US 5,290,798 AGranted

(hetero-arylmethoxy)indoles as inhibitors of leukotriene biosynthesis

AssigneeMerck Frosst Canada, Inc.

InventorsJohn W. Gillard, John H. Hutchinson, Michel Therien

Life of this patent

Estimating the term…

Abstract

Compounds having the formula I: ##STR1## are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea, and migraine.

Claims14

Dependent claims

A compound of the formula I:

##STR13## wherein:
Het is ArR.sup.1 R.sup.2 ;
Ar is a monocyclic aromatic 5-membered ring containing one O or S atom and 0 to 2N atoms;
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.10 are independently hydrogen, halogen, perhalo lower alkenyl, lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3, --C(OH)R.sup.11 R.sup.11, --CO.sub.2 R.sup.12, --SR.sup.14, --S(O)R.sup.14, --S(O).sub.2 R.sup.14, --S(O).sub.2 NR.sup.15 R.sup.15, --OR.sup.15, --NR.sup.15 R.sup.15, --NR.sup.12 CONR.sup.15 R.sup.15, --COR.sup.16, CONR.sup.15 R.sup.15, or --(CH.sub.2).sub.t R.sup.21 ;
R.sup.5 is hydrogen, --CH.sub.3, CF.sub.3, --C(O)H, X.sup.1 --R.sup.6 or X.sup.2 --R.sup.7 ;
R.sup.6 and R.sup.9 are independently alkyl, alkenyl, --(CH.sub.2).sub.u Ph(R.sup.10).sub.2 or --(CH.sub.2).sub.u Th(R.sup.10).sub.2, wherein Ph is phenyl and Th is 2- or 3-thienyl;
R.sup.7 is --CF.sub.3 or R.sup.6 ;
R.sup.8 is hydrogen or X.sup.3 --R.sup.9 ;
each R.sup.11 is independently hydrogen or lower alkyl, or two R.sup.11 's on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;
R.sup.12 is hydrogen, lower alkyl or --CH.sub.2 R.sup.21 ;
R.sup.13 is lower alkyl or --(CH.sub.2).sub.r R.sup.21 ;
R.sup.14 is --CF.sub.3 or R.sup.13 ;
R.sup.15 is hydrogen, --COR.sup.16, R.sup.13, or two R.sup.15 's on the same nitrogen may be joined to form a monocyclic heterocyclic ring of 4 to 6 atoms containing up to 2 heteroatoms chosen from O, S, or N;
R.sup.16 is hydrogen, --CF.sub.3, lower alkyl, lower alkenyl, lower alkynyl or (CH.sub.2).sub.r R.sup.21 ;
R.sup.17 is --(CH.sub.2).sub.s --C(R.sup.18 R.sup.18)--(CH.sub.2).sub.s --R.sup.19 or --CH.sub.2 CONR.sup.15 R.sup.15 ;
R.sup.18 is hydrogen or lower alkyl;
R.sup.19 is
a) 2,5-dioxy-1-pyrrolidinyl, (3-pyridinylcarbonyl)amino, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl, 2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl, 2-oxo-1,3-dioxolen-4-yl, piperidin-1-yl, morpholin-1-yl, or piperazin-1-yl, or
b) the radical W-R.sup.20 ;
R.sup.20 is alkyl or --COR.sup.23 ;
R.sup.21 is phenyl substituted with 1 or 2 R.sup.22 groups;
R.sup.22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, --CF.sub.3, --CN, --NO.sub.2 or --N.sub.3 ;
R.sup.23 is alkyl, cycloalkyl, or monocyclic monoheterocyclic ring of 5 to 7 members containing only 1 heteroatom selected from N, S, or O;
R.sup.24 is the residual structure of a standard amino acid, or R.sup.18 and R.sup.24 attached to the same N can cyclize to form a proline residue;
m is 0 or 1;
n is 0 to 3;
p is 1 to 3 when m is 1;
p is 0 to 3 when m is 0;
r is 0 to 2;
s is 0 to 3;
t is 0 to 2;
u is 0 to 3;
W is 0, S or NR.sup.15 ;
X.sup.1 is O or NR.sup.15 ;
X.sup.2 is CO, CR.sup.11 R.sup.11, S, S(O), or S(0).sub.2 ;
X.sup.3 is CO, CR.sup.11 R.sup.11, S(0).sub.2, or a bond;
X.sup.4 is CH.dbd.CH, CH.sub.2 --Y.sup.1, or Y.sup.1 --CH.sub.2 ;
Y is X.sup.1 or X.sup.2 ;
Y.sup.1 is O, S, S(0).sub.2, or CH.sub.2 ;
Q is --CO.sub.2 R.sup.12, --CONHS(O).sub.2 R.sup.14, --NHS(O).sub.2 R.sup.14, --S(O).sub.2 NHR.sup.15, --CONR.sup.15 R.sup.15, --CO.sub.2 R.sup.17, --CONR.sup.18 R.sup.24, --CR.sup.11 R.sup.11 OH, or 1H- or 2H-tetrazol-5-yl;
or a pharmaceutically acceptable salt thereof.

38 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A compound of the formula I:

##STR13## wherein:
Het is ArR.sup.1 R.sup.2 ;
Ar is a monocyclic aromatic 5-membered ring containing one O or S atom and 0 to 2N atoms;
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.10 are independently hydrogen, halogen, perhalo lower alkenyl, lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3, --C(OH)R.sup.11 R.sup.11, --CO.sub.2 R.sup.12, --SR.sup.14, --S(O)R.sup.14, --S(O).sub.2 R.sup.14, --S(O).sub.2 NR.sup.15 R.sup.15, --OR.sup.15, --NR.sup.15 R.sup.15, --NR.sup.12 CONR.sup.15 R.sup.15, --COR.sup.16, CONR.sup.15 R.sup.15, or --(CH.sub.2).sub.t R.sup.21 ;
R.sup.5 is hydrogen, --CH.sub.3, CF.sub.3, --C(O)H, X.sup.1 --R.sup.6 or X.sup.2 --R.sup.7 ;
R.sup.6 and R.sup.9 are independently alkyl, alkenyl, --(CH.sub.2).sub.u Ph(R.sup.10).sub.2 or --(CH.sub.2).sub.u Th(R.sup.10).sub.2, wherein Ph is phenyl and Th is 2- or 3-thienyl;
R.sup.7 is --CF.sub.3 or R.sup.6 ;
R.sup.8 is hydrogen or X.sup.3 --R.sup.9 ;
each R.sup.11 is independently hydrogen or lower alkyl, or two R.sup.11 's on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;
R.sup.12 is hydrogen, lower alkyl or --CH.sub.2 R.sup.21 ;
R.sup.13 is lower alkyl or --(CH.sub.2).sub.r R.sup.21 ;
R.sup.14 is --CF.sub.3 or R.sup.13 ;
R.sup.15 is hydrogen, --COR.sup.16, R.sup.13, or two R.sup.15 's on the same nitrogen may be joined to form a monocyclic heterocyclic ring of 4 to 6 atoms containing up to 2 heteroatoms chosen from O, S, or N;
R.sup.16 is hydrogen, --CF.sub.3, lower alkyl, lower alkenyl, lower alkynyl or (CH.sub.2).sub.r R.sup.21 ;
R.sup.17 is --(CH.sub.2).sub.s --C(R.sup.18 R.sup.18)--(CH.sub.2).sub.s --R.sup.19 or --CH.sub.2 CONR.sup.15 R.sup.15 ;
R.sup.18 is hydrogen or lower alkyl;
R.sup.19 is
a) 2,5-dioxy-1-pyrrolidinyl, (3-pyridinylcarbonyl)amino, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl, 2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl, 2-oxo-1,3-dioxolen-4-yl, piperidin-1-yl, morpholin-1-yl, or piperazin-1-yl, or
b) the radical W-R.sup.20 ;
R.sup.20 is alkyl or --COR.sup.23 ;
R.sup.21 is phenyl substituted with 1 or 2 R.sup.22 groups;
R.sup.22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, --CF.sub.3, --CN, --NO.sub.2 or --N.sub.3 ;
R.sup.23 is alkyl, cycloalkyl, or monocyclic monoheterocyclic ring of 5 to 7 members containing only 1 heteroatom selected from N, S, or O;
R.sup.24 is the residual structure of a standard amino acid, or R.sup.18 and R.sup.24 attached to the same N can cyclize to form a proline residue;
m is 0 or 1;
n is 0 to 3;
p is 1 to 3 when m is 1;
p is 0 to 3 when m is 0;
r is 0 to 2;
s is 0 to 3;
t is 0 to 2;
u is 0 to 3;
W is 0, S or NR.sup.15 ;
X.sup.1 is O or NR.sup.15 ;
X.sup.2 is CO, CR.sup.11 R.sup.11, S, S(O), or S(0).sub.2 ;
X.sup.3 is CO, CR.sup.11 R.sup.11, S(0).sub.2, or a bond;
X.sup.4 is CH.dbd.CH, CH.sub.2 --Y.sup.1, or Y.sup.1 --CH.sub.2 ;
Y is X.sup.1 or X.sup.2 ;
Y.sup.1 is O, S, S(0).sub.2, or CH.sub.2 ;
Q is --CO.sub.2 R.sup.12, --CONHS(O).sub.2 R.sup.14, --NHS(O).sub.2 R.sup.14, --S(O).sub.2 NHR.sup.15, --CONR.sup.15 R.sup.15, --CO.sub.2 R.sup.17, --CONR.sup.18 R.sup.24, --CR.sup.11 R.sup.11 OH, or 1H- or 2H-tetrazol-5-yl;
or a pharmaceutically acceptable salt thereof.

38 more elements