|Title:|| Benzofuran 2-carboxylic acid hydrazides useful as inhibitors of leukotriene biosynthesis|
|Abstract:||Compounds of the Formula I: ##STR1## and pharmaceutically acceptable salts thereof are inhibitors of leukotriene biosynthesis. These compounds inhibit the mammalian 5-lipoxygenase enzyme, thus preventing the metabolism of arachidonic acid to the leukotrienes. These compounds are thus useful in the treatment of asthma, allergic disorders, inflammation, skin diseases and certain cardiovascular disorders.|
|Inventor(s):|| Atkinson; Joseph G. (Montreal, CA), Guindon; Yvan (Ile Bizard, CA), Lau; Cheuk K. (Pierrefonds, CA) |
|Assignee:|| Merck Frosst Canada, Inc. (Quebec, CA) |
|Filing Date:||Feb 04, 1988|
|Claims:||1. A compound of the formula: ##STR12## wherein the substituents for a compound are selected from the following groups: |
2. A compound of claim 1 which is: 117-133, 135-161, or 287.
3. A compound of claim 1 which is: 117, 126, 127, 132, 138, 146, or 154.
4. A compound of the Formula Ic: ##STR29## wherein R.sub.1 is hydrogen, C.sub.1 to C.sub.6 alkyl, Ar.sub.1 --C.sub.1 to C.sub.3 alkyl, Ar.sub.1 or CH.sub.2 OH;
R.sub.3, R.sub.4 and T are each independently selected from:
(2) alkyl having 1 to 4 carbon atoms;
(3) alkenyl having 2 to 4 carbon atoms;
(4) --(CH.sub.2).sub.n M wherein
n is 0 or 1, and
(a) --OR.sub.5 ;
(c) --CF.sub.3 ;
(d) --SR.sub.5 ;
(e) Ar.sub.1 ;
(f) --COOR.sub.6 ;
(g) ##STR30## wherein R.sub.12 is H, C.sub.1 to C.sub.6 alkyl, or Ar.sub.1 ; (h) ##STR31## (i) ##STR32## (j) ##STR33## (k) ##STR34## (l) NR.sub.8 R.sub.9 ; (m) --NHSO.sub.2 R.sub.10 wherein R.sub.10 is C.sub.1 to C.sub.6 alkyl, phenyl, p-tolyl or CF.sub.3 ;
(n) --SOR.sub.5 ;
(o) --CONR.sub.8 R.sub.9 ;
(p) --SO.sub.2 NR.sub.8 R.sub.9 ;
(q) --SO.sub.2 R.sub.5 ;
(r) k--NO.sub.2 ; or
or any two of R.sub.3, R.sub.4 and T may be joined to form a saturated ring having 5 or 6 ring atoms, said ring atoms comprising 0, 1 or 2 oxygen atoms, the remaining ring atoms being carbon;
each R.sub.5 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl Ar.sub.1, perfluoro-C.sub.1 -C.sub.4 alkyl, CH.sub.2 --R.sub.11 wherein R.sub.11 is hydroxy C.sub.2 to C.sub.5 alkyl, CH.sub.2 COOR.sub.6, or CH.sub.2 CO--R.sub.7 ;
each R.sub.6 is independently H or C.sub.1 to C.sub.6 alkyl;
each R.sub.7 is independently C.sub.1 to C.sub.6 alkyl, benzyl, Ar.sub.1, NR.sub.8 R.sub.9, NHAr.sub.1, O--C.sub.1 to C.sub.4 alkyl;
each R.sub.8 and each R.sub.9 is independently H or C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the N to which they are attached to form a heterocycloalkyl ring having 5 to 8 ring atoms;
each R.sub.13 is independently hydrogen, R.sub.8, R.sub.9, or Ar.sub.1, and
each Ar.sub.1 is independently 1- or 2-naphthyl, phenyl or mono- or disubstituted phenyl, wherein the substituents on the phenyl are independently selected from C.sub.1 to C.sub.3 alkyl, I, Br, Cl, F, COOR.sub.6, (CH.sub.2).sub.n --NR.sub.8 R.sub.9 wherein n is 0 to 2, methylenedioxy, C.sub.1 to C.sub.3 alkoxy, OH, CN, NO.sub.2, CF.sub.3, C.sub.1 to C.sub.4 acyl, NR.sub.8 R.sub.9, S--C.sub.1 to C.sub.6 alkyl, SO--C.sub.1 to C.sub.6 alkyl, and SO.sub.2 --C.sub.1 to C.sub.6 alkyl; with the proviso that at least one of the R.sub.13 groups in the Formula Ic is Ar.sub.1, and one of R.sub.3, R.sub.4 and T is OR.sub.5 or --OCOR.sub.7 ;
or a pharmaceutically acceptable salt thereof.
5. A method of inhibiting mammalian leukotriene biosynthesis or actin which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of claim 1.
6. A method of claim 5 wherein the mammal is a human.
7. A method of treating pulmonary conditions, inflammation, allergies, pain, cardiovascular conditions, or skin conditions which comprises administering to a human in need of such treatment a pharmaceutically effective amount of a compound of claim 1.
8. A pharmaceutical composition useful for inhibiting the biosynthesis of mammalian leukotrienes comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1.