Claims
- 1. A compound of Formula I ##STR72## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is:
- (a) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
- i) aryl as defined below,
- ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- iii) Cl, Br, I, F,
- iv) OH,
- v) NH.sub.2,
- vi) NH(C.sub.1 -C.sub.4)-alkyl,
- vii) N[(C.sub.1 -C.sub.4)-alkyl)].sub.2,
- viii) NHSO.sub.2 R.sup.2,
- ix) CF.sub.3,
- x) COOR.sup.2, or
- xi) SO.sub.2 NHR.sup.2a ; and
- (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
- i) Br, I, Cl, F,
- ii) (C.sub.1 -C.sub.4)-alkyl,
- iii) (C.sub.1 -C.sub.4)-alkoxy,
- iv) NO.sub.2
- v) CF.sub.3
- vi) SO.sub.2 NR.sup.2a R.sup.2a,
- vii) (C.sub.1 -C.sub.4)-alkylthio,
- viii) hydroxy,
- ix) amino,
- x) (C.sub.3 -C.sub.7)-cycloalkyl,
- xi) (C.sub.3 -C.sub.10)-alkenyl; and
- (c) (C.sub.1 -C.sub.4)-perfluoroalkyl; and
- E is a single bond; and
- n is 0 to 2; and
- J.sup.1 is (a)--C(.dbd.O)--, (b) J.sup.1 and L are connected together to form a 6-carbon aromatic ring substituted with R.sup.7a, R.sup.7b, R.sup.8a and R.sup.8b ; and
- K.sup.1 is (a)--C(.dbd.O)--, (b) K.sup.1 and L are connected together to form a 6-carbon aromatic ring substituted with R.sup.7a, R.sup.7b, R.sup.8a and R.sup.8b ; and
- one of a.sup.1 or b.sup.1 is a double bond provided that when J.sup.1 is --C(.dbd.O)-- then b.sup.1 is a double bond and when K.sup.1 is --C(.dbd.O)-- then a.sup.1 is a double bond,
- L is the point of attachment of the 6-membered fused aromatic ring optionally having one nitrogen atom; and
- R.sup.2 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.6)-alkyl; and
- R.sup.2a is:
- (a) R.sup.2,
- (b) benzyl, or
- (c) phenyl; and
- R.sup.7a and R.sup.7b are independently
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl,
- (c) Cl, Br, I, F, or
- (d) CF.sub.3 ;
- R.sup.8a and R.sup.8b are independently
- (a) H,
- (b) aryl-(C.sub.1 -C.sub.4)-alkyl,
- (c) (C.sub.1 -C.sub.6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R.sup.2a).sub.2, --S(O).sub.n --R.sup.21, --CONHSO.sub.2 R.sup.21, --SO.sub.2 NHCOR.sup.21, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.21, --OH, --NH.sub.2, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.2a, --CONHR.sup.2a, --O--COR.sup.2a, or aryl,
- (d) --CO-aryl,
- (e) (C.sub.3 -C.sub.7)-cycloalkyl,
- (f) Cl, Br, I, F,
- (g) --OH,
- (h) --OR.sup.21,
- (i) --SH,
- (j) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
- (k) --COR.sup.2a,
- (l) --CO.sub.2 H,
- (m) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
- (n) --SO.sub.3 H,
- (o) --NR.sup.2 R.sup.21,
- (p) --NR.sup.2 COR.sup.21,
- (q) --NR.sup.2 COOR.sup.21,
- (r) --SO.sub.2 NHR.sup.2a,
- (s) --SO.sub.2 NR.sup.2 R.sup.2a,
- (t) --NO.sub.2,
- (u) --NHSO.sub.2 CF.sub.3,
- (v) --CONR.sup.2a R.sup.2a,
- (w) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
- (x) --COOR.sup.2,
- (y) --SO.sub.3 H,
- (z) --N(R.sup.2)SO.sub.2 R.sup.21,
- (aa) --NR.sup.2 CONR.sup.2a R.sup.21,
- (bb) --OC(.dbd.O)NR.sup.21 R.sup.2a,
- (cc) -aryl,
- (dd) --NHSO.sub.2 CF.sub.3,
- (ee) --SO.sub.2 NHCOR.sup.21,
- (ff)--CONHSO.sub.2 R.sup.21,
- (gg) --PO(OR.sup.2).sub.2,
- (hh) --SO.sub.2 NHCN; and
- R.sup.9 and R.sup.10 are independently:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
- (c) (C.sub.2 -C.sub.6)-alkenyl,
- (d) (C.sub.2 -C.sub.6)-alkynyl,
- (e) Cl, Br, F, I,
- (f) (C.sub.1 -C.sub.6)-alkoxy,
- (g) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form an phenyl ring,
- (h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
- (i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
- (j) aryl,
- (k) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
- (l) hydroxy-(C.sub.1 -C.sub.6)-alkyl,
- (m) --CF.sub.3,
- (n) --CO.sub.2 R.sup.2a,
- (o) --OH,
- (p) --NR.sup.2 R.sup.21,
- (q) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21,
- (r) --NO.sub.2,
- (s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.2).sub.2,
- (t) --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or
- (u) --CON(R.sup.2).sub.2 ;
- X is:
- (a) --O--,
- (b) --S(O).sub.n --,
- (c) --NR.sup.13 --
- (d) --CH.sub.2 O--,
- (e) --CH.sub.2 S(O).sub.n,
- (f) --CH.sub.2 NR.sup.13 --,
- (g) --OCH.sub.2 --,
- (h) --NR.sup.13 CH.sub.2 --,
- (i) --S(O).sub.n CH.sub.2 --,
- (j) --CH.sub.2 --,
- (k) --(CH.sub.2).sub.2 --,
- (l) single bond, or
- (m) --CH.dbd., wherein Y and R.sup.12 are absent forming a --C.dbd.C-- bride to the carbon bearing Z and R.sup.11 ; and
- Y is:
- (a) single bond,
- (b) --O--,
- (c) --S(O).sub.n --,
- (d) --NR.sup.13 --, or
- (e) --CH.sub.2 --; and
- except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO.sub.2);
- R.sup.11 and R.sup.12 are independently:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
- (i) aryl,
- (ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- (iii) NR.sup.2 R.sup.21,
- (iv) OH,
- (v) CO.sub.2 R.sup.2a, or
- (vi) CON(R.sup.2).sub.2,
- (c) aryl or aryl-(C.sub.1 -C.sub.2)-alkyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of:
- (i) Cl, Br, I, F,
- (ii) (C.sub.1 -C.sub.6)-alkyl,
- (iii) [(C.sub.1 -C.sub.5)-alkenyl]CH.sub.2 --,
- (iv) [(C.sub.1 -C.sub.5)-alkynyl]CH.sub.2 --,
- (v) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
- (vi) --CF.sub.3,
- (vii) --CO.sub.2 R.sup.2a,
- (viii) --OH,
- (ix) --NR.sup.2 R.sup.21,
- (x) --NO.sub.2,
- (xi) --NR.sup.2 COR.sup.2,
- (xii) --CON(R.sup.2)2, or
- (xiii) --G--[(C.sub.1 -C.sub.6)-alkyl]-R.sup.23 ;
- and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F,
- G is: a single bond, O, S(O).sub.x or NR.sup.23 ; and
- Z is:
- (a) --CO.sub.2 H, or
- (b) --CO.sub.2 R.sup.24 ;
- R.sup.14 is:
- (a) H,
- (b) (C.sub.1 -C.sub.8)-alkyl,
- (c) (C.sub.1 -C.sub.8)-perfluoroalkyl,
- (d) (C.sub.3 -C.sub.6)-cycloalkyl,
- (e) phenyl, or
- (f) benzyl; and
- R.sup.21 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
- i) NH.sub.2,
- ii) NH[(C.sub.1 -C.sub.4)-alkyl],
- iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- iv) CO.sub.2 H,
- v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
- vi) OH,
- vii) SO.sub.3 H, or
- viii) SO.sub.2 NH.sub.2 ; and
- R.sup.23 is:
- (a) OH,
- (b) NR.sup.2 R.sup.21,
- (c) CO.sub.2 R.sup.2a,
- (d) CON(R.sup.2).sub.2, or
- (e) S(O).sub.x --(C.sub.1 -C.sub.4)-alkyl;
- R.sup.24 is:
- (a) (C.sub.1 -C.sub.4)-alkyl,
- (b) CHR.sup.25 --O--COR.sup.26,
- (c) CH.sub.2 CH.sub.2 --N[(C.sub.1 -C.sub.2)-alkyl].sub.2,
- (d) (CH.sub.2 CH.sub.2 O).sub.y --O--[(C.sub.1 -C.sub.4)-alkyl], wherein y is 1 or 2,
- (e) aryl or CH.sub.2 -aryl, where aryl is as defined above and is substituted or unsubstituted with CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, ##STR73## R.sup.25 and R.sup.26 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.
- 2. The compound of claim 1 of structural formula ##STR74## or a pharmaceutically acceptable salt thereof.
- 3. The compound of claim 1 of structural formula ##STR75## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is:
- (a) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
- i) aryl as defined below,
- ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- iii) Cl, Br, I, F,
- iv) OH,
- v) NH.sub.2,
- vi) NH(C.sub.1 -C.sub.4)-alkyl,
- vii) N[((C.sub.1 -C.sub.4)-alkyl)].sub.2,
- viii) NHSO.sub.2 R.sup.2,
- ix) CF.sub.3,
- x) COOR.sup.2, or
- xi) SO.sub.2 NHR.sup.2a ; and
- (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
- i) Br, I, Cl, F,
- ii) (C.sub.1 -C.sub.4)-alkyl,
- iii) (C.sub.1 -C.sub.4)-alkoxy,
- iv) NO.sub.2
- v) CF.sub.3
- vi) SO.sub.2 NR.sup.2a R.sup.2a,
- vii) (C.sub.1 -C.sub.4)-alkylthio,
- viii) hydroxy,
- ix) amino,
- x) (C.sub.3 -C.sub.7)-cycloalkyl,
- xi) (C.sub.3 -C.sub.10)-alkenyl; and
- (c) (C.sub.1 -C.sub.4)-perfluoroalkyl; and
- R.sup.2 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.6)-alkyl; and
- R.sup.2a is:
- (a) R.sup.2,
- (b) CH.sub.2 -aryl, or
- (c) aryl; and
- R.sup.8a and R.sup.8b are independently
- (a) H,
- (b) aryl-(C.sub.1 -C.sub.4)-alkyl,
- (c) (C.sub.1 -C.sub.6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R.sup.2a).sub.2, --S(O).sub.n --R.sup.21, --CONHSO.sub.2 R.sup.21, --SO.sub.2 NHCOR.sup.21, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.21, --OH, --NH.sub.2, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.2a, --CONHR.sup.2a, --O--COR.sup.2a, or aryl,
- (d) --CO-aryl,
- (e) (C.sub.3 -C.sub.7)-cycloalkyl,
- (f) Cl, Br, I, F,
- (g) --OH,
- (h) --OR.sup.21,
- (i) --SH,
- (j) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
- (k) --COR.sup.2a,
- (l) --CO.sub.2 H,
- (m) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
- (n) --NR.sup.2 R.sup.21,
- (o) --NR.sup.2 COR.sup.21,
- (p) --NR.sup.2 COOR.sup.21,
- (q) --SO.sub.2 NR.sup.2 R.sup.2a,
- (r) --NO.sub.2,
- (s) --NHSO.sub.2 CF.sub.3,
- (t) --CONR.sup.2a R.sup.2a,
- (u) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
- (v) --COOR.sup.2,
- (w) --SO.sub.3 H,
- (x) --N(R.sup.2)SO.sub.2 R.sup.21,
- (y) --NR.sup.2 CONR.sup.2a R.sup.21,
- (z) --OC(.dbd.O)NR.sup.21 R.sup.2a,
- (aa) --aryl,
- (bb) --NHSO.sub.2 CF.sub.3,
- (cc) --SO.sub.2 NHCOR.sup.21,
- (dd) --CONHSO.sub.2 R.sup.21, or
- (ee) --SO.sub.2 NHCN; and
- R.sup.9 and R.sup.10 are independently:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
- (c) (C.sub.2 -C.sub.6)-alkenyl,
- (d) (D.sub.2 -C.sub.6)-alkynyl,
- (e) Cl, Br, F, I,
- (f) (C.sub.1 -C.sub.6)-alkoxy,
- (g) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form a phenyl ring,
- (h) (C.sub.1 -C.sub.6)-perfluoroalkyl,
- (i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
- (j) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
- (k) hydroxy-(C.sub.1 -C.sub.6)-alkyl,
- (l) --CF.sub.3,
- (m) --CO.sub.2 R.sup.2a,
- (n) --OH,
- (o) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21,
- (p) --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or
- (q) --CON(R.sup.2).sub.2 ; and
- X is:
- (a) --O--,
- (b) --S(O).sub.n --,
- (c) --CH.sub.2 O--,
- (d) --CH.sub.2 S(O).sub.n --,
- (e) --OCH.sub.2 --,
- (f) --S(O).sub.n CH.sub.2 --,
- (g) --CH.sub.2 --,
- (h) --(CH.sub.2).sub.2 --, or
- (i) single bond, or
- R.sup.11 is:
- (a) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
- (i) aryl,
- (ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- (iii) NR.sup.2 R.sup.21,
- (iv) OH,
- (v) CO.sub.2 R.sup.2a, or
- (vi) CON(R.sup.2).sub.2,
- (b) aryl or aryl-(C.sub.1 -C.sub.2)-alkyl, unsubstituted or substituted with 1 to 3 substitutents selected from the group consisting of:
- (i) Cl, Br, I, F,
- (ii) (C.sub.1 -C.sub.6)-alkyl,
- (iii) [(C.sub.1 -C.sub.5)-alkenyl]CH.sub.2 --,
- (iv) [(C.sub.1 -C.sub.5)-alkynyl]CH.sub.2 --,
- (v) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
- (vi) --CF.sub.3,
- (vii) --CO.sub.2 R.sup.2a,
- (viii) --OH,
- (ix) --NR.sup.2 R.sup.21,
- (x) --NO.sub.2,
- (xi) --NR.sup.2 COR.sup.2,
- (xii) --CON(R.sup.2)2,
- (xiii) --G--[(C.sub.1 -C.sub.6)-alkyl]-R.sup.23,
- and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F;
- G is: a single bond, O, S(O).sub.x or NR.sup.23 ; and
- Z is:
- (a) --CO.sub.2 H, or
- (b) --CO.sub.2 R.sup.24, and
- R.sup.21 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
- i) NH.sub.2,
- ii) NH[(C.sub.1 -C.sub.4)-alkyl],
- iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- iv) CO.sub.2 H,
- v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
- vi) OH,
- vii) SO.sub.3 H, or
- viii) SO.sub.2 NH.sub.2 ; and
- R.sup.22 is:
- (a) H,
- (b) (C.sub.1 -C.sub.4)-alkyl,
- (c) (C.sub.1 -C.sub.4)-alkoxyl,
- (d) aryl,
- (e) aryl-(C.sub.1 -C.sub.4)-alkyl,
- (f) CO.sub.2 R.sup.2a,
- (g) CON(R.sup.2).sub.2,
- (h) SO.sub.2 R.sup.2a,
- (i) SO.sub.2 N(R.sup.2).sub.2,
- R.sup.24 is:
- (a) (C.sub.1 -C.sub.4)-alkyl,
- (b) CHR.sup.25 --O--COR.sup.26,
- (c) CH.sub.2 CH.sub.2 --N[(C.sub.1 -C.sub.2)-alkyl].sub.2,
- (e) (CH.sub.2 CH.sub.2 O).sub.y --O--[(C.sub.1 -C.sub.4)-alkyl], wherein y is 1 or 2,
- (f) aryl or CH.sub.2 -aryl, where aryl is as defined above or optionally substituted with CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl; and
- R.sup.25 and R.sup.26 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.
- 4. A compound of structural formula ##STR76## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is:
- (a) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
- i) aryl as defined below,
- ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- iii) Cl, Br, I, F,
- iv) OH,
- v) NH.sub.2,
- vi) NH(C.sub.1 -C.sub.4)-alkyl,
- vii) N[((C.sub.1 -C.sub.4)-alkyl)].sub.2,
- viii) NHSO.sub.2 R.sup.2,
- ix) CF.sub.3,
- x) COOR.sup.2, or
- xi) SO.sub.2 NHR.sup.2a ; and
- (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
- i) Br, I, Cl, F,
- ii) (C.sub.1 -C.sub.4)-alkyl,
- iii) (C.sub.1 -C.sub.4)-alkoxy,
- iv) NO.sub.2
- v) CF.sub.3
- vi) SO.sub.2 NR.sup.2a R.sup.2a,
- vii) (C.sub.1 -C.sub.4)-alkylthio,
- viii) hydroxy,
- ix) amino,
- x) (C.sub.3 -C.sub.7)-cycloalkyl,
- xi) (C.sub.3 -C.sub.10)-alkenyl, or
- (c) (C.sub.1 -C.sub.4)-perfluoroalkyl; and
- n is 0 to 2; and
- R.sup.2 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.6)-alkyl; and
- R.sup.2a is:
- (a) R.sup.2,
- (b) CH.sub.2 -aryl, or
- (c) aryl; and
- R.sup.8b is:
- (a) H,
- (d) (C.sub.1 -C.sub.6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R.sup.2a).sub.2, --S(O).sub.n --R.sup.21, --CONHSO.sub.2 R.sup.21, --SO.sub.2 NHCOR.sup.21, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.21, --OH, --NH.sub.2, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.2a, --CONHR.sup.2a, --O--COR.sup.2a, or aryl,
- (g) Cl, Br, I, F,
- (h) --OR.sup.21,
- (i) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
- (j) --COR.sup.2a,
- (k) --NR.sup.2 R.sup.21,
- (l) --NR.sup.2 COR.sup.21,
- (m) --NR.sup.2 COOR.sup.21,
- (n) --NO.sub.2,
- (o) --COOR.sup.2, or
- (p) --NR.sup.2 CONR.sup.2a R.sup.21 ; and
- R.sup.9 and R.sup.10 are independently:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
- (c) (C.sub.2 -C.sub.6)-alkenyl,
- (d) (C.sub.2 -C.sub.6)-alkynyl,
- (e) Cl, Br, F, I,
- (f) (C.sub.1 -C.sub.6)-alkoxy,
- (g) (C.sub.1 -C.sub.6)-perfluoroalkyl,
- (h) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl;
- X is:
- (a) --O--,
- (b) --S(O).sub.n --,
- (c) --CH.sub.2 --, or
- (d) --CH.dbd., which is double bonded to the carbon bearing Z and R.sup.11 ; and
- R.sup.11 is:
- (a) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
- (i) aryl,
- (ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- (iii) NR.sup.2 R.sup.21,
- (iv) OH,
- (v) CO.sub.2 R.sup.2a, or
- (vi) CON(R.sup.2).sub.2,
- (c) phenyl or phenyl-(C.sub.1 -C.sub.2)-alkyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of:
- (i) Cl, Br, I, F,
- (ii) (C.sub.1 -C.sub.6)-alkyl,
- (iii) [(C.sub.1 -C.sub.5)-alkenyl]CH.sub.2 --,
- (iv) [(C.sub.1 -C.sub.5)-alkynyl]CH.sub.2 --,
- (v) (C.sub.1 -C.sub.4)alkoxy,
- (vi) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
- (vi) --CF.sub.3,
- (vii) --CO.sub.2 R.sup.2a,
- (viii) --OH,
- (ix) --NR.sup.2 R.sup.21,
- (x) --NR.sup.2 COR.sup.2,
- (xi) --CON(R.sup.2)2,
- and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F,
- Z is:
- (a) --CO.sub.2 H, or
- (b) --CO.sub.2 R.sup.24, and
- R.sup.21 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
- i) NH.sub.2,
- ii) NH[(C.sub.1 -C.sub.4)-alkyl],
- iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- iv) CO.sub.2 H,
- v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
- vi) OH,
- vii) SO.sub.3 H, or
- viii) SO.sub.2 NH.sub.2 ; and
- R.sup.24 is:
- (a) (C.sub.1 -C.sub.4)-alkyl,
- (b) CHR.sup.25 --O--COR.sup.26,
- (c) CH.sub.2 CH.sub.2 O).sub.y --O--[(C.sub.1 -C.sub.4)-alkyl], wherein y is 1 or 2,
- R.sup.25 and R.sup.26 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.
- 5. A compound of structural formula ##STR77## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is:
- (a) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
- i) phenyl,
- ii) (C.sub.3 -C.sub.7)-cycloalkyl,
- iii) Cl, Br, I, F,
- iv) CF.sub.3,
- (b) phenyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
- i) Br, I, Cl, F,
- ii) (C.sub.1 -C.sub.4)-alkyl,
- iii) (C.sub.1 -C.sub.4)-alkoxy,
- iv) NO.sub.2
- v) CF.sub.3
- vi) SO.sub.2 NR.sup.2a R.sup.2a,
- vii) (C.sub.1 -C.sub.4)-alkylthio, or
- viii) (C.sub.3 -C.sub.10)-alkenyl, or
- (c) perfluoro-(C.sub.1 -C.sub.4)-alkyl; and
- R.sup.2 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.6)-alkyl; and
- R.sup.2a is:
- (a) R.sup.2,
- (b) CH.sub.2 -phenyl, or
- (c) phenyl; and
- R.sup.8b is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R.sup.2a).sub.2, --CONHSO.sub.2 R.sup.21, --NR.sup.2 COOR.sup.21, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, --COOR.sup.2a, --CONHR.sup.2a
- (c) --CO-aryl,
- (d) Cl, Br, I, F,
- (e) --OR.sup.21,
- (f) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
- (g) --NR.sup.2 R.sup.21,
- (h) --NR.sup.2 COR.sup.21,
- (i) --NR.sup.2 COOR.sup.21,
- (j) --NO.sub.2,
- (k) --NHSO.sub.2 CF.sub.3,
- (l) --C.sub.1 -C.sub.4 -perfluoroalkyl,
- (m) --N(R.sup.2)SO.sub.2 R.sup.21,
- (n) --NR.sup.2 CONR.sup.4 R.sup.21,
- n is 0 to 2; and
- R.sup.9 and R.sup.10 are independently:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
- (c) (C.sub.2 -C.sub.6)-alkenyl,
- (d) (C.sub.2 -C.sub.6)-alkynyl,
- (e) Cl, Br, F, I,
- (f) (C.sub.1 -C.sub.6)-alkoxy,
- (g) (C.sub.1 -C.sub.6)-perfluoroalkyl,
- (h) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
- X is O; and
- R.sup.11 is:
- (a) phenyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
- i) Cl, Br, I, F,
- ii) (C.sub.1 -C.sub.6)-alkyl,
- iii) [(C.sub.1 -C.sub.5)-alkenyl]CH.sub.2 --,
- iv) [(C.sub.1 -C.sub.5)-alkynyl]CH.sub.2 --,
- v) (C.sub.1 -C.sub.6)-alkoxy,
- vi) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
- vii) hydroxy-(C.sub.1 -C.sub.6)-alkyl,
- viii) --CF.sub.3,
- ix) --CO.sub.2 R.sup.2a,
- x) --OH,
- xi) --NR.sup.2 R.sup.21,
- xii) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21,
- xiii) --NO.sub.2,
- xiv) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.2).sub.2,
- xv) --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or
- xvi) --CON(R.sup.2)2;
- (b) phenyl-(C.sub.1 -C.sub.2)-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
- i) Cl, Br, I, F,
- ii) (C.sub.1 -C.sub.6)-alkyl,
- iii) [(C.sub.1 -C.sub.5)-alkenyl]CH.sub.2 --,
- iv) [(C.sub.1 -C.sub.5)-alkynyl]CH.sub.2 --,
- v) (C.sub.1 -C.sub.4)-alkoxy,
- vi) (C.sub.1 -C.sub.4)-alkylthio,
- vii) hydroxy-(C.sub.1 -C.sub.6)-alkyl,
- viii) --CF.sub.3,
- ix) --CO.sub.2 R.sup.2a,
- x) --OH,
- xi) --NR.sup.2 R.sup.21,
- xii) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21,
- xiii) --NO.sub.2,
- xiv) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.2).sub.2,
- xv) --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or
- xvi) --CON(R.sup.2)2,
- Z is:
- (a) --CO.sub.2 H, or
- (b) --CO.sub.2 --(C.sub.1 -C.sub.6)-alkyl, and
- R.sup.21 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.4)-alkyl.
- 6. A compound or its pharmaceutically acceptable salt which is selected from the group consisting of:
- 2-butyl-3-[4-(1-carboxy-1-phenyl)methoxy)phenyl]methyl-6-methylquinazolin-4(3H)-one;
- 2-butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-allyl]phenyl]methyl-6-methylquinazolin-4(3H)-one;
- 2-butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propylphenyl]methyl-6-methylquinazolin-4(3H)-one;
- 2-butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-chlorophenyl]methyl-6-methylquinazolin-4(3H)-one;
- 3-[4-((1-carboxy-1-phenyl)methoxy)-3-chloro-5-methoxyphenyl]methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-propylquinazolin-4(3H)-one; or
- 3-[4-((1-carboxy-1-phenyl)methoxy)-3-propylphenyl]methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-propylquinazolin-4(3H)-one.
- 7. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.
- 8. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.
BACKGROUND OF THE INVENTION
The present application is a continuation in part of copending application Ser. No. 671,552 filed on Mar. 19, 1991, now abandoned which is a continuation in part application of copending Ser. No. 479,786 filed on Feb. 13, 1990 (now abandoned).
US Referenced Citations (3)
Continuations (1)
|
Number |
Date |
Country |
Parent |
479786 |
Feb 1990 |
|
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
671552 |
Mar 1991 |
|