US 5,175,164 AGranted

Angiotensin II antagonists incorporating a substituted indole or dihydroindole

AssigneeMerck & Co., Inc.

InventorsScott Bagley, William J. Greenlee, Daljit S. Dhanoa, Arthur A. Patchett

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Abstract

Substituted heterocycles attached through a methylene bridge to novel substituted indole or dihydroindole derivative of the Formula I are useful as angiotensin II antagonists. ##STR1##

Claims12

Dependent claims

A compound of structural formula I or a pharmaceutically acceptable salt ##STR53## wherein the heterocycle is defined as:

##STR54## 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 ;
(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, or
xi) (C.sub.3 -C.sub.10)-alkenyl;
(c) heteroaryl, wherein heteroaryl is selected from the group consisting of pyridyl, thienyl, furyl, imidazolyl and thiazolyl 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, monosubstituted or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, or 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;
E is:
(a) a single bond,
(b) --S(O).sub.n (CH.sub.2).sub.s --, or
(c) --O--;
n is 0 to 2;
s is 0 to 5;
J.sup.1 is (a)--C(.dbd.M)--, (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 or (c) J.sup.1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J.sup.1, substituted with R.sup.7a, R.sup.7b, R.sup.8a and R.sup.8b ;
K.sup.1 is (a)--C(.dbd.M)--, (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, or (c) K.sup.1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted on the carbon atoms with R.sup.7a, R.sup.7b and R.sup.8b ;
provided that one and only one of J.sup.1 and K.sup.1 is --C(.dbd.M)--;
one of a.sup.1 or b.sup.1 is a double bond in structures Ia provided that when J.sup.1 is --C(.dbd.M)-- then b.sup.1 is a double bond and when K.sup.1 is --C(.dbd.M)-- then a.sup.1 is a double bond;
L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom;
M is O, S or NR.sup.15 ;
R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
R.sup.2a is:
(a) R.sup.2,
(b) CH.sub.2 -aryl, or
(c) aryl;
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,
(d) CF.sub.3, or
(e) when R.sup.7a and R.sup.7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
R.sup.8a and R.sup.8b are independently
(a) H,
(b) aryl-(C.sub.1 -C.sub.4)-alkyl,
(c) heteroaryl-(C.sub.1 -C.sub.4)-alkyl,
(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, --heteroaryl, --S(O).sub.x --R.sup.21, --tetrazol-5-yl, --CONHSO.sub.2 R.sup.21, --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.21, --PO(OR.sup.2).sub.2, --PO(OR.sup.2a).sub.2, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.21, --OH, --NH.sub.2, guanidino, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkyl-amino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.2a, --CONHR.sup.2a, --O--COR.sup.2a, or aryl,
(e) --CO-aryl,
(f) (C.sub.3 -C.sub.7)-cycloalkyl,
(g) Cl, Br, I, F,
(h) --OH,
(i) --OR.sup.21,
(j) --SH,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --COR.sup.2a,
(m) --CO.sub.2 H,
(n) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
(o) --SO.sub.3 H,
(p) --NR.sup.2 R.sup.21,
(q) --NR.sup.2 COR.sup.21,
(r) --NR.sup.2 COOR.sup.21,
(s) --SO.sub.2 NHR.sup.2a,
(t) --SO.sub.2 NR.sup.2 R.sup.2a,
(u) --NO.sub.2,
(v) --NHSO.sub.2 CF.sub.3,
(w) --CONR.sup.2a R.sup.2a,
(x) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(y) --COOR.sup.2,
(z) --SO.sub.3 H,
(aa) --N(R.sup.2)SO.sub.2 R.sup.21,
(bb) --NR.sup.2 CONR.sup.4 R.sup.21,
(cc) --OC(.dbd.O)NR.sup.21 R.sup.2a,
(dd) --aryl,
(ee) --NHSO.sub.2 CF.sub.3,
(ff) --SO.sub.2 NH-heteroaryl,
(gg) --SO.sub.2 NHCOR.sup.21,
(hh) --CONHSO.sub.2 R.sup.21,
(ii) --PO(OR.sup.2).sub.2,
(jj) --tetrazol-5-yl,
(kk) --CONH(tetrazol-5-yl),
(ll) --SO.sub.2 NHCN, or
(mm) --heteroaryl;
X is:
(a) O,
(b) H;
H,
(c) H;
CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
(d) H;
CO.sub.2 H,
(e) H;
CN,
(f) H;
tetrazolyl, or
(g) H;
CONHSO.sub.2 R.sup.14,
R.sup.9 and R.sup.10 are each independently:
(a) H,
(b) Cl, Br, I, F,
(c) NO.sub.2,
(d) (C.sub.1 -C.sub.6 -alkyl,
(e) (C.sub.1 -C.sub.6)-acyloxy,
(f) (C.sub.3 -C.sub.6)-cycloalkyl,
(g) (C.sub.1 -C.sub.6)-alkoxy,
(h) --NHSO.sub.2 R.sup.2a,
(i) hydroxy-(C.sub.1 -C.sub.4)-alkyl,
(j) (C.sub.1 -C.sub.4)-alkyl-aryl,
(k) S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(n) NR.sup.2a R.sup.2a,
(q) CF.sub.3,
(r) --SO.sub.2 NHR.sup.2a,
(s) furyl,
(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted or substituted with one or two substituents selected from the group consisting of:
Cl, Br, I, F, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, NO.sub.2, CF.sub.3, (C.sub.1 -C.sub.4)-alkylthio, OH, NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --CO.sub.2 H, or --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, or
(u) when R.sup.9 and R.sup.10 are bonded to adjacent carbon atoms, they can be joined to form an aryl ring;
R.sup.11 and R.sup.12 are independently:
(a) H,
(b) Cl, Br, I, F,
(c) NO.sub.2,
(d) NH.sub.2,
(e) NH[(C.sub.1 -C.sub.4)-alkyl],
(f) N](C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) SO.sub.2 NHR.sup.2a,
(h) CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) (C.sub.1 -C.sub.4)-alkoxy, or
(k) when R.sup.11 and R.sup.12 are bonded to adjacent carbon atoms, they can be joined to form an aryl ring;
Z is:
(a) --H,
(b) --CO.sub.2 R.sup.2a,
(c) --SO.sub.3 R.sup.13,
(d) --NHSO.sub.2 CF.sub.3,
(e) --PO(OR.sup.13).sub.2,
(f) --SO.sub.2 NHR.sup.14,
(g) --CONHOR.sup.13, ##STR55## (i) --CN, (j) --SO.sub.2 NH-heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring Selected from the group consisting of pyridine, thienyl, furyl, imidazolyl and thiazolyl and wherein the substituents are members selected from the group consisting of:
--OH, --SH, --(C.sub.1 -C.sub.4)-alkyl, --(C.sub.1 -C.sub.4)-alkoxy, --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] and --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(k) --CH.sub.2 SO.sub.2 NH-heteroaryl,
(l) --SO.sub.2 NH--CO--R.sup.14,
(m) --CH.sub.2 SO.sub.2 NH--CO--R.sup.14,
(n) --CONH--SO.sub.2 R.sup.14,
(o) --CH.sub.2 CONH--SO.sub.2 R.sup.14,
(p) --NHSO.sub.2 NHCO--R.sup.14,
(q) --NHCONHSO.sub.2 --R.sup.14,
(r) --NHCO.sub.2 R.sup.2a, ##STR56## R.sup.14 is (a) aryl,
(b) heteroaryl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl, or
(d) (C.sub.1 -C.sub.4)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
aryl, heteroaryl, --OH, --SH, (C.sub.1 -C.sub.4)-alkyl, --(C.sub.1 -C.sub.4)-alkoxy, --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, --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --PO.sub.3 H or PO(OH)(O--(C.sub.1 -C.sub.4)-alkyl;
R.sup.15 is
(a) H,
(b) aryl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Cl, Br, I, F --O--(C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkyl, --NO.sub.2, --CF.sub.3, --SO.sub.2 NR.sup.2 R.sup.2a, --S--(C.sub.1 -C.sub.4)-alkyl, --OH, --NH.sub.2, (C.sub.3 -C.sub.7)-cycloalkyl, (C.sub.3 -C.sub.10)-alkenyl;
(c) (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:
aryl, (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, --NH--SO.sub.2 R.sup.2a, --COOR.sup.2a, --SO.sub.2 NHR.sup.2a ;
or
(d) an unsubstituted, monosubstituted or disubstituted hetero aryl selected from the group consisting of pyridyl, thienyl, furyl, imidazolyl and thiazolyl, and wherein the substituents are members selected from the group consisting of --OH, --SH, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkyloxy, --CF.sub.3, Cl, Br, I, F, or NO.sub.2 ;
and
R.sup.19 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) (C.sub.2 -C.sub.4)-alkenyl,
(d) (C.sub.1 -C.sub.4)-alkoxy, or
(e) benzyl, wherein the phenyl is unsubstituted or substituted with a substituent selected from the group consisting of:
--NO.sub.2, --NH.sub.2, --OH or --OCH.sub.3 ;
R.sup.20 is --CN, --NO.sub.2, --CO.sub.2 R.sup.2a, or --CF.sub.3 ;
and
R.sup.21 is:
(a) aryl, 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 ;
or a pharmaceutically acceptable salt thereof.

195 more elements

Dependencies are inferred from the claim text.

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