US 5,281,614 AGranted

Substituted 1,2,4-triazoles bearing acidic functional groups as angiotensin II antagonists

AssigneeMerck & Co., Inc.

InventorsWallace T. Ashton, Prasun K. Chakravarty, Linda L. Chang, William J. Greenlee, Dooseop Kim, Nathan B. Mantlo, Arthur A. Patchett

Life of this patent

Estimating the term…

Abstract

Novel substituted triazolinone, triazolinethione, and triazolinimine compounds of the formula I are useful as angiotensin II antagonists. ##STR1##

Claims11

Dependent claims

A compound having the formula (I):

##STR75## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is ##STR76## Y is O or S;
Z is O, S(O).sub.p or NR.sup.11 ;
R.sup.2a and R.sup.2b are each independently:
(a) hydrogen,
(b) halogen (Cl, Br, I, F),
(c) --NO.sub.2,
(d) NH.sub.2,
(e) C.sub.1 -C.sub.4 -alkylamino,
(f) --SO.sub.2 NHR.sup.9,
(g) CF.sub.3,
(h) C.sub.1 -C.sub.6 -alkyl substituted with:
(1) H,
(2) F,
(3) aryl,
(4) thiophenyl,
(5) furyl,
(6) pyridyl,
(7) imidazoyl,
(8) pyrimidinyl,
(9) C.sub.1 -C.sub.6 -alkoxy,
(10) --O(CH.sub.2).sub.m --O--C.sub.1 -C.sub.4 -alkyl, wherein m is 2 to 4, or
(11) C.sub.3 -C.sub.7 -cycloalkyl, or
when R.sup.2a and R.sup.2b are on adjacent carbons, they can be bonded together to form a phenyl ring;
R.sup.3a is
(a) H,
(b) halo (Cl, Br, I, F)
(c) C.sub.1 -C.sub.6 -alkyl,
(d) C.sub.1 -C.sub.6 -alkoxy,
(e) C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.4 -alkyl;
R.sup.3b is
(a) H,
(b) halo (Cl, Br, I, F),
(c) NO.sub.2,
(d) C.sub.1 -C.sub.6 -alkyl,
(e) C.sub.1 -C.sub.5 -alkylcarbonyloxy,
(f) C.sub.3 -C.sub.6 -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,
(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) di(C.sub.1 -C.sub.4 -alkyl)amino,
(q) CF.sub.3,
(r) --SO.sub.2 --NHR.sup.9,
(s) aryl,
(t) furyl, or
when R.sup.3a and R.sup.3b are on adjacent carbons, they can be bonded together to form a phenyl ring;
wherein aryl is phenyl, biphenyl or naphthyl unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo (Cl, Br, I, F), 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 -alkyl-S(O).sub.p --, CF.sub.3 SO.sub.2 --, --OH, --NR.sup.9 R.sup.10, --SO.sub.2 NR.sup.9 R.sup.10, C.sub.3 -C.sub.7 -cycloalkyl, --CO.sub.2 H, --CO.sub.2 --C.sub.1 -C.sub.4 -alkyl, --CONR.sup.21 R.sup.22, --CN, C.sub.3 -C.sub.10 -alkenyl, --NHCOR.sup.9, --OCF.sub.3, phenyl-C.sub.1 -C.sub.2 -alkyl, phenyl-S(O).sub.p and phenyl-C.sub.1 -C.sub.2 -alkyl-S(O).sub.p ;
R.sup.4 is H, straight chain or branched C.sub.1 -C.sub.6 alkyl, --CH.sub.2 -aryl or aryl;
R.sup.5 is H or --CH(R.sup.4)--O--CO--R.sup.4a ;
wherein R.sup.4a is C.sub.1 -C.sub.6 -alkyl, aryl or --CH.sub.2 -aryl;
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(CH.sub.2).sub.s --, or --CO--;
R.sup.6 is
(a) phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I or F, --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 and C.sub.3 -C.sub.10 -alkenyl;
(b) straight chain or branched 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 one or more substituents selected from the group consisting of aryl as defined above, C.sub.3 -C.sub.7 -cycloalkyl, halo (Cl, Br, I, F), --OH, --O--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, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, --SO.sub.2 NHR.sup.9, --S--C.sub.1 -C.sub.4 -alkyl;
(c) heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five- or six-membered aromatic ring which contains 1 to 2 heteroatoms selected from the group consisting of O, N and 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 -alkoxy, --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) and --N(C.sub.1 -C.sub.4 -alkyl).sub.2 ;
(d) mono-, di-, tri- or polyfluoro-C.sub.1 -C.sub.5 -alkyl;
(e) C.sub.3 -C.sub.7 -cycloalkyl optionally substituted with one or more substituents selected from the group consisting of C.sub.1 -C.sub.4 -alkyl, O--C.sub.1 -C.sub.4 -alkyl, S--C.sub.1 -C.sub.4 -alkyl, OH, perfluoro-C.sub.1 -C.sub.4 -alkyl, or halo (Cl, Br, F, I);
or
(f) C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.3 -alkyl wherein the cycloalkyl is substituted as in (e) above;
A is O, S or NR.sup.21 ;
B is
(a) H provided A is not NR.sup.21,
(b) C.sub.1 -C.sub.10 -alkyl,
(c) substituted C.sub.1 -C.sub.10 -alkyl in which one or more substituent(s) is selected from
(1) halogen (I, Br, Cl, F),
(2) hydroxy,
(3) C.sub.1 -C.sub.10 -alkoxy,
(4) C.sub.1 -C.sub.5 -alkoxycarbonyl,
(5) C.sub.1 -C.sub.4 -alkylcarbonyloxy,
(6) C.sub.3 -C.sub.8 -cycloalkyl,
(7) phenyl, biphenyl or naphthyl,
(8) substituted phenyl, biphenyl or naphthyl in which the substituents are V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(9) C.sub.1 -C.sub.10 -alkyl-S(O).sub.p,
(10) C.sub.3 -C.sub.8 -cycloalkyl-S(O).sub.p,
(11) phenyl-S(O).sub.p,
(12) substituted phenyl-S(O).sub.p in which the substituents are V.sub.1 -V.sub.5,
(13) oxo,
(14) carboxy,
(15) NR.sup.9 R.sup.9,
(16) C.sub.1 -C.sub.5 -alkylaminocarbonyl,
(17) di(C.sub.1 -C.sub.5 -alkyl)aminocarbonyl,
(18) cyano,
(19) --OCONR.sup.21 R.sup.22,
(20) --NR.sup.21 COR.sup.22,
(21) --NR.sup.21 CO.sub.2 R.sup.22,
(22) --NR.sup.21 CONR.sup.21 R.sup.22,
(23) --NR.sup.21 CON(CH.sub.2 CH.sub.2).sub.2 L,
(24) --OCON(CH.sub.2 CH.sub.2).sub.2 L, wherein L is a single bond, CH.sub.2, O, S(O).sub.p or NR.sup.9,
(d) C.sub.2 -C.sub.10 -alkenyl,
(e) C.sub.2 -C.sub.10 -alkynyl,
(f) C.sub.3 -C.sub.8 -cycloalkyl,
(g) substituted C.sub.3 -C.sub.8 -cycloalkyl or substituted C.sub.3 -C.sub.8 -cycloalkyl-C.sub.1 -C.sub.4 -alkyl having one or more substituents selected from the group:
(1) halo (Cl, Br, F, I),
(2) hydroxy,
(3) C.sub.1 -C.sub.6 -alkyl,
(4) C.sub.1 -C.sub.6 -alkoxy,
(5) C.sub.1 -C.sub.4 -alkylcarbonyloxy,
(6) C.sub.1 -C.sub.5 -alkoxycarbonyl,
(7) carboxy,
(8) oxo,
(9) C.sub.1 -C.sub.5 -alkylaminocarbonyl,
(10) di(C.sub.1 -C.sub.5 -alkyl)aminocarbonyl,
(11) C.sub.1 -C.sub.4 -alkylcarbonyl,
(12) aryl,
(13) substituted phenyl or naphthyl in which the substituents are V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(14) --NR.sup.21 COR.sup.22,
(15) --NR.sup.21 CO.sub.2 R.sup.22,
(16) --OCONR.sup.21 R.sup.22, and
(17) --CN,
(h) phenyl, biphenyl or naphthyl,
(i) substituted phenyl, biphenyl or naphthyl in which the substituents are V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(j) phenyl-(CH.sub.2).sub.r --(Q).sub.c --(CH.sub.2).sub.t --,
(k) substituted phenyl-(CH.sub.2).sub.r --(Q).sub.c --(CH.sub.2).sub.t -- in which the phenyl group is substituted with V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(l) heterocycle-(CH.sub.2).sub.r --(Q).sub.c --(CH.sub.2).sub.t --, wherein the heterocycle is 5- or 6-membered containing one or two heteroatoms such as pyridine, furan, pyrrole, imidazole or thiazole and unsubstituted or substituted with V.sub.1 and V.sub.2 ;
R.sup.9 is H, C.sub.1 -C.sub.5 -alkyl, aryl or --CH.sub.2 -aryl;
R.sup.10 is H, C.sub.1 -C.sub.4 -alkyl, or
R.sup.9 and R.sup.10 together can be --(CH.sub.2).sub.m -- where m is 3-6;
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, or --CH.sub.2 --C.sub.6 H.sub.4 R.sup.20 ;
R.sup.12 is --CN, --NO.sub.2 or --CO.sub.2 R.sup.4 ;
R.sup.13 is H, C.sub.2 -C.sub.4 -alkanoyl, 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 -cycloalkyl, phenyl or benzyl;
R.sup.15 is H, C.sub.1 -C.sub.6 -alkyl, or hydroxy;
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, --NHSO.sub.2 CF.sub.3, ##STR77## 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) H,
(b) phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I or F, --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, --COOR.sup.4, C.sub.3 -C.sub.7 -cycloalkyl and C.sub.3 -C.sub.10 -alkenyl,
(c) straight chain or branched 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 one or more substituents selected from the group consisting of aryl as defined above, C.sub.3 -C.sub.7 -cycloalkyl, halo (Cl, Br, I, F), --OH, --O--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, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, --SO.sub.2 NHR.sup.9, and --S--C.sub.1 -C.sub.4 -alkyl,
(d) heteroaryl as defined hereinabove, or
(e) C.sub.3 -C.sub.7 -cycloalkyl unsubstituted or substituted with one or more substituents selected from the group consisting of C.sub.1 -C.sub.4 -alkyl, --O--C.sub.1 -C.sub.4 -alkyl, --S--C.sub.1 -C.sub.4 -alkyl, --OH, --COOR.sup.4, perfluoro-C.sub.1 -C.sub.4 -alkyl or halo (Cl, Br, F, I);
R.sup.22 is R.sup.21, excluding H;
R.sup.23 is
(a) H,
(b) aryl as defined above, or
(c) C.sub.1 -C.sub.6 -alkyl unsubstituted or 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.24 is
(a) aryl as defined above,
(b) C.sub.1 -C.sub.6 -alkyl unsubstituted or 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, --O--C.sub.1 -C.sub.6 -alkyl wherein alkyl is as defined in (b);
R.sup.25 is
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl unsubstituted or 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, or
(c) F, Cl, Br;
X is
(a) a single bond,
(b) --CO--,
(c) --O--,
(d) --S--, ##STR78## (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 --, ##STR79## Q is --C(O)--, --S--, --O-- or --NR.sup.4 ;
c is 0 or 1;
p, r and t are 0 to 2;
V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5 are each independently selected from:
(a) H,
(b) C.sub.1 -C.sub.5 -alkoxy,
(c) C.sub.1 -C.sub.5 -alkyl,
(d) hydroxy,
(e) C.sub.1 -C.sub.5 -alkyl-S(O).sub.p,
(f) --CN,
(g) --NO.sub.2,
(h) --NR.sup.9 R.sup.10,
(i) C.sub.1 -C.sub.5 -alkyl-CONR.sup.21 R.sup.22,
(j) --CONR.sup.21 R.sup.22,
(k) --CO.sub.2 R.sup.9,
(l) --(CH.sub.2).sub.t COR.sup.22,
(m) CF.sub.3,
(n) halogen (I, Br, Cl, F),
(o) hydroxy-C.sub.1 -C.sub.4 -alkyl-,
(p) carboxy-C.sub.1 -C.sub.4 -alkyl-,
(q) -1H-tetrazol-5-yl,
(r) --NH--SO.sub.2 CF.sub.3,
(s) aryl,
(t) C.sub.1 -C.sub.5 -alkyl-CO.sub.2 R.sup.9,
(u) aryloxy,
(v) aryl-C.sub.1 -C.sub.3 -alkoxy,
(w) aryl-C.sub.1 -C.sub.3 -alkyl,
(x) carboxyphenyl,
(y) heteroaryl,
(z) 2-oxazolin-2-yl optionally bearing one or more C.sub.1 -C.sub.4 -alkyl substituents,
(aa) --(CH.sub.2).sub.t OCOR.sup.22,
(bb) --(CH.sub.2).sub.t OCONR.sup.21 R.sup.22,
(cc) --(CH.sub.2).sub.t NR.sup.21 COR.sup.22,
(dd) --(CH.sub.2).sub.t NR.sup.21 CO.sub.2 R.sup.22,
(ee) --(CH.sub.2).sub.t NR.sup.21 CONR.sup.21 R.sup.22,
(ff) --(CH.sub.2).sub.t NR.sup.21 CON(CH.sub.2 CH.sub.2).sub.2 L,
(gg) --(CH.sub.2).sub.t OCON(CH.sub.2 CH.sub.2).sub.2 L,
(hh) --N(CH.sub.2 CH.sub.2).sub.2 L,
(ii) --C.sub.1 -C.sub.5 -alkyl-CON(CH.sub.2 CH.sub.2).sub.2 L, or
(jj) --CON(CH.sub.2 CH.sub.2).sub.2 L,
wherein L is a single bond, O, CH.sub.2, S(O).sub.p or NR.sup.9 ;
u is 1 or 2;
and
Z is O, NR.sup.13 or S.

208 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/970,360Filed 2 Nov 1992 · continuation in part
Priority: 10 May 1991
Granted: 25 Jan 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 413/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Family

Serial698,505Parent of this continuation-in-part · filed 10 May 1991
Serial875,038Parent of this continuation-in-part · filed 1 May 1992
US 5,281,614 AThis patent

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

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Abstract

Novel substituted triazolinone, triazolinethione, and triazolinimine compounds of the formula I are useful as angiotensin II antagonists. ##STR1##

A compound having the formula (I):

##STR75## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is ##STR76## Y is O or S;
Z is O, S(O).sub.p or NR.sup.11 ;
R.sup.2a and R.sup.2b are each independently:
(a) hydrogen,
(b) halogen (Cl, Br, I, F),
(c) --NO.sub.2,
(d) NH.sub.2,
(e) C.sub.1 -C.sub.4 -alkylamino,
(f) --SO.sub.2 NHR.sup.9,
(g) CF.sub.3,
(h) C.sub.1 -C.sub.6 -alkyl substituted with:
(1) H,
(2) F,
(3) aryl,
(4) thiophenyl,
(5) furyl,
(6) pyridyl,
(7) imidazoyl,
(8) pyrimidinyl,
(9) C.sub.1 -C.sub.6 -alkoxy,
(10) --O(CH.sub.2).sub.m --O--C.sub.1 -C.sub.4 -alkyl, wherein m is 2 to 4, or
(11) C.sub.3 -C.sub.7 -cycloalkyl, or
when R.sup.2a and R.sup.2b are on adjacent carbons, they can be bonded together to form a phenyl ring;
R.sup.3a is
(a) H,
(b) halo (Cl, Br, I, F)
(c) C.sub.1 -C.sub.6 -alkyl,
(d) C.sub.1 -C.sub.6 -alkoxy,
(e) C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.4 -alkyl;
R.sup.3b is
(a) H,
(b) halo (Cl, Br, I, F),
(c) NO.sub.2,
(d) C.sub.1 -C.sub.6 -alkyl,
(e) C.sub.1 -C.sub.5 -alkylcarbonyloxy,
(f) C.sub.3 -C.sub.6 -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,
(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) di(C.sub.1 -C.sub.4 -alkyl)amino,
(q) CF.sub.3,
(r) --SO.sub.2 --NHR.sup.9,
(s) aryl,
(t) furyl, or
when R.sup.3a and R.sup.3b are on adjacent carbons, they can be bonded together to form a phenyl ring;
wherein aryl is phenyl, biphenyl or naphthyl unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo (Cl, Br, I, F), 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 -alkyl-S(O).sub.p --, CF.sub.3 SO.sub.2 --, --OH, --NR.sup.9 R.sup.10, --SO.sub.2 NR.sup.9 R.sup.10, C.sub.3 -C.sub.7 -cycloalkyl, --CO.sub.2 H, --CO.sub.2 --C.sub.1 -C.sub.4 -alkyl, --CONR.sup.21 R.sup.22, --CN, C.sub.3 -C.sub.10 -alkenyl, --NHCOR.sup.9, --OCF.sub.3, phenyl-C.sub.1 -C.sub.2 -alkyl, phenyl-S(O).sub.p and phenyl-C.sub.1 -C.sub.2 -alkyl-S(O).sub.p ;
R.sup.4 is H, straight chain or branched C.sub.1 -C.sub.6 alkyl, --CH.sub.2 -aryl or aryl;
R.sup.5 is H or --CH(R.sup.4)--O--CO--R.sup.4a ;
wherein R.sup.4a is C.sub.1 -C.sub.6 -alkyl, aryl or --CH.sub.2 -aryl;
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(CH.sub.2).sub.s --, or --CO--;
R.sup.6 is
(a) phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I or F, --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 and C.sub.3 -C.sub.10 -alkenyl;
(b) straight chain or branched 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 one or more substituents selected from the group consisting of aryl as defined above, C.sub.3 -C.sub.7 -cycloalkyl, halo (Cl, Br, I, F), --OH, --O--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, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, --SO.sub.2 NHR.sup.9, --S--C.sub.1 -C.sub.4 -alkyl;
(c) heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted five- or six-membered aromatic ring which contains 1 to 2 heteroatoms selected from the group consisting of O, N and 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 -alkoxy, --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) and --N(C.sub.1 -C.sub.4 -alkyl).sub.2 ;
(d) mono-, di-, tri- or polyfluoro-C.sub.1 -C.sub.5 -alkyl;
(e) C.sub.3 -C.sub.7 -cycloalkyl optionally substituted with one or more substituents selected from the group consisting of C.sub.1 -C.sub.4 -alkyl, O--C.sub.1 -C.sub.4 -alkyl, S--C.sub.1 -C.sub.4 -alkyl, OH, perfluoro-C.sub.1 -C.sub.4 -alkyl, or halo (Cl, Br, F, I);
or
(f) C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.3 -alkyl wherein the cycloalkyl is substituted as in (e) above;
A is O, S or NR.sup.21 ;
B is
(a) H provided A is not NR.sup.21,
(b) C.sub.1 -C.sub.10 -alkyl,
(c) substituted C.sub.1 -C.sub.10 -alkyl in which one or more substituent(s) is selected from
(1) halogen (I, Br, Cl, F),
(2) hydroxy,
(3) C.sub.1 -C.sub.10 -alkoxy,
(4) C.sub.1 -C.sub.5 -alkoxycarbonyl,
(5) C.sub.1 -C.sub.4 -alkylcarbonyloxy,
(6) C.sub.3 -C.sub.8 -cycloalkyl,
(7) phenyl, biphenyl or naphthyl,
(8) substituted phenyl, biphenyl or naphthyl in which the substituents are V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(9) C.sub.1 -C.sub.10 -alkyl-S(O).sub.p,
(10) C.sub.3 -C.sub.8 -cycloalkyl-S(O).sub.p,
(11) phenyl-S(O).sub.p,
(12) substituted phenyl-S(O).sub.p in which the substituents are V.sub.1 -V.sub.5,
(13) oxo,
(14) carboxy,
(15) NR.sup.9 R.sup.9,
(16) C.sub.1 -C.sub.5 -alkylaminocarbonyl,
(17) di(C.sub.1 -C.sub.5 -alkyl)aminocarbonyl,
(18) cyano,
(19) --OCONR.sup.21 R.sup.22,
(20) --NR.sup.21 COR.sup.22,
(21) --NR.sup.21 CO.sub.2 R.sup.22,
(22) --NR.sup.21 CONR.sup.21 R.sup.22,
(23) --NR.sup.21 CON(CH.sub.2 CH.sub.2).sub.2 L,
(24) --OCON(CH.sub.2 CH.sub.2).sub.2 L, wherein L is a single bond, CH.sub.2, O, S(O).sub.p or NR.sup.9,
(d) C.sub.2 -C.sub.10 -alkenyl,
(e) C.sub.2 -C.sub.10 -alkynyl,
(f) C.sub.3 -C.sub.8 -cycloalkyl,
(g) substituted C.sub.3 -C.sub.8 -cycloalkyl or substituted C.sub.3 -C.sub.8 -cycloalkyl-C.sub.1 -C.sub.4 -alkyl having one or more substituents selected from the group:
(1) halo (Cl, Br, F, I),
(2) hydroxy,
(3) C.sub.1 -C.sub.6 -alkyl,
(4) C.sub.1 -C.sub.6 -alkoxy,
(5) C.sub.1 -C.sub.4 -alkylcarbonyloxy,
(6) C.sub.1 -C.sub.5 -alkoxycarbonyl,
(7) carboxy,
(8) oxo,
(9) C.sub.1 -C.sub.5 -alkylaminocarbonyl,
(10) di(C.sub.1 -C.sub.5 -alkyl)aminocarbonyl,
(11) C.sub.1 -C.sub.4 -alkylcarbonyl,
(12) aryl,
(13) substituted phenyl or naphthyl in which the substituents are V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(14) --NR.sup.21 COR.sup.22,
(15) --NR.sup.21 CO.sub.2 R.sup.22,
(16) --OCONR.sup.21 R.sup.22, and
(17) --CN,
(h) phenyl, biphenyl or naphthyl,
(i) substituted phenyl, biphenyl or naphthyl in which the substituents are V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(j) phenyl-(CH.sub.2).sub.r --(Q).sub.c --(CH.sub.2).sub.t --,
(k) substituted phenyl-(CH.sub.2).sub.r --(Q).sub.c --(CH.sub.2).sub.t -- in which the phenyl group is substituted with V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5,
(l) heterocycle-(CH.sub.2).sub.r --(Q).sub.c --(CH.sub.2).sub.t --, wherein the heterocycle is 5- or 6-membered containing one or two heteroatoms such as pyridine, furan, pyrrole, imidazole or thiazole and unsubstituted or substituted with V.sub.1 and V.sub.2 ;
R.sup.9 is H, C.sub.1 -C.sub.5 -alkyl, aryl or --CH.sub.2 -aryl;
R.sup.10 is H, C.sub.1 -C.sub.4 -alkyl, or
R.sup.9 and R.sup.10 together can be --(CH.sub.2).sub.m -- where m is 3-6;
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, or --CH.sub.2 --C.sub.6 H.sub.4 R.sup.20 ;
R.sup.12 is --CN, --NO.sub.2 or --CO.sub.2 R.sup.4 ;
R.sup.13 is H, C.sub.2 -C.sub.4 -alkanoyl, 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 -cycloalkyl, phenyl or benzyl;
R.sup.15 is H, C.sub.1 -C.sub.6 -alkyl, or hydroxy;
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, --NHSO.sub.2 CF.sub.3, ##STR77## 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) H,
(b) phenyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I or F, --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, --COOR.sup.4, C.sub.3 -C.sub.7 -cycloalkyl and C.sub.3 -C.sub.10 -alkenyl,
(c) straight chain or branched 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 one or more substituents selected from the group consisting of aryl as defined above, C.sub.3 -C.sub.7 -cycloalkyl, halo (Cl, Br, I, F), --OH, --O--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, --NH--SO.sub.2 R.sup.4, --COOR.sup.4, --SO.sub.2 NHR.sup.9, and --S--C.sub.1 -C.sub.4 -alkyl,
(d) heteroaryl as defined hereinabove, or
(e) C.sub.3 -C.sub.7 -cycloalkyl unsubstituted or substituted with one or more substituents selected from the group consisting of C.sub.1 -C.sub.4 -alkyl, --O--C.sub.1 -C.sub.4 -alkyl, --S--C.sub.1 -C.sub.4 -alkyl, --OH, --COOR.sup.4, perfluoro-C.sub.1 -C.sub.4 -alkyl or halo (Cl, Br, F, I);
R.sup.22 is R.sup.21, excluding H;
R.sup.23 is
(a) H,
(b) aryl as defined above, or
(c) C.sub.1 -C.sub.6 -alkyl unsubstituted or 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.24 is
(a) aryl as defined above,
(b) C.sub.1 -C.sub.6 -alkyl unsubstituted or 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, --O--C.sub.1 -C.sub.6 -alkyl wherein alkyl is as defined in (b);
R.sup.25 is
(a) H,
(b) C.sub.1 -C.sub.6 -alkyl unsubstituted or 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, or
(c) F, Cl, Br;
X is
(a) a single bond,
(b) --CO--,
(c) --O--,
(d) --S--, ##STR78## (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 --, ##STR79## Q is --C(O)--, --S--, --O-- or --NR.sup.4 ;
c is 0 or 1;
p, r and t are 0 to 2;
V.sub.1, V.sub.2, V.sub.3, V.sub.4 and V.sub.5 are each independently selected from:
(a) H,
(b) C.sub.1 -C.sub.5 -alkoxy,
(c) C.sub.1 -C.sub.5 -alkyl,
(d) hydroxy,
(e) C.sub.1 -C.sub.5 -alkyl-S(O).sub.p,
(f) --CN,
(g) --NO.sub.2,
(h) --NR.sup.9 R.sup.10,
(i) C.sub.1 -C.sub.5 -alkyl-CONR.sup.21 R.sup.22,
(j) --CONR.sup.21 R.sup.22,
(k) --CO.sub.2 R.sup.9,
(l) --(CH.sub.2).sub.t COR.sup.22,
(m) CF.sub.3,
(n) halogen (I, Br, Cl, F),
(o) hydroxy-C.sub.1 -C.sub.4 -alkyl-,
(p) carboxy-C.sub.1 -C.sub.4 -alkyl-,
(q) -1H-tetrazol-5-yl,
(r) --NH--SO.sub.2 CF.sub.3,
(s) aryl,
(t) C.sub.1 -C.sub.5 -alkyl-CO.sub.2 R.sup.9,
(u) aryloxy,
(v) aryl-C.sub.1 -C.sub.3 -alkoxy,
(w) aryl-C.sub.1 -C.sub.3 -alkyl,
(x) carboxyphenyl,
(y) heteroaryl,
(z) 2-oxazolin-2-yl optionally bearing one or more C.sub.1 -C.sub.4 -alkyl substituents,
(aa) --(CH.sub.2).sub.t OCOR.sup.22,
(bb) --(CH.sub.2).sub.t OCONR.sup.21 R.sup.22,
(cc) --(CH.sub.2).sub.t NR.sup.21 COR.sup.22,
(dd) --(CH.sub.2).sub.t NR.sup.21 CO.sub.2 R.sup.22,
(ee) --(CH.sub.2).sub.t NR.sup.21 CONR.sup.21 R.sup.22,
(ff) --(CH.sub.2).sub.t NR.sup.21 CON(CH.sub.2 CH.sub.2).sub.2 L,
(gg) --(CH.sub.2).sub.t OCON(CH.sub.2 CH.sub.2).sub.2 L,
(hh) --N(CH.sub.2 CH.sub.2).sub.2 L,
(ii) --C.sub.1 -C.sub.5 -alkyl-CON(CH.sub.2 CH.sub.2).sub.2 L, or
(jj) --CON(CH.sub.2 CH.sub.2).sub.2 L,
wherein L is a single bond, O, CH.sub.2, S(O).sub.p or NR.sup.9 ;
u is 1 or 2;
and
Z is O, NR.sup.13 or S.

208 more elements

Facts

Application

07/970,360Filed 2 Nov 1992 · continuation in part

Priority

10 May 1991

Granted

25 Jan 1994

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 413/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
A61P 25/18
Drugs for disorders of the nervous system: antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia