US 5,395,844 AGranted

Imidazole 5-position substituted angiotensin II antagonists

AssigneeThe Du Pont Merck Pharmaceutical Company

InventorsJohn J. V. Duncia, Carol L. Ensinger, Richard E. Olson, Mimi L. Quan, Joseph B. Santella, III, Mary K. Vanatten

Life of this patent

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Abstract

Novel substituted imidazoles of Formula (III), which are useful as angiotensin-II antagonists, are disclosed: ##STR1## These compounds, exemplified by the compound 1-((2'-((i-Amyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)me thyl)-5-[2-(N-butyryl-N-pyridin-3-ylamino) ethylcarbonyl]-4-ethyl-2-propyl-1H-imidazole, are useful as antihypertensive agents.

Claims5

Dependent claims

A compound of formula (III) ##STR574## wherein R.sup.2 is independently

(a) H,
(b) halo, or
(c) C.sub.1 -C.sub.4 -alkyl,
R.sup.3 is independently
(a) H, or
(b) halo,
R.sup.6 is
(a) C.sub.1 -C.sub.10 -alkyl,
(b) C.sub.3 -C.sub.10 -alkenyl, or
(c) C.sub.3 -C.sub.10 -alkynyl,
R.sup.7 is
(a) C.sub.1 -C.sub.6 -alkyl,
(b) C.sub.3 -C.sub.6 -cycloalkyl,
(c) aryl, or
(d) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or --NO.sub.2 ;
R.sup.8 is
(a) H,
(b) halo,
(c) aryl,
(d) C.sub.1 -C.sub.6 -alkyl, optionally substituted with
i) OR.sup.25,
ii) S(O).sub.r R.sup.10,
iii) NR.sup.23 R.sup.24,
iv) NR.sup.26 COR.sup.11,
v) NR.sup.26 CO.sub.2 R.sup.7,
vi) NR.sup.26 CONR.sup.23 R.sup.24,
vii) OCONR.sup.23 R.sup.24,
viii) OCOR.sup.11,
ix) aryl;
(e) C.sub.2 -C.sub.6 -alkenyl,
(f) --C.sub.1 -C.sub.4 -alkyl-aryl,
(h) C.sub.1 -C.sub.4 -alkoxy,
(i) C.sub.v F.sub.2v+1 where v=1 to 3,
(j) --S(O).sub.r R.sup.10,
(k) --S(O).sub.2 NR.sup.23 R.sup.24,
(l) --CONR.sup.23 R.sup.24,
(m) --COR.sup.7, or
(n) --CO.sub.2 R.sup.12 ;
R.sup.9 is
(a) H,
(b) C.sub.1 -C.sub.5 -alkyl,
(c) aryl, or
(d) --(C.sub.1 -C.sub.4 -alkyl)-aryl;
R.sup.10 is
(a) aryl,
(b) C.sub.3 -C.sub.7 -cycloalkyl,
(c) C.sub.1 -C.sub.4 -perfluoroalkyl, or
(d) C.sub.1 -C.sub.4 -alkyl, optionally substituted with a substituent selected from the group consisting of aryl, --OH, --SH, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, --CF.sub.3, halo, --NO.sub.2, --CO.sub.2 R.sup.12, --NH.sub.2, C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.4 -dialkylamino, --PO.sub.3 H.sub.2,
R.sup.11, R.sup.11a and R.sup.11b are independently
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) C.sub.3 -C.sub.6 -cycloalkyl,
(d) aryl,
(e) --(C.sub.1 -C.sub.5 -alkyl)-aryl, or
(f) heteroaryl;
R.sup.12 is
(a) H,
(b) methyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-3 substituents selected from the group consisting of halo, C.sub.1 - to C.sub.4 -alkyl, C.sub.1 - to C.sub.4 -alkoxy, or --NO.sub.2 ;
R.sup.13 is
(a) --CO.sub.2 H,
(b) --CH.sub.2 CO.sub.2 H,
(c) --C(CF.sub.3).sub.2 OH,
(d) --CONHNHSO.sub.2 CF.sub.3,
(e) --CONHOR.sup.12,
(f) --CONHSO.sub.2 R.sup.10,
(g) --CONHSO.sub.2 NHR.sup.9,
(h) --C(OH)R.sup.9 PO.sub.3 H.sub.2,
(i) --NHCOCF.sub.3,
(j) --NHCONHSO.sub.2 R.sup.10,
(k) --NHPO.sub.3 H.sub.2,
(l) --NHSO.sub.2 R.sup.10,
(m) --NHSO.sub.2 NHCOR.sup.10,
(n) --OPO.sub.3 H.sub.2,
(o) --OSO.sub.3 H,
(p) --PO(OH)R.sup.9,
(q) --PO.sub.3 H.sub.2,
(r) --SO.sub.3 H,
(s) --SO.sub.2 NHR.sup.9,
(t) --SO.sub.2 NHCOR.sup.10,
(u) --SO.sub.2 NHCONHR.sup.9,
(v) --SO.sub.2 NHCO.sub.2 R.sup.10, ##STR575## R.sup.16 is (a) H,
(b) C.sub.1 -C.sub.6 -alkyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or --NO.sub.2 ;
R.sup.23 and R.sup.24 are, independently
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) aryl, or
(d) --(C.sub.1 -C.sub.4 -alkyl)-aryl, or
(e) R.sup.23 and R.sup.24 when taken together constitute a pyrrolidine, piperidine or morpholine ring;
R.sup.25 is
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) aryl,
(d) --(C.sub.1 -C.sub.4 -alkyl)-aryl,
(e) C.sub.3 -C.sub.6 -alkenyl, or
(f) --(C.sub.3 -C.sub.6 -alkenyl)-aryl;
R.sup.26 is
(a) H,
(b) C.sub.1 -C.sub.4 -alkyl,
(c) aryl, or
(d) --CH.sub.2 -aryl;
R.sup.28 is
(a) aryl, or
(b) heteroaryl;
R.sup.29 is
(a) --CHO,
(b) --CONH.sub.2,
(c) --NHCHO,
(d) --CO--(C.sub.1 -C.sub.6 perfluoroalkyl,
(e) --S(O).sub.r --(C.sub.1 -C.sub.6 perfluoroalkyl),
(f) --O--(C.sub.1 -C.sub.6 perfluoroalkyl), or
(g) --NR.sup.11a --(C.sub.1 -C.sub.6 perfluoroalkyl);
G is
(a) --(T).sub.y --(B).sub.y --X.sup.2 --(B).sub.y --R.sup.28
(b) --T--(B).sub.y --R.sup.28
(c) --(T).sub.y --(B).sub.y --X.sup.2 --B', or
(d) --T--(B).sub.y --R.sup.29
L.sup.2 is --CO--,
B' is C.sub.1 -C.sub.6 alkyl;
B is C.sub.1-6 alkylene
T is arylene or heteroarylene;
X.sup.2 is
(a) --CO--,
(b) --O--,
(c) --S(O).sub.r --,
(d) --(C.sub.1 -C.sub.4 -alkylene)--,
(e) --NR.sup.11a CONR.sup.11b --,
(f) --CONR.sup.11a --,
(g) --NR.sup.11a CO--,
(h) --SO.sub.2 NR.sup.16 --,
(i) --NR.sup.16 SO.sub.2 --,
(j) --CONR.sup.11a SO.sub.2 --,
(k) --SO.sub.2 NR.sup.11a CO--,
(l) --SO.sub.2 NR.sup.11a CO.sub.2 --,
(m) --OCONR.sup.11a SO.sub.2 --,
(n) --SO.sub.2 NR.sup.11a CONR.sup.11b --,
(o) --NR.sup.11a CONR.sup.11b SO.sub.2 --,
(p) --SO.sub.2 NR.sup.11a SO.sub.2 --,
(q) --CONR.sup.11a SO.sub.2 NR.sup.11b --, or
(r) --NR.sup.11a SO.sub.2 NR.sup.11b CO--;
n is 0 to 2;
r is 0 to 2;
y is 0 to 1;
wherein aryl is phenyl, biphenyl, naphthyl, or fluorenyl optionally substituted with one to three substituents selected form the group consisting of --OH, --SH, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --CF.sub.3, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 --benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 ;
wherein heteroaryl is 2-, 3- or 4-pyridyl;
2- or 3-furyl;
2- or 3-thienyl;
2-, 3- or 4-quinolinyl;
or 1-, 3- or 4-isoquinolinyl optionally substituted with one to three substituents 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, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 -benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 ;
wherein arylene is 1,2-phenyl, 1,3-phenyl, 1,3-phenyl, 1,4-phenyl, 4,4'-biphenyl, 3,3'-biphenyl, and 2,2'-biphenyl optionally substituted with one to three substituents 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, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 -benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2,
and wherein heteroarylene is 2,3-pyridyl, 3,4-pyridyl, 2,3-furyl, 3,4-furyl, 2,3-thiophenyl, 3,4-thiophenyl, 2,3-quinolinyl, 3,4-quionolinyl and 1,4-isoquinolinyl optionally substituted with one to three substituents 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, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 -benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2 ;
and pharmaceutically acceptable salts of these compounds.

150 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula (III) ##STR574## wherein R.sup.2 is independently

(a) H,
(b) halo, or
(c) C.sub.1 -C.sub.4 -alkyl,
R.sup.3 is independently
(a) H, or
(b) halo,
R.sup.6 is
(a) C.sub.1 -C.sub.10 -alkyl,
(b) C.sub.3 -C.sub.10 -alkenyl, or
(c) C.sub.3 -C.sub.10 -alkynyl,
R.sup.7 is
(a) C.sub.1 -C.sub.6 -alkyl,
(b) C.sub.3 -C.sub.6 -cycloalkyl,
(c) aryl, or
(d) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or --NO.sub.2 ;
R.sup.8 is
(a) H,
(b) halo,
(c) aryl,
(d) C.sub.1 -C.sub.6 -alkyl, optionally substituted with
i) OR.sup.25,
ii) S(O).sub.r R.sup.10,
iii) NR.sup.23 R.sup.24,
iv) NR.sup.26 COR.sup.11,
v) NR.sup.26 CO.sub.2 R.sup.7,
vi) NR.sup.26 CONR.sup.23 R.sup.24,
vii) OCONR.sup.23 R.sup.24,
viii) OCOR.sup.11,
ix) aryl;
(e) C.sub.2 -C.sub.6 -alkenyl,
(f) --C.sub.1 -C.sub.4 -alkyl-aryl,
(h) C.sub.1 -C.sub.4 -alkoxy,
(i) C.sub.v F.sub.2v+1 where v=1 to 3,
(j) --S(O).sub.r R.sup.10,
(k) --S(O).sub.2 NR.sup.23 R.sup.24,
(l) --CONR.sup.23 R.sup.24,
(m) --COR.sup.7, or
(n) --CO.sub.2 R.sup.12 ;
R.sup.9 is
(a) H,
(b) C.sub.1 -C.sub.5 -alkyl,
(c) aryl, or
(d) --(C.sub.1 -C.sub.4 -alkyl)-aryl;
R.sup.10 is
(a) aryl,
(b) C.sub.3 -C.sub.7 -cycloalkyl,
(c) C.sub.1 -C.sub.4 -perfluoroalkyl, or
(d) C.sub.1 -C.sub.4 -alkyl, optionally substituted with a substituent selected from the group consisting of aryl, --OH, --SH, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, --CF.sub.3, halo, --NO.sub.2, --CO.sub.2 R.sup.12, --NH.sub.2, C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.4 -dialkylamino, --PO.sub.3 H.sub.2,
R.sup.11, R.sup.11a and R.sup.11b are independently
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) C.sub.3 -C.sub.6 -cycloalkyl,
(d) aryl,
(e) --(C.sub.1 -C.sub.5 -alkyl)-aryl, or
(f) heteroaryl;
R.sup.12 is
(a) H,
(b) methyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-3 substituents selected from the group consisting of halo, C.sub.1 - to C.sub.4 -alkyl, C.sub.1 - to C.sub.4 -alkoxy, or --NO.sub.2 ;
R.sup.13 is
(a) --CO.sub.2 H,
(b) --CH.sub.2 CO.sub.2 H,
(c) --C(CF.sub.3).sub.2 OH,
(d) --CONHNHSO.sub.2 CF.sub.3,
(e) --CONHOR.sup.12,
(f) --CONHSO.sub.2 R.sup.10,
(g) --CONHSO.sub.2 NHR.sup.9,
(h) --C(OH)R.sup.9 PO.sub.3 H.sub.2,
(i) --NHCOCF.sub.3,
(j) --NHCONHSO.sub.2 R.sup.10,
(k) --NHPO.sub.3 H.sub.2,
(l) --NHSO.sub.2 R.sup.10,
(m) --NHSO.sub.2 NHCOR.sup.10,
(n) --OPO.sub.3 H.sub.2,
(o) --OSO.sub.3 H,
(p) --PO(OH)R.sup.9,
(q) --PO.sub.3 H.sub.2,
(r) --SO.sub.3 H,
(s) --SO.sub.2 NHR.sup.9,
(t) --SO.sub.2 NHCOR.sup.10,
(u) --SO.sub.2 NHCONHR.sup.9,
(v) --SO.sub.2 NHCO.sub.2 R.sup.10, ##STR575## R.sup.16 is (a) H,
(b) C.sub.1 -C.sub.6 -alkyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or --NO.sub.2 ;
R.sup.23 and R.sup.24 are, independently
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) aryl, or
(d) --(C.sub.1 -C.sub.4 -alkyl)-aryl, or
(e) R.sup.23 and R.sup.24 when taken together constitute a pyrrolidine, piperidine or morpholine ring;
R.sup.25 is
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl,
(c) aryl,
(d) --(C.sub.1 -C.sub.4 -alkyl)-aryl,
(e) C.sub.3 -C.sub.6 -alkenyl, or
(f) --(C.sub.3 -C.sub.6 -alkenyl)-aryl;
R.sup.26 is
(a) H,
(b) C.sub.1 -C.sub.4 -alkyl,
(c) aryl, or
(d) --CH.sub.2 -aryl;
R.sup.28 is
(a) aryl, or
(b) heteroaryl;
R.sup.29 is
(a) --CHO,
(b) --CONH.sub.2,
(c) --NHCHO,
(d) --CO--(C.sub.1 -C.sub.6 perfluoroalkyl,
(e) --S(O).sub.r --(C.sub.1 -C.sub.6 perfluoroalkyl),
(f) --O--(C.sub.1 -C.sub.6 perfluoroalkyl), or
(g) --NR.sup.11a --(C.sub.1 -C.sub.6 perfluoroalkyl);
G is
(a) --(T).sub.y --(B).sub.y --X.sup.2 --(B).sub.y --R.sup.28
(b) --T--(B).sub.y --R.sup.28
(c) --(T).sub.y --(B).sub.y --X.sup.2 --B', or
(d) --T--(B).sub.y --R.sup.29
L.sup.2 is --CO--,
B' is C.sub.1 -C.sub.6 alkyl;
B is C.sub.1-6 alkylene
T is arylene or heteroarylene;
X.sup.2 is
(a) --CO--,
(b) --O--,
(c) --S(O).sub.r --,
(d) --(C.sub.1 -C.sub.4 -alkylene)--,
(e) --NR.sup.11a CONR.sup.11b --,
(f) --CONR.sup.11a --,
(g) --NR.sup.11a CO--,
(h) --SO.sub.2 NR.sup.16 --,
(i) --NR.sup.16 SO.sub.2 --,
(j) --CONR.sup.11a SO.sub.2 --,
(k) --SO.sub.2 NR.sup.11a CO--,
(l) --SO.sub.2 NR.sup.11a CO.sub.2 --,
(m) --OCONR.sup.11a SO.sub.2 --,
(n) --SO.sub.2 NR.sup.11a CONR.sup.11b --,
(o) --NR.sup.11a CONR.sup.11b SO.sub.2 --,
(p) --SO.sub.2 NR.sup.11a SO.sub.2 --,
(q) --CONR.sup.11a SO.sub.2 NR.sup.11b --, or
(r) --NR.sup.11a SO.sub.2 NR.sup.11b CO--;
n is 0 to 2;
r is 0 to 2;
y is 0 to 1;
wherein aryl is phenyl, biphenyl, naphthyl, or fluorenyl optionally substituted with one to three substituents selected form the group consisting of --OH, --SH, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --CF.sub.3, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 --benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 ;
wherein heteroaryl is 2-, 3- or 4-pyridyl;
2- or 3-furyl;
2- or 3-thienyl;
2-, 3- or 4-quinolinyl;
or 1-, 3- or 4-isoquinolinyl optionally substituted with one to three substituents 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, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 -benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --N(C.sub.1 -C.sub.4 alkyl).sub.2 ;
wherein arylene is 1,2-phenyl, 1,3-phenyl, 1,3-phenyl, 1,4-phenyl, 4,4'-biphenyl, 3,3'-biphenyl, and 2,2'-biphenyl optionally substituted with one to three substituents 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, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 -benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2,
and wherein heteroarylene is 2,3-pyridyl, 3,4-pyridyl, 2,3-furyl, 3,4-furyl, 2,3-thiophenyl, 3,4-thiophenyl, 2,3-quinolinyl, 3,4-quionolinyl and 1,4-isoquinolinyl optionally substituted with one to three substituents 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, halo, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 CH.sub.3, --CO.sub.2 -benzyl, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2 ;
and pharmaceutically acceptable salts of these compounds.

150 more elements