US 5,334,598 AGranted

Six-membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives

AssigneeMerck & Co., Inc.

InventorsScott W. Bagley, Prasun K. Chakravarty, Anna Chen, Daljit S. Dhanoa, Kenneth J. Fitch, William J. Greenlee, Elizabeth M. Naylor, Thomas F. Walsh, David L. Williams, Jr.

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Abstract

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

Claims8

Dependent claims

A compound of structural Formula I:

##STR24## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 is:
(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 a substituent selected from the group consisting of:
i) phenyl or naphthyl as defined in R.sup.1 (c),
ii) (C.sub.3 -C.sub.7)-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) (C.sub.1 -C.sub.4)-perfluoroalkyl,
x) COOR.sup.2, or
xi) SO.sub.2 NHR.sup.3,
xii) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl, or
xiii) --O--(C.sub.1 -C.sub.4)-alkyl,
(c) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted, mono- or disubstituted with 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.3 R.sup.3,
vii) (C.sub.1 -C.sub.4)-alkylthio,
viii) hydroxy,
ix) amino,
x) (C.sub.3 -C.sub.7)-cycloalkyl, or
xi) (C.sub.3 -C.sub.10)-alkenyl,
(d) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety selected from the group consisting of thiophene, furan, thiazole, oxazole, pyridine or pyrimidine, which is unsubstituted, 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,
(e) (C.sub.1 -C.sub.4)-perfluoroalkyl,
(f) --O--(C.sub.1 -C.sub.6)-alkyl,
(g) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
(h) --CONR.sup.3 R.sup.3,
(i) --NR.sup.3 CO--O(C.sub.1 -C.sub.4)-alkyl, or
(j) (C.sub.3 -C.sub.7)-cycloalkyl;
and
--A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is:
##STR25## n is:
0 to 2;
and R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.3 is:
(a) R.sup.2,
(b) benzyl, or
(c) phenyl;
and
R.sup.4 groups are independently:
(a) H,
(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 of the following substituents,
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.5 -(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.5,
vi) --COOR.sup.5,
vii) --CONHR.sup.7,
ix) --CONR.sup.5 R.sup.13, or
x) (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.5,
(g) --CONR.sup.5 R.sup.13,
(h) --NR.sup.5 R.sup.13,
(i) --NR.sup.5 CONR.sup.5 R.sup.13,
(j) --NR.sup.5 COOR.sup.13,
(k) --SO.sub.2 NR.sup.5 R.sup.13,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.13 ;
and
R.sup.5 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R.sup.1 (c),
(d) --CH.sub.2 -aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R.sup.1 (c), or
(e) (C.sub.3 -C.sub.7)-cycloalkyl;
and
R.sup.6 and R.sup.7 on adjacent carbon atoms are joined together to form a ring structure:
##STR26## A represents:
(a) --Y--[C(R.sup.12)(R.sup.12)].sub.s --Y--;
and
s is 1 or 2;
and
Y is --O--, --S(O).sub.n -- and NR.sup.5 ;
and
R.sup.8a and R.sup.8b are independently:
(a) H,
(b) F, Cl, Br, or I,
(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.5,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) --OR.sup.5,
(k) --S(O)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)m--OR.sup.5,
(p) --CONR.sup.5 R.sup.13, or
(q) --COOR.sup.5 ;
and
m is 2, 3, or 4;
and
R.sup.9 and R.sup.10 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(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) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form a phenyl ring,
(h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(j) aryl, wherein aryl is phenyl or naphthyl,
(k) (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n -(CH.sub.2).sub.n --,
(l) hydroxy-(C.sub.1 -C.sub.6)-alkyl or dihydroxy-(C.sub.1 -C.sub.6)-alkyl,
(m) --CF.sub.3,
(n) --CO.sub.2 R.sup.5,
(o) --OH,
(p) --NR.sup.5 R.sup.13,
(q) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.5 R.sup.13,
(r) --NO.sub.2,
(s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.5).sub.2,
(t) --NR.sup.5 CO-(C.sub.1 -C.sub.4)-alkyl, or
(u) --CON(R.sup.5).sub.2 ;
X is:
(a) --O--,
(b) --S(O).sub.n --,
(c) --NR.sup.5 --
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.n,
(f) --CH.sub.2 NR.sup.5 --,
(g) --OCH.sub.2 --,
(h) --NR.sup.5 CH.sub.2 --,
(i) --S(O).sub.n CH.sub.2 --, or
(j) single bond,
R.sup.11 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
(i) -aryl, wherein aryl is phenyl or naphthyl,
(ii) -(C.sub.3 -C.sub.7)-cycloalkyl,
(iii) --NR.sup.5 R.sup.13,
(iv) -morpholin-4-yl,
(v) --OH,
(vi) --CO.sub.2 R.sup.5, or
(vii) --CON(R.sup.5).sub.2,
(c) aryl, wherein aryl is phenyl or naphthyl, which is 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.5 R.sup.13,
iv) F, Cl, Br or I, or
v) --COOR.sup.5 ;
R.sup.12 is:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl unsubstituted or substituted with one of the following substituents:
i) --OH,
ii) --NR.sup.5 R.sup.13,
iii) --COOR.sup.5,
iv) --CONHR.sup.5, or
v) --CONR.sup.5 R.sup.13 ;
Z is:
(a) --CO.sub.2 H,
(b) --CO.sub.2 R.sup.14,
(c) -tetrazol-5-yl,
(d) --CONH(tetrazol-5-yl)
(e) --CONHSO.sub.2 -phenyl or --CONHSO.sub.2 -naphthyl, wherein phenyl or naphthyl is unsubstituted or substituted as defined in R.sup.1 (c),
(f) --CONHSO.sub.2 -(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --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], or --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) --CONHSO.sub.2 -(C.sub.1 -C.sub.4)-perfluoroalkyl,
(h) --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is as defined in R.sup.1 (d),
(i) --CONHSO.sub.2 NR.sup.3 R.sup.3,
(j) --SO.sub.2 NHCO-phenyl or --SO.sub.2 NHCO-naphthyl, wherein phenyl or naphthyl is unsubstituted or substituted as defined in R.sup.1 (c),
(k) --SO.sub.2 NHCO-(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(l) --SO.sub.2 NHCO-(C.sub.1 -C.sub.4)-perfluoroalkyl,
(m) --SO.sub.2 NHCO-heteroaryl, wherein heteroaryl is as defined in R.sup.1 (d),
(n) --SO.sub.2 CONR.sup.3 R.sup.3,
(o) --PO(OH).sub.2,
(p) --PO(OR.sup.2).sub.2, or
(q) --PO(OH)(OR.sup.2);
and
R.sup.13 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) allyl,
(d) (C.sub.3 -C.sub.6)-cycloalkyl,
(e) (C.sub.1 -C.sub.4)-acyl,
(f) benzyl, or
(g) phenyl;
and
R.sup.14 is:
(a) (C.sub.1 -C.sub.4)-alkyl,
(b) CHR.sup.15 --O--COR.sup.16,
(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, ##STR27## R.sup.15 and R.sup.16 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.

210 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of structural Formula I:

##STR24## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 is:
(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 a substituent selected from the group consisting of:
i) phenyl or naphthyl as defined in R.sup.1 (c),
ii) (C.sub.3 -C.sub.7)-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) (C.sub.1 -C.sub.4)-perfluoroalkyl,
x) COOR.sup.2, or
xi) SO.sub.2 NHR.sup.3,
xii) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl, or
xiii) --O--(C.sub.1 -C.sub.4)-alkyl,
(c) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted, mono- or disubstituted with 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.3 R.sup.3,
vii) (C.sub.1 -C.sub.4)-alkylthio,
viii) hydroxy,
ix) amino,
x) (C.sub.3 -C.sub.7)-cycloalkyl, or
xi) (C.sub.3 -C.sub.10)-alkenyl,
(d) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety selected from the group consisting of thiophene, furan, thiazole, oxazole, pyridine or pyrimidine, which is unsubstituted, 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,
(e) (C.sub.1 -C.sub.4)-perfluoroalkyl,
(f) --O--(C.sub.1 -C.sub.6)-alkyl,
(g) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl,
(h) --CONR.sup.3 R.sup.3,
(i) --NR.sup.3 CO--O(C.sub.1 -C.sub.4)-alkyl, or
(j) (C.sub.3 -C.sub.7)-cycloalkyl;
and
--A.sup.1 --A.sup.2 --A.sup.3 --A.sup.4 -- is:
##STR25## n is:
0 to 2;
and R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.3 is:
(a) R.sup.2,
(b) benzyl, or
(c) phenyl;
and
R.sup.4 groups are independently:
(a) H,
(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 of the following substituents,
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.5 -(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.5,
vi) --COOR.sup.5,
vii) --CONHR.sup.7,
ix) --CONR.sup.5 R.sup.13, or
x) (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.5,
(g) --CONR.sup.5 R.sup.13,
(h) --NR.sup.5 R.sup.13,
(i) --NR.sup.5 CONR.sup.5 R.sup.13,
(j) --NR.sup.5 COOR.sup.13,
(k) --SO.sub.2 NR.sup.5 R.sup.13,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n -(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.13 ;
and
R.sup.5 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R.sup.1 (c),
(d) --CH.sub.2 -aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R.sup.1 (c), or
(e) (C.sub.3 -C.sub.7)-cycloalkyl;
and
R.sup.6 and R.sup.7 on adjacent carbon atoms are joined together to form a ring structure:
##STR26## A represents:
(a) --Y--[C(R.sup.12)(R.sup.12)].sub.s --Y--;
and
s is 1 or 2;
and
Y is --O--, --S(O).sub.n -- and NR.sup.5 ;
and
R.sup.8a and R.sup.8b are independently:
(a) H,
(b) F, Cl, Br, or I,
(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.5,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) --OR.sup.5,
(k) --S(O)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)m--OR.sup.5,
(p) --CONR.sup.5 R.sup.13, or
(q) --COOR.sup.5 ;
and
m is 2, 3, or 4;
and
R.sup.9 and R.sup.10 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(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) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form a phenyl ring,
(h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(j) aryl, wherein aryl is phenyl or naphthyl,
(k) (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n -(CH.sub.2).sub.n --,
(l) hydroxy-(C.sub.1 -C.sub.6)-alkyl or dihydroxy-(C.sub.1 -C.sub.6)-alkyl,
(m) --CF.sub.3,
(n) --CO.sub.2 R.sup.5,
(o) --OH,
(p) --NR.sup.5 R.sup.13,
(q) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.5 R.sup.13,
(r) --NO.sub.2,
(s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.5).sub.2,
(t) --NR.sup.5 CO-(C.sub.1 -C.sub.4)-alkyl, or
(u) --CON(R.sup.5).sub.2 ;
X is:
(a) --O--,
(b) --S(O).sub.n --,
(c) --NR.sup.5 --
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.n,
(f) --CH.sub.2 NR.sup.5 --,
(g) --OCH.sub.2 --,
(h) --NR.sup.5 CH.sub.2 --,
(i) --S(O).sub.n CH.sub.2 --, or
(j) single bond,
R.sup.11 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
(i) -aryl, wherein aryl is phenyl or naphthyl,
(ii) -(C.sub.3 -C.sub.7)-cycloalkyl,
(iii) --NR.sup.5 R.sup.13,
(iv) -morpholin-4-yl,
(v) --OH,
(vi) --CO.sub.2 R.sup.5, or
(vii) --CON(R.sup.5).sub.2,
(c) aryl, wherein aryl is phenyl or naphthyl, which is 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.5 R.sup.13,
iv) F, Cl, Br or I, or
v) --COOR.sup.5 ;
R.sup.12 is:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl unsubstituted or substituted with one of the following substituents:
i) --OH,
ii) --NR.sup.5 R.sup.13,
iii) --COOR.sup.5,
iv) --CONHR.sup.5, or
v) --CONR.sup.5 R.sup.13 ;
Z is:
(a) --CO.sub.2 H,
(b) --CO.sub.2 R.sup.14,
(c) -tetrazol-5-yl,
(d) --CONH(tetrazol-5-yl)
(e) --CONHSO.sub.2 -phenyl or --CONHSO.sub.2 -naphthyl, wherein phenyl or naphthyl is unsubstituted or substituted as defined in R.sup.1 (c),
(f) --CONHSO.sub.2 -(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --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], or --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) --CONHSO.sub.2 -(C.sub.1 -C.sub.4)-perfluoroalkyl,
(h) --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is as defined in R.sup.1 (d),
(i) --CONHSO.sub.2 NR.sup.3 R.sup.3,
(j) --SO.sub.2 NHCO-phenyl or --SO.sub.2 NHCO-naphthyl, wherein phenyl or naphthyl is unsubstituted or substituted as defined in R.sup.1 (c),
(k) --SO.sub.2 NHCO-(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --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], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(l) --SO.sub.2 NHCO-(C.sub.1 -C.sub.4)-perfluoroalkyl,
(m) --SO.sub.2 NHCO-heteroaryl, wherein heteroaryl is as defined in R.sup.1 (d),
(n) --SO.sub.2 CONR.sup.3 R.sup.3,
(o) --PO(OH).sub.2,
(p) --PO(OR.sup.2).sub.2, or
(q) --PO(OH)(OR.sup.2);
and
R.sup.13 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) allyl,
(d) (C.sub.3 -C.sub.6)-cycloalkyl,
(e) (C.sub.1 -C.sub.4)-acyl,
(f) benzyl, or
(g) phenyl;
and
R.sup.14 is:
(a) (C.sub.1 -C.sub.4)-alkyl,
(b) CHR.sup.15 --O--COR.sup.16,
(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, ##STR27## R.sup.15 and R.sup.16 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl.

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