IL43546A - Diuretic and saluretic compositions containing a 1,2-dihydro-or a 1,2,3,4-tetrahydro phthalazine and certain novel phthalazines - Google Patents

Abstract

1398549 Phthalazine derivatives and their use in pharmaceutical compositions BOOTS CO Ltd 6 Nov 1973 [6 Nov 1972] 50973/72 Heading C2C Compounds of the formula or its enol or enthiol form of the formula wherein Q is COOH, CH 2 OH or COOR 6 , where R 6 is an ester forming group, X is oxygen or sulphur, R is hydrogen or alkyl, Z is hydrogen or acyl, and Ar is a phenyl group unsubstituted in the ortho positions and which may have one or more substituents, or to which an optionally substituted mono- or polycyclic is fused, which ring or rings may contain one or more hetero atoms; or pharmaceutically acceptable salts thereof with inorganic or organic bases, may be prepared by conventional methods. Compounds of the above formulµ with the proviso that when (i) Q is COOH, COOMe or COOEt, X is oxygen, and R is hydrogen or methyl, then Ar is not phenyl, m- or p-chlorophenyl, m- or p-nitrophenyl, p-(p-nitrophenylazo)phenyl or p-phenylazophenyl, or (ii) when Q is COOH, X is oxygen and R is hydrogen, then Ar is not m- or p-anilino or m- or p-acetamido phenyl, are claimed to be novel. Preferred compounds in which the radical Ar has the formula wherein R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, halogen, nitro, nitroso, cyano, isocyano, carboxy, optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, aryl, cycloalkenyl, optionally substituted alkoxy, alkenyloxy, cycloalkoxy, cycloalkenyloxy, acyloxy, optionally substituted alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, alkylsulphonyl, alkylsulphinyl, optionally substituted acyl, aryl, heteroaroyl, hydroxy, mercapto, carbamoyl, thiocarbamoyl, optionally substituted sulphamoyl, optionally substituted heterocyclic rings, or R 3 and R 4 together form a portion of a carbocyclic or heterocyclic ring fused to the benzene ring, which rings may be substituted, may be prepared, for example, by a process which comprises the steps of (a) reacting a salt of 2-naphthol-1-sulphonic acid with a compound of the formula wherein R 2 is hydrogen, iodine, bromide or chlorine and Y is the anion of a mineral acid, (b) treating the product from (a) with a mild base, (c) treating the product from (b) with an alkali metal hydroxide, followed by acidification to give a compound of the formula (d) optionally modifying at least one of the groups R 3 , R 4 or R 5 and/or, if R 2 is iodine, bromine or chlorine, converting it to hydrogen, and/or converting the 1-acetic acid group to a hydroxyethyl group, (e) treating the product from (c) or (d) with an aqueous acid or an alcoholic acid to give a compound of the formula in which R is hydrogen and X is oxygen, (f) in the case where R 2 is iodine, bromine, or chlorine, converting it to hydrogen, (g) in the case when the compound obtained from (d), (e) or (f) is one falling within the proviso, modifying at least one of the groups Q, X, Z, R, R 3 , R 4 or R 5 , to give a compound not falling within the proviso, (h) modifying at least one of the groups in the product obtained from (e), (f) or (g), and (i) optionally forming a pharmaceutically acceptable salt with an organic or inorganic base of any compound which is an acid. The products possess pharmaceutical properties and they may be formulated and applied in a conventional manner. [GB1398549A]

Claims (3)

1. WHAT IS CLAIMED IS: 43546/2 1. Therapeutic compositions comprising a compound of formula I or its enol or enthiol form. of formula la in which Q is COOH, CHgOH or COORg, wherein Rg is a lower alkyl group, X is oxygen or sulphur, R is hydrogen or alkyl, Z is hydrogen or alkanoyl and R^, R^ and R^ may he the same or different and are selected from hydrogen; fluorine; chlorine, "bromine; iodine; nitro; cyano; alkyl; trifluoro-inethyl; hydroxyalkyl ; al oxyalkyl; phenyl; alkoxy; alkylthio phenylthio; trifluoromethylthio ; alkylsulphonyl ; alkyl-sulphinyl; alkanoyl; benzoyl; thenoyl; dialk lsulphamoyl ; pyrroLyl ; -or where' is hydrogen or lower alkyl and Rg is hydrogen, amino, lower alkyl, phenyl lov/er alkyl, lower alkanoyl, lov/er alkylsulphonyl, benzoyl lower alkylsulphonyl ,. phenylsulphonyl (in which the benzene ring ma 43546/2 be substituted by lower alk l) or benzylidene; or and R^ together form a portion of a carbocyclic or heterocyclic ring fused to the benzene ring to form a group selected from or p?iarrnaceutically acceptable salts with inorganic and organic bases of those compounds which are acids, in admixture with a pharmaceutically acceptable diluent.

2. Compositions according to claim 1 in which R^ is hydrogen and one of and R. is nitro or chloro and the other is j 4 hydrogen.

3. Compositions according to claim 2 which comprise 2-( 3-chlorophenyl)-4-hydroxy~1 , 2-dihydrophthalazine-1 -acetic acid. · 4. Compounds of formula I or their enol or enthiol form of formula la 43546/2 in which Q, X, Z, R^, R^ and R^ are as .defined, in claim 1 , with the proviso that when (i) Q is COOH, COOMe or COOEt, X is oxygen, R is hydrogen or methyl and one of R^ and R4 is H, CI, or 02 or (ii) Q is COOH, X is oxygen, R is hydrogen and one of R^ and R^ is amino or acetamido, then at least two of R^, R^ and R^ are groups as defined for ^, R^ and R^ other than hydrogen, together with pharmaceutically acceptable salts with inorganic and organic bases Of those compounds which are acids.' 5. Compounds according to claim in which Q is' COOH. 6. Compounds according to claim 4 or 5 in which Z is dro;';en. 7. Compounds according to any one of claims 4 to 6 in which X is oxygen. 8. Compounds according to any one of claims 4 to 7 in which R is hydrogen. 9. Compounds according to any one of claims 4 to 7 in whic R is methyl or ethyl. 10. Compounds according to any one of claims 4 to 9 in which ^ is hydrogen. 11. Compounds according to any one of claims 4 to 10 in which R.-. is other than hydrogen. 12. Compounds Jacccording to any one of claims 4 to 11 in v.' ich an ' r mo liy thio, ethylthio, methyl, ethyl, chlorine, iodine, bromine, mcthoxy, etho , isooropox.y , acetyl , cUneihyl!!ul ph.'irno l , A3546/2 13. Compounds according to any one of .claims to 11 in which and/or R^ is Ν,Ν-dimethylamino , N-meth l-_-tolue e-sulphonamido or -methylacetamido and R is methyl or ethyl. 14. 4-Hydroxy-2-(3-trifluoromethylphenyl)-1 ,2-dihydro-phthalazine-1 -acetic acid. 15. 2-( 3-Bromophenyl)-4-hydroxy-1 ,2-dihydrophthalazine-1 -acetic acid. 16. 4-Hydroxy-2-( 3-iodophenyl) -1 , 2-dihydrophthalazine-1 -acetic ,acid. ' 17. 2-( 3-Ethylphenyl)-4-hydroxy-1 , 2-dihydrophthalazine-1 -acetic acid. 18. 4-Hydroxy-2-( 3-isopropoxyphenyl) -1 , 2-dihydrophthalazine-1 -acetic acid. 19. 2-(3-N,N-Dimethylaminophenyl)-3-methyl-4-oxo-1 ,2,3,4-tetrahydrophthalazine-t-acetic acid and its methyl ester. 20. 3-Methyl-2-[ 3- -methyl-p_-toluenesulphonamido) phenyl ]-4-oxo-1 ,2,3, 4-tetrahydrophthalazine-1 -acetic acid. 21. 4-Hydroxy-2-( 3-methylthiophenyl) -1 ,2-dihydrophthalazine-1-acetic acid. 22. 2-( 3-Ethylthiophenyl) -4-hydroxy-1 ,2-^dihydrophthalazine- 1 -acetic acid. 23. 2-(Benzo-1 ,2 , 3-thiadiazol-5-yl)-4-hydroxy-1 ,2-dihydro-phthalazine-1-acetic acid. 2 . 2-(B-?ir.o-[b] thlen-5-./l ) -4-hydroxy-1 , 2^dihydroph halazine 1 -acetic acid. 25. 2-(Benzothiazol-5-.yl ) -4-hydroxy-1 , 2-dihy rophthalazino- 43546/2 27. Compounds according to claim 4 substantially as herein-oefore described. ; :·.- 28. Compounds according to claim 4 as described in any one of Examples 1 to 18, 50, 52, 95, and 100. 29. Compounds according to claim 4 as described in any one of Examples 19 to 49, 51 ,53 to 94, 96 to 99 and 101 to 114. 30. Compoiiitions according to claim 1 which comprise a compound claimed in any one of claims 4 to 29. 31. Compositions according to any one of claims 1 to 3 or 30 suitable for oral administration and in the form of tablets, capsules, lozenges, powders, effervescent granules, syrups, or aqueous or oily suspensions. 32. Compositions according to any one of claims 1 to 3 or 30 suitable for rectal administration and in the form of a suppository. 33. Compositions according to any one of claims 1 to 3 or 30 to 32 comprising 0.1 to 90 by weight of the compound. 34. Compositions according to any one of claims 1 to 3 or 30 to 33 in unit dose form comprising 3 mg. to 500 mg. of the compound. 35. Therapeutic compositions substantially as hereinbefore described.