US 5,177,095 AGranted

Triazole angiotensin II antagonists incorporating a substituted benzyl element

AssigneeMerck & Co., Inc.

InventorsWilliam J. Greenlee, Arthur A. Patchett, David Hangauer, Wallace Ashton, Kenneth J. Fitch, Thomas F. Walsh, Ralph A. Rivero, Daljit S. Dhanoa

Life of this patent

Estimating the term…

Abstract

Substituted triazoles attached through a methylene bridge to novel substituted phenyl derivatives of the Formula I, are useful as angiotensin II antagonists. ##STR1##

Claims9

Dependent claims

A compound of Formula I wherein:

##STR33## 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 one or more substituents selected from the group consisting of:
i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
1) Cl, Br, I, F,
2) (C.sub.1 -C.sub.4)-alkyl,
3) (C.sub.1 -C.sub.4)-alkoxy,
4) NO.sub.2,
5) CF.sub.3,
6) SO.sub.2 NR.sup.2a R.sup.2a,
7) (C.sub.1 -C.sub.4)-alkylthio,
8) hydroxy,
9) amino,
10) (C.sub.3 -C.sub.7)-cycloalkyl,
11) (C.sub.3 -C.sub.10)-alkenyl;
and
ii) (C.sub.3 -C.sub.7)-cycloalkyl,
iii) Cl, Br, I, F, or
iv) COOR.sup.2,
v) --CF.sub.2 CF.sub.3, or
vi) --CH.sub.2 CF.sub.3 ;
and
(b) (C.sub.1 -C.sub.4)-perfluoroalkyl, or
(c) (C.sub.3 -C.sub.6)-cycloalkyl, unsubstituted or substituted with one or more substituents from the group consisting of:
(C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkyl- thio, perfluoro-(C.sub.1 -C.sub.4)-alkyl, hydroxy, or halogen (F,Cl,Br,I);
and
E is:
(a) a single bond,
(b) --S(O).sub.n (CH.sub.2).sub.s --, or
--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
(d) when R.sup.2 and R.sup.2a are alkyl substituents on the same nitrogen then can be joined to form a ring;
and
wherein there is more than one R.sup.2a group in the definition of a structure of Formula I they may be the same or different;
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)-alkoxyl,
(g) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form an 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) 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) --CO.sub.2 R.sup.2a,
(n) --OH,
(o) --NR.sup.2 R.sup.21,
(p) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21,
(q) --NO.sub.2,
(r) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.2).sub.2,
(s) --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or
(t) --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-- 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).sub.2,
(xiii) --G--[(C.sub.1 -C.sub.6)-alkyl]-R.sup.23,
(xiv) --N[CH.sub.2 CH.sub.2 ].sub.2 Q, 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;
G is:
a single bond, O, S(O).sub.n or NR.sup.23 ;
and
Q is:
O, S(O).sub.n or NR.sup.22 ;
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.0)--,
(e) (C.sub.1 -C.sub.6)-alkyl--(C.dbd.0)--,
(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.24,
(c) --tetrazol-5-yl,
(d) --CO--NH(tetrazol-5-yl),
(e) --CONHSO.sub.2 --aryl,
(f) --CONH-SO.sub.2 --(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent chosen 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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(g) --CONH--SO.sub.2 -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(h) --CONH--SO.sub.2 -heteroaryl, wherein heteroaryl is as defined below,
(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 chosen 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], --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, or
(n) --SO.sub.2 NHCONR.sup.2a R.sup.2a ;
and
T is --S(O).sub.n --, --O--, --NHCH.sub.2 --, --NHC(.dbd.O)--, --C(.dbd.O)N(R.sup.20)-, or --N(R.sup.20)-;
and
b is 0 or 1;
and
R.sup.15 is
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) phenyl, or
(d) benzyl;
and
R.sup.16 is
(a) (C.sub.1 -C.sub.10)-alkyl;
(b) substituted (C.sub.1 -C.sub.10)-alkyl in which one or more substituent(s) is selected from
(1) I, Br, Cl, F,
(2) hydroxy,
(3) (C.sub.1 -C.sub.10)-alkoxy,
(4) (C.sub.1 -C.sub.5)-alkoxycarbonyl,
(5) (C.sub.1 -C.sub.5)-acyloxy,
(6) (C.sub.3 -C.sub.8)-cycloalkyl,
(7) aryl,
(8) substituted aryl in which the substituents are V and W,
(9) (C.sub.1 -C.sub.10)-alkyl--S(O).sub.n,
(10) (C.sub.3 -C.sub.8)-cycloalkyl--S(O).sub.n,
(11) phenyl-S(O).sub.n,
(12) substituted phenyl-S(O).sub.n in which the substituents are V and W,
(13) oxo,
(14) carboxy,
(15) NR.sup.2 R.sup.2a,
(16) (C.sub.1 -C.sub.5)-alkylaminocarbonyl,
(17) di(C.sub.1 -C.sub.5)-alkylaminocarbonyl, or
(18) cyano,
(c) perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(d) (C.sub.2 -C.sub.10)-alkenyl,
(e) (C.sub.2 -C.sub.10)-alkynyl,
(f) (C.sub.3 -C.sub.8)-cycloalkyl,
(g) substituted (C.sub.3 -C.sub.8)-cycloalkyl in which the substituent is selected from:
(1) (C.sub.1 -C.sub.5)-alkyl, or
(2) (C.sub.1 -C.sub.5)-alkoxy,
(3) (C.sub.1 -C.sub.5)-alkoxycarbonyl,
(4) (C.sub.1 -C.sub.5)-acyloxy,
(5) (C.sub.1 -C.sub.5)-acyl,
(6) hydroxy,
(7) Br, Cl, F, I,
(8) (C.sub.3 -C.sub.8)-cycloalkyl,
(9) aryl,
(10) substituted aryl in which the substituents are V and W,
(11) (C.sub.1 -C.sub.10)-alkyl-S(O).sub.n,
(12) (C.sub.3 -C.sub.8)-cycloalkyl-S(O).sub.n,
(13) phenyl-S(O).sub.n,
(14) substituted phenyl-S(O).sub.n in which the substituents are V and W,
(15) oxo,
(16) carboxy,
(17) NR.sup.2 R.sup.2a,
(18) (C.sub.1 -C.sub.5)-alkylaminocarbonyl,
(19) di(C.sub.1 -C.sub.5)-alkylaminocarbonyl, or
(20) cyano,
(h) CO.sub.2 R.sup.2a,
(i) aryl,
(j) substituted aryl in which the substituents are V and W,
(k) aryl--(CH.sub.2).sub.r --(M.sub.1).sub.z --(CH.sub.2).sub.t --
(l) substituted aryl--(CH.sub.2).sub.r --(M.sub.1).sub.z --(CH.sub.2).sub.t -- in which the aryl group is substituted with V and W, ##STR34## M.sub.1 is O, S, --N(R.sup.15)--, or --C(O)--;
and z is 0 or 1;
and
r and t are 0 to 2;
and
heteroaryl is:
a 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group consisting of N, O or S;
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) ((C.sub.1 -C.sub.5)-alkyl)S(O).sub.n,
(f) --CN,
(g) --NO.sub.2,
(h) --NR.sup.2 R.sup.2a,
(i) ((C.sub.1 -C.sub.5)-alkyl)CO--NR.sup.2 R.sup.2a,
(j) --CO.sub.2 R.sup.2a,
(k) ((C.sub.1 -C.sub.5)--alkyl)CO--,
(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,
(r) aryl,
(s) --O--CONR.sup.2 R.sup.2a,
(t) --NR.sup.2a --CO.sub.2 R.sup.2a,
(u) --NR.sup.2a --CONR.sup.2a R.sup.2a,
(v) --NR.sup.2a --CON(CH.sub.2 CH.sub.2).sub.2 Q,
(w) --OCON(CH.sub.2 CH.sub.2).sub.2 Q;
or
(x) --CONR.sup.2 R.sup.2a ;
and
Q.sub.1 is O, S(O).sub.n, or NR.sup.2a ;
and
R.sup.18 is:
phenyl, unsubstituted or substituted with:
V and W, (C.sub.1 -C.sub.4)-alkyl, or perfluoro-(C.sub.1 -C.sub.4)-alkyl;
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, 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,
(j) P(O)[(C.sub.1 -C.sub.4)-alkoxyl].sub.2, or
(k) imidazol-2-yl or imidazol-4-yl, in which the imidazole can be substituted with (C1-C4)-alkyl;
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.n -(C.sub.1 -C.sub.4)-alkyl;
and
R.sup.24 is:
(a) (C.sub.1 -C.sub.4)-alkyl,
(b) CHR.sup.26 --O--COR.sup.27,
(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, ##STR35## 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 and R.sup.27 are (C.sub.1 -C.sub.6)-alkyl or phenyl.

309 more elements

A compound which is ##STR36## 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 with a substituent selected from the group consisting of:
ii) (C.sub.3 -C.sub.7)-cycloalkyl,
iii) Cl, Br, I, F, or
iv) COOR.sup.2,
v) --CF.sub.2 CF.sub.3, or
vi) --CH.sub.2 CF.sub.3 ;
and
(b) perfluoro-(C.sub.1 -C.sub.4)-alkyl, or
(c) (C.sub.3 -C.sub.6)-cycloalkyl;
and
R.sup.2 is:
H, or (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.2a is:
R.sup.2, benzyl, or phenyl;
and when R.sup.2 and R.sup.2a are alkyl substituents on the same nitrogen then can be joined to form a ring;
R.sup.9 and R.sup.10 are independently:
H, (C.sub.1 -C.sub.6 -alkyl, (C.sub.2 -C.sub.6)-alkenyl, (C.sub.2 -C.sub.6)-alkynyl, Cl, Br, F, I, (C.sub.1 -C.sub.6)-alkoxy, aryl, or R.sup.9 and R.sup.10 join to form a phenyl ring;
and
X and Y are:
--CH.sub.2 --, --O--, --S--, --NR.sup.13 --, single bond, or --CH.dbd., which is double bonded to the carbon bearing Z and R.sup.11, except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously bonded to two heteroatoms (O, N, or S(O).sub.n);
and
Z is:
(a) --CO.sub.2 H,
(b) --CO.sub.2 --(C.sub.1 -C.sub.6)-alkyl,
(c) -tetrazol-5-yl,
(d) --CO--NH(tetrazol-5-yl)
(e) --CONH--SO.sub.2 --aryl,
(f) --CONH--SO.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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(g) --CONH--SO.sub.2 --perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(h) --CONH--SO.sub.2 -heteroaryl, or
(i) --CONHSO.sub.2 NR.sup.2 R.sup.2a ;
and
R.sup.11 and R.sup.12 are independently:
H, (C.sub.1 -C.sub.6)-alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, 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 ;
and
R.sup.13 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) aryl, wherein aryl is 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.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, --NR.sup.2a R.sup.2a,
(c) [(C.sub.2 -C.sub.5)-alkenyl]CH.sub.2 --,
(d) [(C.sub.2 -C.sub.5)-alkynyl]CH.sub.2 --,
(e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Cl, Br, I, F, (C.sub.1 -C.sub.4)-alkyl, (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, hydroxy, amino, (C.sub.3 -C.sub.7)-cycloalkyl, or (C.sub.3 -C.sub.10)-alkenyl,
(f) aryl[(C.sub.1 -C.sub.6)-alkyl]CO--, or
(g) [(C.sub.1 -C.sub.6)-alkyl]CO--;
and
T is --S(O)n--, --O--, --NHCH.sub.2 --, NHC(.dbd.O)--, --C(.dbd.O)NR.sup.30, or --N(R.sup.20);
and
b is 0 or 1;
and
R.sup.16 is
(a) (C.sub.1 -C.sub.10)-alkyl in which one or more substituent(s) is selected from the group consisting of:
hydroxy, oxy, carboxy, (C.sub.1 -C.sub.5)-alkoxy-carbonyl, (C.sub.3 -C.sub.8)-cycloalkyl, aryl, or substituted aryl in which the substituents are V and W, and
(b) aryl, unsubstituted or substituted in which the substituents are V and W;
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) ((C.sub.1 -C.sub.5)-alkyl)S(O).sub.n,
(f) --CN,
(g) --NO.sub.2,
(h) --NR.sup.2 R.sup.2a,
(i) [(C.sub.1 -C.sub.5)-alkyl]CO-NR.sup.2 R.sup.2a,
(j) --CO.sub.2 R.sup.2a,
(k) [(C.sub.1 -C.sub.5)-alkyl]CO-,
(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,
(r) aryl,
(s) --O--CONR.sup.2 R.sup.2a,
(t) NR.sup.2a --CO.sub.2 R.sup.2a,
(u) --NR.sup.2a --CONR.sup.2a R.sup.2a,
(v) --NR.sup.2a --CON(CH.sub.2 CH.sub.2).sub.2 Q,
(w) --OCON(CH.sub.2 CH.sub.2).sub.2 Q, or
(x) --CONR.sup.2 R.sup.2a ;
and
Q is:
O, S(O).sub.n, or NR.sup.2a ;
and
R.sup.20 is:
H or (C.sub.1 -C.sub.6)-alkyl;
and
heteroaryl is:
pyridyl, thienyl, furyl, imidazolyl or thiazolyl.

91 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/744,554Filed 13 Aug 1991 · continuation in part
Priority: 13 Feb 1990
Granted: 5 Jan 1993
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 249/08
Not condensed with other rings: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
C07D 249/12
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D
Heterocyclic compounds

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Serial479,779Parent of this continuation-in-part · filed 13 Feb 1990
Serial671,598Parent of this continuation-in-part · filed 19 Mar 1991
US 5,177,095 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Substituted triazoles attached through a methylene bridge to novel substituted phenyl derivatives of the Formula I, are useful as angiotensin II antagonists. ##STR1##

A compound of Formula I wherein:

##STR33## 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 one or more substituents selected from the group consisting of:
i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
1) Cl, Br, I, F,
2) (C.sub.1 -C.sub.4)-alkyl,
3) (C.sub.1 -C.sub.4)-alkoxy,
4) NO.sub.2,
5) CF.sub.3,
6) SO.sub.2 NR.sup.2a R.sup.2a,
7) (C.sub.1 -C.sub.4)-alkylthio,
8) hydroxy,
9) amino,
10) (C.sub.3 -C.sub.7)-cycloalkyl,
11) (C.sub.3 -C.sub.10)-alkenyl;
and
ii) (C.sub.3 -C.sub.7)-cycloalkyl,
iii) Cl, Br, I, F, or
iv) COOR.sup.2,
v) --CF.sub.2 CF.sub.3, or
vi) --CH.sub.2 CF.sub.3 ;
and
(b) (C.sub.1 -C.sub.4)-perfluoroalkyl, or
(c) (C.sub.3 -C.sub.6)-cycloalkyl, unsubstituted or substituted with one or more substituents from the group consisting of:
(C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkyl- thio, perfluoro-(C.sub.1 -C.sub.4)-alkyl, hydroxy, or halogen (F,Cl,Br,I);
and
E is:
(a) a single bond,
(b) --S(O).sub.n (CH.sub.2).sub.s --, or
--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
(d) when R.sup.2 and R.sup.2a are alkyl substituents on the same nitrogen then can be joined to form a ring;
and
wherein there is more than one R.sup.2a group in the definition of a structure of Formula I they may be the same or different;
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)-alkoxyl,
(g) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form an 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) 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) --CO.sub.2 R.sup.2a,
(n) --OH,
(o) --NR.sup.2 R.sup.21,
(p) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.2 R.sup.21,
(q) --NO.sub.2,
(r) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.2).sub.2,
(s) --NR.sup.2 CO--(C.sub.1 -C.sub.4)-alkyl, or
(t) --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-- 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).sub.2,
(xiii) --G--[(C.sub.1 -C.sub.6)-alkyl]-R.sup.23,
(xiv) --N[CH.sub.2 CH.sub.2 ].sub.2 Q, 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;
G is:
a single bond, O, S(O).sub.n or NR.sup.23 ;
and
Q is:
O, S(O).sub.n or NR.sup.22 ;
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.0)--,
(e) (C.sub.1 -C.sub.6)-alkyl--(C.dbd.0)--,
(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.24,
(c) --tetrazol-5-yl,
(d) --CO--NH(tetrazol-5-yl),
(e) --CONHSO.sub.2 --aryl,
(f) --CONH-SO.sub.2 --(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent chosen 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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(g) --CONH--SO.sub.2 -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(h) --CONH--SO.sub.2 -heteroaryl, wherein heteroaryl is as defined below,
(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 chosen 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], --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, or
(n) --SO.sub.2 NHCONR.sup.2a R.sup.2a ;
and
T is --S(O).sub.n --, --O--, --NHCH.sub.2 --, --NHC(.dbd.O)--, --C(.dbd.O)N(R.sup.20)-, or --N(R.sup.20)-;
and
b is 0 or 1;
and
R.sup.15 is
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) phenyl, or
(d) benzyl;
and
R.sup.16 is
(a) (C.sub.1 -C.sub.10)-alkyl;
(b) substituted (C.sub.1 -C.sub.10)-alkyl in which one or more substituent(s) is selected from
(1) I, Br, Cl, F,
(2) hydroxy,
(3) (C.sub.1 -C.sub.10)-alkoxy,
(4) (C.sub.1 -C.sub.5)-alkoxycarbonyl,
(5) (C.sub.1 -C.sub.5)-acyloxy,
(6) (C.sub.3 -C.sub.8)-cycloalkyl,
(7) aryl,
(8) substituted aryl in which the substituents are V and W,
(9) (C.sub.1 -C.sub.10)-alkyl--S(O).sub.n,
(10) (C.sub.3 -C.sub.8)-cycloalkyl--S(O).sub.n,
(11) phenyl-S(O).sub.n,
(12) substituted phenyl-S(O).sub.n in which the substituents are V and W,
(13) oxo,
(14) carboxy,
(15) NR.sup.2 R.sup.2a,
(16) (C.sub.1 -C.sub.5)-alkylaminocarbonyl,
(17) di(C.sub.1 -C.sub.5)-alkylaminocarbonyl, or
(18) cyano,
(c) perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(d) (C.sub.2 -C.sub.10)-alkenyl,
(e) (C.sub.2 -C.sub.10)-alkynyl,
(f) (C.sub.3 -C.sub.8)-cycloalkyl,
(g) substituted (C.sub.3 -C.sub.8)-cycloalkyl in which the substituent is selected from:
(1) (C.sub.1 -C.sub.5)-alkyl, or
(2) (C.sub.1 -C.sub.5)-alkoxy,
(3) (C.sub.1 -C.sub.5)-alkoxycarbonyl,
(4) (C.sub.1 -C.sub.5)-acyloxy,
(5) (C.sub.1 -C.sub.5)-acyl,
(6) hydroxy,
(7) Br, Cl, F, I,
(8) (C.sub.3 -C.sub.8)-cycloalkyl,
(9) aryl,
(10) substituted aryl in which the substituents are V and W,
(11) (C.sub.1 -C.sub.10)-alkyl-S(O).sub.n,
(12) (C.sub.3 -C.sub.8)-cycloalkyl-S(O).sub.n,
(13) phenyl-S(O).sub.n,
(14) substituted phenyl-S(O).sub.n in which the substituents are V and W,
(15) oxo,
(16) carboxy,
(17) NR.sup.2 R.sup.2a,
(18) (C.sub.1 -C.sub.5)-alkylaminocarbonyl,
(19) di(C.sub.1 -C.sub.5)-alkylaminocarbonyl, or
(20) cyano,
(h) CO.sub.2 R.sup.2a,
(i) aryl,
(j) substituted aryl in which the substituents are V and W,
(k) aryl--(CH.sub.2).sub.r --(M.sub.1).sub.z --(CH.sub.2).sub.t --
(l) substituted aryl--(CH.sub.2).sub.r --(M.sub.1).sub.z --(CH.sub.2).sub.t -- in which the aryl group is substituted with V and W, ##STR34## M.sub.1 is O, S, --N(R.sup.15)--, or --C(O)--;
and z is 0 or 1;
and
r and t are 0 to 2;
and
heteroaryl is:
a 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group consisting of N, O or S;
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) ((C.sub.1 -C.sub.5)-alkyl)S(O).sub.n,
(f) --CN,
(g) --NO.sub.2,
(h) --NR.sup.2 R.sup.2a,
(i) ((C.sub.1 -C.sub.5)-alkyl)CO--NR.sup.2 R.sup.2a,
(j) --CO.sub.2 R.sup.2a,
(k) ((C.sub.1 -C.sub.5)--alkyl)CO--,
(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,
(r) aryl,
(s) --O--CONR.sup.2 R.sup.2a,
(t) --NR.sup.2a --CO.sub.2 R.sup.2a,
(u) --NR.sup.2a --CONR.sup.2a R.sup.2a,
(v) --NR.sup.2a --CON(CH.sub.2 CH.sub.2).sub.2 Q,
(w) --OCON(CH.sub.2 CH.sub.2).sub.2 Q;
or
(x) --CONR.sup.2 R.sup.2a ;
and
Q.sub.1 is O, S(O).sub.n, or NR.sup.2a ;
and
R.sup.18 is:
phenyl, unsubstituted or substituted with:
V and W, (C.sub.1 -C.sub.4)-alkyl, or perfluoro-(C.sub.1 -C.sub.4)-alkyl;
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, 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,
(j) P(O)[(C.sub.1 -C.sub.4)-alkoxyl].sub.2, or
(k) imidazol-2-yl or imidazol-4-yl, in which the imidazole can be substituted with (C1-C4)-alkyl;
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.n -(C.sub.1 -C.sub.4)-alkyl;
and
R.sup.24 is:
(a) (C.sub.1 -C.sub.4)-alkyl,
(b) CHR.sup.26 --O--COR.sup.27,
(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, ##STR35## 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 and R.sup.27 are (C.sub.1 -C.sub.6)-alkyl or phenyl.

309 more elements

Facts

Application

07/744,554Filed 13 Aug 1991 · continuation in part

Priority

13 Feb 1990

Granted

5 Jan 1993

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 249/08
Not condensed with other rings: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
C07D 249/12
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D
Heterocyclic compounds