US 5,350,760 AGranted

Aza-5,5-fused hetrocyclic acids as leukotriene antagonists

AssigneeMerck Frosst Canada, Inc.

InventorsMark LaBelle, Yibin Xiang, Claude Dufresne, Michel Belley

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Abstract

Compounds having the formula I: ##STR1## are antagonists of the actions of leukotrienes. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.

Claims14

Dependent claims

A compound of the formula:

##STR15## wherein:
R.sup.1 is H or R.sup.2 ;
R.sup.2 is lower alkyl, lower alkenyl, lower alkynyl, fluoro lower alkyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.2 groups joined to the same carbon can form a ring of up to 8 members containing up to 2 heteroatoms chosen from O,S, and N;
R.sup.3 is H or R.sup.2 ;
R.sup.4 is R.sup.3, halogen, --NO.sub.2, --CN, --CF.sub.3, --OR.sup.3, N(R.sup.3).sub.2, NR.sup.3 COR.sup.7, --SR.sup.2, S(O)R.sup.2 or S(O).sub.2 R.sup.2 ;
CR.sup.3 R.sup.22 can be the radical of a conventional amino acid;
R.sup.5 is H, halogen, --NO.sub.2, --N.sub.3, --CN, --SR.sup.2, --S(O)R.sup.2, S(O).sub.2 R.sup.2, --N(R.sup.10).sub.2, --OR.sup.3, --COR.sup.3, lower alkyl or fluoro lower alkyl;
R.sup.6 is --(CH.sub.2).sub.S --C(R.sup.7).sub.2 --(CH.sub.2).sub.S --R.sup.8 or --CH.sub.2 CON(R.sup.20).sub.2 ;
R.sup.7 is H or lower alkyl;
R.sup.8 is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S or O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or B) the radical W--R.sup.9 ;
R.sup.9 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
R.sup.10 is R.sup.12 ;
R.sup.11 is lower alkyl, --COR.sup.14, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2 CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.12 is H, R.sup.11, or two R.sup.12 groups joined to the same N can form a saturated ring of 5 or 6 members containing up to two heteroatoms chosen from O, S, and N;
R.sup.13 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2 or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.14 is H or R.sup.13 ;
R.sup.15 is H or R.sup.11 ;
R.sup.16 is H, lower alkyl, or OH;
R.sup.17 is lower alkyl, lower alkenyl, lower alkynyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2 or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.18 is R.sup.13 ;
R.sup.19 is H, lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, Ph, CH.sub.2 Ph, or CH.sub.2 CH.sub.2 Ph;
R.sup.20 is H, lower alkyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.20 groups joined to the same N can form a saturated ring of 5 or 6 members containing up to two heteroatoms chosen from O, S, and N;
R.sup.21 is H or R.sup.17 ;
R.sup.22 is R.sup.4, CHR.sup.7 OR.sup.3 or CHR.sup.7 SR.sup.2 ;
R.sup.23, R.sup.24 and R.sup.25 are each independently H, lower alkyl, --CN, --CF.sub.3, COR.sup.3, CO.sub.2 R.sup.7, CON(R.sup.20).sub.2, OR.sup.3, SR.sup.2, S(O)R.sup.2, S(O).sub.2 R.sup.2, N(R.sup.12).sub.2, halogen, or an electron pair;
R.sup.26 is H, lower alkyl, --COR.sup.7, CO.sub.2 R.sup.7, CON(R.sup.19).sub.2, --CN, CF.sub.3, NO.sub.2, SCF.sub.3, SR.sup.27, OR.sup.28, N(R.sup.28).sub.2, or halogen;
R.sup.27 is lower alkyl, phenyl or benzyl;
R.sup.28 is H, R.sup.27 or COR.sup.7, or two R.sup.28 groups joined to the same N can form a saturated ring of 5 or 6 members comprising carbon atoms and up to 2 heteroatoms chosen from O, S or N;
m and m' are independently 0-8;
p and p' are independently 0-8;
m+p is 1-10 when X.sup.2 is O, S, S(O), or S(O).sub.2 and Z.sup.1 is a bond;
m+p is 0-10 when Z.sup.1 is HET(R.sup.23 R.sup.24 R.sup.25);
m+p is 0-10 when X.sup.2 is CR.sup.3 R.sup.16 ;
m'+p' is 1-10 when X.sup.3 is O, S, S(O), or S(O).sub.2 and Z.sup.2 is a bond;
m'+p' is 0-10 when Z.sup.2 is HET(R.sup.23 R.sup.24 R.sup.25);
m'+p' is 0-10 when X.sup.3 is CR.sup.3 R.sup.16 ;
s is 0-3;
Q.sup.1 is tetrazol-5-yl, --CO.sub.2 R.sup.3, --CO.sub.2 R.sup.6, --CONHS(O).sub.2 R.sup.13, --CN, --CON(R.sup.20).sub.2, NR.sup.21 S(O).sub.2 R.sup.13, --NR.sup.21 CON(R.sup.20).sub.2, --NR.sup.21 COR.sup.14, OCON(R.sup.20).sub.2, --COR.sup.19, --S(O)R.sup.18, --S(O).sub.2 R.sup.18, --S(O).sub.2 N(R.sup.12).sub.2, --NO.sub.2, NR.sup.21 CO.sub.2 R.sup.17, --C(N(R.sup.12).sub.2).dbd.NR.sup.21, --C(R.sup.19).dbd.NOH, C(R.sup.3).sub.2 OR.sup.3 ;
or if Q.sup.1 is CO.sub.2 H and R.sup.22 is --OH, --SH, CHR.sup.7 OH or --NHR.sup.3, then Q.sup.1 and R.sup.22 and the carbons through which they are attached can form a heterocyclic ring by loss of water;
Q.sup.2 is H, OR.sup.15, lower alkyl, fluoro lower alkyl, halogen or Q.sup.1 ;
W is O, S, or NR.sup.3 ;
X.sup.1 is O, S, --S(O)--, --S(O).sub.2 --,--NR.sup.3, --C(R.sup.3).sub.2 --, or a bond;
X.sup.2 and X.sup.3 are independently O, S, S(O), S(O).sub.2, CR.sup.3 R.sup.16 or a bond;
Y is --CR.sup.3 .dbd.CR.sup.3 --, --C(R.sup.3).sub.2 --X.sup.1 --, --X.sup.1 --C(R.sup.3).sub.2 --, --C(R.sup.3).sub.2 --X.sup.1 --C(R.sup.3).sub.2 --, --C.tbd.C--, --CO--, --NR.sup.3 CO--, --CONR.sup.3 --, O, S, or NR.sup.3 ;
Z.sup.1 and Z.sup.2 are independently HET(R.sup.23 R.sup.24 R.sup.25) or a bond;
HET is the diradical of benzene, pyridine, furan, thiophene or 1,2,5-thiadiazole;
HETA is HE.sup.1 or HE.sup.2 ;
wherein
HE.sup.1 is ##STR16## HE.sup.2 is ##STR17## each A is O, S, S(O).sub.2 ;
each B is independently O, S, S(O) or S(O).sub.2 ;
each D is independently N or CR.sup.4 ;
E is CR4 except when D is N, then E is CR3;
or a pharmaceutically acceptable salt thereof.

50 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

##STR15## wherein:
R.sup.1 is H or R.sup.2 ;
R.sup.2 is lower alkyl, lower alkenyl, lower alkynyl, fluoro lower alkyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.2 groups joined to the same carbon can form a ring of up to 8 members containing up to 2 heteroatoms chosen from O,S, and N;
R.sup.3 is H or R.sup.2 ;
R.sup.4 is R.sup.3, halogen, --NO.sub.2, --CN, --CF.sub.3, --OR.sup.3, N(R.sup.3).sub.2, NR.sup.3 COR.sup.7, --SR.sup.2, S(O)R.sup.2 or S(O).sub.2 R.sup.2 ;
CR.sup.3 R.sup.22 can be the radical of a conventional amino acid;
R.sup.5 is H, halogen, --NO.sub.2, --N.sub.3, --CN, --SR.sup.2, --S(O)R.sup.2, S(O).sub.2 R.sup.2, --N(R.sup.10).sub.2, --OR.sup.3, --COR.sup.3, lower alkyl or fluoro lower alkyl;
R.sup.6 is --(CH.sub.2).sub.S --C(R.sup.7).sub.2 --(CH.sub.2).sub.S --R.sup.8 or --CH.sub.2 CON(R.sup.20).sub.2 ;
R.sup.7 is H or lower alkyl;
R.sup.8 is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S or O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or B) the radical W--R.sup.9 ;
R.sup.9 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
R.sup.10 is R.sup.12 ;
R.sup.11 is lower alkyl, --COR.sup.14, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2 CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.12 is H, R.sup.11, or two R.sup.12 groups joined to the same N can form a saturated ring of 5 or 6 members containing up to two heteroatoms chosen from O, S, and N;
R.sup.13 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2 or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.14 is H or R.sup.13 ;
R.sup.15 is H or R.sup.11 ;
R.sup.16 is H, lower alkyl, or OH;
R.sup.17 is lower alkyl, lower alkenyl, lower alkynyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2 or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.18 is R.sup.13 ;
R.sup.19 is H, lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, Ph, CH.sub.2 Ph, or CH.sub.2 CH.sub.2 Ph;
R.sup.20 is H, lower alkyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.20 groups joined to the same N can form a saturated ring of 5 or 6 members containing up to two heteroatoms chosen from O, S, and N;
R.sup.21 is H or R.sup.17 ;
R.sup.22 is R.sup.4, CHR.sup.7 OR.sup.3 or CHR.sup.7 SR.sup.2 ;
R.sup.23, R.sup.24 and R.sup.25 are each independently H, lower alkyl, --CN, --CF.sub.3, COR.sup.3, CO.sub.2 R.sup.7, CON(R.sup.20).sub.2, OR.sup.3, SR.sup.2, S(O)R.sup.2, S(O).sub.2 R.sup.2, N(R.sup.12).sub.2, halogen, or an electron pair;
R.sup.26 is H, lower alkyl, --COR.sup.7, CO.sub.2 R.sup.7, CON(R.sup.19).sub.2, --CN, CF.sub.3, NO.sub.2, SCF.sub.3, SR.sup.27, OR.sup.28, N(R.sup.28).sub.2, or halogen;
R.sup.27 is lower alkyl, phenyl or benzyl;
R.sup.28 is H, R.sup.27 or COR.sup.7, or two R.sup.28 groups joined to the same N can form a saturated ring of 5 or 6 members comprising carbon atoms and up to 2 heteroatoms chosen from O, S or N;
m and m' are independently 0-8;
p and p' are independently 0-8;
m+p is 1-10 when X.sup.2 is O, S, S(O), or S(O).sub.2 and Z.sup.1 is a bond;
m+p is 0-10 when Z.sup.1 is HET(R.sup.23 R.sup.24 R.sup.25);
m+p is 0-10 when X.sup.2 is CR.sup.3 R.sup.16 ;
m'+p' is 1-10 when X.sup.3 is O, S, S(O), or S(O).sub.2 and Z.sup.2 is a bond;
m'+p' is 0-10 when Z.sup.2 is HET(R.sup.23 R.sup.24 R.sup.25);
m'+p' is 0-10 when X.sup.3 is CR.sup.3 R.sup.16 ;
s is 0-3;
Q.sup.1 is tetrazol-5-yl, --CO.sub.2 R.sup.3, --CO.sub.2 R.sup.6, --CONHS(O).sub.2 R.sup.13, --CN, --CON(R.sup.20).sub.2, NR.sup.21 S(O).sub.2 R.sup.13, --NR.sup.21 CON(R.sup.20).sub.2, --NR.sup.21 COR.sup.14, OCON(R.sup.20).sub.2, --COR.sup.19, --S(O)R.sup.18, --S(O).sub.2 R.sup.18, --S(O).sub.2 N(R.sup.12).sub.2, --NO.sub.2, NR.sup.21 CO.sub.2 R.sup.17, --C(N(R.sup.12).sub.2).dbd.NR.sup.21, --C(R.sup.19).dbd.NOH, C(R.sup.3).sub.2 OR.sup.3 ;
or if Q.sup.1 is CO.sub.2 H and R.sup.22 is --OH, --SH, CHR.sup.7 OH or --NHR.sup.3, then Q.sup.1 and R.sup.22 and the carbons through which they are attached can form a heterocyclic ring by loss of water;
Q.sup.2 is H, OR.sup.15, lower alkyl, fluoro lower alkyl, halogen or Q.sup.1 ;
W is O, S, or NR.sup.3 ;
X.sup.1 is O, S, --S(O)--, --S(O).sub.2 --,--NR.sup.3, --C(R.sup.3).sub.2 --, or a bond;
X.sup.2 and X.sup.3 are independently O, S, S(O), S(O).sub.2, CR.sup.3 R.sup.16 or a bond;
Y is --CR.sup.3 .dbd.CR.sup.3 --, --C(R.sup.3).sub.2 --X.sup.1 --, --X.sup.1 --C(R.sup.3).sub.2 --, --C(R.sup.3).sub.2 --X.sup.1 --C(R.sup.3).sub.2 --, --C.tbd.C--, --CO--, --NR.sup.3 CO--, --CONR.sup.3 --, O, S, or NR.sup.3 ;
Z.sup.1 and Z.sup.2 are independently HET(R.sup.23 R.sup.24 R.sup.25) or a bond;
HET is the diradical of benzene, pyridine, furan, thiophene or 1,2,5-thiadiazole;
HETA is HE.sup.1 or HE.sup.2 ;
wherein
HE.sup.1 is ##STR16## HE.sup.2 is ##STR17## each A is O, S, S(O).sub.2 ;
each B is independently O, S, S(O) or S(O).sub.2 ;
each D is independently N or CR.sup.4 ;
E is CR4 except when D is N, then E is CR3;
or a pharmaceutically acceptable salt thereof.

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