US 5,330,987 AGranted

Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists

AssigneeMerck & Co., Inc.

InventorsEric E. Allen, Prasun K. Chakravarty, Stephen E. de Laszlo, William J. Greenlee, Arthur A. Patchett, Thomas F. Walsh

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Abstract

Novel substituted pyridopyrimidinones of formula (I), which are useful as angiotensin II antagonists, are disclosed. ##STR1##

Claims15

Dependent claims

A compound of formula (I):

##STR56## or a pharmaceutically acceptable salt thereof wherein:
M is a C atom;
L is C or N when connected to K or J to form a ring as defined below;
J is --C(.dbd.Y)-where Y is O or NR.sup.21 and K and L are connected together to form a 6 membered aromatic ring containing one N atom that is not at K and five C atoms which can be substituted at the carbon atoms with R.sup.8a and R.sup.8b ;
K is --C(.dbd.Y)- where Y is O or NR.sup.21 and J and L are connected together to form a 6 membered aromatic ring containing one N atom that is not at J and five C atoms which may be substituted at the carbon atoms with R.sup.8a and R.sup.8b provided that only one of J and K is --C(.dbd.Y)--;
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 --NH--R.sup.9,
(f) --CONHOR.sup.5, ##STR57## (i) --SO.sub.2 NH-heteroaryl as defined below, (j) --CH.sub.2 SO.sub.2 NH-heteroaryl as defined below,
(k) --SO.sub.2 NH--CO--R.sup.22,
(l) --CH.sub.2 SO.sub.2 NH--CO--R.sup.22,
(m) --CONH--SO.sub.2 R.sup.22,
(n) --CH.sub.2 CONH--SO.sub.2 R.sup.22,
(o) --NHSO.sub.2 NHCO--R.sup.22,
(p) --NHCONHSO.sub.2 --R.sup.22, ##STR58## wherein Z is O, --S(O).sub.x, --N(R.sup.11)--, --NCOR.sup.22, --NSO.sub.2 R.sup.22, --NCO.sub.2 R.sup.22 or --NCON(R.sup.4)R.sup.22 ;
(ff) --NHSO.sub.2 NHSO.sub.2 R.sup.22, ##STR59## wherein G is O or S:
wherein heteroaryl is are unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N or S,
wherein said ring is selected from the group consisting of pyridine pyrimidine pyrazine, triazine, furan, thiophene, oxazole, thiazole, imidazole, triazole, or thiadiazole, 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, halo (Cl, Br, F, I), --NO.sub.2, --CO.sub.2 --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 each independently
(a) H,
(b) halogen, (Cl, Br, I, F)
(c) NO.sub.2,
(d) NH.sub.2,
(e) C.sub.1 -C.sub.4 -alkylamino,
(f) di(C.sub.1 -C.sub.4 -alkyl)amino
(g) SO.sub.2 NHR.sup.9,
(h) CF.sub.3,
(i) C.sub.1 -C.sub.6 -alkyl,
(j) C.sub.1 -C.sub.6 -alkoxy,
(k) C.sub.1 -C.sub.6 -alkyl--S--,
(l) C.sub.2 -C.sub.6 -alkenyl,
(m) C.sub.2 -C.sub.6 -alkynyl;
(n) aryl as defined below,
(o) aryl(C.sub.1 -C.sub.4 -alkyl), wherein aryl is defined below;
(p) C.sub.3 -C.sub.7 -cycloalkyl;
R.sup.3a is
(a) H,
(b) halo,
(c) C.sub.1 -C.sub.6 -alkyl,
(d) C.sub.1 -C.sub.6 -alkoxy,
(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.3 -C.sub.7 -cycloalkyl,
(g) C.sub.1 -C.sub.6 -alkoxy,
(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), wherein aryl is defined below;
(k) C.sub.1 -C.sub.4 -alkylthio,
(l) C.sub.1 -C.sub.4 -alkyl sulfinyl,
(m) C.sub.1 -C.sub.4 -alkyl sulfonyl,
(n) NH.sub.2,
(o) C.sub.1 -C.sub.4 -alkylamino,
(p) di(C.sub.1 -C.sub.4 -alkyl)amino,
(q) fluoro-C.sub.1 -C.sub.4 -alkyl-,
(r) --SO.sub.2 --NHR.sup.9,
(s) aryl as defined below,
(t) furyl,
(u) CF.sub.3,
(v) C.sub.2 -C.sub.6 -alkenyl,
(w) C.sub.2 -C.sub.6 -alkynyl;
wherein aryl is phenyl or naphthyl optionally substituted with one or two substituents selected from the group consisting of halogen, N(R.sup.4).sub.2, CO.sub.2 R.sup.4, 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, ##STR60## R.sup.4 is H, aryl as defined above or straight chain or branched C.sub.1 -C.sub.6 alkyl optionally substituted with aryl or heteroaryl as defined above;
R.sup.4a is aryl as defined above or straight chain or branched C.sub.1 -C.sub.6 -alkyl optionally substituted with aryl as defined above ##STR61## E is a single bond, --NR.sup.13 (CH.sub.2).sub.s --, --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 optionally substituted with 1 or 2 substituents selected from the group consisting of halo --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.9 R.sup.10, --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;
(b) straight chain or branched C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.5 -alkenyl or C.sub.2 -C.sub.5 -alkynyl each of which can be optionally substituted with a substituent selected from the group consisting of aryl as defined above, C.sub.3 -C.sub.7 -cycloalkyl, halo, CF.sub.3, CF.sub.2 CF.sub.3, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --OR.sup.4 --N(C.sub.1 -C.sub.4 -alkyl).sub.2, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, --SO.sub.2 NHR.sup.9 ;
or
(c) heteroaryl, as defined above,
(d) C.sub.3 -C.sub.7 -cycloalkyl;
(e) perfluoro-C.sub.1 -C.sub.4 -alkyl,
(f) H;
R.sup.8a and R.sup.8b are independently
(a) H, provided they are not both H,
(b) C.sub.1 -C.sub.8 -alkyl substituted with a substituent selected from the group consisting of guanidino, --O--COR.sup.4 -aryl, as defined above, -heteroaryl, as defined above, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.22, --SO.sub.2 NH-heteroaryl, wherein heteroaryl is defined above, --SO.sub.2 NHCOR.sup.22, --PO(OR.sup.4).sub.2, --PO(OR.sup.4)R.sup.9, --SO.sub.2 NH--CN, --NR.sup.10 COOR.sup.22, morpholino, 4-R.sup.22 -piperazin-1-y, and 4-COR.sup.22 -piperazin-1-yl;
(c) --CO-aryl,
(d) -C.sub.3 -C.sub.7 -cycloalkyl,
(e) --COOR.sup.4,
(f) --SO.sub.3 H,
(g) --NR.sup.4 R.sup.22,
(h) --NR.sup.4 COR.sup.22,
(i) --NR.sup.4 COOR.sup.22,
(j) --SO.sub.2 NR.sup.4 R.sup.9,
(k) --NO.sub.2,
(l) N(R.sup.4)SO.sub.2 R.sup.22,
(m) --NR.sup.4 CONR.sup.4 R.sup.22, ##STR62## (o) -aryl or -heteroaryl as defined above, (p) --NHSO.sub.2 CF.sub.3,
(q) --SO.sub.2 NH-heteroaryl, wherein heteroaryl is defined above;
(r) --SO.sub.2 NHCOR.sup.22,
(s) --CONHSO.sub.2 R.sup.22,
(t) --PO(OR.sup.4).sub.2,
(u) --PO(OR.sup.4)R.sup.4,
(v) -tetrazol-5-yl,
(w) --CONH(tetrazol-5-yl),
(x) --COR.sup.4,
(y) --SO.sub.2 NHCN,
(z) --NR.sup.4 SO.sub.2 NR.sup.4 R.sup.22,
(aa) --NR.sup.4 SO.sub.2 OR.sup.22,
(bb) --CONR.sup.4 R.sup.22, ##STR63## R.sup.9 is H, C.sub.1 -C.sub.5 -alkyl, aryl or arylmethyl, wherein aryl is defined above;
R.sup.10 is H, C.sub.1 -C.sub.4 -alkyl;
R.sup.11 is H, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.4 -alkenyl, C.sub.1 -C.sub.4 -alkoxyalkyl, or ##STR64## R.sup.12 is --CN, --NO.sub.2 or --CO.sub.2 R.sup.4 ;
R.sup.13 is H, (C.sub.1 -C.sub.4 -alkyl)CO--, C.sub.1 -C.sub.6 -alkyl, allyl, C.sub.3 -C.sub.6 -cycloalkyl, aryl or arylmethyl, wherein aryl is defend above;
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 -cycloalkyl, aryl or arylmethyl, wherein aryl is defined above;
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, aryl or arylmethyl, wherein aryl is defined above;
R.sup.17 is --NR.sup.9 R.sup.10, --OR.sup.10, --NHCONH.sub.2, --NHCSNH.sub.2, ##STR65## 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, --NH.sub.2, --OH or --OCH.sub.3 ;
R.sup.21 is
(a) aryl as defined above,
(b) heteroaryl as defined above,
(c) C.sub.1 -C.sub.4 -alkyl optionally substituted with a substituent selected from the group consisting of aryl as defined above, heteroaryl as defined above, --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 R.sup.4a, halo, --CF.sub.3 ;
R.sup.22 is
(a) aryl as defined above,
(b) heteroaryl as defined above,
(c) C.sub.3 -C.sub.7 -cycloalkyl,
(d) C.sub.1 -C.sub.8 -alkyl optionally substituted with a substituent 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 (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, --PO.sub.3 H.sub.2, --PO(OH)(O--C.sub.1 -C.sub.4 -alkyl);
--PO(OR.sup.4)R.sup.9 or --C.sub.3 -C.sub.6 -cycloalkyl, or;
(e) perfluoro-C.sub.1 -C.sub.4 -alkyl;
R.sup.25 is
(a) H,
(b) aryl as defined above, or
C.sub.1 -C.sub.6 -alkyl optionally substituted with aryl, F, Cl, Br, --OH, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, or CF.sub.3 ;
R.sup.26 is
(a) aryl as defined above,
(b) C.sub.1 -C.sub.6 -alkyl optionally substituted with aryl, F, Cl, Br, --OH, --NH.sub.2, --NH(C.sub.1 -C.sub.4 -alkyl), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, CF.sub.3, --COOR.sup.4, or CN,
(c) --OCH(R.sup.4)--O--CO--R.sup.4a, or
(d) --OH or --O--C.sub.1 -C.sub.6 -alkyl wherein alkyl is as defined in (b);
R.sup.27 is
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl optionally substituted with aryl, as defined above F, Cl, Br, --OH, --NH.sub.2 , --NH(C.sub.1 -C.sub.4 -alkyl ), --N(C.sub.1 -C.sub.4 -alkyl).sub.2, CF.sub.3, --COOR.sup.4, or CN, or
X is
(a) a carbon-carbon single bond,
(b) --CO--,
(c) --O--,
(d) --S--, ##STR66## and r is 1 or 2.

138 more elements

Dependencies are inferred from the claim text.

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