Claims
- 1. A compound of Formula I wherein: ##STR99## 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 in R.sup.1 (b),
- 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 and is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
- i) Br, Cl, F, I,
- 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) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the heteroaryl is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
- i) Br, Cl, F, I,
- ii) OH,
- iii) SH,
- iv) NO.sub.2,
- v) (C.sub.1 -C.sub.4)-alkyl,
- vi) (C.sub.2 -C.sub.4)-alkenyl,
- vii) (C.sub.2 -C.sub.4)-alkynyl,
- viii) (C.sub.1 -C.sub.4)-alkoxy, or
- ix) CF.sub.3, or
- (d) (C.sub.1 -C.sub.4)-perfluoroalkyl; and
- --A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 --is: ##STR100## E is: (a) a single bond,
- (b) --S(0).sub.n (CH.sub.2).sub.s --, or
- (c) --O--; and
- n is 0 to 2; and
- s is 0 to 5; 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.4 groups 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, each of which is unsubstituted or substituted with:
- i) OH,
- ii) (C.sub.1 -C.sub.4)-alkoxy,
- iii) CO.sub.2 R.sup.2,
- iv) OCOR.sup.2,
- v) CONHR.sup.2a,
- vi) CON(R.sup.2a).sub.2,
- vii) N(R.sup.2a)C(.dbd.O)R.sup.2,
- viii) NH.sub.2,
- ix) (C.sub.1 -C.sub.4)-alkylamino,
- x) di[(C.sub.1 -C.sub.4)-alkyl]amino,
- xi) --S--(C.sub.1 -C.sub.4)-alkyl,
- xii) aryl,
- xiii) heteroaryl,
- (c) Cl, Br, I, F,
- (d) CF.sub.3,
- (e) CO.sub.2 R.sup.2a,
- (f) C(.dbd.O)N(R.sup.2a).sub.2, or
- (g) --C(.dbd.O)-aryl,
- (h) (C.sub.3 -C.sub.7)-cycloalkyl,
- (i) --OR.sup.24,
- (j) --SH,
- (k) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
- (l) --SO.sub.3 H,
- (m) --NR.sup.2 R.sup.21,
- (n) --NR.sup.2 C(.dbd.O)R.sup.21,
- (o) --NR.sup.2 COOR.sup.21,
- (p) --SO.sub.2 NR.sup.2a R.sup.2a,
- (q) --NO.sub.2,
- (r) --NHSO.sub.2 -(C.sub.1 -C.sub.4)-alkyl, or
- (s) when R.sup.4 groups are on adjacent carbon atoms they may join to form a phenyl ring; and
- R.sup.5 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl, optionally substituted with:
- i) hydroxy, or
- ii) (C.sub.1 -C.sub.4)-alkoxy; and
- R.sup.5a is
- (a) R.sup.5, or
- (b) (C.sub.1 -C.sub.4)-acyl; and
- R.sup.6 is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl, or
- (c) (C.sub.1 -C.sub.6)-alkyl substituted with hydroxy; and
- R.sup.6a is:
- (a) R.sup.6, or
- (b) (C.sub.1 -C.sub.6)-alkyl substituted with:
- i) CO.sub.2 R.sup.2,
- ii) CONHR.sup.2,
- iii) CON(R.sup.2).sub.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) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form a 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.2a R.sup.2a,
- (q) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2a R.sup.2a,
- (r) --NO.sub.2,
- (s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.2 a).sub.2,
- (t) --NR.sup.2a CO-(C.sub.1 -C.sub.4)-alkyl, or
- (u) --CON(R.sup.2a)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-- bridge 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) morpholin-4-yl,
- (v) OH,
- (vi) CO.sub.2 R.sup.2a, or
- (vii) 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,
- (xiii) -G.sup.1 -[(C.sub.1 -C.sub.6)-alkyl]-R.sup.27,
- (xiv) -N[CH.sub.2 CH.sub.2 ].sub.2 Q.sup.1, or
- (xv) -P(O)[O-(C.sub.1 -C.sub.4)-alkyl].sub.2,
- and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F,
- (d) (C.sub.3 -C.sub.7)-cycloalkyl, or
- (e) when Y is single bond, R.sup.11 and R.sup.12 can be joined to form a ring of 5 to 7 carbon atoms, the ring can be benzo-fused and one carbon of which can be replaced with a heteroatom selected from the group consisting of: O, S(O).sub.x and NR.sup.26 ; and
- with the proviso that when --A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is --N.dbd.CH--CH.dbd.CH--, --CH.dbd.N--CH.dbd.CH--, --CH.dbd.CH--N.dbd.CH--, or --CH.dbd.CH--CH.dbd.N--; R.sup.1 is CH.sub.3 ; E.dbd.Y.dbd.single bond; X is single bond, --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --; R.sup.9 and R.sup.10 are H; Z is CO.sub.2 R.sup.28 ; and R.sup.28 is (C.sub.1 -C.sub.4)-alkyl, then one and only one R.sup.11 and R.sup.12 is H;
- G.sup.1 is: a single bond, O, S(O).sub.n or NR.sup.27 ; and
- Q.sup.1 is: O, S(O).sub.n or NR.sup.26 ; and
- R.sup.13 is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl,
- (c) aryl,
- (d) aryl-(C.sub.1 -C.sub.6)-alkyl-(C.dbd.O)-,
- (e) (C.sub.1 -C.sub.6)-alkyl-(C.dbd.O)-,
- (f) [(C.sub.2 -C.sub.5)-alkenyl]CH.sub.2 -,
- (g) [(C.sub.2 -C.sub.5)-alkynyl]CH.sub.2 -, or
- (h) aryl-CH.sub.2 -; and
- Z is:
- (a) --CO.sub.2 H,
- (b) --CO.sub.2 R.sup.28,
- (c) -tetrazol-5-yl,
- (d) --CONH(tetrazol-5-yl)
- (e) --CONHSO.sub.2 -aryl,
- (f) --CONHSO.sub.2 -(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C.sub.1 -C.sub.4)--alkyl, --S--(C.sub.1 -C.sub.4)--alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4)--alkyl, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], or --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- (g) --CONHSO.sub.2 -(C.sub.1 -C.sub.4)-perfluoroalkyl,
- (h) --CONHSO.sub.2 -heteroaryl,
- (i) --CONHSO.sub.2 NR.sup.2a R.sup.2a,
- (j) --SO.sub.2 NHCO-aryl,
- (k) --SO.sub.2 NHCO-(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S-(C.sub.1 -C.sub.4)-alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 -(C.sub.1 -C.sub.4)-alkyl, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], or --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- (l) --SO.sub.2 NHCO-(C.sub.1 -C.sub.4)-perfluoroalkyl,
- (m) --SO.sub.2 NHCO-heteroaryl,
- (n) --SO.sub.2 NHCONR.sup.2a R.sup.2a,
- (o) --PO(OH).sub.2,
- (p) --PO(OR.sup.2).sub.2, or
- (q) --PO(OH)(OR.sup.2); and
- R.sup.20 is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl,
- (c) allyl,
- (d) (C.sub.3 -C.sub.6)-cycloalkyl,
- (e) (C.sub.1 -C.sub.4)-acyl,
- (f) benzyl, or
- (g) phenyl; and
- R.sup.21 is:
- (a) H, or
- (b) (C.sub.1 -C.sub.4)-alkyl, 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 groups 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, each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C.sub.3 -C.sub.7)-cycloalkyl, Cl, Br, I, F, --OH, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --NHSO.sub.2 R.sup.25, --CO.sub.2 R.sup.25, (C.sub.1 -C.sub.4)-alkoxyl, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-acyl, or C(.dbd.O)NH.sub.2,
- (c) aryl,
- (d) substituted aryl in which the substituents are V or W, as defined below,
- (e) aryl-(C.sub.1 -C.sub.4)-alkyl, which can be substituted with V or W as defined below,
- (f) Cl, Br, I, F,
- (g) hydroxyl,
- (h) amino,
- (i) NH[C.sub.1 -C.sub.4)-alkyl],
- (j) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- (k) (C.sub.1 -C.sub.6)-alkoxy,
- (l) CF.sub.3,
- (m) CO.sub.2 R.sup.25,
- (n) C(.dbd.O)N(R.sup.25).sub.2,
- (o) N(R.sup.25)-C(.dbd.O)R.sup.25,
- (p) (C.sub.1 -C.sub.4)-alkylsulfonyl,
- (q) (C.sub.1 -C.sub.4)-alkylsulfinyl, or
- (r) (C.sub.1 -C.sub.4)-alkylthio; and
- R.sup.23 is:
- (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 each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C.sub.3 -C.sub.7)-cycloalkyl, Cl, Br, I, F, --OH, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --NHSO.sub.2 R.sup.25, --CO.sub.2 R.sup.25, (C.sub.1 -C.sub.4)-alkoxyl, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-acyl, or C(.dbd.O)NH.sub.2,
- (c) --C(.dbd.O)R.sup.25,
- (d) --CO.sub.2 R.sup.25,
- (e) aryl, which is unsubstituted or substituted with substituents V or W,
- (f) aryl-(C.sub.1 -C.sub.4)-alkyl, which is unsubstituted or substituted with V or W; and
- R.sup.24 groups 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 each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C.sub.3 -C.sub.7)-cycloalkyl, Cl, Br, I, F, --OH, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --NHSO.sub.2 R.sup.25, --CO.sub.2 R.sup.25, (C.sub.1 -C.sub.4)-alkoxyl, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-acyl, or C(.dbd.O)NH.sub.2,
- (c) aryl or aryl-(C.sub.1 -C.sub.4)-alkyl which is unsubstituted or substituted with V or W; and
- V and W are each independently selected from:
- (a) H,
- (b) (C.sub.1 -C.sub.5)-alkoxy,
- (c) (C.sub.1 -C.sub.5)-alkyl,
- (d) hydroxy,
- (e) --S(O).sub.n -(C.sub.1 -C.sub.5)-alkyl,
- (f) --CN,
- (g) --NO.sub.2,
- (h) --NR.sup.2 R.sup.2a,
- (i) --[(C.sub.1 -C.sub.5)-alkyl]-CONR.sup.2 R.sup.2a,
- (j) --CO.sub.2 R.sup.2a,
- (k) --CO-(C.sub.1 -C.sub.5)-alkyl,
- (l) CF.sub.3,
- (m) I, Br, Cl, F
- (n) hydroxy-(C.sub.1 -C.sub.4)-alkyl-,
- (o) carboxy-(C.sub.1 -C.sub.4)-alkyl-,
- (p) -tetrazol-5-yl,
- (q) --NH--SO.sub.2 CF.sub.3, or
- (r) aryl; and
- R.sup.25 is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl,
- (c) aryl, or
- (d) aryl-(C.sub.1 -C.sub.5)-alkyl; and
- R.sup.26 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,
- (j) P(O)[(C.sub.1 -C.sub.4)-alkoxyl].sub.2, or
- (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C.sub.1 -C.sub.4)-alkyl; and
- R.sup.27 is:
- (a) OH,
- (b) NR.sup.2 R.sup.21,
- (c) CO.sub.2 R.sup.2a,
- (d) CON(R.sup.2).sub.2,
- (e) S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
- (f) N(CH.sub.2 CH.sub.2).sub.2 Q; and
- R.sup.28 is:
- (a) (C.sub.1 -C.sub.4)-alkyl,
- (b) CHR.sup.29 --O--COR.sup.30,
- (c) CH.sub.2 CH.sub.2 --N[(C.sub.1 -C.sub.2)-alkyl].sub.2,
- (d) CH.sub.2 CH.sub.2 -N[CH.sub.2 CH.sub.2 ].sub.2 O,
- (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 CO2-(C.sub.1 -C.sub.4)-alkyl,
- R.sup.29 and R.sup.30 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.
- 2. The compound of claim 1 of structural formula: ##STR101## or a pharmaceutically acceptable salt thereof.
- 3. A compound which is ##STR102## 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,
- 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 and is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
- i) Cl, Br, I, 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) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the heteroaryl is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
- i) Cl, Br, I, F,
- ii) OH,
- iii) SH,
- iv) NO.sub.2,
- v) (C.sub.1 -C.sub.4)-alkyl,
- vi) (C.sub.2 -C.sub.4)-alkenyl,
- vii) (C.sub.2 -C.sub.4)-alkynyl,
- viii) (C.sub.1 -C.sub.4)-alkoxy, or
- ix) CF.sub.3, or
- (d) (C.sub.1 -C.sub.4)-perfluoroalkyl; and
- R.sup.2a is: H, (C.sub.1 -C.sub.6)-alkyl, benzyl, or phenyl; and
- R.sup.4 groups are independently:
- (C.sub.1 -C.sub.4)-alkyl,
- (C.sub.2 -C.sub.4)-alkenyl,
- (C.sub.2 -C.sub.4)-alkynyl,
- (C.sub.3 -C.sub.5)-cycloalkyl,
- CO.sub.2 R.sup.2a
- Br, Cl, F, I,
- --NR.sup.2a R.sup.2a,
- S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
- O--(C.sub.1 -C.sub.4)-alkyl,
- OH,
- CF.sub.3,
- CN,
- hydroxy-(C.sub.1 -C.sub.4)-alkyl, or
- phenyl, unsubstituted or substituted with: (C.sub.1 -C.sub.4)-alkyl, Br, Cl, F, I or, methoxy; and
- n is 0, 1 or 2,
- R.sup.9 and R.sup.10 are independently: H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl, aryl, (C.sub.2 -C.sub.6)-alkynyl, (C.sub.1 -C.sub.6)-alkoxyl, Br, Cl, I, F or R.sup.9 and R.sup.10 join to form a phenyl ring and
- 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., which is double bonded to the carbon bearing Z and R.sup.11 ; and
- Z is:
- (a) --CO.sub.2 H,
- (b) --CO.sub.2 --(C.sub.1 -C.sub.6)-alkyl,
- (c) -tetrazol-5-yl,
- (d) --CONH(tetrazol-5-yl)
- (e) --CONHSO.sub.2 -aryl,
- (f) --CONHSO.sub.2 -(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substitutent selected from the group consisting of:
- --OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --NH.sub.2, --CO.sub.2 -(C.sub.1 -C.sub.4)-alkyl, --NH[(C.sub.1 -C.sub.4)-alkyl], or --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
- (g) --CONHSO.sub.2 -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
- (h) --CONHSO.sub.2 -heteroaryl, or
- (i) --CONHSO.sub.2 NR.sup.2a R.sup.2a ; and
- R.sup.11 is: aryl-CH.sub.2 -- or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
- Br, I, Cl, F, (C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.4)-alkenyl, (C.sub.2 -C.sub.4)-alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, (C.sub.1 -C.sub.4)-alkylthio, hydroxyl, --NR.sup.2a R.sup.2a ; and
- R.sup.13 is:
- (a) H,
- (b) (C.sub.1 -C.sub.6)-alkyl,
- (c) aryl, wherein aryl is unsubstituted or --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21, substituted with 1 or 2 substituents --NO.sub.2, selected from the group consisting of:
- Br, I, Cl, F, (C.sub.1 -C.sub.4)-alkyl, --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or (C.sub.1 -C.sub.4)-alkoxy, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, --CON(R.sup.2)2; (C.sub.1 -C.sub.4)-alkylthio, hydroxy, --NR.sup.2a R.sup.2a,
- (d) aryl-(C.sub.1 -C.sub.6)-alkyl-(C.dbd.O)--, or
- (e) (C.sub.1 -C.sub.6)-alkyl-(C.dbd.O)--.
- 4. A compound which is ##STR103## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is: (C.sub.1 -C.sub.4)-alkyl and cyclopropyl; and
- R.sup.2a is: H, (C.sub.1 -C.sub.6)-alkyl, benzyl, or phenyl; and
- R.sup.4 groups are independently: hydrogen, (C.sub.1 -C.sub.4)-alkyl, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, CH.sub.2 OH, CO.sub.2 H, (C.sub.1 -C.sub.4)-alkoxy or NHCH.sub.3 ; and
- R.sup.9 and R.sup.10 are: (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkenyl or (C.sub.1 -C.sub.6)-alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, Cl, Br, I, F, (C.sub.3 -C.sub.8)-cycloalkyl, or aryl; and
- R.sup.11 is: aryl or aryl-CH.sub.2 --, wherein the aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl, F, I, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxyl, NO.sub.2, CF.sub.3, (C.sub.1 -C.sub.4)-alkylthio, OH, --NR.sup.2a R.sup.2a and
- X is: O, NR.sup.13, CH.sub.2, or --CH.dbd., which is double bonded to the carbon bearing Z and R.sup.11 ; and
- R.sup.13 is: H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkenyl, aryl; and
- Z is: CO.sub.2 H, CO.sub.2 -(C.sub.1 -C.sub.4)-alkyl, 1H-tetrazol-5-yl, --CONHSO.sub.2 -aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
- H, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, (C.sub.1 -C.sub.4)-alkylthio, hydroxy, amino, (C.sub.3 -C.sub.7)-cycloalkyl, (C.sub.3 -C.sub.10)-alkenyl, or
- --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S, and is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
- Br, Cl, F, I, OH, SH, NO.sub.2, (C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.4)-alkenyl, (C.sub.2 -C.sub.4)-alkynyl, (C.sub.1 -C.sub.4)-alkoxy, or CF.sub.3.
- 5. The compound of claim 1 of structural formula: ##STR104## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is: (C.sub.1 -C.sub.4)-alkyl,
- R.sup.4c is: hydrogen, methyl or ethyl; and
- R.sup.4d is: R.sup.4c, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, CH.sub.2 OH, CO.sub.2 H, (C.sub.1 -C.sub.4)-alkyl or NHCH.sub.3 ; and
- R.sup.9 and R.sup.10 are: (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkenyl or (C.sub.1 -C.sub.6)-alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, Cl, Br, I, F, or phenyl; and
- X is O or NR.sup.13 ; and
- R.sup.11 is: benzyl or phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
- Br, I, Cl, F, (C.sub.1 -C.sub.4)-alkyl, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, (C.sub.1 -C.sub.4)-alkylthio, hydroxyl, NR.sup.2a R.sup.2a,
- Z is: CO.sub.2 H, CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl or 1H-tetrazol-5yl.
- 6. The compound of claim 1 of structural formula: ##STR105## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is: (C.sub.1 -C.sub.4)-alkyl,
- R.sup.4c is: hydrogen, methyl or ethyl; and
- R.sup.4d is: R.sup.4c, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, CH.sub.2 OH, CO.sub.2 H, (C.sub.1 -C.sub.4)-alkyl or NHCH.sub.3 ; and
- R.sup.9 and R.sup.10 are: (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkenyl or (C.sub.1 -C.sub.6)-alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, Cl, Br, I, F, or phenyl; and
- R.sup.11 is: benzyl or phenyl, wherein phenyl is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
- Br, I, Cl, F, (C.sub.1 -C.sub.4)-alkyl, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, (C.sub.1 -C.sub.4)-alkylthio, hydroxyl, --NR.sup.2a R.sup.2a
- Z is: CO.sub.2 H, CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, or 1H-tetrazol-5-yl.
- 7. The compound of claim 1 of structural formula: ##STR106## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is: (C.sub.1 -C.sub.4)-alkyl; and
- R.sup.4c is: hydrogen, methyl or ethyl; and
- R.sup.4d is: R.sup.4c, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, CH.sub.2 OH, CO.sub.2 H, (C.sub.1 -C.sub.4)-alkyl or NHCH.sub.3 ; and
- R.sup.9 and R.sup.10 are: (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkenyl or (C.sub.1 -C.sub.6)-alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, Cl, Br, I, F, or phenyl; and
- R.sup.11 is: benzyl or phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
- Br, I, Cl, F, (C.sub.1 -C.sub.4)-alkyl, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, (C.sub.1 -C.sub.4)-alkylthio, hydroxyl, --NR.sup.2a R.sup.2a
- Z is: CO.sub.2 H, CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, or 1H-tetrazol-5-yl.
- 8. A compound which is ##STR107## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is: (C.sub.1 -C.sub.4)-alkyl,
- R2a is: hydrogen or (C.sub.1 -C.sub.4)-alkyl; and
- R.sup.4c is: hydrogen, methyl or ethyl; and
- R.sup.4d is: R.sup.4c, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, CH.sub.2 OH, CO.sub.2 H, CO.sub.2 CH.sub.2 (C.sub.1 -C.sub.4)-alkyl or NHCH.sub.3 ; and
- R.sup.9 and R.sup.10 are: (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkenyl or (C.sub.1 -C.sub.6)-alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, Cl, Br, I, F, or phenyl; and
- R.sup.11 is: benzyl or phenyl, wherein phenyl unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
- Br, I, Cl, F, (C.sub.1 -C.sub.4)-alkyl, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkynyl, (C.sub.1 -C.sub.4)-alkoxyl, NO.sub.2, CF.sub.3, SO.sub.2 NR.sup.2a R.sup.2a, (C.sub.1 -C.sub.4)-alkylthio, hydroxyl, --NR.sup.2a R.sup.2a
- R.sup.13 is: (C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.4)-alkenyl, or phenyl; and
- Z is: CO.sub.2 H, CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, or 1H-tetrazol-5-yl.
- 9. The compound of claim 1 wherein said compound or its pharmaceutically acceptable salt is selected from the group consisting of:
- 3-[4-(1-Carboxy-1-(2-methylphenyl))methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-(1-Carboxy-1-(2-bromophenyl))methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[3-Chloro-4-((1-carboxy-1-phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-(1-Carboxy-1-(3-methylnaphth-2-yl))methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-phenyl)methoxy)-3-methylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-(2-methylphenyl))methoxy)-3-chlorophenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-phenyl)methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-(2methylphenyl))methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-(2,5-dibromo-3,4-dimethoxyphenyl))methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-((1-Carboxy-1-phenyl)methoxy)-3,5-dipropylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-N-(1-Carboxy-1-phenyl)methyl)-N-allylaminophenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-(1-Carboxy-1-phenyl)methoxy-3-propylphenyl]methyl-5-carbomethoxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;
- 3-[4-(1-Carboxy-1-phenyl)methoxy-3-propylphenyl]methyl-5-carbobenzyloxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;
- 5,7-Dimethyl-2-ethyl-3-[3-chloro-4-((1-(N-phenylsulfonyl)carboxamido)-1-phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine;
- 5,7-Dimethyl-2-ethyl-3-[3-ethyl-4-((1-(N-phenylsulfonyl)carboxamido)-1-phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine;
- 5,7-Dimethyl-2-ethyl-3-[3,5-dipropyl-4-((1-(N-phenylsulfonyl)carboxamido)-1-phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine.
- 10. A method of treating hypertension which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 11. 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.
- 12. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of claim 1.
- 13. A method of treating cognitive dysfunction, anxiety, or depression comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of claim 1.
Parent Case Info
The present application is a continuation in part of copending U.S. application Ser. No. 671,551 filed on Mar. 19, 1991, (now abandoned) which is a continuation in part application of copending U.S. Ser. No. 479,786 filed on Feb. 13, 1991 (now abandoned).
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Continuation in Parts (2)
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Number |
Date |
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Parent |
671551 |
Mar 1991 |
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Parent |
479786 |
Feb 1991 |
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