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US 5,326,776 AGranted
Angiotensin II receptor antagonists
AssigneeAbbott Laboratories
InventorsMartin Winn, Biswanath De, Thomas M. Zydowsky, Daniel J. Kerkman, John F. DeBernardis, Saul H. Rosenberg, Kazumi Shiosaki, Fatima Z. Basha, Kenneth P. Spina, Thomas W. von Geldern, Steven Boyd, Diane M. Yamamoto, Anthony K. L. Fung
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Abstract
Compounds are disclosed having the formula: ##STR1## wherein the substituents are defined herein. The compounds of the invention are angiotensin II receptor antagonists.
Claims26
A compound of the formula:
- ##STR13## wherein A is
- (i) a covalent bond,
- (ii) --O--,
- (iii) --C(O)--,
- (iv) --CH.sub.2 --,
- (v) --S--, --S(O)-- or --S(O).sub.2 --;
- E--G is
- (i) --N(R.sub.5)--,
- (ii) --O--,
- (iii) --S--,
- (iv) --N(R.sub.5)--CH(R.sub.5)--,
- (v) --O--CH(R.sub.5)--,
- (vi) --S--CH(R.sub.5)--,
- (vii) --CH(R.sub.5)--N(R.sub.5)--,
- (viii) --CH(R.sub.5)--O--,
- (ix) --CH(R.sub.5)--S--,
- (x) --N(R.sub.5)--N(R.sub.5)--,
- (xi) --C(R.sub.5).dbd.C(R.sub.5)-- or
- (xii) --CH(R.sub.5)--C(R.sub.5 ')(R.sub.5)--N(R.sub.5)-- wherein at each occurrence R.sub.5 is independently selected from hydrogen, loweralkyl, alkoxy-substituted loweralkyl, halo-substituted loweralkyl, carboxy-substituted loweralkyl, heterocyclic-substituted loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl and R.sub.5 ' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy;
- L, L', M and M' are independently selected from
- (i) hydrogen,
- (ii) loweralkyl,
- (iii) halo-substituted loweralkyl,
- (iv) halo,
- (v) --CN,
- (vi) --NO.sub.2,
- (vii) --OH,
- (vii) hydroxy-substituted loweralkyl,
- (ix) alkoxy-substituted loweralkyl,
- (x) --NH.sub.2,
- (xi) alkylamino,
- (xii) dialkylamino,
- (xiii) --SH,
- (xiv) alkoxy and
- (xv) thioalkoxy;
- R.sub.1 and R.sub.1 ' are independently selected from
- (i) tetrazolyl, ##STR14## and (iv) hydrogen:
- with the proviso that one of R.sub.1 and R.sub.1 ' is hydrogen, but R.sub.1 and R.sub.1 ' are not both hydrogen;
- and
- D is a 5-membered heterocyclic ring comprising 1, 2, 3 or 4 nitrogen atoms or 2 nitrogen atoms and 1 oxygen atom or 2 nitrogen atoms and 1 sulfur atom, the remaining ring atoms being carbon atoms and the 5-membered heterocyclic ring comprising 0, 1 or 2 double bonds;
- the nitrogen atoms of the 5-membered heterocyclic ring can be substituted with a substituent R.sub.2 wherein at each occurrence R.sub.2 is independently selected from hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl;
- one or two carbon atoms of the 5-membered heterocyclic ring can also be substituted with an oxo (.dbd.O) substituent and the sulfur atoms of the 5-membered heterocyclic ring can be substituted with one or two oxo (.dbd.O) substituents;
- the nitrogen atoms of the 5-membered heterocyclic ring can be oxidized;
- the 5-membered heterocyclic ring can also be substituted with one or two substituents independently selected from R.sub.3 and R.sub.4, R.sub.3 being bonded to a carbon atom or a nitrogen atom of the 5-membered heterocyclic ring and R.sub.4 being bonded to a carbon atom or a nitrogen atom of the 5-membered heterocyclic ring, wherein
- R.sub.3 is
- (i) hydrogen
- (ii) loweralkyl,
- (iii) halo,
- (iv) halo-substituted loweralkyl,
- (v) thioalkoxy,
- (vi) alkoxy-substituted loweralkyl,
- (vii) thioalkoxy-substituted loweralkyl,
- (viii) aryl,
- (ix) arylalkyl,
- (x) --NO.sub.2, or
- (xi) --COOR.sub.8 wherein R.sub.8 is hydrogen or a carboxy-protecting group, and
- R.sub.4 is
- (i) hydrogen,
- (ii) loweralkyl,
- (iii) halo-substituted loweralkyl,
- (iv) --CN,
- (v) --NO.sub.2,
- (vi) --NH.sub.2,
- (vii) --NH--C(.dbd.N(R.sub.25a))(R.sub.26a) wherein R.sub.25a is hydrogen, --CN or --NO.sub.2 and R.sub.26a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
- (viii) --CHO or --CH(.dbd.N--OH),
- (ix) --NHS(O).sub.2 R.sub.20 or --CH.sub.2 NHS(I).sub.2 R.sub.20 or --NHC(O)R.sub.21 or --N(OH)C(O)R.sub.21 or --CH.sub.2 NHC(O)R.sub.21 or --CH.sub.2 N(OH)C(O)R.sub.21 wherein R.sub.20 is loweralkyl, halo-substituted loweralkyl or --NR.sub.27a R.sub.27b wherein R.sub.27a and R.sub.27b are independently selected from hydrogen, --OH and loweralkyl and R.sub.21 is loweralkyl, halo-substituted loweralkyl, amino, alkylamino, dialkylamino or --COOH,
- (x) --CH(OH)R.sub.22 or --C(O)R.sub.22 wherein R.sub.22 is loweralkyl, halo-substituted loweralkyl, --CF.sub.2 COOR.sub.23 or --CH.sub.2 COOR.sub.23 wherein R.sub.23 is hydrogen or a carboxy-protecting group,
- (xi) --COOR.sub.24 or --CH.sub.2 COOR.sub.24 wherein R.sub.24 is hydrogen or a carboxy-protecting group,
- (xii) --C(O)NR.sub.25 R.sub.26 or --CH.sub.2 C(O)NR.sub.25 R.sub.26 or --NHC(O)NR.sub.25 R.sub.26 or --CH.sub.2 NHC(O)NR.sub.25 R.sub.26 or --NHC(S)NR.sub.25 R.sub.26 or --CH.sub.2 NHC(S)NR.sub.25 R.sub.26 wherein R.sub.25 and R.sub.26 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxy-substituted loweralkyl, alkoxy-substituted loweralkyl, alkoxy-substituted alkoxy and --S(O).sub.2 R.sub.28a wherein R.sub.28a is loweralkyl or aryl;
- (xiii) --CH.sub.2 OR.sub.27 wherein R.sub.27 is selected from hydrogen, loweralkyl and --C(O)R.sub.28 wherein R.sub.28 is hydrogen, loweralkyl or aryl;
- (xiv) --CH.sub.2 NR.sub.29 R.sub.30 wherein R.sub.29 is selected from hydrogen, loweralkyl, --C(O)R.sub.31, --C(O)NR.sub.31 R.sub.32 and --S(O).sub.2 R.sub.33 wherein R.sub.31 is selected from hydrogen, loweralkyl and aryl and R.sub.33 is selected from loweralkyl and halo-substituted loweralkyl and wherein R.sub.30 and R.sub.32 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
- (xv) --SO.sub.3 H, --OSO.sub.3 H or --CH.sub.2 SO.sub.3 H,
- (xvi) --OPO.sub.3 H, --PO.sub.3 H.sub.2 or --CH.sub.2 PO.sub.3 H.sub.2,
- (xvii) --SO.sub.2 NR.sub.25 R.sub.26 or --CH.sub.2 SO.sub.2 NR.sub.25 R.sub.26 wherein R.sub.25 and R.sub.26 are defined as above or
- (xviii) --C(O)NHSO.sub.2 R.sub.59, --C(O)NHC(O)R.sub.59 or --C(O)NHNHSO.sub.2 R.sub.59 wherein R.sub.59 is loweralkyl, halo-substituted loweralkyl or aryl;
- or a pharmaceutically acceptable salt or prodrug thereof.
73 more elements
A compound of the formula:
- ##STR15## wherein A is
- (i) a covalent bond,
- (ii) --O--,
- (iii) --C(O)--,
- (iv) --CH.sub.2 --,
- (v) --S--, --S(O)-- or --S(O).sub.2 --;
- E--G is
- (i) --N(R.sub.5)--,
- (ii) --O--,
- (iii) --S--,
- (iv) --N(R.sub.5)--CH(R.sub.5)--,
- (v) --O--CH(R.sub.5)--,
- (vi) --S--CH(R.sub.5)--,
- (vii) --CH(R.sub.5)--N(R.sub.5)--,
- (viii) --CH(R.sub.5)--O--,
- (ix) --CH(R.sub.5)--S--,
- (x) --N(R.sub.5)--N(R.sub.5)--,
- (xi) --C(R.sub.5).dbd.C(R.sub.5)-- or
- (xii) --CH(R.sub.5)--C(R.sub.5 ')(R.sub.5)--N(R.sub.5)-- wherein at each occurrence R.sub.5 is independently selected from hydrogen, loweralkyl, alkoxy-substituted loweralkyl, halo-substituted loweralkyl, carboxy-substituted loweralkyl, heterocyclic-substituted loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl and R.sub.5 ' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy;
- L, L', M and M' are independently selected from
- (i) hydrogen,
- (ii) loweralkyl,
- (iii) halo-substituted loweralkyl,
- (iv) halo,
- (v) --CN,
- (vi) --NO.sub.2,
- (vii) --OH,
- (viii) hydroxy-substituted loweralkyl,
- (ix) alkoxy-substituted loweralkyl,
- (x) --NH.sub.2,
- (xi) alkylamino,
- (xii) dialkylamino,
- (xiii) --SH,
- (xiv) alkoxy and
- (xv) thioalkoxy;
- R.sub.1 and R.sub.1 ' are independently selected from
- (i) tetrazolyl, ##STR16## and (iv) hydrogen:
- with the proviso that one of R.sub.1 and R.sub.1 ' is hydrogen, but R.sub.1 and R.sub.1 ' are not both hydrogen;
- and
- D is ##STR17## wherein R.sub.2 is hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl, and
- R.sub.4 is
- (i) hydrogen,
- (ii) loweralkyl,
- (iii) halo-substituted loweralkyl,
- (iv) --CN,
- (v) --NO.sub.2,
- (vi) --NH.sub.2,
- (vii) --NH--C(.dbd.N(R.sub.25a))(R.sub.26a) wherein R.sub.25a is hydrogen, --CN or --NO.sub.2 and R.sub.26a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
- (viii) --CHO or --CH(.dbd.N--OH),
- (ix) --NHS(O).sub.2 R.sub.20 or --CH.sub.2 NHS(O).sub.2 R.sub.20 or --NHC(O)R.sub.21 or --N(OH)C(O)R.sub.21 or --CH.sub.2 NHC(O)R.sub.21 or --CH.sub.2 N(OH)C(O)R.sub.21 wherein R.sub.20 is loweralkyl, halo-substituted loweralkyl or --NR.sub.27a R.sub.27b wherein R.sub.27a and R.sub.27b are independently selected from hydrogen, --OH and loweralkyl and R.sub.21 is loweralkyl, halo-substituted loweralkyl, amino, alkylamino, dialkylamino or --COOH,
- (x) --CH(OH)R.sub.22 or --C(O)R.sub.22 wherein R.sub.22 is loweralkyl, halo-substituted loweralkyl, --CF.sub.2 COOR.sub.23 or --CH.sub.2 COOR.sub.23 wherein R.sub.23 is hydrogen or a carboxy-protecting group,
- (xi) --COOR.sub.24 or --CH.sub.2 COOR.sub.24 wherein R.sub.24 is hydrogen or a carboxy-protecting group,
- (xii) --C(O)NR.sub.25 R.sub.26 or --CH.sub.2 C(O)NR.sub.25 R.sub.26 or --NHC(O)NR.sub.25 R.sub.26 or --CH.sub.2 NHC(O)NR.sub.25 R.sub.26 or --NHC(S)NR.sub.25 R.sub.26 or --CH.sub.2 NHC(S)NR.sub.25 R.sub.26 wherein R.sub.25 and R.sub.26 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxy-substituted loweralkyl, alkoxy-substituted loweralkyl, alkoxy-substituted alkoxy and --S(O).sub.2 R.sub.28a wherein R.sub.28a is loweralkyl or aryl;
- (xiii) --CH.sub.2 OR.sub.27 wherein R.sub.27 is selected from hydrogen, loweralkyl and --C(O)R.sub.28 wherein R.sub.28 is hydrogen, loweralkyl or aryl;
- (xiv) --CH.sub.2 NR.sub.29 R.sub.30 wherein R.sub.29 is selected from hydrogen, loweralkyl, --C(O)R.sub.31, --C(O)NR.sub.31 R.sub.32 and --S().sub.2 R.sub.33 wherein R.sub.31 is selected from hydrogen, loweralkyl and aryl and R.sub.33 is selected from loweralkyl and halo-substituted loweralkyl and wherein R.sub.30 and R.sub.32 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
- (xv) --SO.sub.3 H, --OSO.sub.3 H or --CH.sub.2 SO.sub.3 H,
- (xvi) --OPO.sub.3 H, --PO.sub.3 H.sub.2 or --CH.sub.2 PO.sub.3 H.sub.2,
- (xvii) --SO.sub.2 NR.sub.25 R.sub.26 or --CH.sub.2 SO.sub.2 NR.sub.25 R.sub.26 wherein R.sub.25 and R.sub.26 are defined as above or
- (xviii) --C(O)NHSO.sub.2 R.sub.59, --C(O)NHC(O)R.sub.59 or --C(O)NHNHSO.sub.2 R.sub.59 wherein R.sub.59 is loweralkyl, halo-substituted loweralkyl or aryl;
- or a pharmaceutically acceptable salt or prodrug thereof.
57 more elements
A compound of the formula:
- ##STR18## wherein A is a covalent bond;
- E--G is --N(R.sub.5)--CH.sub.2 -- wherein R.sub.5 is hydrogen, loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl;
- L, L', M and M' are independently selected from
- (i) hydrogen,
- (ii) loweralkyl,
- (iii) halo-substituted loweralkyl,
- (iv) halo,
- (v) --OH and
- (vi) alkoxy;
- R.sub.1 is tetrazolyl;
- R.sub.1 ' is hydrogen;
- and
- D is ##STR19## wherein R.sub.2 is hydrogen or loweralkyl, and R.sub.4 is --COOR.sub.24 wherein R.sub.24 is hydrogen or a carboxy-protecting group;
- or a pharmaceutically acceptable salt or prodrug thereof.
11 more elements
A compound of the formula:
- ##STR20## wherein R.sub.1 is tetrazolyl;
- R.sub.2 is hydrogen or loweralkyl;
- R.sub.4 is --COOR.sub.24 wherein R.sub.24 is hydrogen or a carboxy-protecting group;
- and R.sub.5 is hydrogen, loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
2 more elements
A compound of the formula:
- ##STR21## wherein R.sub.1 is tetrazolyl;
- R.sub.4 is --COOR.sub.24 wherein R.sub.24 is hydrogen or a carboxy-protecting group;
- and R.sub.5 is hydrogen, loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl;
- or a pharmaceutically acceptable salt or prodrug thereof.
1 more element
A compound selected from the group consisting of:
- ethyl 4-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methyl-2 -(methylthio)imidazole-5-carboxylate;
- ethyl 4-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methylim idazole-5-carboxylate;
- tert-butyl 4-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-(N-ethyl )imidazole-5-carboxylate;
- 4-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-(N-ethyl) imidazole;
- ethyl 5-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methylim idazole-4-carboxylate;
- 5-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methylimi dazole-4-carboxylic acid;
- ethyl 5-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1,2,3-thia diazole-4-carboxylate;
- 5-[N-butyl-N-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]-1,2,3-thiad iazole-4-carboxylic acid;
- ethyl 2-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1,3,4-thia diazole-5-carboxylate;
- 2-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1,3,4-thiad iazole;
- ethyl 1-methyl-3-{N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}p yrazole-4-carboxylate;
- 1-methyl-3-{N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}py razole-4-carboxylic acid;
- ethyl 5-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methylpy razole-4-carboxylate;
- 5-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-(methyl)p yrazole-4-carboxylic acid;
- 4-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methyl-1H -1,2,3-triazole-5-carboxylic acid;
- 4-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-isobutyl- 1H-1,2,3-triazole-5-carboxylic acid;
- 1-n-butyl-4-{N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1H-1,2,3- triazole-5-carboxylic acid;
- and
- 4-{N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1,2,5-thia diazole-4-carboxylic acid;
- or a pharmaceutically acceptable salt or ester thereof.
17 more elements
Dependencies are inferred from the claim text.