Benzyl esters of benzofuran-2-carboxylic acids 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.

Description

Claims

1. A compound of the Formula Id: ##STR3## 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:

(1) hydrogen;

(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

M is

(a) --OR.sub.5 ;

(b) halogen;

(c) --CF.sub.3 ;

(d) --SR.sub.5 ;

(e) Ar.sub.1 ;

(f) --COOR.sub.6 ;

(g) ##STR4## wherein R.sub.12 is H, C.sub.1 to C.sub.6 alkyl, or Ar.sub.1 ; (h) ##STR5## (i) ##STR6## (j) ##STR7## (k) ##STR8## (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) --NO.sub.2 ; or

(s) --CN;

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 C.sub.1 to C.sub.5 alkyldimethylamino, 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 indenpendently C.sub.1 to C.sub.6 alkyl, benzyl, Ar.sub.1, NR.sub.8 R.sub.9, NHAr.sub.1, or 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; 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 R.sub.3, R.sub.4 or T is either OR.sub.5 or --OCOR.sub.7 ;

or a pharmaceutically acceptable salt thereof.

2. A compound of Formula I ##STR9## wherein the compound is selected from the following group:

__________________________________________________________________________Compound R.sub.1 R.sub.2 R.sub.3 R.sub.4 T.sup.c__________________________________________________________________________223 CH.sub.3 OCH.sub.2 Php-OMe ##STR10## H H224 CH.sub.3 OCH.sub.2 Php-Cl ##STR11## H H232 CH.sub.3 OCH.sub.2 Ph3,4-Cl.sub.2 ##STR12## H H233 CH.sub.3 OCH.sub.2 Ph3,4-Cl.sub.2 4-OAc H H234 CH.sub.3 OCH.sub.2 Ph ##STR13## 5-CH.sub.2 CHCH.sub.2 H235 CH.sub.3 OCH.sub.2 Ph ##STR14## H H239 CH.sub.3 OCH.sub.2 Php-Cl 4-OAc H H240 CH.sub.3 OCH.sub.2 Ph 4-OAc H H255 CH.sub.3 OCH.sub.2 Ph 4-OH H H256 CH.sub.3 OCH.sub.2 Ph3,4-Cl.sub.2 4-OH H H257 CH.sub.3 OCH.sub.2 Php-Cl 4-OH H H258 CH.sub.3 OCH.sub.2 Php-OMe 4-OH H H275 CH.sub.3 OCH.sub.2 Php-F 5-OH 6-OH H276 CH.sub.3 OCH.sub.2 Php-Cl 5-OH 6-OH H277 CH.sub.3 OCH.sub.2 Php-OCH.sub.3 5-OH 6-OH H280 CH.sub.3 OCH.sub.2 Ph 4-OH 5-CH.sub.2 SCH.sub.3 H290 CH.sub.3 OCH.sub.2Php-OMe 4-OAc H H292 CH.sub.3 OCH.sub.2 Ph 4-OH 7-OH H293 CH.sub.3 OCH.sub.2 Ph 4-OAc 7-OAc H294 CH.sub.3 OCH.sub.2 Ph 4-OH 7-OH 5-CH.sub.2 CH.sub.2 CH.sub.3295 CH.sub.3 OCH.sub.2 Ph 4-OAc 7-OAc 5-CH.sub.2 CH.sub.2 CH.sub.3333 CH.sub.3 OCH.sub.2 Ph H H .sup.c334 CH.sub.3 OCH.sub.2 Php-OMe H H .sup.c335 CH.sub.3 OCH.sub.2 Php-Cl H H .sup.c364 CH.sub.3 OCH.sub.2 Ph 5-CH.sub.2 CH.sub.2 CH.sub.3 H .sup.c368 CH.sub.3 OCH.sub.2 Ph 4-OH 5-CH.sub.2 CH.sub.2 CH.sub.3 7-F369 CH.sub.3 OCH.sub.2 Ph 4-OH 5-CH.sub.2 CH.sub.2 CH.sub.3 7-Cl__________________________________________________________________________ .sup.c In compounds 223 to 295, V is H; in compounds 333 to 364 T and V are located at positions 4 and 7 respectively and are both simultaneously OH, OCOCH.sub.3 or OCO.sub.2 CH.sub.3.

3. A compound of claim 2 which is: 223, 224, 232-235, 239, 240, 255, 256, 258, 290, 333, 364, 368, or 369.

4. A compound of claim 2 which is: 333, 364, 368, or 369.

5. A method of inhibiting mammalian leukotriene biosynthesis or action which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim 2.

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 2.

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 2.

9. A composition of claim 8, wherein the compound is: 223, 224, 232-235, 239, 240, 255, 256, 258, 290, 333, 364, 368, or 369.

10. A composition of claim 8, wherein the compound is: 255, 333, 364, 368, or 369.

11. A method of inhibiting mammalian leukotriene biosynthesis or action which comprises administering to a mammal pharmaceutically effective amount of a composition of claim 8.

12. A method of claim 11 wherein the mammal is a human.

13. 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 composition of claim 8.

14. A pharmaceutical composition according to claim 8 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steriodal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; antihistaminic agents; prostaglandin antagonists; and thromboxane antagonists.

15. A pharmaceutical composition according to claim 14, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

16. A pharmaceutical composition according to claim 15, wherein said non-steroidal anti-inflammatory drug is indomethacin.

17. A pharmaceutical composition according to claim 8 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steriodal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; antihistaminic agents; prostaglandin antagonists; and thromboxane antagonists, wherein the weight ratio of the compound described in claim 8 to said second active ingredient ranges from about 1000:1 to 1:1000.

18. A pharmaceutical composition according to claim 17, wherein the weight ratio ranges from about 200:1 to 1:200.

19. A pharmaceutical composition according to claim 17, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

20. A pharmaceutical composition according to claim 19, wherein the non-steroidal anti-inflammatory drug is indomethacin.