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US 5,332,744 AGranted
Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
AssigneeMerck & Co., Inc.
InventorsPrasun K. Chakravarty, William J. Greenlee, Nathan B. Mantlo, Arthur A. Patchett, Thomas F. Walsh
Life of this patent
Estimating the term…
Abstract
Substituted Imidazo-fused 6-membered heterocycles of structural formula: ##STR1## wherein A, B, C, and D are independently carbon atoms or nitrogen atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
Claims21
A compound of structural formula:
- ##STR33## or a pharmaceutically acceptable salt thereof, wherein:
- R.sup.1 is
- (a) --CO.sub.2 R.sup.4,
- (b) --SO.sub.3 R.sup.5,
- (c) --NHSO.sub.2 CF.sub.3,
- (d) --PO(OR.sup.5).sub.2,
- (e) --SO.sub.2 NHR.sup.9,
- (f) --CONHOR.sup.5, ##STR34## (h) --SO.sub.2 NH-heteroaryl, (i) --CH.sub.2 SO.sub.2 NH-heteroaryl,
- (j) --SO.sub.2 NHCOR.sup.23,
- (k) --CH.sub.2 SO.sub.2 NHCOR.sup.23,
- (l) --CONHSO.sub.2 R.sup.23,
- (m) --CH.sub.2 CONHSO.sub.2 R.sup.23,
- (n) --NHSO.sub.2 NHCOR.sup.23,
- (o) --NHCONHSO.sub.2 R.sup.23,
- (p) --SO.sub.2 NHCONR.sup.23, ##STR35## wherein heteroaryl is an unsustituted, monosubstituted or disubstituted five- or six-membered aromatic ring which contains 1 to 3 heteroatoms selected from the group consisting of O, N or S and wherein the sustituents are members selected from the group consisting of --OH, --SH, --C.sub.1 -C.sub.4 alkoxy, halo, --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 ;
- R.sup.2a and R.sup.2b are independently H, halo, --NO.sub.2, --NH.sub.2, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino --SO.sub.2 NHR.sup.9, CF.sub.3, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
- R.sup.3a is
- (a) H,
- (b) halo,
- (c) C.sub.1 -C.sub.6 alkyl,
- (d) C.sub.1 -C.sub.6 alkoxy, or
- (e) C.sub.1 -C.sub.6 alkoxyalkyl;
- R.sup.3b is
- (a) H,
- (b) halo,
- (c) NO.sub.2,
- (d) C.sub.1 -C.sub.6 alkyl,
- (e) C.sub.1 -C.sub.6 acyloxy,
- (f) C.sub.1 -C.sub.6 cycloalkyl,
- (g) C.sub.1 -C.sub.6 alkyoxy,
- (h) --NHSO.sub.2 R.sup.4,
- (i) hydroxy C.sub.1 -C.sub.4 alkyl,
- (j) aryl C.sub.1 -C.sub.4 alkyl,
- (k) C.sub.1 -C.sub.4 alkylthio,
- (l) C.sub.1 -C.sub.4 alkylsulfinyl,
- (m) C.sub.1 -C.sub.4 alkylsulfonyl,
- (n) NH.sub.2,
- (o) C.sub.1 -C.sub.4 alkylamino,
- (p) C.sub.1 -C.sub.4 dialkylamino,
- (q) fluoro C.sub.1 -C.sub.4 alkyl,
- (r) --SO.sub.2 NHR.sup.9,
- (s) aryl, or
- (t) furyl;
- wherein aryl is phenyl or naphthyl either unsubstituted or substituted with one or two substituents selected form the group consisting of halo, 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, and CO.sub.2 --C.sub.1 -C.sub.4 alkyl;
- R.sup.4 is H, straight chain or branched C.sub.1 -C.sub.6 alkyl, aryl or --CH.sub.2 aryl where aryl is as defined above;
- R.sup.4a is C.sub.1 -C.sub.6 alkyl, aryl or --CH.sub.2 aryl where aryl is as defined above;
- R.sup.5 is H, ##STR36## E is a single bond, --NR.sup.13 CCH.sub.2).sub.s 13 , --S(O).sub.x --(CH.sub.2).sub.s --, where x is 0 to 2 and s is 0 to 5, --CH(OH)--, --O--, --CO--;
- R.sup.6 is
- (a) aryl as defined above which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halo, --OC.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkyl, --NO.sub.2, --CF.sub.3, --SO.sub.2 NR.sup.9 R.sup.10, --SC.sub.1 -C.sub.4 alkyl, --OH, --NH.sub.2, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.10 alkenyl;
- (b) straight chain or branched C.sub.1 1.varies.C.sub.9 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 consisiting of aryl as defined above, C.sub.3 -C.sub.7 cycloalkyl, halo, --OH, --NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), --CF.sub.2 CF.sub.3, --N(C.sub.1 -C.sub.4 alkyl).sub.2, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, --CF.sub.3, --CF.sub.2 CH.sub.3, --SO.sub.2 NHR.sup.9 ;
- or
- (c) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which contains one or two members selected from the group consisting of N, O, S, 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, halo, or NO.sub.2,
- (d) perfluoro C.sub.1 -C.sub.4 alkyl,
- (e) C.sub.3 -C.sub.7 cycloalkyl which is unsubstituted mono- or disubstituted with C.sub.1 -C.sub.4 alkyl or --CF.sub.3 ;
- R.sup.9 is H, C.sub.1 -C.sub.5 alkyl, aryl or --CH.sub.2 aryl, where aryl is as defined above;
- R.sup.10 is H, or C.sub.1 -C.sub.4 alkyl;
- R.sup.11 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy--C.sub.1 -C.sub.4 alkyl, ##STR37## R.sup.12 is --CN, --NO.sub.2 or --CO.sub.2 R.sup.4 ;
- R.sup.13 is H, --CO(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.6 alkyl, allyl, C.sub.3 -C.sub.6 cycloalkyl, phenyl or benzyl;
- R.sup.14 is H, C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 perfluoroalkyl, C.sub.3 -C.sub.6 cycloalky, phenyl or benzyl;
- R.sup.15 is H, C.sub.1 -C.sub.6 alkyl;
- R.sup.16 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, phenyl or benzyl;
- R.sup.17 is --NR.sup.9 R.sup.10, --OR.sup.10, --NHCONH.sub.2, --NHCSNH.sub.2, ##STR38## R.sup.18 and R.sup.19 are independently C.sub.1 -C.sub.4 alkyl or taken together are --(CH.sub.2).sub.q --, where q is 2 or 3;
- R.sup.20 is H, --NO.sub.2, --OH or --OCH.sub.3 ;
- R.sup.23 is
- (a) aryl as defined above,
- (b) neteroaryl as defined above,
- (c) C.sub.3 -C.sub.4 cycloalkyl,
- (d) C.sub.1 -C.sub.4 alkyl which is unsubstituted or substituted wiht a substituent that is a member selected from the group consisting of aryl as defined above, heteroaryl as defined above, --OH, --Sh, --C.sub.1 -C.sub.4 alkyl, --O(C.sub.1 -C.sub.4 alkyl), --S(C.sub.1 -C.sub.4 alkyl), --CF.sub.3 halo --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), --NHCOR.sup.4a, --N(C.sub.1 -C.sub.4 alkyl).sub.2, --PO.sub.3 H, --PO(OH)(C.sub.1 -C.sub.4 alkyl), --PO(OH)(aryl) or --PO(OH)(O--C.sub.1 -C.sub.4 alkyl),
- (e) perfluoroC.sub.1 -C.sub.4 alkyl;
- X is
- (a) a carbon-carbon single bond,
- (b) --CO--,
- (c) --O--,
- (d) --S--, ##STR39## (h) --OCH.sub.2 --, (i) --CH.sub.2 O--
- (j) --SCH.sub.2 --,
- (k) --CH.sub.2 S--,
- (l) --NHC(R.sup.9)(R.sup.10)--,
- (m) --NR.sup.9 SO.sub.2 --,
- (n) --SO.sub.2 NR.sup.9 --,
- (o) --C(R.sup.9)(R.sup.10)NH--,
- (p) --CH.dbd.CH--,
- (q) --CF.dbd.CF--,
- (r) --CH.dbd.CF--,
- (s) --CF.dbd.CH--,
- (t) --CH.sub.2 CH.sub.2 --,
- (u) --CF.sub.2 CF.sub.2 --, ##STR40## --A--B--C--D-- represents the constituent atoms of a 6-member saturated or unsaturated heterocyclic ring with the imidazole to which they are attached containing 1 to 3 nitrogen atoms and is selected from the following:
- ##STR41## R.sup.7 groups can be the same or different and represent:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 straight or branched chain alkyl, or C.sub.2 -C.sub.6 alkenyl, or alkynyl each of which is unsubstituted or substituted with:
- i) --OH
- ii) C.sub.1 -C.sub.4 alkoxy,
- iii) --CO.sub.2 R.sup.4,
- iv) --OCOR.sup.4, ##STR42## vii) --N--CR.sup.4 viii) --N(R.sup.4).sub.2,
- ix) aryl as defined above,
- x) heterocyclic as defined in (o) below,
- xi) --S(O).sub.x R.sup.23,
- xii) tetrazol--5--yl,
- xiii) --CONHSO.sub.2 R.sup.23,
- xiv) --SO.sub.2 NH--heteroaryl,
- xv) --SO.sub.2 NHCOR.sup.23, ##STR43## xix) --PO(OR.sup.4).sub.2, xx) --PO(OR.sup.4)R.sup.9,
- c) chloro, bromo or iodo,
- d) perfluoro--C.sub.1 -C.sub.4 alkyl,
- e) --OH,
- f) --NH.sub.2, ##STR44## i) --OR.sup.23, j) --CO.sub.2 R.sup.4,
- k) --CON(R.sup.4).sub.2,
- l) --NHC.sub.3 -C.sub.7 cycloalkyl,
- m) C.sub.3 -C.sub.7 cycloalkyl,
- n) aryl as defined above, or
- o) heterocyclic which is a five- or six- membered saturated or unsaturated ring containing up to three heteroatoms selected from the group consisting of O, N or S wherein S may in the form of sulfoxide or sulfone and which is unsubstituted or substituted with one or two substituents which are members selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C=hd 4 alkoxy, C.sub.1 -C.sub.4 alkyl--S(O).sub.x -- where x is as defined above, CF.sub.3, NO.sub.2, OH, 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) or N(R.sup.4).sub.2 ;
- p) --CN,
- q) (CH.sub.2).sub.n N-- where n is 4 to 6,
- r) --SO.sub.2 N(R.sup.4).sub.2 ;
- s) tetrazol-5-yl,
- t) --CONHSO.sub.2 R.sup.23,
- u) --PO(OR.sup.4).sub.2,
- v) --NHSO.sub.2 CF.sub.3,
- w) --SO.sub.2 NH--heteroaryl,
- x) --SO.sub.2 NHCOR.sup.23,
- y) --S(O).sub.x R.sup.23, ##STR45## aa) --PO(OR.sup.4)R.sup.9, bb) --NHSO.sub.2 R.sup.23,
- cc) --NHSO.sub.2 NHR.sup.23,
- dd) --NHSO.sub.2 NHCOR.sup.23,
- ee) NHCONHSO.sub.2 R.sup.23,
- ff) --N(R.sup.4)CO.sub.2 R.sup.23, ##STR46## hh) --CO--aryl, ##STR47## jj) --COC.sub.1.sup.-C.sub.4 alkyl, kk) --SO.sub.2 NH--CN, ##STR48## R.sup.8 groups can be the same or different and represent:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl or alkenyl either unsubstituted or substituted with hydroxy, C.sub.1 -C.sub.4 alkoxy, --N(R.sup.4).sub.2, --CO.sub.2 R.sup.4, or C.sub.3 -C.sub.5 cycloalkyl,
- c) C.sub.3 -C.sub.5 cycloalkyl,
- R.sup.8a is R.sup.8 or C.sub.1 -C.sub.4 acyl;
- and
- R.sup.9a groups can be the same or different and represent:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl either unsubstituted or substituted with
- i) hydroxy,
- ii) --CO.sub.2 R.sup.4,
- iii) --CONHR.sup.4, or
- iv) --CON(R.sup.4).sub.2.
132 more elements
A compound of structural formula:
- ##STR49## or a pharmaceutically acceptable salt thereof, wherein:
- R.sup.1 is
- a) --CO.sub.2 R.sup.4, ##STR50## c) --NHS0.sub.2 CF.sub.3, d) --SO.sub.2 NH--heteroaryl,
- e) --CH.sub.2 SO.sub.2 NH--heteroaryl,
- f) --SO.sub.2 NHCOR.sup.23,
- g) --CH.sub.2 SO.sub.2 NHCOR.sup.23,
- h) --CONHSO.sub.2 R.sup.23, or
- i) --CH.sub.2 CONHSO.sub.2 R.sup.23 ;
- heteroaryl is an unsubstituted, monsubstituted or disubstituted five- or six-membered aromatic ring which contains 1 to 3 heteroatoms selected from the group consisting of O, N or S and wherein the substituent are members selected from the group consisting of --OH, --SH, --C.sub.1 -C.sub.4 alkyl, --C.sub.1 -C.sub.4 alkoxy, halo, --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 ;
- R.sup.2a and R.sup.2b are independently
- a) C.sub.1 -C.sub.4 alkyl,
- b) chloro, or
- c) hydrogen;
- R.sup.3a and R.sup.3b are independently
- a) C.sub.1 -C.sub.4 alkyl,
- b) chloro,
- c) C.sub.1 -C.sub.4 alkoxy, or
- d) hydrogen;
- R.sup.4 is hydrogen or C.sub.1 -C.sub.4 alkyl;
- E is a single bond;
- R.sup.6 is
- a) branched or straight chain C.sub.1 -C.sub.c alkyl, alkenyl or C.sub.2 -C.sub.6 alkynyl each of which is either unsubstituted or substituted with CF.sub.3, CF.sub.2 CH.sub.3 or CF.sub.2 CH.sub.3,
- b) C.sub.3 -C.sub.7 cycloalkyl, or
- c) perfluoro--C.sub.1;
- -C.sub.4 alkyl;
- --A--B--C--D-- represents the constituent atoms of a 6-member heterocyclic ring with imidazole to which they are attached of the following formula:
- ##STR51## R.sup.7 groups are the same or different and represent:
- a) hydrogen,
- b) --C.sub.1 -C.sub.4 alkyl, either unsubstituted or substituted with --OH or --CO.sub.2 R.sup.4,
- c) halo,
- d) --OH,
- e) --N(R.sup.4).sub.2,
- f) --C.sub.1 -C.sub.4 alkoxy,
- g) --C).sub.2 R.sup.4,
- h) aryl,
- i) heterocyclic,
- j) --CF.sub.3, or
- k) tetrazol-5-yl;
- aryl is phenyl or naphthyl either unsubstituted or substituted with one or two substituents selected from the group consisting of halo, 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(C.sub.1 -C.sub.4 alkyl), N(C.sub.1 -C.sub.4 alkyl).sub.2, C).sub.2 H, and CO.sub.2 --C.sub.1 -C.sub.4 alkyl;
- hetero cyclic which is a five- or six-membered saturated or unsaturated ring containing up to three heteroatoms selected from the group consisting of O, N or S wherein S may in the form of sulfoxide or sulfone and which is unsubstituted or substituted with one or two substituents which are members selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 --S(O).sub.x -- where x is 0 to 2, CF.sub.3, N).sub.2, OH, CO.sub.2 --C.sub.1 -C.sub.4 alkyl, NH.sub.2, NH(C.sub.1 -C.sub.4 alkyl) or N(R.sup.4).sub.2 ;
- R.sup.8 is
- a) hydrogen, or
- b) C.sub.1 -C.sub.4 alkyleither unsubstituted or substituted with --OH or --CO.sub.2 R.sup.4 ;
- X is a single bond;
- R.sup.23 is
- a) aryl,
- b) heteroaryl,
- c) C.sub.1 -C.sub.4 cycloalkyl,
- d) C.sub.1 -C.sub.4 alkyl which is unsubstituted or substituted with a substituent that is a member selected from the group consisting of aryl, heteroaryl, --OH, --SH, --C.sub.1 -C.sub.4 alkyl, --O(C.sub.1 -C.sub.4 alkyl), --S(C.sub.1 -C.sub.4 alkyl, --CF.sub.3, halo, --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). --NHCOR.sup.4a, --N(C.sub.1 -C.sub.4 alkyl).sub.2, --PO.sub.3 H, --PO(OH)(C.sub.1 -C.sub.4 alkyl), --PO(OH)(aryl) or --PO(OH)(O--C.sub.1 -C.sub.4 alkyl),
- e) perfluoro--C.sub.1 -C.sub.4 alkyl;
- and
- R.sup.4a is C.sub.1 -C.sub.6 alkyl, aryl or --CH.sub.2 aryl.
49 more elements
Dependencies are inferred from the claim text.