4-hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl›b!pyran-2-ones useful to treat retroviral infections

A method of inhibiting a retrovirus in a mammalian cell infected with said retrovirus which comprises treating said cell with an effective amount of a compound of the formula I ##STR4## wherein R.sub.10 and R.sub.20 taken together are ##STR5## wherein R.sub.0 is --H;

• wherein R.sub.1 is
• a) --H,
• b) --OCH.sub.n H.sub.2n+1,
• c) --F,
• d) --NH.sub.2 --, or
• e) --O--C.sub.n H.sub.2n Het;
• wherein R.sub.2 is
• a) --H,
• b) --OC.sub.n H.sub.2n+1,
• c) --CF.sub.3,
• d) --O--C.sub.n H.sub.2n --CH.dbd.CH.sub.2, or
• e) --O--C.sub.n H.sub.2n --Het;
• or wherein R.sub.1 and R.sub.2 taken together are phenyl;
• or wherein R.sub.0 and R.sub.2 taken together are phenyl;
• wherein R.sub.3 is ##STR6## b) diphenylethyl-, c) diphenylethenyl-,
• d) --CH--(C.sub.3 -C.sub.6 cycloalkyl).sub.2,
• e) -5,6,7,8,9-tetrahydro-5H-benzocycloheptenyl,
• f) -1,2,3,4-tetrahydro-naphthalenyl substituted by one (1) or two (2) --OC.sub.n H.sub.2n+1 or --CH.sub.3,
• g) --CH(C.sub.n H.sub.2n+1)--C(O)--O--C.sub.n H.sub.2n+1,
• h) --CH(CH.sub.2 -phenyl).sub.2,
• i) --C.sub.v H.sub.2v --CH(R.sub.4)--C.sub.v H.sub.2v --Het--R.sub.5,
• j) --C.sub.v H.sub.2v --CH(R.sub.4)--C.sub.v H.sub.2v --Het,
• k) diphenylmethyl-,
• l) diphenylpropyl-, or
• m) phenylcyclobutyl-;
• wherein R.sub.4 is
• a) --C.sub.m H.sub.2m+1,
• b) --CH.sub.2 --C(O)--O--C.sub.n H.sub.2n+1,
• c) --C.sub.3 -C.sub.6 cycloalkyl,
• d) --C.sub.n H.sub.2n --C.sub.3 -C.sub.6 cycloalkyl, or
• e) C.sub.2 -C.sub.6 alkenyl;
• wherein each R.sub.5 is independently
• a) --H,
• b) --NH.sub.2,
• c) --C(O)--C.sub.n H.sub.2n+1,
• d) (o-) or (m-) --O--C.sub.n H.sub.2n --CH.dbd.CH.sub.2,
• e) --C.sub.1 -C.sub.5 alkoxy substituted on each carbon atom by zero (0) or one (1) hydroxy,
• f) --O--C(O)--C.sub.n H.sub.2n+1,
• g) --Br,
• h) --CN,
• i) --C.sub.m H.sub.2m --X.sub.1 --C.sub.t H.sub.2t+1,
• j) --X.sub.1 --C.sub.n H.sub.2n -halo,
• k) --X.sub.1 --C.sub.n H.sub.2n --NH.sub.2,
• l) --X.sub.1 --C.sub.n H.sub.2n --NH--C(O)--O--C.sub.n H.sub.2n+1
• m) --X.sub.1 --C.sub.n H.sub.2n --CH(NH--C(O)--O--C.sub.n H.sub.2n+1)C(O)--O--C.sub.n H.sub.2n+1,
• n) --X.sub.1 --C.sub.m H.sub.2m --CH(NH--C(O)--O--C.sub.n H.sub.2n+1)C.sub.n H.sub.2n --Het,
• o) --X.sub.1 --C.sub.n H.sub.2n --CH(NH.sub.2)COOH,
• p) --X.sub.1 --C.sub.n H.sub.2n --C(O)--O--C.sub.n H.sub.2n+1,
• q) --X.sub.1 --C.sub.n H.sub.2n --C.sub.3 -C.sub.6 cycloalkyl,
• r) --C.sub.m H.sub.2m --X.sub.1 --C.sub.m H.sub.2m -aryl,
• s) --X.sub.1 --C.sub.m H.sub.2m --O-aryl,
• t) --C.sub.m H.sub.2m --X.sub.1 --C.sub.m H.sub.2m --O--C.sub.n H.sub.2n+1,
• u) --C.sub.m H.sub.2m --X.sub.1 --C.sub.m H.sub.2m --Het,
• v) --X.sub.1 --C.sub.n H.sub.2n --C(O)--Het,
• w) --X.sub.1 --C.sub.n H.sub.2n --C(O)--NH--C.sub.n H.sub.2n -Het,
• x) --X.sub.1 --C.sub.n H.sub.2n --S--Het,
• y) --C.sub.m H.sub.2m --X.sub.1 --O--C.sub.n H.sub.2n -aryl,
• z) --C.sub.m H.sub.2m --X.sub.1 --O--C.sub.n H.sub.2n -Het,
• a1) --X.sub.1 --H,
• b1) --X.sub.1 --CH.dbd.CH.sub.2,
• c1) --X.sub.1 --CH.dbd.CH-aryl,
• d1) --X.sub.1 --N(R.sub.40).sub.2,
• e1) --X.sub.1 --C.sub.n H.sub.2n -phthalimido,
• f1) --X.sub.1 -(penta-fluoro)-phenyl,
• g1) --X.sub.1 --C.sub.n H.sub.2n -bicyclo›2.2.1!heptane,
• h1) --C.sub.u --H.sub.2u --R.sub.30.
• i1) --N.dbd.C--(NH--CH(C.sub.n H.sub.2n+1).sub.2).sub.2,
• j1) --NH--P(O)(R.sub.9)-aryl,
• k1) --NH--P(O)(O--R.sub.11)-aryl,
• l1) --NH--C(S)--NH--R.sub.42, or
• m1) --NH--C(S)--CH.sub.2 --R.sub.42 ;
• wherein X.sub.1 is
• a) --NH--C(O)--,
• b) --C(O)--NH--,
• c) --NH--SO.sub.2 --,
• d) --SO.sub.2 --NH--,
• e) --NH--SO.sub.2 --NH--,
• f) --C(O)--O--,
• g) --O--C(O)--,
• h) --N(C.sub.n H.sub.2n -aryl)--C(O)--,
• i) --NH--C(O)--NH--,
• j) --N(C.sub.n H.sub.2n -aryl)--SO.sub.2 --, or
• k) --N(C.sub.m H.sub.2m --C.sub.n H.sub.2n+1)--SO.sub.2 --;
• wherein m is zero (0) to five (5) inclusive;
• wherein n is one (1) to five (5) inclusive;
• wherein p is one (1) to eight (8) inclusive;
• wherein q is zero (0) to five (5) inclusive;
• wherein r is one (1) to eight (8) inclusive;
• wherein s is one (1) to six (6) inclusive;
• wherein t is one (1) to twelve (12) inclusive;
• wherein u is two (2) to six (6) inclusive;
• wherein v is zero (0) to two (2) inclusive;
• wherein w is one (1) or two (2);
• wherein aryl is
• a) phenyl substituted by zero (0) to three (3) R.sub.6,
• b) naphthyl substituted by zero (0) to three (3) R.sub.6, or
• c) biphenyl substituted by zero (0) to three (3) R.sub.6 ;
• wherein Het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
• and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle;
• and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen;
• and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms;
• and if chemically feasible, the nitrogen atom may be in the protected form;
• and substituted by zero (0) to three (3) R.sub.7 ;
• wherein R.sub.6 and R.sub.7 are independently
• a) --C.sub.1 --C.sub.5 alkyl, substituted by zero (0) to three (3) halo or substituted on each carbon atom by zero (0) or one (1) hydroxy,
• b) --OH,
• c) --C.sub.1 -C.sub.5 alkyl-OH,
• d) --O--C.sub.1 -C.sub.5 alkyl substituted by zero (0) to three (3) halo or substituted on each carbon atom by zero (0) or one (1) hydroxy,
• e) --O--C.sub.2 -C.sub.7 alkenyl substituted by zero (0) or one (1) hydroxy,
• f) halo,
• g) --NH.sub.2,
• h) --NH.sub.2 --C.sub.1 -C.sub.5 alkyl,
• i) mono-or di-C.sub.1 -C.sub.5 alkylamino,
• j) --NH--OH,
• k) --N(C.sub.n H.sub.2n --OH).sub.2,
• l) --C(O)--NH.sub.2,
• m) --C(O)--C.sub.1 -C.sub.5 alkyl,
• n) --CHO,
• o) --COOH,
• p) --COX.sub.2,
• q) nitro,
• r) --CN,
• s) --SO.sub.3 H,
• t) --SO.sub.2 NH.sub.2,
• u) --SO.sub.2 --R.sub.42,
• v) --NR.sub.40 --SO.sub.2 --R.sub.42,
• w) --SO.sub.2 --NR.sub.40 R.sub.41,
• x) --O›C.sub.n H.sub.2n O!.sub.q C.sub.n H.sub.2n+1,
• y) --C(O)--O--C.sub.n H.sub.2n+1,
• z) --NR.sub.40 --C(O)--C.sub.n H.sub.2n+1,
• a1) --C.sub.n H.sub.2n --NR.sub.40 --C(O)--R.sub.41,
• b1) --N.dbd.N-phenyl substituted by zero (0) or one (1) --N(C.sub.n H.sub.2n+1).sub.2,
• c1) isoxazolyl,
• d1) pyridinyl,
• e1) --X.sub.3 --C.sub.u H.sub.2u --R.sub.30,
• f1) morpholino,
• g1) piperidino,
• h1) piperazino,
• i1) --NR.sub.40 R.sub.41,
• j1) --OR.sub.40, ##STR7## l1) --C.sub.n H.sub.2n --O--C.sub.n H.sub.2n --OC.sub.n H.sub.2n+1, m1) --N-methyl-piperazino,
• n) --SO.sub.2 -morpholino,
• o1) --SO.sub.2 -piperazino,
• p1) --SO.sub.2 --N-methyl-piperazino,
• q1) --SO.sub.2 -piperidino, or
• r1) --NR.sub.40 --C(O)--C.sub.n H.sub.2n --O--R.sub.41 ;
• wherein X.sub.2 is --NR.sub.40 R.sub.41 ;
• wherein X.sub.3 is
• a) --O--,
• b) --CH.sub.2 --O--,
• c) --SO.sub.2 NR.sub.40 --,
• d) --NR.sub.40 SO.sub.2 --,
• e) --C(O)--,
• f) --C(O)NR.sub.40 --,
• g) --NR.sub.40 C(O), or
• h) --NR.sub.40 --;
• wherein R.sub.8 is
• a) --H,
• b) --C.sub.n H.sub.2n -phenyl substituted by zero (0) to three (3) R.sub.6,
• c) --C.sub.n H.sub.2n -Het,
• d) --C.sub.n H.sub.2n --C.sub.3 -C.sub.6 cycloalkyl,
• e) --C.sub.r --H.sub.2r+1,
• f) --C.sub.n --H.sub.2n --CH.dbd.CH.sub.2,
• g) --C.sub.S H.sub.2S+1 substituted by one (1) or two (2) hydroxy,
• h) --CH.sub.2 -epoxide,
• i) --C.sub.n H.sub.2n -oxiranyl,
• j) --(C.sub.n H.sub.2n --O).sub.n --C.sub.n H.sub.2n+1,
• k) --C(O)--C.sub.S H.sub.2S+1, or
• l) --CH(OH)--C.sub.3 -C.sub.6 cycloalkyl;
• wherein R.sub.9 is
• a) C.sub.1 -C.sub.4 alkyl, or
• b) aryl;
• wherein R.sub.11 is
• a) --H,
• b) --C.sub.1 -C.sub.4 alkyl,
• c) aryl, or
• d) pharmaceutically acceptable salts;
• wherein R.sub.12 is
• a) C.sub.1 -C.sub.4 alkyl,
• b) C.sub.1 -C.sub.3 alkoxy,
• c) dimethylamino,
• d) diethylamino,
• e) CF.sub.3,
• f) CN,
• g) halo,
• h) --NH.sub.2,
• i) --OH,
• j) --SO.sub.2 --NH.sub.2, or
• k) --C(O)--NH.sub.2 ;
• wherein R.sub.30 is
• a) morpholino,
• b) piperidino,
• c) piperazino,
• d) --NR.sub.40 R.sub.41,
• e) --OR.sub.40, ##STR8## g) --N-methyl-piperazino, or h) halo;
• wherein R.sub.40 and R.sub.41 are independently
• a) --H,
• b) --C.sub.1 -C.sub.4 alkyl,
• c) phenyl substituted by zero (0) to three (3) R.sub.12, or
• d) --C.sub.n H.sub.2n -phenyl substituted by zero (0) to three (3) R.sub.12 ;
• wherein R.sub.42 is
• a) C.sub.1 -C.sub.4 alkyl,
• b) phenyl substituted by zero (0) to three (3) R.sub.12, or
• c) --C.sub.n H.sub.2n -phenyl substituted by zero (0) to three (3) R.sub.12 ;
• provided that:
• 1) when R.sub.10 and R.sub.20 taken together are the moiety of formula II, and R.sub.1 and R.sub.2 are independently --H, --F, or --OC.sub.n H.sub.2n+1, and R.sub.3 is the moiety of formula IVA, and R.sub.4 is --C.sub.m H.sub.2m+1 or cyclohexyl, then R.sub.5 is other than --H, --Br or --OC.sub.n H.sub.2n+1 ;
• 2) when R.sub.5 is --C.sub.m H.sub.2m --X.sub.1 --O--C.sub.n H.sub.2n -aryl, --C.sub.m H.sub.2m --X.sub.1 --O--C.sub.n H.sub.2n --Het, or X.sub.1 --N(R.sub.40).sub.2, X.sub.1 is not --C(O)--NH--, --NHSO.sub.2 --, --SO.sub.2 --NH--, --NH--SO.sub.2 --NH--, --C(O)--O--, --NH--C(O)--NH--, --N(C.sub.n H.sub.2n -aryl)--SO.sub.2 --;
• 3) when R.sub.5 is --X.sub.1 --C.sub.m H.sub.2m --O-aryl or --C.sub.m H.sub.2m --X.sub.1 --C.sub.m --H.sub.2m --O--C.sub.n H.sub.2n+1, and m is zero (0), then X.sub.1 is not --C(O)--NH--, --NH--SO.sub.2 --, --SO.sub.2 --NH--, --NH--SO.sub.2 --NH--, --C(O)--O--, --NH--C(O)--NH--, --N--(CH.sub.n H.sub.2n -aryl)--SO.sub.2 --, or --N(C.sub.m H.sub.2m --C.sub.n H.sub.2n+1)--SO.sub.2 --;
• 4) R.sub.4 in the moiety of formula IVA is C.sub.2 -C.sub.6 alkenyl only when R.sub.10 and R.sub.20 taken together are the moiety of formula III;
• 5) R.sub.3 is diphenylethyl, diphenylmethyl, diphenylpropyl, diphenylethenyl or phenylcyclobutyl, only when R.sub.10 and R.sub.20 taken together are the moiety of formula III;
• and
• 6) when R.sub.10 and R.sub.20 taken together are the moiety of formula II, and R.sub.1 and R.sub.2 are independently --H, --F, --OC.sub.n H.sub.2n+1 or --NH.sub.2, R.sub.3 is other than --CH(C.sub.n H.sub.2n+1)--C(O)--O--C.sub.n H.sub.2n+1 ;
• or a pharmaceutically acceptable salts thereof.