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US 4,859,667 AGranted
Pharmaceutical compositions of phenothiazone derivatives and analogs
AssigneeMerck Frosst Canada, Inc.
InventorsCheuk K. Lau, Christiane Yoakim, Joshua Rokach, Rejean Fortin, Yvan Guindon
Life of this patent
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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.
Claims25
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 H S H H SCF.sub.3 H H H H S H H CHO H H H H S H H COCF.sub.3 H H H H S H H H H SCH.sub.3 H H S H H H H CO.sub.2 CH.sub.3 H H S H H H H CO.sub.2 H H H S H H H H CHO H H S H H H H CONH.sub.2 H H S H H H H CH.sub.2 OH H H S H H Cl H Co.sub.2 Me H H S H H Cl H CO.sub.2 H H H S H H Cl H CHO H H S H H Cl H COHN.sub.2 H H S H H Cl H CH.sub.2 OH H H S H Obenzyl Cl H H H H S H OEt Cl H F H H S H OEt Cl H CH.sub.3 H H S CH.sub.3 H Cl H CH.sub.3 H H S H CH.sub.3 Cl H CH.sub.3 H H S H OMe Br H OMe H H S H OMe Cl H OMe H H S H OEt Br H OEt H H S H OEt Cl H OEt H H S H OMe Cl H OEt H H S H OMe H H SMe H H O H OMe Br H OMe H H O H OMe Cl H OMe H H S H OMe Br H Me H H SO.sub.2 H H OH H H H H SO.sub.2 H OMe OH H OMe H H SO.sub.2 OMe OMe Me H H H H SO.sub.2 H H OMe H H H H SO.sub.2 H OMe OMe H OMe H H S OCH.sub.3 OCH.sub.3 Me H H H H S H H COCH.sub.3 H H H H S OCH.sub.3 H Br H OCH.sub.3 H H S OCH.sub.3 Cl Cl H OCH.sub.3 H H S OCH.sub.3 H Cl H OCH.sub.3 H H S H ##STR10## H H OCH.sub.3 H H S H ##STR11## Br H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 OH H OCH.sub.3 H H SO.sub.2 NHPr H NHPr H H H H SO.sub.2 ##STR12## H ##STR13## H H H H SO.sub.2 H OCH.sub.3 ##STR14## H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 Br H OCH.sub.3 H H S NHPr H NHPr H H H H S NHPr H NHPr H OCH.sub.3 H H S H NHPr NHPr H H H H S H NHPr NHPr H OCH.sub.3 H H S H OCH.sub.3 NH.sub.2 H OCH.sub.3 H H S H OCH.sub.3 NHPr H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 NHPr H OCH.sub.3 H H O OCH.sub.3 H Cl H OCH.sub.3 H H O OCH.sub.3 H Br H OCH.sub.3 H H O NHPr H NHPr H H H H SO.sub.2 H OCH.sub.3 CN H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 NHCH.sub.2 CO.sub.2 R H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 Sn-Bu H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 CH.sub.2 CO.sub.2 R H OCH.sub.3 H H SO.sub.2 H OCH.sub.3 SO.sub.2 CH.sub.3 H OCH.sub.3 H H S H Sn-Bu H H H H H S H H Sn-Bu H H H H S H CH.sub.3 Sn-Bu H H H H S H OMe Br H CF.sub.3 H H S H OMe Br H F H H S H OMe Br H Cl H H S H OMe Br H Br H H S H OMe Br H NMe.sub.2 H H S H OMe Br H SMe H H S H OMe Br H SO.sub.2 Me H H S H OMe Br H Ph H H ______________________________________ and R is H or C.sub.2 to C.sub.4 alkyl.
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 H t-Bu t-Bu F H t-Bu t-Bu Me H t-Bu t-Bu SMe H t-Bu t-Bu H OMe ______________________________________
2-S-glutathionyl-3H-phenothiazin-3-one;
- or 4-chloro-2-S-glutathionyl-phenothiazin-3-one.
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## H S 2-t-Bu 4-t-Bu S, SO, or SO.sub.2 2-CN H " H 3-CO.sub.2 Et " H 3-Cl " H H " H H " 2-Cl H S H H S 2-Cl 3-Cl S 2-Br 3-Br S H H S 2-Cl H S 2-F H S 2-Br H S 2-CF.sub.3 H S 2-SCF.sub.3 H S 2-SO.sub.2 CF.sub.3 H S H 3-Cl S H 3-CO.sub.2 Et S H 3-CO.sub.2 H S H 3-CN S H 3-SCF.sub.3 S H H S H H S 2-Br H S 2-Cl H S 2-Cl H S 2-Cl H S 2-Cl H S 2-Cl H S H 3-CONMe.sub.2 S 2-Cl H S ##STR23## H S 2-SO.sub.2 CH.sub.3 H S 2-CH.sub.2 CHCH.sub.2 H S H 3-N(CH.sub.3).sub.2 S H H S 2-CH.sub.2 CO.sub.2 H H S 2-Cl H S 2-COCH.sub.3 H S H H S H H S 2-COCH.sub.3 H S H H S 4-Cl H SO H H SO.sub.2 H H SO.sub.2 4-Cl H S 2-t-Bu 9-t-Bu S 2-t-Bu 7-t-Bu S 2-t-Bu 7-t-Bu S 2-t-Bu 7-t-Bu ______________________________________ R.sub.3 R.sub.4 T ______________________________________ H H H H H H H H H H H H H H H H H H H H H 4-Cl H H 4-SO.sub.2 CH.sub.3 H H 4-Cl H H H H H 4-Cl 7-Cl 9-Cl 4-Br 7-Br 9-Br H 7-SO.sub.2 CH.sub.3 H 4-SO.sub.2 CH.sub.3 H H 4-Cl H H H H H H H H H H H H H H H H H H H H H H H H H H H H H 4-Cl H H 4-SCF.sub.3 H H 4-Br H H H 8-CN H H 8-CO.sub.2 Et H H 8-CO.sub.2 H H H 8-CF.sub.3 H H 7-SO.sub.2 CH.sub.3 H H H H H 7-OCH.sub.3 H H H H H H H 4-CH.sub.2 CHCH.sub.2 H H H H H 4-Cl 7-SC.sub.6 H.sub.5 H H H H 4-SCH.sub.2 CO.sub.2 H H H H H 7-CF.sub.3 4-COC.sub.6 H.sub.5 H 7-CF.sub.3 H H H H 7-OCH.sub.3 H 4-COC.sub.6 H.sub.5 7-OCH.sub.3 H H H H H H H H H H H H H 4-OMe H H 4-F H H 4-Me H H 4-SMe H H ______________________________________
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 are R.sub.1 R.sub.2 R.sub.3 R.sub.4 T __________________________________________________________________________ 2-N(Me).sub.2 H H H H 2-SMe H H H H 2-SpPAA H H H H 2-C(O)CH.sub.3 H H H H H 2-SO.sub.3 H H H H H H 7-OH 6-propyl H 4-Cl 1-CH.sub.2 COOH H H H 4-Cl 2-CH.sub.2 COOH H H H 4-OH 2-OMe 7-OMe H H 4-Me 1-OMe 2-OMe H H 4-Cl H 6-CH.sub.2 COOH H H 4-Cl H 7-CH.sub.2 COOH H H 4-Cl H 8-CH.sub.2 COOH H H 4-Cl 2-N(Me).sub.2 H H H 4-Cl 1-N(Me).sub.2 H H H 4-Cl 2-N(Me).sub.2 7-OMe H H 4-Cl 2-N(Me).sub.2 7-Cl H H 4-Cl 2-SMe H H H 4-Cl 2-SCH.sub.2 COOH H H H 4-Cl 2-SpPAA H H H 4-Cl 1-SpPAA H H H 4-Cl 2-SpPAA 7-OMe H H 4-Cl 2-SO.sub.3 H H H H 4-Cl 2-OMe 7-Cl H H 4-OMe 2-SMe H H H 4-SMe H H H H 4-Cl H 7/8-(CH.sub.2).sub.4 H 4-Cl H 7/8-(CH.sub.2).sub.3 H 4-Br 2-OMe 7-OMe H H 7-NH.sub.2 H H H H 2-Me 7-N(Me).sub.2 H H H 7-N(Me).sub.2 H H H H 1-CO.sub.2 H 4-OH 7-NMe.sub.2 H H 1-Me 7-Me H H 4-Cl 2-Me 7-Me H H 4-Cl 1-OMe 2-OMe 7-Me H H 2-OMe 7-SMe H H H 4-COMe H H H H 2 n-Bu H H H H 4-Sn-Bu H H H H 2-Me 4-Sn-Bu H H H 1-OMe 2-OMe 4-Me H H 1-OMe 7-OMe H H 4-Br 1-OMe 7-OMe 2-Cl H 4-Cl 1-OMe 7-OMe H H 4-Cl ##STR25## 7-OMe H H H ##STR26## 7-OMe H H 4-Br 2-OMe 4-OH 7-OMe H H 1-NHPr 4-NHPr H H H ##STR27## ##STR28## H H H 4-COMe H H H H 2-NHPr 4-NHPr H H H 2-OME 4-CN 7-OMe H H 2-OMe ##STR29## 7-OMe H H 2-OMe 4-NHPr 7-OMe H H 1-NHPr 4-NHPr H H H 1-NHPr 4-NHPr 7-OMe H H 2-NHPr 4-NHPr 7-OMe H H 2-OMe 4-NH.sub.2 7-OMe H H 2-OMe 4-NHPr 7-OMe H H 1-OMe 4-Cl 7-OMe H H 1-OMe 4-Br 7-OMe H H 1-OMe 4-CN 7-OMe H H 2-OMe 4-NHCH.sub.2 CO.sub.2 R 7-OMe H H 2-OMe 4-Sn-Bu 7-OMe H H 2-OMe 4-CH.sub.2 CO.sub.2 R 7-OMe H H 2-OMe 4-SO.sub.2 Me 7-OMe H H 2-Sn-Bu H H H H 4-Sn-Bu H H H H 2-Me 4-Sn-Bu H H H 2-OMe 7-Me H H 4-Br 2-OMe 7-CF.sub.3 H H 4-Br 2-OMe 7-F H H 4-Br 2-OMe 7-Cl H H 4-Br 2-OMe 7-Br H H 4-Br 2-OMe 7-NMe.sub.2 H H 4-Br 2-OMe 7-SMe H H 4-Br 2-OMe 7-SO.sub.2 Me H H 4-Br 2-OMe 7-Ph H H 4-Br 1-Me 7-Me H H 4-Cl 2-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.
2 more elements
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-Br 1-OMe 7-OMe H H 2-Br 1-OMe 7-OMe H H 4-Br 1-OMe 7-OMe H H 2-Cl 1-OMe 7-OMe H H 4-Cl 2-OMe 7-OMe H H 1-Cl 2-OMe 7-OMe H H 4-Cl 2-OEt 7-OEt H H 1-Br 2-OEt 7-OEt H H 4-Br 2-OEt 7-OEt H H 1-Cl 2-OEt 7-OEt H H 4-Cl 2-OMe 7-OMe 8-OMe H 1-Br 2-OMe 7-OMe 8-OMe H 4-Br 2-OMe 7-OMe H H 4-F 2-OMe 7-OMe H H 4-CF.sub.3 2-OMe 7-OEt H H 4-Br 2-OMe 7-OEt H H 4-Cl 2-OMe 7-OEt H H 4-F 2-OMe 7-OEt H H 4-CF.sub.3 2-OEt 7-OMe H H 4-Br 2-OEt 7-OMe H H 4-Cl 2-OEt 7-OMe H H 4-F 2-OEt 7-OMe H H 4-CF.sub.3 2-OMe 7-OMe H H 4-Br ______________________________________
Dependencies are inferred from the claim text.