US 5,668,176 A · Phenoxyphenylacetic acid derivatives

Abstract

Phenoxyphenylacetic acids and derivatives of the general structural formula I ##STR1## have endothelin antagonist activity and are useful in treating cardiovascular disorders, such as hypertension, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, endotoxic shock, benign prostatic hyperplasia, inflammatory diseases including Raynaud's disease and asthma.

A compound of structural Formula IIa:

##STR54## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.3a and R.sup.3b are independently:
(a) H, except when either of the other of R.sup.3a or R.sup.3b is F, Cl, Br, I, or --OR.sup.7, where R.sup.7 is (C.sub.1 -C.sub.6)-alkyl,
(b) F, Cl, Br, or I, except when either of the other of R.sup.3a or R.sup.3b is H, F, Cl, Br, I, or --OR.sup.7, where R.sup.7 is (C.sub.1 -C.sub.6)-alkyl,
(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.7,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.6)-alkyl,
(j) --OR.sup.7, except when either of the other of R.sup.3a or R.sup.3b is H, F, Cl, Br, or I,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(m) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(n) --CH.sub.2 O--(C.sub.1 -C.sub.4)-alkyl,
(o) --O--(CH.sub.2).sub.m --OR.sup.7,
(p) --CONR.sup.7 R.sup.11,
(q) --COOR.sup.7, or
(r) -phenyl;
R.sup.1 and R.sup.2 on adjacent carbon atoms join together to form a ring structure:
##STR55## A represents:
--C(R.sup.4).dbd.C(R.sup.5)--C(R.sup.4).dbd.C(R.sup.5)--;
n is:
0, 1 or 2;
m is:
2, 3 or 4;
s is:
1 or 2;
R.sup.4 and R.sup.5 are independently:
(a) H, except when one and only one of the R.sup.4 or R.sup.5 substituents is F, Cl, Br, I, or --O--(C.sub.1 -C.sub.4)-alkyl,
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.7 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.7,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.11, or
ix) --CONR.sup.7 R.sup.11,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I, except when one and only one of the R.sup.4 or R.sup.5 substituents is H, F, Cl, Br, I, or --O--(C.sub.1 -C.sub.4)-alkyl,
(e) CF.sub.3,
(f) --COOR.sup.7,
(g) --CONR.sup.7 R.sup.11,
(h) --NR.sup.7 R.sup.11,
(i) --NR.sup.7 CONR.sup.7 R.sup.11,
(j) --NR.sup.7 COOR.sup.11,
(k) --SO.sub.2 NR.sup.7 R.sup.11,
(l) --O--(C.sub.1 -C.sub.4)-alkyl, except when one and only one of the R.sup.4 or R.sup.5 substituents is H, F, Cl, Br, or I,
(m) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.11 ;
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) phenyl,
(d) (C.sub.1 -C.sub.6)-alkylphenyl,
(e) (C.sub.3 -C.sub.7)-cycloalkyl, or
(f) R.sup.7 and R.sup.11 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl;
R.sup.8 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
(i) -phenyl,
(ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
(iii) --NR.sup.7 R.sup.11,
(iv) -morpholin-4-yl,
(v) --OH,
(vi) --CO.sub.2 R.sup.7, or
(vii) --CON(R.sup.7).sub.2,
(c) phenyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl
ii) --O--(C.sub.1 -C.sub.4)-alkyl
iii) --CONR.sup.7 R.sup.11,
iv) F, Cl, Br or I, or
v) --COOR.sup.7 ;
R.sup.9 and R.sup.10 are independently:
(a) H, provided that one and only one of R.sup.9 and R.sup.10 is H, when R12 is hydroxy(C.sub.1 -C.sub.6)-alkyl,
(b) (C.sub.2 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl or --CO.sub.2 R.sup.7, provided that the other of R.sup.9 or R.sup.10 is other than H,
(c) (C.sub.2 -C.sub.6)-alkenyl,
(d) (C.sub.2 -C.sub.6)-alkynyl,
(e) Cl, Br, F, I,
(f) (C.sub.1 -C.sub.6)-alkoxy,
(g) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(h) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(i) phenyl,
(j) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
(k) --CF.sub.3,
(l) --CO.sub.2 R.sup.7,
(m) --NR.sup.7 R.sup.11,
(n) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.7 R.sup.11,
(o) --NO.sub.2,
(p) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.7).sub.2,
(q) --NR.sup.7 CO--(C.sub.1 -C.sub.4)-alkyl, or
(r) --CON(R.sup.7).sub.2 ;
R.sup.11 is:
(a) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) --OR.sup.7,
ii) --N[R.sup.7 ].sub.2,
iii) --NH.sub.2,
iv) --COOR.sup.7,
v) --N[CH.sub.2 CH.sub.2 ].sub.2 Q,
vi) --CF.sub.3, or
vii) --CON(R.sup.7).sub.2 ;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CO[NR.sup.7 ].sub.2,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) --NH.sub.2,
vii) --NH[(C.sub.1 -C.sub.4)-alkyl],
viii) --N[(C.sub.1 -C.sub.4)-alkyl].sub.2, or
ix) --CON[CH.sub.2 CH.sub.2 ].sub.2 Q;
(c) --(C.sub.1 -C.sub.4)-alkylaryl, wherein aryl is as defined above,
(d) (C.sub.3 -C.sub.7)-cycloalkyl, ##STR56## (f) CF.sub.3 ;
Q is:
O, S or --NR.sup.7 ;
R.sup.12 is:
(a) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH, except when R.sup.12 represents hydroxy(C.sub.1 -C.sub.6)-alkyl, then either of R.sup.9 or R.sup.10 cannot be H, when the other of R.sup.9 or R.sup.10 is H or (C.sub.2 -C.sub.6)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --O--(C.sub.1 -C.sub.4)-cycloalkyl,
iv) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
v) --NR.sup.7 R.sup.11,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.11,
ix) --CONR.sup.7 R.sup.11,
x) --NR.sup.7 CONR.sup.7 R.sup.11,
xi) --NR.sup.7 COOR.sup.11,
xii) --C(R.sup.6)(OH)--C(R.sup.6)(R.sup.7)(OH),
xiii) --SO.sub.2 NR.sup.7 R.sup.11,
xiv) CN, or ##STR57## (b) (C.sub.3 -C.sub.7)-cycloalkyl, (c) --OR.sup.7, R.sup.7 is other than hydrogen,
(d) --COOR.sup.7,
(e) --CONH.sub.2,
(f) --CONR.sup.16 OR.sup.7,
(g) --CONR.sup.7 R.sup.11,
(h) --CONR.sup.7 CO.sub.2 R.sup.7,
(i) --NH.sub.2,
(j) --NR.sup.7 R.sup.11,
(k) --NR.sup.7 CONR.sup.7 R.sup.11,
(l) --NR.sup.7 COOR.sup.11,
(m) --C(R.sup.6)(OH)--C(R.sup.6)(R.sup.7)(OH),
(n) --SO.sub.2 NR.sup.7 R.sup.11,
(o) --S(O).sub.2 NR.sup.7 COR.sup.11,
(p) --S(O).sub.2 NR.sup.7 CO.sub.2 R.sup.11,
(q) --S(O).sub.2 NR.sup.7 CONR.sup.7 R.sup.11,
(r) --NHSO.sub.2 R.sup.11,
(s) --NR.sup.7 SO.sub.2 NR.sup.7 R.sup.11,
(t) --CONHSO.sub.2 R.sup.11,
(u) --CO-amino acid, wherein amino acid is defined as an L- or D-amino acid selected from the group consisting of Ala, Ile, Phe, Asp, Pro and Val and which can be further substituted as a (C.sub.1 -C.sub.6)-alkyl ester or an amide, or ##STR58## X is:
(a) --O--,
(b) --S(O).sub.n --,
(c) --NR.sup.7 --,
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.n --,
(f) --CH.sub.2 NR.sup.7 --,
(g) --OCH.sub.2 --,
(h) --N(R.sup.7)CH.sub.2 --,
(i) --S(O).sub.n CH.sub.2 --, or
(j) -single bond;
Z is:
(a) --CO.sub.2 H,
(b) --CO.sub.2 R.sup.13,
(c) --CONH-(tetrazol-5-yl),
(d) --CONHSO.sub.2 OR.sup.11,
(e) --CONHSO.sub.2 NR.sup.7 R.sup.11,
(f) --CONHSO.sub.2 -aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.11,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) --NH.sub.2,
vii) --NH[(C.sub.1 -C.sub.4)-alkyl],
viii) --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
ix) -phenyl,
x) --OH,
xi) --OCH.sub.2 CH.sub.2 OH,
xii) --CF.sub.3 ;
(g) --CONHSO.sub.2 --(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in R.sup.4 (b),
(h) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(i) -tetrazol-5-yl,
(j) --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.11,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) --NR.sup.7 CONR.sup.7 R.sup.11, and
vii) --NR.sup.7 COOR.sup.11 ;
(k) --SO.sub.2 NHCO-aryl, wherein aryl is defined in Z(d) above,
(l) --SO.sub.2 NHCO-(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in R.sup.4 (b),
(m) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(n) --SO.sub.2 NHCO-heteroaryl, wherein heteroaryl is as defined in Z(g) above, or
(o) --SO.sub.2 NHCON(R.sup.11).sub.2 wherein the R.sup.11 groups are the same or different;
R.sup.13 is:
(a) (C.sub.1 -C.sub.4)alkyl,
(b) CHR.sup.14 --O--COR.sup.15,
(c) CH.sub.2 CH.sub.2 --N[(C.sub.1 -C.sub.2)-alkyl].sub.2,
(d) CH.sub.2 CH.sub.2 --N[CH.sub.2 CH.sub.2 ].sub.2 O,
(e) (CH.sub.2 CH.sub.2 O).sub.y --O--[(C.sub.1 -C.sub.4)-alkyl], wherein y is 1 or 2,
(f) phenyl, naphthyl, CH.sub.2 -phenyl or CH.sub.2 -naphthyl, where phenyl or naphthyl is substituted or unsubstituted with CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, ##STR59## R.sup.14 and R.sup.15 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl;
and
R.sup.16 is:
H, (C.sub.1 -C.sub.6)-alkyl or (C.sub.1 -C.sub.6)-alkylphenyl.

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Phenoxyphenylacetic acid derivatives

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Phenoxyphenylacetic acid derivatives

Life of this patent

Abstract

Claims14