Pyrazol-5-ones

Abstract

1-Substituted pyrazole-5-ones of the formula ##STR1## and pharmaceutically acceptable, nontoxic salts thereof, wherein R is hydrogen or amino; R 1 is hydrogen, alkyl, alkenyl, unsubstituted or substituted aryl or unsubstituted or substituted aralky; X is a. ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, ethylene wherein 1 hydrogen atom on each of the two carbon atoms is substituted by alkyl of 1 to 4 carbon atoms or said ethylene which is linked to R 2 via an oxygen or sulphur atom; b. propenyl, propenyl wherein 1 hydrogen atom on one, two or three of the carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, said propenyl being linked to the N 1 atom of the pyrazol ring via its methylene moiety; or c. methylene; provided that when X is methylene, R 1 is not hydrogen if R is amino; R 2 is aryl unsubstituted or substituted by: a. 1 or 2 of the same or different substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and lower alkoxy; b. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms; c. alkylamino, dialkylamino, cyano, trifluoromethoxy, nitro, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, or said carbamoyl wherein the nitrogen atom is a member of a heterocyclic ring, sulphamyl, alkylsulphamyl, dialkylsulphamyl, or said sulphamyl wherein the nitrogen is a member of a heterocyclic ring, or --SO n alkyl wherein n is 0, 1 or 2; d. alkylamino, dialkylamino, cyano, trifluoromethoxy, nitro, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, or said carbamoyl wherein the nitrogen atom is a member of a heterocyclic ring, sulphamyl, alkylsulphamyl, dialkylsulphamyl or said sulphamyl wherein the nitrogen is a member of a heterocyclic ring, or --SO n -- alkyl wherein n is 0, 1 or 2, and 1 or 2 of the same or different substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, and trifluoromethyl; or e. a fused, saturated or unsaturated 5-, 6-, or 7-membered ring or said ring containing 1 or 2 oxygen or sulphur atoms; are useful for their diuretic, saluretic, antihypertensive and antithrombotic effects.

What is claimed is: 
     
       1. A pharmaceutical composition useful for effecting diuresis or saluresis in humans and animals and for treating hypertension in humans and animals which comprises a diuretically effective amount, a saluretically effective amount or an antihypertensive amount of a compound of the formula ##STR48## or a pharmaceutically acceptable nontoxic salt thereof, wherein R is amino; R 1  is .[.hydrogen,.]. lower alkyl or lower alkenyl;   X is ethylene, ethylene wherein 1 hydrogen atom on 1 of the carbon atoms is substituted by alkyl of 1 to 4 carbon atoms or ethylene wherein 1 hydrogen atom on each of the two carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, linked to R 2  via an oxygen or sulphur atom;     R 2  is aryl of 6 to 10 carbon atoms unsubstituted or substituted by: a. 1 or 2 of the same or different substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms and lower alkoxy;   b. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms;   c. nitro or   d. nitro, and 1 or 2 of the same or different substituents selected from the group consisting of lower alkyl, lower alkenyl, lwer alkoxy, halogen and trifluoromethyl in combination with a pharmaceutically-acceptable, nontoxic, inert diluent or carrier.       
     
     
       2. A composition according to claim 1 wherein R 2  is aryl of 6 to 10 carbon atoms unsubstituted or substituted by: a. 1 or 2 of the same or different substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms;   b. nitro or   c. nitro, and 1 or 2 of the same or different substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of 2 to 4 carbon atoms, halogen and trifluoromethyl.     
     
     
       3. A composition according to claim 1 wherein R 1  is .[.hydrogen,.]. alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and   R 2  is phenyl; naphthyl; or phenyl substituted by: a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 8 carbon atoms, or alkenyl moieties of 2 to 8 carbon atoms;   b. 1 to 2 alkoxy moieties of 1 to 6 carbon atoms;   c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 to 7 carbon atoms;   d. 1 or 2 halogens;   e. 1 or 2 trifluoromethyl moieties; or     f. nitro.   
     
     
       4. A composition according to claim 1 wherein R 1  is .[.hydrogen,.]. alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and   R 2  is phenyl; naphthyl; or phenyl substituted by: a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 4 carbon atoms or alkenyl moieties of 2 to 4 carbon atoms;   b. 1 or 2 alkoxy moieties of 1 to 4 carbon atoms;   c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms;   d. 1 or 2 fluoro, chloro or bromo moieties;   e. 1 to 2 trifluoromethyl moieties; or   f. nitro.     
     
     
       5. A composition according to claim 1 wherein R 1  is .[.hydrogen,.]. alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and   R 2  is phenyl; naphthyl; or phenyl substituted by: a. 1 to 2 members selected from the group consisting of straight or branched-chain alkyl and trifluoromethyl moieties of 1 to 4 carbon atoms;   b. alkoxy of 1 to 4 carbon atoms;   c. cycloalkyl of 5 or 6 carbon atoms;   d. 1 or 2 fluoro, chloro, bromo or iodo moieties;   e. chloro or bromo and alkyl of 1 to 2 carbon atoms, trifluoromethyl; or   f. nitro.     
     
     
       6. A composition according to claim 1 wherein R 1  is .[.hydrogen,.]. methyl or ethyl;   X is ethylene, ethylene wherein 1 hydrogen atom on one of the carbon atoms is substituted by alkyl of 1 or 2 carbons or ethylene wherein 1 hydrogen atom on each of the two carbon atoms are substituted by alkyl of 1 to 2 carbon atoms, linked to R 2  via an oxygen or sulphur atom; and   R 2  is phenyl; naphthyl; or phenyl substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyclohexyl, dichlorine, chlorine and methyl, chlorine and bromine, chlorine and fluorine, chlorine and trifluoromethyl, dibromine or methyl and trifluoromethyl.   
     
     
       7. A composition according to claim 6 wherein X is ethylene, ethylene where 1 hydrogen on one of the carbon atoms is substituted by methyl or ethyl or ethylene wherein 1 hydrogen atom on each of the two carbon atoms is substituted by methyl, linked to R 2  via an oxygen or sulphur atom.   
     
     
       8. A composition according to claim 1 wherein R 1  is .[.hydrogen or.]. alkyl of 1 to 4 carbon atoms;   X is ethylene or ethylene wherein 1 hydrogen atom on one of the carbon atoms is substituted by methyl, linked to R 2  via an oxygen or sulphur atom; and   R 2  is phenyl; naphthyl; or phenyl substituted by 1 or 2 chlorine, methyl, ethyl or trifluoromethyl moieties.   
     
     
       9. A composition according to claim 1 wherein R 1  is .[.hydrogen or.]. alkyl of 1 to 4 carbon atoms;   X is ethylene or ethylene wherein 1 hydrogen atom of one of the carbon atoms is substituted by methyl, linked to R 2  via an oxygen or sulphur atom; and   R 2  is naphthyl; phenyl; or phenyl substituted by chlorine, methyl, trifluoromethyl, dichlorine, dimethyl, methyl and ethyl or methyl and trifluoromethyl.  .[.10. A composition according to claim 1 wherein the compound is ##STR49##   
     
     
         .[.11.  A composition according to claim 1 wherein the compound is ##STR50## 
     
     
         .[.12.  A composition according to claim 1 wherein the compound is ##STR51## 
     
     
         .[.13.  A composition according to claim 1 wherein the compound is ##STR52## 
     
     
         .[.14.  A composition according to claim 1 wherein the compound is ##STR53## 
     
     
         .[.15.  A composition according to claim 1 wherein the compound is ##STR54## 
     
     
         .[.16.  A composition according to claim 1 wherein the compound is ##STR55## 
     
     
         .[.17.  A composition according to claim 1 wherein the compound is ##STR56## 
     
     
         18. A composition according to claim 1 wherein the compound is ##STR57## 
     
     
        19. A composition according to claim 1 wherein the compound is ##STR58## 
     
     
         .[.20.  A composition according to claim 1 wherein the compound is ##STR59## 
     
     
        21. A method of effecting diuresis and saluresis in humans and animals and treating hypertension in humans and animals which comprises administering to such human or animal a diuretically effective amount, a saluretically effective amount or an antihypertensive amount of a compound of the formula ##STR60## or a pharmaceutically acceptable nontoxic salt thereof, wherein R is amino; R 1  is .[.hydrogen,.]. lower alkyl or lower alkenyl;   X is ethylene, ethylene wherein 1 hydrogen atom on 1 of the carbon atoms is substituted by alkyl of 1 to 4 carbon atoms or ethylene wherein 1 hydrogen atom on each of the two carbon atoms is substituted by alkyl of 1 to 4 carbon atoms, linked to R 2  via an oxygen or sulphur atom;   R 2  is aryl of 6 to 10 carbon atoms unsubstituted or substituted by: a. 1 to 2 of the same or different substitutents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms and lower alkoxy;   b. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms;   c. nitro; or   d. nitro and 1 or 2 of the same or different substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, halogen and trifluoromethyl; in combination with a pharmaceutically-acceptable, nontoxic, inert diluent       
     
     
        or carrier. 22. A method according to claim 21 wherein R 2  is aryl of 6 to 10 carbon atoms unsubstituted or substituted by: a. 1 or 2 of the same or different substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms;   b. nitro; or   c. nitro and 1 or 2 of the same or different substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon     
     
     
        atoms, alkoxy of 2 to 4 carbon atoms, halogen and trifluoromethyl. 23. A method according to claim 21 wherein R 1  is .[.hydrogen,.]. alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and   R 2  is phenyl; naphthyl; or phenyl substituted by: a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 8 carbon atoms, or alkenyl moieties of 2 to 8 carbon atoms;   b. 1 or 2 alkoxy moieties or 1 to 6 carbon atoms;   c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms;   d. 1 or 2 halogens;   e. 1 or 2 trifluoromethyl moieties; or     
     
     
       f. nitro. 24. A method according to claim 21 wherein R 1  is .[.hydrogen,.]. alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and   R 2  phenyl; naphthyl; or phenyl substituted by: a. 1 or 2 straight or branched-chain alkyl moieties of 1 to 4 carbon atoms or alkenyl moieties of 2 to 4 carbon atoms;   b. 1 or 2 alkoxy moieties of 1 to 4 carbon atoms;   c. cycloalkyl of 5, 6 or 7 carbon atoms or cycloalkenyl of 5, 6 or 7 carbon atoms;   d. 1 or 2 fluoro, chloro or bromo moieties;   e. 1 or 2 trifluoromethyl moieties; or     
     
     
       f. nitro. 25. A method according to claim 21 wherein R 1  is .[.hydrogen,.]. alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms; and   R 2  is phenyl; naphthyl or phenyl substituted by: a. 1 or 2 members selected from the group consisting of straight or branched-chain alkyl and trifluoromethyl moieties of 1 to 4 carbon atoms;   b. alkoxy of 1 to 4 carbon atoms;   c. cycloalkyl of 5 to 6 carbon atoms;   d. 1 or 2 fluoro, chloro, bromo or iodo moieties;   e. chloro or bromo and alkyl of 1 or 2 carbon atoms, trifluoromethyl; or     
     
     
       f. nitro. 26. A method according to claim 21 wherein R 1  is .[.hydrogen,.]. methyl or ethyl;   X is ethylene, ethylele wherein 1 hydrogen atom on one of the carbon atoms is substituted by alkyl of 1 or 2 carbons or ethylene wherein 1 hydrogen atom on each of the two carbon atoms are substituted by alkyl of 1 or 2 carbon atoms, linked to R 2  via an oxygen or sulphur atom; and   R 2  is phenyl; naphthyl; or phenyl substituted by fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyclohexyl, dichlorine, chlorine and methyl, chlorine and bromine, chlorine and fluorine, chlorine and   
     
     
        trifluoromethyl, dibromine or methyl and trifluoromethyl. 27. A method according to claim 21 wherein X is ethylene, ethylene wherein 1 hydrogen on one of the carbon atoms is substituted by methyl or ethyl or ethylene wherein 1 hydrogen atom on each of the two carbon atoms is substituted by methyl, linked to R 2  via an   
     
     
        oxygen or sulphur atom. 28. A method according to claim 21 wherein R 1  is .[.hydrogen or.]. alkyl or 1 to 4 carbon atoms;   X is ethylene or ethylene wherein 1 hydrogen atom on one of the carbon atoms is substituted by methyl and linked to R 2  via an oxygen or sulphur atom; and   R 2  is phenyl; naphthyl; or phenyl substituted by 1 or 2 chlorine,   
     
     
        methyl, ethyl or trifluoromethyl moieties. 29. A method according to claim 21 wherein R 1  is .[.hydrogen or.]. alkyl of 1 to 4 carbon atoms;   X is ethylene or ethylene wherein 1 hydrogen atom of one of the carbon atoms is substituted by methyl, linked to R 2  via an oxygen or sulphur atom; and   R 2  is naphthyl; phenyl; or phenyl substituted by chlorine, methyl, trifluoromethyl, dichlorine, dimethyl, methyl and ethyl or methyl and   
     
     
        trifluoromethyl. .[.30.  A method according to claim 21 wherein the compound is ##STR61## 
     
     
        .[.31.  A method according to claim 21 wherein the compound is ##STR62## 
     
     
        .[.32.  A method according to claim 21 wherein the compound is ##STR63## 
     
     
        .[.33.  A method according to claim 21 wherein the compound is ##STR64## 
     
     
        .[.34.  A method according to claim 21 wherein the compound is ##STR65## 
     
     
        .[.35.  A method according to claim 21 wherein the compound is ##STR66## 
     
     
         .[.36.  A method according to claim 21 wherein the compound is ##STR67## 
     
     
        37. A method according to claim 21 wherein the compound is ##STR68## 
     
     
        38. A method according to claim 21 wherein the compound is ##STR69## 
     
     
        .[.39.  A method according to claim 21 wherein the compound is ##STR70## 
     
     
        .[.40.  A method according to claim 21 wherein the compound is ##STR71##