TREA

Pharmaceutical compositions of phenothiazone derivatives and analogs

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Information

  • Patent Grant
  • 4859667
  • Patent Number
    4,859,667
  • Date Filed
    Wednesday, January 14, 1987
    37 years ago
  • Date Issued
    Tuesday, August 22, 1989
    34 years ago
Information
Abstract
Phenothiazone derivatives and analogs thereof, pharmaceutical compositions and methods of treatment are disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation.
Description
Claims
  • 1. A pharmaceutical composition for inhibiting mammalian leukotriene biosynthesis or action containing a pharmaceutically acceptable carrier and an effective amount of a compound of the formula:
  • ______________________________________ ##STR9##wherein the substituents are:Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H SCH.sub.3 H H H H HS H H SCF.sub.3 H H H HS H H CHO H H H HS H H COCF.sub.3 H H H HS H H H H SCH.sub.3 H HS H H H H CO.sub.2 CH.sub.3 H HS H H H H CO.sub.2 H H HS H H H H CHO H HS H H H H CONH.sub.2 H HS H H H H CH.sub.2 OH H HS H H Cl H Co.sub.2 Me H HS H H Cl H CO.sub.2 H H HS H H Cl H CHO H HS H H Cl H COHN.sub.2 H HS H H Cl H CH.sub.2 OH H HS H Obenzyl Cl H H H HS H OEt Cl H F H HS H OEt Cl H CH.sub.3 H HS CH.sub.3 H Cl H CH.sub.3 H HS H CH.sub.3 Cl H CH.sub.3 H HS H OMe Br H OMe H HS H OMe Cl H OMe H HS H OEt Br H OEt H HS H OEt Cl H OEt H HS H OMe Cl H OEt H HS H OMe H H SMe H HO H OMe Br H OMe H HO H OMe Cl H OMe H HS H OMe Br H Me H HSO.sub.2 H H OH H H H HSO.sub.2 H OMe OH H OMe H HSO.sub.2 OMe OMe Me H H H HSO.sub.2 H H OMe H H H HSO.sub.2 H OMe OMe H OMe H HS OCH.sub.3 OCH.sub.3 Me H H H HS H H COCH.sub.3 H H H HS OCH.sub.3 H Br H OCH.sub.3 H HS OCH.sub.3 Cl Cl H OCH.sub.3 H HS OCH.sub.3 H Cl H OCH.sub.3 H HS H ##STR10## H H OCH.sub.3 H HS H ##STR11## Br H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 OH H OCH.sub.3 H HSO.sub.2 NHPr H NHPr H H H HSO.sub.2 ##STR12## H ##STR13## H H H HSO.sub.2 H OCH.sub.3 ##STR14## H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 Br H OCH.sub.3 H HS NHPr H NHPr H H H HS NHPr H NHPr H OCH.sub.3 H HS H NHPr NHPr H H H HS H NHPr NHPr H OCH.sub.3 H HS H OCH.sub.3 NH.sub.2 H OCH.sub.3 H HS H OCH.sub.3 NHPr H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 NHPr H OCH.sub.3 H HO OCH.sub.3 H Cl H OCH.sub.3 H HO OCH.sub.3 H Br H OCH.sub.3 H HO NHPr H NHPr H H H HSO.sub.2 H OCH.sub.3 CN H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 NHCH.sub.2 CO.sub.2 R H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 Sn-Bu H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 CH.sub.2 CO.sub.2 R H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 SO.sub.2 CH.sub.3 H OCH.sub.3 H HS H Sn-Bu H H H H HS H H Sn-Bu H H H HS H CH.sub.3 Sn-Bu H H H HS H OMe Br H CF.sub.3 H HS H OMe Br H F H HS H OMe Br H Cl H HS H OMe Br H Br H HS H OMe Br H NMe.sub.2 H HS H OMe Br H SMe H HS H OMe Br H SO.sub.2 Me H HS H OMe Br H Ph H H______________________________________ and R is H or C.sub.2 to C.sub.4 alkyl.
  • 2. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H OMe Br H OMe H HS H OMe Cl H OMe H HS H OEt Br H OEt H HS H OEt Cl H OEt H HS H OMe Cl H OEt H H.______________________________________
  • 3. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S OCH.sub.3 H Br H OCH.sub.3 H HS OCH.sub.3 Cl Cl H OCH.sub.3 H HS OCH.sub.3 H Cl H OCH.sub.3 H H.______________________________________
  • 4. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________O H OMe Br H OMe H HO H OMe Cl H OMe H H.______________________________________
  • 5. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________O OCH.sub.3 H Cl H OCH.sub.3 H HO OCH.sub.3 H Br H OCH.sub.3 H H.______________________________________
  • 6. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H SCH.sub.3 H H H H HS H H H H SCH.sub.3 H HS H OMe H H SMe H HS H S--n-Bu H H H H HS H H S--n-Bu H H H HS H CH.sub.3 S--n-Bu H H H HS H OMe Br H SMe H HS H OMe Br H SO.sub.2 Me H H.______________________________________
  • 7. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H H H H CO.sub.2 CH.sub.3 H HS H H H H CO.sub.2 H H HS H H H H CONH.sub.2 H HS H H Cl H CO.sub.2 Me H HS H H Cl H CO.sub.2 H H HS H H Cl H CONH.sub.2 H HSO.sub.2 H OCH.sub.3 CH.sub.2 CO.sub.2 R H OCH.sub.3 H H.______________________________________
  • 8. A composition of claim 1 wherein the substituents are:
  • __________________________________________________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g__________________________________________________________________________S H ##STR15## H H OCH.sub.3 H HS H ##STR16## Br H OCH.sub.3 H HSO.sub.2 ##STR17## H ##STR18## H H H HSO.sub.2 H OCH.sub.3 ##STR19## H OCH.sub.3 H H__________________________________________________________________________
  • 9. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H OCH.sub.3 NH.sub.2 H OCH.sub.3 H HS H OCH.sub.3 NHPr H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 NHCH.sub.2 CO.sub.2 R H OCH.sub.3 H H.______________________________________
  • 10. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H H H H CHO H HS H H H H CH.sub.2 OH H HS H H Cl H CHO H HS H H Cl H CH.sub.2 OH H H.______________________________________
  • 11. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S NHPr H NHPr H H H HS NHPr H NHPr H OCH.sub.3 H HS H NHPr NHPr H H H HS H NHPr NHPr H OCH.sub.3 H HO NHPr H NHPr H H H H.______________________________________
  • 12. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H OEt Cl H CH.sub.3 H HS H OMe Br H Me H HS H OMe Br H CF.sub.3 H HS H OMe Br H F H HS H OMe Br H Cl H HS H OMe Br H Br H HS H OMe Br H NMe.sub.2 H HS H OMe Br H Ph H H.______________________________________
  • 13. A composition of claim 1 wherein the substitutents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________SO.sub.2 H H OH H H H HSO.sub.2 H OMe OH H OMe H HSO.sub.2 OMe OMe Me H H H HSO.sub.2 H H OMe H H H HSO.sub.2 H OMe OMe H OMe H HSO.sub.2 NHPr H NHPr H H H HSO.sub.2 H OCH.sub.3 Br H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 NHPr H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 CN H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 S--n-Bu H OCH.sub.3 H HSO.sub.2 H OCH.sub.3 SO.sub.2 CH.sub.3 H OCH.sub.3 H H.______________________________________
  • 14. A composition of claim 1 wherein the substituents are:
  • ______________________________________Y R.sub.a R.sub.b R.sub.c R.sub.d R.sub.e R.sub.f R.sub.g______________________________________S H H CHO H H H HS H H COCF.sub.3 H H H HS H O--benzyl Cl H H H HS CH.sub.3 H Cl H CH.sub.3 H HS H CH.sub.3 Cl H CH.sub.3 H HS OCH.sub.3 OCH.sub.3 Me H H H HS H H COCH.sub.3 H H H H.______________________________________
  • 15. A composition of claim 1 wherein the compound is: 4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one.
  • 16. A composition of claim 1 wherein the compound is: 4-chloro-2,7-dimethoxy-3H-phenothiazin-3-one.
  • 17. A composition of claim 1 wherein the compound is: 4-bromo-2,7-diethoxy-3H-phenothiazin-3-one.
  • 18. A composition of claim 1 wherein the compound is: 4-chloro-2,7-diethoxy-3H-phenothiazin-3-one.
  • 19. A composition of claim 1 wherein the compound is: 4-bromo-2,7-dimethoxy-3H-phenoxazin-3-one.
  • 20. A composition of claim 1 wherein the compound is: 4-chloro-2,7-dimethoxy-3H-phenoxazin-3-one.
  • 21. A pharmaceutical composition for inhibiting mammalian luekotrine biosynthesis or action containing a pharmaceutically acceptable carrier and an effective amount of a compound of the formula:
  • ______________________________________ ##STR20##wherein the substituents are:R.sub.a R.sub.b R.sub.c R.sub.d______________________________________t-Bu t-Bu H Ht-Bu t-Bu F Ht-Bu t-Bu Me Ht-Bu t-Bu SMe Ht-Bu t-Bu H OMe______________________________________
  • 22. 2-S-glutathionyl-3H-phenothiazin-3-one; or 4-chloro-2-S-glutathionyl-phenothiazin-3-one.
  • 23. A pharmaceutical composition for inhibiting mammalian luekotrine biosynthesis or action containing a pharmaceutically acceptable carrier and an effective amount of a compound of the formula:
  • ______________________________________ ##STR21##wherein the substituents are:Y R.sub.1 R.sub.2______________________________________S, SO, or SO.sub.2 2-Cl H" 2-SCF.sub.3 H ##STR22## HS 2-t-Bu 4-t-BuS, SO, or SO.sub.2 2-CN H" H 3-CO.sub.2 Et" H 3-Cl" H H" H H" 2-Cl HS H HS 2-Cl 3-ClS 2-Br 3-BrS H HS 2-Cl HS 2-F HS 2-Br HS 2-CF.sub.3 HS 2-SCF.sub.3 HS 2-SO.sub.2 CF.sub.3 HS H 3-ClS H 3-CO.sub.2 EtS H 3-CO.sub.2 HS H 3-CNS H 3-SCF.sub.3S H HS H HS 2-Br HS 2-Cl HS 2-Cl HS 2-Cl HS 2-Cl HS 2-Cl HS H 3-CONMe.sub.2S 2-Cl HS ##STR23## HS 2-SO.sub.2 CH.sub.3 HS 2-CH.sub.2 CHCH.sub.2 HS H 3-N(CH.sub.3).sub.2S H HS 2-CH.sub.2 CO.sub.2 H HS 2-Cl HS 2-COCH.sub.3 HS H HS H HS 2-COCH.sub.3 HS H HS 4-Cl HSO H HSO.sub.2 H HSO.sub.2 4-Cl HS 2-t-Bu 9-t-BuS 2-t-Bu 7-t-BuS 2-t-Bu 7-t-BuS 2-t-Bu 7-t-Bu______________________________________R.sub.3 R.sub.4 T______________________________________H H HH H HH H HH H HH H HH H HH H H4-Cl H H4-SO.sub.2 CH.sub.3 H H4-Cl H HH H H4-Cl 7-Cl 9-Cl4-Br 7-Br 9-BrH 7-SO.sub.2 CH.sub.3 H4-SO.sub.2 CH.sub.3 H H4-Cl H HH H HH H HH H HH H HH H HH H HH H HH H HH H H4-Cl H H4-SCF.sub.3 H H4-Br H HH 8-CN HH 8-CO.sub.2 Et HH 8-CO.sub.2 H HH 8-CF.sub.3 HH 7-SO.sub.2 CH.sub.3 HH H HH 7-OCH.sub.3 HH H HH H H4-CH.sub.2 CHCH.sub.2 H HH H H4-Cl 7-SC.sub.6 H.sub.5 HH H H4-SCH.sub.2 CO.sub.2 H H HH H 7-CF.sub.34-COC.sub.6 H.sub.5 H 7-CF.sub.3H H HH 7-OCH.sub.3 H4-COC.sub.6 H.sub.5 7-OCH.sub.3 HH H HH H HH H HH H H4-OMe H H4-F H H4-Me H H4-SMe H H______________________________________
  • 24. A pharmaceutical composition for inhibiting mammalian luekotrine biosynthesis or action containing a pharmaceutically acceptable carrier and an effective amount of a compound of the formula:
  • __________________________________________________________________________ ##STR24##wherein the substituents areR.sub.1 R.sub.2 R.sub.3 R.sub.4 T__________________________________________________________________________2-N(Me).sub.2 H H H H2-SMe H H H H2-SpPAA H H H H2-C(O)CH.sub.3 H H H HH 2-SO.sub.3 H H H HH H 7-OH 6-propyl H4-Cl 1-CH.sub.2 COOH H H H4-Cl 2-CH.sub.2 COOH H H H4-OH 2-OMe 7-OMe H H4-Me 1-OMe 2-OMe H H4-Cl H 6-CH.sub.2 COOH H H4-Cl H 7-CH.sub.2 COOH H H4-Cl H 8-CH.sub.2 COOH H H4-Cl 2-N(Me).sub.2 H H H4-Cl 1-N(Me).sub.2 H H H4-Cl 2-N(Me).sub.2 7-OMe H H4-Cl 2-N(Me).sub.2 7-Cl H H4-Cl 2-SMe H H H4-Cl 2-SCH.sub.2 COOH H H H4-Cl 2-SpPAA H H H4-Cl 1-SpPAA H H H4-Cl 2-SpPAA 7-OMe H H4-Cl 2-SO.sub.3 H H H H4-Cl 2-OMe 7-Cl H H4-OMe 2-SMe H H H4-SMe H H H H4-Cl H 7/8-(CH.sub.2).sub.4 H4-Cl H 7/8-(CH.sub.2).sub.3 H4-Br 2-OMe 7-OMe H H7-NH.sub.2 H H H H2-Me 7-N(Me).sub.2 H H H7-N(Me).sub.2 H H H H1-CO.sub.2 H 4-OH 7-NMe.sub.2 H H1-Me 7-Me H H 4-Cl2-Me 7-Me H H 4-Cl1-OMe 2-OMe 7-Me H H2-OMe 7-SMe H H H4-COMe H H H H2 n-Bu H H H H4-Sn-Bu H H H H2-Me 4-Sn-Bu H H H1-OMe 2-OMe 4-Me H H1-OMe 7-OMe H H 4-Br1-OMe 7-OMe 2-Cl H 4-Cl1-OMe 7-OMe H H 4-Cl ##STR25## 7-OMe H H H ##STR26## 7-OMe H H 4-Br2-OMe 4-OH 7-OMe H H1-NHPr 4-NHPr H H H ##STR27## ##STR28## H H H4-COMe H H H H2-NHPr 4-NHPr H H H2-OME 4-CN 7-OMe H H2-OMe ##STR29## 7-OMe H H2-OMe 4-NHPr 7-OMe H H1-NHPr 4-NHPr H H H1-NHPr 4-NHPr 7-OMe H H2-NHPr 4-NHPr 7-OMe H H2-OMe 4-NH.sub.2 7-OMe H H2-OMe 4-NHPr 7-OMe H H1-OMe 4-Cl 7-OMe H H1-OMe 4-Br 7-OMe H H1-OMe 4-CN 7-OMe H H2-OMe 4-NHCH.sub.2 CO.sub.2 R 7-OMe H H2-OMe 4-Sn-Bu 7-OMe H H2-OMe 4-CH.sub.2 CO.sub.2 R 7-OMe H H2-OMe 4-SO.sub.2 Me 7-OMe H H2-Sn-Bu H H H H4-Sn-Bu H H H H2-Me 4-Sn-Bu H H H2-OMe 7-Me H H 4-Br2-OMe 7-CF.sub.3 H H 4-Br2-OMe 7-F H H 4-Br2-OMe 7-Cl H H 4-Br2-OMe 7-Br H H 4-Br2-OMe 7-NMe.sub.2 H H 4-Br2-OMe 7-SMe H H 4-Br2-OMe 7-SO.sub.2 Me H H 4-Br2-OMe 7-Ph H H 4-Br1-Me 7-Me H H 4-Cl2-NH.sub.2 H H H H__________________________________________________________________________
  • where Y is S, SO, or So.sub.2 ;
  • pPAA is paraphenylacetic acid; and
  • R is H or C.sub.1 to C.sub.4 alkyl.
  • 25. A pharmaceutical composition for inhibiting mammalian luekotrine biosynthesis or action containing a pharmaceutically acceptable carrier and an effective amount of a compound of the formula:
  • ______________________________________ ##STR30##wherein the substituents are:R.sub.1 R.sub.2 R.sub.3 R.sub.4 T______________________________________2-OMe 7-OMe H H 1-Br1-OMe 7-OMe H H 2-Br1-OMe 7-OMe H H 4-Br1-OMe 7-OMe H H 2-Cl1-OMe 7-OMe H H 4-Cl2-OMe 7-OMe H H 1-Cl2-OMe 7-OMe H H 4-Cl2-OEt 7-OEt H H 1-Br2-OEt 7-OEt H H 4-Br2-OEt 7-OEt H H 1-Cl2-OEt 7-OEt H H 4-Cl2-OMe 7-OMe 8-OMe H 1-Br2-OMe 7-OMe 8-OMe H 4-Br2-OMe 7-OMe H H 4-F2-OMe 7-OMe H H 4-CF.sub.32-OMe 7-OEt H H 4-Br2-OMe 7-OEt H H 4-Cl2-OMe 7-OEt H H 4-F2-OMe 7-OEt H H 4-CF.sub.32-OEt 7-OMe H H 4-Br2-OEt 7-OMe H H 4-Cl2-OEt 7-OMe H H 4-F2-OEt 7-OMe H H 4-CF.sub.32-OMe 7-OMe H H 4-Br______________________________________
CROSS REFERENCE TO RELATED APPLICATIONS

This is division of U.S. Ser. No. 786,257, filed Oct. 10, 1985, now U.S. Pat. No. 4,667,032 which is a continuation-in-part of application Ser. No. 559,471, filed Dec. 12, 1983, now abandoned, which is a continuation-in-part of application Ser. No. 536,487, filed Sept. 28, 1983, now abandoned, which is a continuation-in-part of application Ser. No. 459,924, filed Jan. 22, 1983, now abandoned. U.S. Pat. No. 4,667,032 (Lau et al.) is incorporated herein by reference in its entirety.

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Divisions (1)
Number Date Country
Parent 786257 Oct 1985
Continuation in Parts (2)
Number Date Country
Parent 536487 Sep 1983
Parent 459924 Jan 1983