5-lipoxygenease inhibitors

Abstract

Compounds of the Formula I: ##STR1## are inhibitors of the mammalian 5-lipoxygenase enzyme system of the arachidonic acid cascade. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation.

Description

U.S. Pat. No. 4,634,766 (Atkinson, et al.) is incorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions containing a compound of the Formula I: ##STR2## or a phrmaceutically acceptable salt thereof, a method of treatment using said composition and novel compounds encompassed by Formula I.

One embodiment of the present invention is a pharmaceutical composition useful for inhibiting leukotriene biosynthesis or action containing a compound of the Formula I: ##STR3## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein:

Z is O, NCN, S, SO or SO.sub.2 ;

R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, benzyl, C.sub.1 to C.sub.6 acyl, C.sub.1 to C.sub.6 lower aminoacyl, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkyl (for example, --CH(CH.sub.3)OCOC(CH.sub.3).sub.3), C.sub.1 to C.sub.6 alkoxy-C.sub.1 to C.sub.6 alkyl (for example, --CH(CH.sub.3)OC.sub.2 H.sub.5), --(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, CN, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxycarbonyl (e.g. --COOCH(O.sub.2 CCH.sub.3)CH.sub.3), --C(R.sub.7).dbd.C(R.sub.7)COOR.sub.6 or SO.sub.2 R.sub.10 ;

R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from:

(1) hydrogen; (2) C.sub.1 to C.sub.6 alkyl; (3) C.sub.2 to C.sub.6 alkenyl; (4) --(CH.sub.2).sub.n M wherein: n is 0 to 6 and M is (a) OR.sub.16 ; (b) halogen; (c) CF.sub.3 ; (d) SR.sub.16 ; (e) phenyl; (f) substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 ; (g) COOR.sub.6 ; (h) ##STR4## (i) tetrazole; (j) ##STR5## (k) NR.sub.8 R.sub.9 ; (l) NHSO.sub.2 R.sub.10 ; (m) ##STR6## (n) SOR.sub.11 wherein R.sub.11 is C.sub.1 to C.sub.6 alkyl, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, (CH.sub.2).sub.m COOR.sub.6 wherein m is 1 to 6, or CF.sub.3 ; (o) CONR.sub.8 R.sub.9 ; (p) SO.sub.2 NR.sub.8 R.sub.9 ; (q) SO.sub.2 R.sub.13 wherein R.sub.13 is OH, C.sub.1 to C.sub.6 alkyl, H, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, (CH.sub.2).sub.m COOR.sub.6 wherein m is 1 to 6, or CF.sub.3 ; (r) NO.sub.2 ; ##STR7## (v) --CN; each R.sub.16 is independently H; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkyl; substituted phenyl wherein the substituents are C.sub.1 to C.sub.3 alkyl, halogen, CN, C.sub.1 to C.sub.3 alkoxy, OH, (CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 0 to 2, CF.sub.3, COOR.sub.6, CH.sub.2 COOR.sub.6 ; --(CH.sub.2).sub.m COOR.sub.6 wherein m is 0 to 6; CN; C.sub.1 to C.sub.5 alkylacyl; C.sub.1 to C.sub.4 perfluoroalkyl; phenyl; benzyl; or CH.sub.2 -R.sub.12 wherein R.sub.12 is C.sub.1 to C.sub.5 alkyldimethylamino; each R.sub.6 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl or phenyl; each R.sub.14 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy, (CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, or is such that R.sub.14 COOH is an essential amino acid; each R.sub.8 and R.sub.9 is independently H, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, or C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the N to form a heterocycloalkyl of 5 to 8 ring atoms (for example, pyrrolidino, piperidino); and each R.sub.7 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, phenyl or C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy; each R.sub.10 is independently OH, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, phenyl or p-tolyl; or any two of R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 may be joined to form an additional ring of 5 to 7 members, said ring optionally containing a carbonyl group as a substituent, optionally containing a hydroxyl group as a substituent, and optionally having 1 or 2 double bonds, wherein if R.sub.1 is a constituent of the ring, one member is nitrogen and the others are carbon and if R.sub.1 is not a constituent of the ring, all the members are carbon; and T is hydrogen or OR.sub.15 wherein R.sub.15 is hydrogen, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkylacyl, phenyl-C.sub.1 to C.sub.8 -alkylacyl, SO.sub.2 R.sub.10, arylsulfonyl, --CO-phenyl or substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16.

A preferred embodiment of the Formula I compounds is one wherein Z is O, S, SO or SO.sub.2 and wherein n is 0 or 1 in the unit --(CH.sub.2).sub.n M. A more preferred embodiment is wherein Z is O, S, SO or SO.sub.2 and wherein n is 0 (zero) in the unit --(CH.sub.2).sub.n M. In both of these embodiments, the remaining substituents are as defined for Formula I.

Another preferred embodiment of the Formula I compounds is one wherein:

Z is O or S;

R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 acyl, --(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxycarbonyl (e.g. --COOCH(O.sub.2 CCH.sub.3)CH.sub.3), --C(H).dbd.C(H)COOR.sub.6, or SO.sub.2 R.sub.10 ;

R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from:

(1) hydrogen; (2) C.sub.1 to C.sub.6 alkyl; (3) --(CH.sub.2).sub.n M wherein: n is 0 and M is (a) OR.sub.16 ; (b) halogen; (c) CF.sub.3 ; (d) NO.sub.2 ; ##STR8## each R.sub.16 is independently H; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkyl; benzyl; phenyl; substituted phenyl wherein the substituents are C.sub.1 to C.sub.3 alkyl, halogen, CN, C.sub.1 to C.sub.3 alkoxy, OH, (CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 0 to 2, CF.sub.3, COOR.sub.6, CH.sub.2 COOR.sub.6 ; --(CH.sub.2).sub.m COOR.sub.6 wherein m is 0 to 6; CN; C.sub.1 to C.sub.5 alkylacyl; C.sub.1 to C.sub.4 perfluoroalkyl; or CH.sub.2 -R.sub.12 wherein R.sub.12 is C.sub.1 to C.sub.5 alkyldimethylamino; each R.sub.6 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl or phenyl; each R.sub.14 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy, (CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, or is such that R.sub.14 COOH is an essential amino acid; each R.sub.8 and R.sub.9 is independently H, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 or C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the N to form a heterocycloalkyl of 5 to 8 ring atoms (for example, pyrrolidino, piperidino); and each R.sub.7 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, phenyl or C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy; and each R.sub.10 is independently OH, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, phenyl or p-tolyl;

T is hydrogen or OR.sub.15 wherein R.sub.15 is hydrogen, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkylacyl, phenyl-C.sub.1 to C.sub.8 -alkylacyl, SO.sub.2 R.sub.10, arylsulfonyl, --CO-phenyl or substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 ; with the proviso that there is a group OR.sub.16 located at one of the 6, 7, 8 or 9-positions.

Claims

1. A method of inhibiting mammalian leukotriene biosynthesis or action which comprises administering to a patient a pharmaceutically effective amount of a composition comprising an effective amount of a compound of Formula I: ##STR9## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein:

Z is O, NCN, S, SO or SO.sub.2 ;

R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, benzyl, C.sub.1 to C.sub.6 acyl, C.sub.1 to C.sub.6 lower aminoacyl, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy-C.sub.1 to C.sub.6 alkyl, --(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, CN, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxycarbonyl, --C(R.sub.7).dbd.C(R.sub.7)COOR.sub.6 or SO.sub.2 R.sub.10 ;

R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from:

(1) hydrogen;

(2) C.sub.1 to C.sub.6 alkyl;

(3) C.sub.2 to C.sub.6 alkenyl;

(4) --CH.sub.2).sub.n M wherein: n is 0 to 6 and M is

(a) OR.sub.16 ;

(b) halogen;

(c) CF.sub.3 ;

(d) SR.sub.16 ;

(e) phenyl;

(f) substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 ;

(g) COOR.sub.6 ;

(h) ##STR10## (i) tetrazole; (j) ##STR11## (k) NR.sub.8 R.sub.9 ; (l) NHSO.sub.2 R.sub.10 ;

(m) ##STR12## (n) SOR.sub.11 wherein R.sub.11 is C.sub.1 to C.sub.6 alkyl, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, (CH.sub.2).sub.m COOR.sub.6 wherein m is 1 to 6, or CF.sub.3 ;

(o) CONR.sub.8 R.sub.9 ;

(p) SO.sub.2 NR.sub.8 R.sub.9 ;

(q) SO.sub.2 R.sub.13 wherein R.sub.13 is OH, C.sub.1 to C.sub.6 alkyl, H, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, (CH.sub.2).sub.m COOR.sub.6 wherein m is 1 to 6, or CF.sub.3 ;

(r) NO.sub.2 ; ##STR13## (v) --CN; each R.sub.16 is independently H; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkyl; substituted phenyl wherein the substituents are C.sub.1 to C.sub.3 alkyl, halogen, CN, C.sub.1 to C.sub.3 alkoxy, OH, (CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 0 to 2, CF.sub.3, COOR.sub.6, or CH.sub.2 COOR.sub.6 ; --(CH.sub.2).sub.m COOR.sub.6 wherein m is 0 to 6; CN; C.sub.1 to C.sub.5 alkylacyl; C.sub.1 to C.sub.4 perfluoroalkyl; phenyl; benzyl; or CH.sub.2 -R.sub.12 wherein R.sub.12 is C.sub.1 to C.sub.5 alkyldimethylamino;

each R.sub.6 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl or phenyl;

each R.sub.14 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy, (CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, or is such that R.sub.14 COOH is an essential amino acid;

each R.sub.8 and R.sub.9 is independently H, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 or C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the N to form a heterocycloalkyl of 5 to 8 ring atoms; and

each R.sub.7 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, phenyl or C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy;

each R.sub.10 is independently OH, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, phenyl or p-tolyl;

or any two of R.sub.1, R.sub.2, R.sub.3, R.sub.4 or R.sub.5 may be joined to form an additional ring of 5 to 7 members, said ring optionally containing a carbonyl group as a substituent, optionally containing a hydroxyl group as a substituent, and optionally having 1 or 2 double bonds, wherein if R.sub.1 is a constituent of the ring, one member is nitrogen and the others are carbon and if R.sub.1 is not a constituent of the ring, all the members are carbon; and

T is hydrogen or OR.sub.15 wherein R.sub.15 is hydrogen, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkylacyl, phenyl-C.sub.1 to C.sub.8 -alkylacyl, SO.sub.2 R.sub.10, arylsulfonyl, --CO-phenyl or substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16.

2. A method of claim 1 wherein Z is O.

3. A method of claim 1 wherein Z is S, SO or SO.sub.2.

4. A method of claim 1 wherein Z is NCN.

5. A method of claim 1, wherein Z is O, S, SO or SO.sub.2 and wherein n is 0 or 1 in the unit --(CH.sub.2).sub.n M.

6. A method of claim 5, wherein n is 0.

7. A method of claim 1, wherein:

Z is O or S;

R.sub.1 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 acyl, --(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxycarbonyl, --C(H).dbd.C(H)COOR.sub.6, or SO.sub.2 R.sub.10 ;

R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from:

(1) hydrogen;

(2) C.sub.1 to C.sub.6 alkyl;

(3) --(CH.sub.2).sub.n M wherein: n is 0 and M is

(a) OR.sub.16 ;

(b) halogen;

(c) CF.sub.3 ;

(d) NO.sub.2 ; ##STR14## each R.sub.16 is independently H; C.sub.1 to C.sub.6 -alkoxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkyl; C.sub.1 to C.sub.6 alkyl; benzyl; phenyl; substituted phenyl wherein the substituents are C.sub.1 to C.sub.3 alkyl, halogen, CN, C.sub.1 to C.sub.3 alkoxy, OH, (CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 0 to 2, CF.sub.3, COOR.sub.6, or CH.sub.2 COOR.sub.6 ; --(CH.sub.2).sub.m COOR.sub.6 wherein m is 0 to 6; CN; C.sub.1 to C.sub.5 alkylacyl; C.sub.1 to C.sub.4 perfluoroalkyl; or CH.sub.2 -R.sub.12 wherein R.sub.12 is C.sub.1 to C.sub.5 alkyldimethylamino;

each R.sub.6 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl or phenyl;

each R.sub.14 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy, (CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 4, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16, or is such that R.sub.14 COOH is an essential amino acid;

each R.sub.8 and R.sub.9 is independently H, phenyl, substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 or C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the N to form a heterocycloalkyl of 5 to 8 ring atoms; and

each R.sub.7 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, phenyl or C.sub.1 to C.sub.6 alkylacyloxy-C.sub.1 to C.sub.6 alkoxy; and

each R.sub.10 is independently OH, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, phenyl or p-tolyl;

T is hydrogen or OR.sub.15 wherein R.sub.15 is hydrogen, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkylacyl, phenyl-C.sub.1 to C.sub.8 -alkylacyl, SO.sub.2 R.sub.10, arylsulfonyl, --CO-phenyl or substituted phenyl wherein substituted phenyl is as defined in the definition of R.sub.16 ;

with the proviso that there is a group OR.sub.16 located at one of the 6, 7, 8 or 9-positions.

8. A method of claim 1 wherein the Formula I substituents are selected from:

__________________________________________________________________________Z R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 T__________________________________________________________________________S H H H H H HS CH.sub.3 H H H H HS CH.sub.2 Ph H H H H HS H 3-NO.sub.2 H H H HS H 2-Cl 3-Cl H H HS H 3-NO.sub.2 7-NO.sub.2 H H HS CH.sub.3 2-NO.sub.2 H H H HS CH.sub.3 3-NO.sub.2 H H H HS n-C.sub.3 H.sub.7 2-Cl 3-Cl H H HS n-C.sub.6 H.sub.13 2-Cl 3-Cl H H HS CH.sub.2 Ph 2-Cl 3-Cl H H HSO H H H H H HSO CH.sub.3 H H H H HSO H 2-Cl 3-Cl H H HSO H 3-NO.sub.2 7-NO.sub.2 H H HSO.sub.2 CH.sub.3 H H H H HSO.sub.2 CH.sub.2 Ph H H H H HSO.sub.2 CH.sub.2 Ph 2-Cl 3-Cl H H HO H H H H H HO H 2-F 3-F H H HO H 2-Cl 3-Cl H H HO H 2-Br 3-Br H H HO H 2-Cl 3-Cl 8-CH.sub.3 H HN--CN H H H H H HN--CN CH.sub.3 2-CH.sub.3 3-CH.sub.3 H H HN--CN CH.sub.3 H H H H 7-OCH.sub.3S H H H H H 7-OCH.sub.3S H H H H 8-Cl 7-OCH.sub.3S CH.sub.3 H H H 8-Cl 7-OCH.sub.3S CH.sub.3 H H H 8-Cl 7-OHS CH.sub.3 H H H H 7-OCH.sub.3S H H H H H 7-OHS CH.sub.3 H H H H 7-OHSO H H H H H 7-OCH.sub.3SO CH.sub.3 H H H H 7-OCH.sub.3S SO.sub.2 Ph--p-Me H H H H 7-OCH.sub.3SO.sub.2 H H H H H 7-OCH.sub.3S COCH.sub.3 H H H H 7-OCH.sub.3S COCH.sub.3 H H H H HSO.sub.2 H H H H H HS CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 H H H H HS CH.sub.2 CO.sub.2 H H H H H HS CO.sub.2 CH.sub.3 H H H H HS CH.dbd.CHCO.sub.2 CH.sub.3 H H H H HS H 2-Cl H H H HS H 3-Cl H H H HS H 8-Cl H H H HS H 2-Me H H H HS H H H H H 7-OCH.sub.3S H H H H 8-Cl 7-OCH.sub.3__________________________________________________________________________

9. A method of claim 1 wherein the Formula I substituents are selected from:

______________________________________Z R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 T______________________________________S CH.sub.3 H H H 8-Cl 7-OCH.sub.3S CH.sub.3 H H H 8-Cl 7-OHS CH.sub.3 H H H H 7-OCH.sub.3S H H H H H 7-OHS CH.sub.3 H H H H 7-OHSO H H H H H 7-OCH.sub.3SO CH.sub.3 H H H H 7-OCH.sub.3S SO.sub.2 Ph--p-Me H H H H 7-OCH.sub.3SO.sub.2 H H H H H 7-OCH.sub.3S COCH.sub.3 H H H H 7-OCH.sub.3S COCH.sub.3 H H H H HSO.sub.2 H H H H H HS CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 H H H H HS CH.sub.2 CO.sub.2 H H H H H HS CO.sub.2 CH.sub.3 H H H H HS CH.dbd.CHCO.sub.2 CH.sub.3 H H H H H______________________________________

10. A method of claim 9 wherein the compound is 7-methoxy-1,4-diaza-10-methylphenothiazine.

11. A method of claim 9 wherein the compound is 7-hydroxy-1,4-diaza-10H-phenothiazine.

12. A method of claim 9 wherein the compound is 7-hydroxy-1,4-diaza-10-methylphenothiazine.

13. A method of claim 9 wherein the compound is 8-chloro-1,4-diaza-7-methoxyphenothiazine.

14. A method of claim 9 wherein the compound is 8-chloro-7-methoxy-1,4-diaza-10-methylphenothiazine.

15. A method of claim 9 wherein the compound is 8-chloro-7-hydroxy-1,4-diaza-10-methylphenothiazine.

16. A method of claim 1 wherein pulmonary conditions are treated or ameliorated.

17. A method of claim 1 wherein inflammation is treated.

18. A method of claim 1 wherein allergies are treated.

19. A method of claim 1 wherein skin conditions are treated.

20. A pharmaceutical composition for inhibiting leukotriene biosynthesis or action comprising an effective amount of a compound of the Formula I': ##STR15## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the Formula I' substituents are selected from:

______________________________________Z R.sub.1 R.sub.5 T______________________________________S H H 7-OCH.sub.3S H 8-Cl 7-OCH.sub.3S CH.sub.3 8-Cl 7-OCH.sub.3S CH.sub.3 8-Cl 7-OHS CH.sub.3 H 7-OCH.sub.3S H H 7-OHS CH.sub.3 H 7-OHSO H H 7-OCH.sub.3SO CH.sub.3 H 7-OCH.sub.3S SO.sub.2 Ph--p-Me H 7-OCH.sub.3SO.sub.2 H H 7-OCH.sub.3S COCH.sub.3 H 7-OCH.sub.3S COCH.sub.3 H HS CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 H HS CH.sub.2 CO.sub.2 H H HS CO.sub.2 CH.sub.3 H HS CH.dbd.CHCO.sub.2 CH.sub.3 H H______________________________________

21. A composition of claim 20 wherein the compound is 7-methoxy-1,4-diaza-10-methylphenothiazine.

22. A composition of claim 20 wherein the compound is 7-hydroxy-1,4-diaza-10H-phenothiazine.

23. A composition of claim 20 wherein the compound is 7-hydroxy-1,4-diaza-10-methylphenothiazine.

24. A composition of claim 20 wherein the compound is 8-chloro-1,4-diaza-7-methoxyphenothiazine.

25. A composition of claim 20 wherein the compound is 8-chloro-7-methoxy-1,4-diaza-10-methylphenothiazine.

26. A composition of claim 20 wherein the compound is 8-chloro-7-hydroxy-1,4-diaza-10-methylphenothiazine.