US 5,177,074 AGranted

Angiotensin II antagonists incorporating a substituted thiophene or furan

AssigneeMerck & Co., Inc.

InventorsEric E. Allen, Ralph A. Rivero, Nancy Kevin

Life of this patent

Estimating the term…

Abstract

There are disclosed substituted thiophene and furan derivatives of Formula I which are useful as angiotensin II antagonists. ##STR1##

Claims15

Dependent claims

A compound of structural formula I:

##STR62## 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 can be unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below in R.sup.1 (b),
ii) (C.sub.3 -C.sub.8)-cycloalkyl,
iii) Cl, Br, I, F,
iv) OH,
v) NH.sub.2,
vi) NH[(C.sub.1 -C.sub.4)-alkyl],
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 ;
(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, I, F,
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;
(c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the heteroaryl is optionally mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, F,
ii) OH,
iii) SH,
iv) NO.sub.2,
v) (C.sub.1 -C.sub.4)-alkyl,
vi) (C.sub.2 -C.sub.4)-alkenyl,
vii) (C.sub.2 -C.sub.4)-alkynyl,
viii) (C.sub.1 -C.sub.4)-alkoxy, or
ix) CF.sub.3,
(d) polyfluoro-(C.sub.1 -C.sub.4)-alkyl, or
(e) (C.sub.3 -C.sub.8)-cycloalkyl;
--A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is:
##STR63## E is:
(a) a single bond,
(b) --S(O).sub.n (CH.sub.2).sub.s --, or
(c) --O--;
n is 0 to 2;
s is 0 to 5;
R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
R.sup.2a is:
(a) R.sup.2,
(b) CH.sub.2 -aryl, or
(c) aryl;
R.sup.4 groups are independently:
(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, each of which is unsubstituted or substituted with:
i) OH,
ii) (C.sub.1 -C.sub.4)-alkoxy,
iii) CO.sub.2 R.sup.2,
iv) OCOR.sup.2,
v) CONHR.sup.2,
vi) CON(R.sup.2).sub.2,
vii) N(R.sup.2)C(.dbd.O)R.sup.2,
viii) NH.sub.2,
ix) (C.sub.1-C.sub.4)-alkylamino,
x) di[(C.sub.1 -C.sub.4)-alkyl]amino,
(c) --C(.dbd.O)-aryl,
(d) (C.sub.3 -C.sub.7)-cycloalkyl,
(e) Cl, Br, I, F,
(f) --OH,
(g) --OR.sup.21,
(h) -(C.sub.1 -C.sub.4)-polyfluoroalkyl,
(i) --SH,
(j) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
(k) --CO.sub.2 R.sup.2a,
(l) --SO.sub.3 H,
(m) --NR.sup.2 R.sup.21,
(n) --NR.sup.2 C(.dbd.O)R.sup.21,
(o) --NR.sup.2 COOR.sup.21,
(p) --SO.sub.2 NR.sup.2 R.sup.2a,
(q) --NO.sub.2,
(r) --NHSO.sub.2 -(C.sub.1 -C.sub.4)-alkyl,
(s) --CO.sub.2 NH.sub.2,
(t) --CONHSO.sub.2 R.sup.14,
(u) 1H-tetrazol-5-yl,
(v) aryl,
(w) heteroaryl,
(x) or morpholinyl,
R.sup.5 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl, unsubstituted or substituted with:
i) hydroxy, or
ii) (C.sub.1 -C.sub.4)-alkoxy;
R.sup.5a is
(a) R.sup.5, or
(b) (C.sub.1 -C.sub.4)-acyl;
--X.sup.1 --X.sup.2 --X.sup.3 --X.sup.4 -- is:
(a) --Y--CR.sup.11 --CR.sup.12 --CZ--,
(b) --CR.sup.11 --Y--CR.sup.12 --CZ--,
(c) --CR.sup.11 --CR.sup.12 --Y--CZ--,
(d) --Y--CR.sup.11 --CZ--CR.sup.12 --,
(e) --CR.sup.11 --Y--CZ--CR.sup.12 --, or
(f) --CR.sup.11 --CR.sup.12 --CZ--Y--;
Y is:
O, S, SO, or SO.sub.2 ;
R.sup.9 and R.sup.10 are each independently:
(a) H,
(b) Cl, Br, I, F,
(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.6)-cycloalkyl,
(g) (C.sub.1 -C.sub.6)-alkoxy,
(h) --NHSO.sub.2 R.sup.2a,
(i) hydroxy-(C.sub.1 -C.sub.4)-alkyl,
(j) (C.sub.1 -C.sub.4)-alkyl-aryl,
(k) S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
(n) NR.sup.2a R.sup.2a,
(q) CF.sub.3,
(r) --SO.sub.2 NHR.sup.2a,
(s) furyl,
(t) aryl, wherein aryl is phenyl or naphthyl unsubstituted or substituted with one or two substituents selected from the group consisting of:
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)-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, or --CO.sub.2 -(C.sub.1 -C.sub.4)-alkyl;
or
(u) when R.sup.9 and R.sup.10 are bonded to adjacent carbon atoms, they can be joined to form an aryl ring;
R.sup.11 and R.sup.12 are independently:
(a) H,
(b) Cl, Br, I, F,
(c) NO.sub.2,
(d) NH.sub.2,
(e) NH[(C.sub.1 -C.sub.4)-alkyl],
(f) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) SO.sub.2 NHR.sup.2a,
(h) CF.sub.3,
(i) (C.sub.1 -C.sub.7)-alkyl,
(j) (C.sub.1 -C.sub.7)-alkoxy,
(k) (C.sub.3 -C.sub.7)-cycloalkyl,
(l) when R.sup.11 and R.sup.12 are bonded to adjacent carbon atoms, they can be joined to form an aryl ring,
(m) O(CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(n) (CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(o) (CH.sub.2)N(R.sup.2a).sub.2,
(p) (CH.sub.2).sub.n N[CH.sub.2 CH.sub.2 ].sub.2 X,
(q) (CH.sub.2).sub.n N[CH.sub.2 CH.sub.2 ].sub.2 CH.sub.2,
(r) CH(OR.sup.2a)[(C.sub.1 -C.sub.7)-alkyl],
(s) CHO,
(t) CO.sub.2 R.sup.2a,
(u) CH.dbd.CHR.sup.2a,
(v) CH.sub.2 CR.sup.2a .dbd.C(R.sup.2a).sub.2,
(w) (CH.sub.2).sub.n NCOR.sup.2a,
(x) CH(R.sup.2a).sub.2, or
(y) (C.sub.1 -C.sub.4)-alkyl-aryl;
X is:
--O--, --S--, or --NR.sup.2a --;
Z is:
(a) --CO.sub.2 R.sup.2a,
(b) --SO.sub.3 R.sup.13,
(c) --NHSO.sub.2 CF.sub.3,
(d) --PO(OR.sup.13).sub.2,
(e) --SO.sub.2 NHR.sup.14,
(f) --CONHOR.sup.13, ##STR64## (h) --CN, (i) --NHSO.sub.2 R.sup.14,
(j) --CH.sub.2 SO.sub.2 NH-heteroaryl, wherein heteroaryl is an 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 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,
(k) --SO.sub.2 NH--CO--R.sup.14,
(l) --CH.sub.2 SO.sub.2 NH--CO--R.sup.14,
(m) --CONH--SO.sub.2 R.sup.14,
(n) --CH.sub.2 CONH--SO.sub.2 R.sup.14,
(o) --NHSO.sub.2 NHCO--R.sup.14,
(p) --NHCONHSO.sub.2 --R.sup.14, ##STR65## R.sup.13 is H, or ##STR66## R.sup.14 is (a) aryl,
(b) heteroaryl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl, or
(d) (C.sub.1 -C.sub.7)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
aryl, heteroaryl, --OH, --SH, (C.sub.1 -C.sub.4)-alkyl, --(C.sub.1 -C.sub.6)-alkoxy, --S(C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, --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, --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --PO.sub.3 H or PO(OH)(O--(C.sub.1 -C.sub.4)-alkyl),
(e) (C.sub.1 -C.sub.7)-alkoxy,
(f) O(CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(g) (CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(h) CH(R.sup.2a).sub.2,
(i) (C.sub.1 -C.sub.6)-polyfluoroalkyl, or
(j) NH(C.sub.1 -C.sub.6)-alkyl;
R.sup.15 is H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.4)-alkenyl, (C.sub.1 -C.sub.4)-alkoxy, or benzyl, wherein the phenyl moiety is unsubstituted or substituted with a substituent selected from the group consisting of:
--NO.sub.2, --NH.sub.2, --OH or --OCH.sub.3 ;
R.sup.17 is --CN, --NO.sub.2, --CO.sub.2 R.sup.2a, or --CF.sub.3 ;
R.sup.21 is:
(a) H, or
(b) (C.sub.1 -C.sub.4)-alkyl 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,
viii) SO.sub.2 NH.sub.2, or
ix) aryl;
or
(c) aryl,
with the proviso that when --A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is --C(Me).dbd.CH--C(Me).dbd.N, E is a single bond, R.sup.1 is ethyl --X.sup.1 --X.sup.2 --X.sup.3 --X.sup.4 -- is --CH--CR.sup.11 --S--CZ--, R.sup.11 is n-butyl, or isobutyl and Z is SO.sub.2 NHCOR.sup.14, then R.sup.14 cannot be O--n--C.sub.4 H.sub.9 or CH.sub.2 O--n--C.sub.4 H.sub.9.

191 more elements

A compound of structural formula:

##STR76## or a pharmaceutically acceptable salt wherein the compound is selected from the table below:
__________________________________________________________________________ R.sup.1 R.sup.4a R.sup.4b R.sup.12 Z __________________________________________________________________________ ethyl CH.sub.3 CH.sub.3 H SO.sub.2 NHCOPh ethyl CH.sub.3 CO.sub.2 H H SO.sub.2 NHCOPh ethyl CH.sub.3 CH.sub.3 H 1H-tetrazol-5-yl n-propyl CH.sub.3 H H 1H-tetrazol-5-yl ethyl CH.sub.3 CO.sub.2 CH.sub.3 H 1H-tetrazol-5-yl propyl CH.sub.3 CO.sub.2 CH.sub.3 H 1H-tetrazol-5-yl ethyl CH.sub.3 CO.sub.2 H H 1H-tetrazol-5-yl n-propyl CH.sub.3 CO.sub.2 H H 1H-tetrazol-5-yl n-propyl CH.sub.3 H H SO.sub.2 NHCOPh ethyl CH.sub.3 CO.sub.2 CH.sub.3 H SO.sub.2 NHCOPh n-propyl CH.sub.3 CO.sub.2 CH.sub.3 H SO.sub.2 NHCOPh n-propyl CH.sub.3 CO.sub.2 CH.sub.3 H SO.sub.2 NHCOPh n-butyl Me H nPr 1H-tetrazol-5-yl n-butyl Me H iBu 1H-tetrazol-5 yl n-butyl Me H nPr SO.sub.2 NHCOPh n-butyl Me H iBu SO.sub.2 NHCOPh n-butyl Me H nPn SO.sub.2 NHCOPh ethyl Me H nPr 1H-tetrazol-5-yl ethyl Me H iBu 1H-tetrazol-5-yl ethyl Me H nPn 1H-tetrazol-5-yl ethyl Me H Bn 1H-tetrazol-5-yl ethyl Me H nPr SO.sub.2 NHCOPh ethyl Me H iBu SO.sub.2 NHCOPh ethyl Me H nPn SO.sub. 2 NHCOPh ethyl Me H Bn SO.sub.2 NHCOPh n-butyl Me Me nPr 1H-tetrazol-5-yl n-butyl Me Me nBu 1H-tetrazol-5-yl n-butyl Me Me iBu 1H-tetrazol-5-yl n-butyl Me Me nPn 1H-tetrazol-5-yl n-butyl Me Me nPr SO.sub.2 NHCOPh n-butyl Me Me iBu SO.sub.2 NHCOPh n-butyl Me Me nPn SO.sub.2 NHCOPh ethyl Me Me nPr 1H-tetrazol-5-yl ethyl Me Me iBu 1H-tetrazol-5-yl ethyl Me Me nPn 1H-tetrazol-5-yl ethyl Me Me Me SO.sub.2 NHCOPh ethyl Me Me Et SO.sub.2 NHCOPh ethyl Me Me nPr SO.sub.2 NHCOPh ethyl Me Me nBu SO.sub.2 NHCOPh ethyl Me Me iBu SO.sub.2 NHCOPh ethyl Me Me nPn SO.sub.2 NHCOPh ethyl Me Me Bn SO.sub.2 NHCOPh ethyl Me Me CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O SO.sub.2 NHCOPh ethyl Me Me CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O SO.sub.2 NHCOCH(Ph).sub.2 n-butyl Me CON(Me).sub.2 nPr 1H-tetrazol-5-yl n-butyl Me CON(Me).sub.2 iBu 1H-tetrazol-5-yl n-butyl Me CON(Me).sub.2 nPr SO.sub.2 NHCOPh ethyl Me CON(Me).sub.2 nPr 1H-tetrazol-5-yl ethyl Me CON(Me).sub.2 nBu 1H-tetrazol-5-yl ethyl Me CON(Me).sub.2 iBu 1H-tetrazol-5-yl ethyl Me CON(Me).sub.2 nPn 1H-tetrazol-5-yl ethyl Me CON(Me).sub.2 nBu SO.sub.2 NHCOPh ethyl Me CON(Me).sub. 2 iBu SO.sub.2 NHCOPh ethyl Me CON(Me).sub.2 Bn SO.sub.2 NHCOPh n-butyl Me CH.sub.2 OH nPr 1H-tetrazol-5-yl n-butyl Me CH.sub.2 OH iBu 1H-tetrazol-5-yl n-butyl Me CH.sub.2 OH nPr SO.sub.2 NHCOPh n-butyl Me CH.sub.2 OH nPn SO.sub.2 NHCOPh ethyl Me CH.sub.2 OH nBu 1H-tetrazol-5-yl ethyl Me CH.sub.2 OH iBu 1H-tetrazol-5-yl ethyl Me CH.sub.2 OH nPn 1H-tetrazol-5-yl ethyl Me Me nPr SO.sub.2 NHCO(CH.sub.2).sub.2 OMe ethyl Me CH.sub.2 OH nBu SO.sub.2 NHCOPh ethyl Me CH.sub.2 OH iBu SO.sub.2 NHCOPh ethyl Me CH.sub.2 OH nPn SO.sub.2 NHCOPh ethyl Me CO.sub.2 H nPr SO.sub.2 NHCOPh propyl Me CO.sub.2 H nPr SO.sub.2 NHCOPh propyl Me CO.sub.2 H iBu SO.sub.2 NHCOPh propyl Me CO.sub.2 H nPn SO.sub.2 NHCOPh ethyl Me Me Me SO.sub.2 NHCOCH.sub.2 Ph ethyl Me Me Me SO.sub.2 NHCOCH(Ph).sub.2 ethyl Me Me Et SO.sub.2 NHCOCH(Ph).sub.2 ethyl Me Me Et SO.sub.2 NHCOCH.sub.2 OEt ethyl Me Me nBu SO.sub.2 NHCOCH.sub.2 OEt propyl Me CO.sub.2 H nPn SO.sub.2 NHCOCH.sub.2 OBu ethyl Me Me nPr SO.sub.2 NHCOOCH.sub.2 CH(Me).sub.2 ethyl Me Me nPr SO.sub.2 NHCOCH.sub.2 OBu ethyl Me Me nPr SO.sub.2 NHCOCH.sub.2 OEt ethyl Me Me nBu SO.sub.2 NHCO(CH.sub.2).sub.2 CycPen ethyl Me CH.sub.2 OH nPr SO.sub.2 NHCOCH.sub.2 OEt ethyl Me CH.sub.2 OH iBu SO.sub.2 NHCOCH.sub.2 OBu ethyl Me CO.sub.2 H iBu SO.sub.2 NHCOCH.sub.2 OBu ethyl Me Me iBu SO.sub.2 NHCOCH.sub.2 OBu ethyl Me Me iBu SO.sub.2 NHCOCH.sub.2 OEt ethyl Me Me nPn SO.sub.2 NHCOCH.sub.2 OEt ethyl Me Me nPn SO.sub.2 NHCOCH.sub.2 OBu ethyl Me Me nPn SO.sub.2 NHCO.sub.2 --N-methylpyrrole ethyl Me Me nPr SO.sub.2 NHCO.sub.2 --N-methylpyrrole ethyl Me Me nPr SO.sub.2 NHCOOCH.sub.2 CH(Me).sub.2 ethyl Me Me iBu SO.sub.2 NHCOO(CH.sub.2).sub.2 OMe ethyl Me Me nPr SO.sub.2 NHCOO(CH.sub.2).sub.2 OMe ethyl Me Me nBu SO.sub.2 NHCOO(CH.sub.2).sub.2 OMe ethyl Me Me nBu SO.sub.2 NHCO(CH.sub.2).sub.5 NHBoc ethyl Me Me nBu SO.sub.2 NHCO(CH.sub.2).sub.5 NH.sub.2 ethyl Me Me iBu SO.sub.2 NHCO(CH.sub.2).sub.5 NHBoc ethyl Me Me iBu SO.sub.2 NHCO(CH.sub.2).sub.5 NH.sub.2 ethyl Me Me nPn SO.sub.2 NHCO(CH.sub.2).sub.5 NHBoc ethyl Me Me nPn SO.sub.2 NHCO(CH.sub.2).sub.5 NH.sub.2 ethyl Me Me nPn SO.sub.2 NHCO(CH.sub.2).sub.4 CH.sub.3 ethyl Me Me nPr SO.sub.2 NHCO(CH.sub.2).sub.4 CH.sub.3 ethyl Me Me nBu SO.sub.2 NHCO(CH.sub.2).sub.4 CH.sub.3 ethyl Me Me iBu SO.sub.2 NHCO(CH.sub.2).sub.4 CH.sub.3 ethyl Me Me nPr SO.sub.2 NHCOcyPr ethyl Me Me Bn SO.sub.2 NHCOcyPr ethyl Me Me nPr SO.sub.2 NHCOO(CH.sub.2).sub.2 OMe ethyl Me CON(Me).sub.2 iBu SO.sub.2 NHCOcyPr ethyl Me Me nPr SO.sub.2 NHCOOBu ethyl Me CO.sub.2 H nPr SO.sub.2 NHCOOBu ethyl Me Me nPn SO.sub.2 NHCOOBu ethyl Me CO.sub.2 H nPn SO.sub.2 NHCOOBu ethyl Me Me iBu SO.sub.2 NHCOCH(Ph).sub.2 ethyl Me Me nPr SO.sub.2 NHCOCH(Ph).sub.2 ethyl Me CON(Me).sub.2 iBu SO.sub.2 NHCOCH(Ph).sub.2 ethyl Me Me nPr SO.sub.2 NHCOCH.sub.2 OEt ethyl Me Me Me 1H-tetrazol-5-yl ethyl Me Me Me SO.sub.2 NHCONHBu. __________________________________________________________________________

Dependencies are inferred from the claim text.

Facts

Application: 07/846,151Filed 11 Mar 1992 · continuation in part
Priority: 26 Mar 1991
Granted: 5 Jan 1993
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
A61P 25/00
Drugs for disorders of the nervous system

Family

Serial675,371Parent of this continuation-in-part · filed 26 Mar 1991
US 5,177,074 AThis patent

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

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A compound of structural formula I:

##STR62## 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 can be unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below in R.sup.1 (b),
ii) (C.sub.3 -C.sub.8)-cycloalkyl,
iii) Cl, Br, I, F,
iv) OH,
v) NH.sub.2,
vi) NH[(C.sub.1 -C.sub.4)-alkyl],
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 ;
(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, I, F,
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;
(c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the heteroaryl is optionally mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, F,
ii) OH,
iii) SH,
iv) NO.sub.2,
v) (C.sub.1 -C.sub.4)-alkyl,
vi) (C.sub.2 -C.sub.4)-alkenyl,
vii) (C.sub.2 -C.sub.4)-alkynyl,
viii) (C.sub.1 -C.sub.4)-alkoxy, or
ix) CF.sub.3,
(d) polyfluoro-(C.sub.1 -C.sub.4)-alkyl, or
(e) (C.sub.3 -C.sub.8)-cycloalkyl;
--A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is:
##STR63## E is:
(a) a single bond,
(b) --S(O).sub.n (CH.sub.2).sub.s --, or
(c) --O--;
n is 0 to 2;
s is 0 to 5;
R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
R.sup.2a is:
(a) R.sup.2,
(b) CH.sub.2 -aryl, or
(c) aryl;
R.sup.4 groups are independently:
(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, each of which is unsubstituted or substituted with:
i) OH,
ii) (C.sub.1 -C.sub.4)-alkoxy,
iii) CO.sub.2 R.sup.2,
iv) OCOR.sup.2,
v) CONHR.sup.2,
vi) CON(R.sup.2).sub.2,
vii) N(R.sup.2)C(.dbd.O)R.sup.2,
viii) NH.sub.2,
ix) (C.sub.1-C.sub.4)-alkylamino,
x) di[(C.sub.1 -C.sub.4)-alkyl]amino,
(c) --C(.dbd.O)-aryl,
(d) (C.sub.3 -C.sub.7)-cycloalkyl,
(e) Cl, Br, I, F,
(f) --OH,
(g) --OR.sup.21,
(h) -(C.sub.1 -C.sub.4)-polyfluoroalkyl,
(i) --SH,
(j) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
(k) --CO.sub.2 R.sup.2a,
(l) --SO.sub.3 H,
(m) --NR.sup.2 R.sup.21,
(n) --NR.sup.2 C(.dbd.O)R.sup.21,
(o) --NR.sup.2 COOR.sup.21,
(p) --SO.sub.2 NR.sup.2 R.sup.2a,
(q) --NO.sub.2,
(r) --NHSO.sub.2 -(C.sub.1 -C.sub.4)-alkyl,
(s) --CO.sub.2 NH.sub.2,
(t) --CONHSO.sub.2 R.sup.14,
(u) 1H-tetrazol-5-yl,
(v) aryl,
(w) heteroaryl,
(x) or morpholinyl,
R.sup.5 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl, unsubstituted or substituted with:
i) hydroxy, or
ii) (C.sub.1 -C.sub.4)-alkoxy;
R.sup.5a is
(a) R.sup.5, or
(b) (C.sub.1 -C.sub.4)-acyl;
--X.sup.1 --X.sup.2 --X.sup.3 --X.sup.4 -- is:
(a) --Y--CR.sup.11 --CR.sup.12 --CZ--,
(b) --CR.sup.11 --Y--CR.sup.12 --CZ--,
(c) --CR.sup.11 --CR.sup.12 --Y--CZ--,
(d) --Y--CR.sup.11 --CZ--CR.sup.12 --,
(e) --CR.sup.11 --Y--CZ--CR.sup.12 --, or
(f) --CR.sup.11 --CR.sup.12 --CZ--Y--;
Y is:
O, S, SO, or SO.sub.2 ;
R.sup.9 and R.sup.10 are each independently:
(a) H,
(b) Cl, Br, I, F,
(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.6)-cycloalkyl,
(g) (C.sub.1 -C.sub.6)-alkoxy,
(h) --NHSO.sub.2 R.sup.2a,
(i) hydroxy-(C.sub.1 -C.sub.4)-alkyl,
(j) (C.sub.1 -C.sub.4)-alkyl-aryl,
(k) S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
(n) NR.sup.2a R.sup.2a,
(q) CF.sub.3,
(r) --SO.sub.2 NHR.sup.2a,
(s) furyl,
(t) aryl, wherein aryl is phenyl or naphthyl unsubstituted or substituted with one or two substituents selected from the group consisting of:
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)-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, or --CO.sub.2 -(C.sub.1 -C.sub.4)-alkyl;
or
(u) when R.sup.9 and R.sup.10 are bonded to adjacent carbon atoms, they can be joined to form an aryl ring;
R.sup.11 and R.sup.12 are independently:
(a) H,
(b) Cl, Br, I, F,
(c) NO.sub.2,
(d) NH.sub.2,
(e) NH[(C.sub.1 -C.sub.4)-alkyl],
(f) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) SO.sub.2 NHR.sup.2a,
(h) CF.sub.3,
(i) (C.sub.1 -C.sub.7)-alkyl,
(j) (C.sub.1 -C.sub.7)-alkoxy,
(k) (C.sub.3 -C.sub.7)-cycloalkyl,
(l) when R.sup.11 and R.sup.12 are bonded to adjacent carbon atoms, they can be joined to form an aryl ring,
(m) O(CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(n) (CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(o) (CH.sub.2)N(R.sup.2a).sub.2,
(p) (CH.sub.2).sub.n N[CH.sub.2 CH.sub.2 ].sub.2 X,
(q) (CH.sub.2).sub.n N[CH.sub.2 CH.sub.2 ].sub.2 CH.sub.2,
(r) CH(OR.sup.2a)[(C.sub.1 -C.sub.7)-alkyl],
(s) CHO,
(t) CO.sub.2 R.sup.2a,
(u) CH.dbd.CHR.sup.2a,
(v) CH.sub.2 CR.sup.2a .dbd.C(R.sup.2a).sub.2,
(w) (CH.sub.2).sub.n NCOR.sup.2a,
(x) CH(R.sup.2a).sub.2, or
(y) (C.sub.1 -C.sub.4)-alkyl-aryl;
X is:
--O--, --S--, or --NR.sup.2a --;
Z is:
(a) --CO.sub.2 R.sup.2a,
(b) --SO.sub.3 R.sup.13,
(c) --NHSO.sub.2 CF.sub.3,
(d) --PO(OR.sup.13).sub.2,
(e) --SO.sub.2 NHR.sup.14,
(f) --CONHOR.sup.13, ##STR64## (h) --CN, (i) --NHSO.sub.2 R.sup.14,
(j) --CH.sub.2 SO.sub.2 NH-heteroaryl, wherein heteroaryl is an 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 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,
(k) --SO.sub.2 NH--CO--R.sup.14,
(l) --CH.sub.2 SO.sub.2 NH--CO--R.sup.14,
(m) --CONH--SO.sub.2 R.sup.14,
(n) --CH.sub.2 CONH--SO.sub.2 R.sup.14,
(o) --NHSO.sub.2 NHCO--R.sup.14,
(p) --NHCONHSO.sub.2 --R.sup.14, ##STR65## R.sup.13 is H, or ##STR66## R.sup.14 is (a) aryl,
(b) heteroaryl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl, or
(d) (C.sub.1 -C.sub.7)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
aryl, heteroaryl, --OH, --SH, (C.sub.1 -C.sub.4)-alkyl, --(C.sub.1 -C.sub.6)-alkoxy, --S(C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, --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, --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, --PO.sub.3 H or PO(OH)(O--(C.sub.1 -C.sub.4)-alkyl),
(e) (C.sub.1 -C.sub.7)-alkoxy,
(f) O(CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(g) (CH.sub.2).sub.n+1 O(CH.sub.2).sub.s CH.sub.3,
(h) CH(R.sup.2a).sub.2,
(i) (C.sub.1 -C.sub.6)-polyfluoroalkyl, or
(j) NH(C.sub.1 -C.sub.6)-alkyl;
R.sup.15 is H, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.4)-alkenyl, (C.sub.1 -C.sub.4)-alkoxy, or benzyl, wherein the phenyl moiety is unsubstituted or substituted with a substituent selected from the group consisting of:
--NO.sub.2, --NH.sub.2, --OH or --OCH.sub.3 ;
R.sup.17 is --CN, --NO.sub.2, --CO.sub.2 R.sup.2a, or --CF.sub.3 ;
R.sup.21 is:
(a) H, or
(b) (C.sub.1 -C.sub.4)-alkyl 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,
viii) SO.sub.2 NH.sub.2, or
ix) aryl;
or
(c) aryl,
with the proviso that when --A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is --C(Me).dbd.CH--C(Me).dbd.N, E is a single bond, R.sup.1 is ethyl --X.sup.1 --X.sup.2 --X.sup.3 --X.sup.4 -- is --CH--CR.sup.11 --S--CZ--, R.sup.11 is n-butyl, or isobutyl and Z is SO.sub.2 NHCOR.sup.14, then R.sup.14 cannot be O--n--C.sub.4 H.sub.9 or CH.sub.2 O--n--C.sub.4 H.sub.9.

191 more elements

Facts

Application

07/846,151Filed 11 Mar 1992 · continuation in part

Priority

26 Mar 1991

Granted

5 Jan 1993

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
A61P 25/00
Drugs for disorders of the nervous system