US 5,183,810 AGranted

Imidazole angiotensin II antagonists incorporating a substituted benzyl element

AssigneeMerck & Co., Inc.

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

Life of this patent

Estimating the term…

Abstract

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

Claims8

Dependent claims

A compound of Formula 1 which is ##STR44## 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) COOR.sup.2,
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) Cl, Br, 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
E is:
(a) a single bond,
(b) --S(O).sub.x (CH.sub.2).sub.s --, or
(c) --O--;
and
x is 0 to 2,
s is 0 to 5;
m is 1 to 5;
p is 0 to 3;
n is 1 to 10;
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.3 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,
(c) Cl, Br, I, F,
(d) NO.sub.2
(e) (C.sub.1 -C.sub.8)-perfluoroalkyl,
(f) C.sub.6 F.sub.5,
(g) CN,
(h) NH.sub.2,
(i) NH[(C.sub.1 -C.sub.4)-alkyl],
(j) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(k) NH[CO(C.sub.1 -C.sub.4)-alkyl],
(l) N[(C.sub.1 -C.sub.4)-alkyl)-(CO(C.sub.1 -C.sub.4)-alkyl)],
(m) N(C.sub.1 -C.sub.4)-alkyl-COaryl,
(n) N(C.sub.1 -C.sub.4)alkyl-SO.sub.2 aryl,
(o) CO.sub.2 H,
(p) CO.sub.2 R.sup.2a,
(q) phenyl,
(r) phenyl-(C.sub.1 -C.sub.3)-alkyl,
(s) phenyl and phenyl-(C.sub.1 -C.sub.3)-alkyl substituted on the phenyl ring with one or two substituents selected from:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) (C.sub.1 -C.sub.4)-alkoxyl,
iii) F, Cl, Br, I,
iv) hydroxyl,
v) methoxyl,
vi) CF.sub.3,
vii) CO.sub.2 R.sup.2a, or
viii) NO.sub.2 ;
and
R.sup.4 is:
(a) H,
(b) CN,
(c) (C.sub.1 -C.sub.8)-alkyl,
(d) (C.sub.3 -C.sub.6)-alkenyl,
(e) (C.sub.1 -C.sub.8)-perfluoroalkyl,
(f) (C.sub.1 -C.sub.8)-perfluoroalkenyl,
(g) NH.sub.2,
(h) NH(C.sub.1 -C.sub.4)-alkyl,
(i) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(j) NH(C.sub.1 -C.sub.4)-acyl,
(k) N[((C.sub.1 -C.sub.4)-acyl)((C.sub.1 -C.sub.4)-alkyl)],
(l) CO.sub.2 H,
(m) CO.sub.2 R.sup.24,
(n) phenyl,
(o) phenyl-(C.sub.2 -C.sub.6)-alkenyl, ##STR45## (z) (CH.sub.2).sub.n NHSO.sub.2 R.sup.16, (aa) (CH.sub.2).sub.n F,
(ab) (CH.sub.2).sub.m -imidazol-1-yl,
(ac) tetrazol-5-yl,
(ad) --CONH--SO.sub.2 -aryl,
(ae) --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
(af) --CONH--SO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(ag) --CONHSO.sub.2 NR.sup.2a R.sup.2a ;
and ##STR46## R.sup.5 is:
(a) CN,
(b) NO.sub.2, or
(c) CO.sub.2 R.sup.2a ;
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) (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.x --(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 ;
and
X is:
(a) --O--,
(b) --S(O).sub.x --,
(c) --NR.sup.13 --
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.x,
(f) --CH.sub.2 NR.sup.13 --,
(g) --OCH.sub.2 --,
(h) --NR.sup.13 CH.sub.2 --,
(i) --S(O).sub.x 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.x --,
(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 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.x --(CH.sub.2).sub.x --,
(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) --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.x or NR.sup.23 ;
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.24,
(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) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(i) --CONHSO.sub.2 NR.sup.2a R.sup.2a ;
and
(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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(l) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(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.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.15 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) (C.sub.3 -C.sub.6)-cycloalkyl,
(d) (CH.sub.2).sub.p -phenyl,
(e) OR.sup.17,
(f) NR.sup.18 R.sup.19 ;
and
R.sup.16 is:
(a) (C.sub.1 -C.sub.8)-alkyl,
(b) (C.sub.1 -C.sub.8)-perfluoroalkyl,
(c) 1-adamantyl,
(d) 1-naphthyl,
(e) (1-naphthyl)ethyl, or
(f) --(CH.sub.2).sub.p -phenyl;
and
R.sup.17 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) (C.sub.3 -C.sub.6)-cycloalkyl,
(d) phenyl, or
(e) benzyl;
and
R.sup.18 and R.sup.19 are independently:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl,
(c) phenyl,
(d) benzyl, or
(e) .alpha.-methylbenzyl;
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 (C.sub.1 -C.sub.4)-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,
(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 or optionally substituted with --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, ##STR47## R.sup.25 and R.sup.26 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.

281 more elements

A compound or its pharmaceutically acceptable salt selected from the group consisting of:

2-Butyl-1-[4-(N-(1(R)-carbomethoxy-1-benzyl)methyl)aminomethylphenyl]methyl -4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl)methyl)aminomethylphenyl]methyl-4-ch loro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(R)-carbomethoxy-1-benzyl)methyl-methyl-N-pentanoyl)amino methylphenyl]-4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl)methyl-N-pentanoyl)aminomethyl-pheny l]methyl-4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1-(R)-carboxy-1-benzyl)methyl-N-(3-phenyl)propionyl)aminom ethylphenyl]methyl-4-chloroimidazole;
2-Butyl-1-[4-N-(1(R)-carbomethoxy-1-benzyl)methyl-N-(phenylacetyl)aminometh ylphenyl]methyl-4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl-methyl-N-(phenylacetyl)aminomethylph enyl]methyl-4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(S)-carbomethoxy-1-benzyl)aminomethylphenyl]methyl-4-chlo ro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(S)-carboxy-1-benzyl)aminomethylphenyl]methyl-4-chloro-5- hydroxy-methylimidazole;
2-Butyl-1-[4-(N-(1(S)-carbomethoxy-1-benzyl)-N-pentanoyl)aminomethylphenyl] methyl-4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1(S)-carboxy-1-benzyl)methyl-N-pentanoyl)aminomethylphenyl ]methyl-4-chloro-5-hydroxymethylimidazole;
2-Butyl-5-t-butyldimethylsilyloxymethyl-1-[4-(1-carbomethoxy-1,1-dibenzyl)m ethyl)aminomethylphenyl]methyl-4-chlorimidazole;
2-Butyl-1-[4-(N-(1-carbomethoxy-1,1-dibenzyl)methyl)aminomethylphenyl]methy l-4-chloro-5-hydroxymethylimidazole;
2-Butyl-1-[4-(N-(1-carboxy-1,1-dibenzyl)methyl)aminomethylphenyl]phenyl]met hyl-4-chloro-5-hydroxymethylimidazole;
1-[4-(1-(N-benzyl-N-pentanoyl)amino-1-(tetrazol-5-ylmethylphenyl]methyl-2-b utyl-5-t-butyldimethylsilyloxymethyl-4-chloroimidazole;
2-Butyl-4-chloro-5-hydroxymethyl-3-[4-(1-(1'-hydroxy-1-phenyl-1-tetrazol-5- yl)methylphenyl]methylimidazole;
2-Butyl-1-[4-(1-carboxy-1-(2-chloro)phenyl)methoxyphenyl]methyl-4-chloro-5- hydroxymethylimidazole;
2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxy-3,5-dipropylphenyl]methyl-4-chloro -5-hydroxymethylimidazole;
2-Butyl-4-chloro-5-hydroxymethyl-1-[4-(1-phenyl-1-tetrazol-5-yl))methylphen yl]methylimidazole;
and
2-Butyl-1-[4-(N-(1-carboxy-1-(2-phenyl)ethyl)aminophenyl]methyl-4-chloro-5- hydroxymethylimidazole.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/744,565Filed 13 Aug 1991 · continuation
Priority: 13 Feb 1990
Granted: 2 Feb 1993
Term ends: Not estimatedThe source records don’t support an estimate.

Classification3 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
C07D 233/68
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
Heterocyclic compounds

Family

Serial479,780Parent of this continuation · filed 13 Feb 1990
Serial671,593Parent of this continuation · filed 19 Mar 1991
US 5,183,810 AThis patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

Substituted imidazoles 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 1 which is ##STR44## 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) COOR.sup.2,
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) Cl, Br, 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
E is:
(a) a single bond,
(b) --S(O).sub.x (CH.sub.2).sub.s --, or
(c) --O--;
and
x is 0 to 2,
s is 0 to 5;
m is 1 to 5;
p is 0 to 3;
n is 1 to 10;
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.3 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,
(c) Cl, Br, I, F,
(d) NO.sub.2
(e) (C.sub.1 -C.sub.8)-perfluoroalkyl,
(f) C.sub.6 F.sub.5,
(g) CN,
(h) NH.sub.2,
(i) NH[(C.sub.1 -C.sub.4)-alkyl],
(j) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(k) NH[CO(C.sub.1 -C.sub.4)-alkyl],
(l) N[(C.sub.1 -C.sub.4)-alkyl)-(CO(C.sub.1 -C.sub.4)-alkyl)],
(m) N(C.sub.1 -C.sub.4)-alkyl-COaryl,
(n) N(C.sub.1 -C.sub.4)alkyl-SO.sub.2 aryl,
(o) CO.sub.2 H,
(p) CO.sub.2 R.sup.2a,
(q) phenyl,
(r) phenyl-(C.sub.1 -C.sub.3)-alkyl,
(s) phenyl and phenyl-(C.sub.1 -C.sub.3)-alkyl substituted on the phenyl ring with one or two substituents selected from:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) (C.sub.1 -C.sub.4)-alkoxyl,
iii) F, Cl, Br, I,
iv) hydroxyl,
v) methoxyl,
vi) CF.sub.3,
vii) CO.sub.2 R.sup.2a, or
viii) NO.sub.2 ;
and
R.sup.4 is:
(a) H,
(b) CN,
(c) (C.sub.1 -C.sub.8)-alkyl,
(d) (C.sub.3 -C.sub.6)-alkenyl,
(e) (C.sub.1 -C.sub.8)-perfluoroalkyl,
(f) (C.sub.1 -C.sub.8)-perfluoroalkenyl,
(g) NH.sub.2,
(h) NH(C.sub.1 -C.sub.4)-alkyl,
(i) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(j) NH(C.sub.1 -C.sub.4)-acyl,
(k) N[((C.sub.1 -C.sub.4)-acyl)((C.sub.1 -C.sub.4)-alkyl)],
(l) CO.sub.2 H,
(m) CO.sub.2 R.sup.24,
(n) phenyl,
(o) phenyl-(C.sub.2 -C.sub.6)-alkenyl, ##STR45## (z) (CH.sub.2).sub.n NHSO.sub.2 R.sup.16, (aa) (CH.sub.2).sub.n F,
(ab) (CH.sub.2).sub.m -imidazol-1-yl,
(ac) tetrazol-5-yl,
(ad) --CONH--SO.sub.2 -aryl,
(ae) --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
(af) --CONH--SO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(ag) --CONHSO.sub.2 NR.sup.2a R.sup.2a ;
and ##STR46## R.sup.5 is:
(a) CN,
(b) NO.sub.2, or
(c) CO.sub.2 R.sup.2a ;
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) (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.x --(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 ;
and
X is:
(a) --O--,
(b) --S(O).sub.x --,
(c) --NR.sup.13 --
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.x,
(f) --CH.sub.2 NR.sup.13 --,
(g) --OCH.sub.2 --,
(h) --NR.sup.13 CH.sub.2 --,
(i) --S(O).sub.x 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.x --,
(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 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.x --(CH.sub.2).sub.x --,
(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) --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.x or NR.sup.23 ;
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.24,
(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) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(i) --CONHSO.sub.2 NR.sup.2a R.sup.2a ;
and
(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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(l) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(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.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.15 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) (C.sub.3 -C.sub.6)-cycloalkyl,
(d) (CH.sub.2).sub.p -phenyl,
(e) OR.sup.17,
(f) NR.sup.18 R.sup.19 ;
and
R.sup.16 is:
(a) (C.sub.1 -C.sub.8)-alkyl,
(b) (C.sub.1 -C.sub.8)-perfluoroalkyl,
(c) 1-adamantyl,
(d) 1-naphthyl,
(e) (1-naphthyl)ethyl, or
(f) --(CH.sub.2).sub.p -phenyl;
and
R.sup.17 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) (C.sub.3 -C.sub.6)-cycloalkyl,
(d) phenyl, or
(e) benzyl;
and
R.sup.18 and R.sup.19 are independently:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl,
(c) phenyl,
(d) benzyl, or
(e) .alpha.-methylbenzyl;
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 (C.sub.1 -C.sub.4)-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,
(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 or optionally substituted with --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, ##STR47## R.sup.25 and R.sup.26 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.

281 more elements

Facts

Application

07/744,565Filed 13 Aug 1991 · continuation

Priority

13 Feb 1990

Granted

2 Feb 1993

Term ends

Not estimatedThe source records don’t support an estimate.

Classification3 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
C07D 233/68
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
Heterocyclic compounds