sub.9 -(CH.sub.2).sub.n naphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH.sub.2).sub.q -OH, -(CH.sub.2).sub.q OC(O)R.sub.9, -(CH.sub.2).sub.q OC(O)-NR.sub.9 R.sub.10,-(1-cyclohexyl-1H-tetrazol-5-yl)C.sub.1 -C.sub.4 alkoxy, ›1-(C.sub.1 -C.sub.5 alkyl)-1H-tetrazol-5-yl!-C.sub.1 -C.sub.4 alkoxy, ›1-(phenyl)-1H-tetrazol-5-yl!C.sub.1 -C.sub.4 alkoxy, -›1-(pyridinyl)-1H-tetrazol-5-yl!C.sub.1 -C.sub.4 alkoxy, -›1-(1-phenylethyl)-1H-tetrazol-5-yl!C.sub.1 -C.sub.4 alkoxyl, -C.sub.1 -C.sub.4 alkoxyl, a group of Formula II ##STR3## wherein R' is methyl or carboxy, R" is hydrogen and R'" is selected from benzyl, C.sub.1 -C.sub.5 alkyl, -(CH.sub.2).sub.n CO.sub.2 H, -CH.sub.2 SH, -CH.sub.2 SCH.sub.3, imidazolinylmethylene, indolinylmethylene, CH.sub.3 CH(OH), CH.sub.2 OH, H.sub.2 N(CH.sub.2).sub.4 -(optionally in protected form) or H.sub.2 NC(NH)NH(CH.sub.2).sub.3 (optionally in protected form);
• with the proviso that when Y is 4-morpholinyl, the compound is other than:
• 6. 7-dimethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one,
• 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-1-benzopyra n-4-one,
• N-cyclohexyl -2-››8-methyl -2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl!oxy!-acetamide,
• 2-››8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl!oxy!-N-phenyl-ace tamide,
• 6-›(1-cyclohexyl -1H-tetrazol -5-yl)methoxy!-2-(4-morpholinyl)-4H-1-Benzopyran-4-one,
• 2-››8-methyl -2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl!oxy!-N-(1-phenylethyl)-aceta mide;
• R.sub.9 and R.sub.10,being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R.sub.9 and R.sub.10 are not both hydrogen;
• (b) C.sub.1 -C.sub.12 alkyl;
• (c) phenyl optionally substituted with one, 2 or 3 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, OH, trifluoromethyl or -CO.sub.2 (C.sub.1 -C.sub.4 alkyl);
• (d)-(CH.sub.2).sub.n phenyl, (e)-(CH.sub.2).sub.n pyridinyl or (f) wherein R.sub.9 and R.sub.10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of
• (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo or trifluoromethyl,
• (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo or trifluoromethyl,
• (cc) 3-amino-1-pyrrolidine,
• (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, OH, -CH.sub.2 OH, or trifluoromethyl,
• (ee) 1-piperidine optionally substituted with one or two members selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, trifluoromethyl, -(CH.sub.2).sub.q OH, -CO.sub.2 H, -CO.sub.2 CH.sub.3, -CO.sub.2 CH.sub.2 CH.sub.3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo or trifluoromethyl),
• (ff) 1-piperazine, 4-(C.sub.1 -C.sub.4 alkyl)-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, trifluoromethyl, -CH.sub.2 OH, -CO.sub.2 H, -CO.sub.2 CH.sub.3 or -CO.sub.2 CH.sub.2 CH.sub.3, and
• (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinacetophenone, 1-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1,2-3,6-tetrahydropyridine, proline, tetrahydrofurylamine, 1-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
• R.sub.15 is selected from H, C.sub.1 -C.sub.5 alkyl, -(CH.sub.2).sub.n phenyl, -(CH.sub.2).sub.n pyridin-1-yl, -(CH.sub.2).sub.n pyridin-2-yl, -(CH.sub.2).sub.n pyridin-3-yl, -(CH.sub.2).sub.n pyridin-4-yl, -CH.sub.2).sub.n -1-(C.sub.1 -C.sub.4 alkyl)-1H-5-tetrazole, -(CH.sub.2).sub.n -pyrimidine, -(CH.sub.2).sub.n -2-benzoxazole, -(CH.sub.2).sub.n -2-benzothiazole, -(CH.sub.2).sub.n -(C.sub.1 -C.sub.4 alkyl)-triazole, -(CH.sub.2).sub.n -(C.sub.1 -C.sub.4 alkyl)-imidazole;
• n is 0-5;
• p is 2-5;
• q is 1-5;
• and pharmaceutically acceptable salts and hydrates thereof;
• and with the overall proviso that when R.sub.5, R.sub.6 and R.sub.8 are selected from:
• H, C.sub.1 -C.sub.8 alkyl, or halogen and Z is H or C.sub.1 -C.sub.5 alkyl, or halogen, then R.sub.7 is other than -OH, -OCH.sub.3, -((CH.sub.2).sub.n C(O)O-(CH.sub.2).sub.p R.sub.9 or -O-(CH.sub.2).sub.n C(O)-NR.sub.9 R.sub.10 wherein n is other than 0, and R.sub.9 and R.sub.10 are selected from H or C.sub.1 -C.sub.12 alkyl.