Thiadiazine derivatives, and pharmaceutical compositions containing them

Claim 2

A heterocyclic compound of the formula:- wherein A is a direct link, or is alkylene of 1 to 4 carbon atoms or alkenylene of 2 to 4 carbon atoms; wherein either X is -CR 1 R 2 -and Y is -O-, -S- or -NR 3 -, wherein R l , R 2 and R 3 , which may be the same of different, each is hydrogen or alkyl of up to 4 carbon atoms; or X is -O-, -S- or -NH- and Y is -CR l R 2_ , wherein R 1 and R 2 have the meanings stated above; and wherein Het is a 5- or 6- membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, which ring may be unsubstituted or may bear one or two substituents selected from:- halogen, cyano, nitro, trifluoromethyl; amino, alkylamino and dialkylamino wherein the one or two alkyls each is of up to 4 carbon atoms; alkyl and alkoxy each of up to 4 carbon atoms; hydroxy, oxo (if on carbon next to nitrogen) and oxy (if on nitrogen or sulphur); substituents of the formula wherein Z is oxygen or sulphur and wherein R 6 , R 7 and R 8 , which may be the same or different, each is hydrogen, alkyl, alkenyl, cycloalkyl or alkoxyalkyl each of up to 6 carbon atoms, or aryl or arylalkyl each of up to 12 carbon atoms, or wherein R 7 and R 8 together with the adjacent nitrogen atom form a 5- or 6- membered fully-saturated heterocyclic ring; and the substituent -CH=CH-CH=CH- (that is, the substituent which forms a benzo-fused heterocyclic ring); provided that when X is -CR 1 R 2 - and A is a direct link, Het is not unsubstituted 2-furyl; or a salt thereof where appropriate.

Claim 3

A heterocyclic compound as claimed in claim 1 wherein A is a direct link or is methylene or vinylene; wherein either X is -CH 2 - or -CH(CH 3 )- and Y is -S-; or X is -CH 2 - and Y is -0- or -NH-; or X is -S- and Y is -CH 2 -, -CH(CH 3 )-; CH( CH 3)2 - CH - or -C( CH 3 ) 2 - or X is -O- or -NH- and Y is -CH 2 -; and wherein Het is 2-, 3- or 4- pyridyl which is unsubstituted or bears one chloro, bromo, cyano, carbamoyl or methyl substituent; or Het is 2- or 3-thienyl which is unsubstituted or which bears one or two chloro or methyl substituents; or Het is unsubstituted benzo[b]thienyl, benzo[b]furyl, indolyl or quinolyl; or Het is 3-methyl-2-quinoxalinyl.

Claim 4

A heterocyclic compound as claimed in claim 1 wherein A is a direct link, one of X and Y is -S- or -NH- and the other of X and Y is -CH 2 - and Het is 2-, 3- and 4-pyridyl which is unsubstituted or which bears one chloro, bromo, cyano, carbamoyl or methyl substituent, or Het is unsubstituted 2-quinolyl or 3-indolyl.

Claim 5

A heterocyclic compound as claimed in claim 1 wherein A is a direct link, X is -CH 2 -, Y is -O-, -S- or -NH- and Het is 2-benzo[b]furyl, 3-benzo[b]thienyl, 2,5-dichlorothien-3-yl or 5-bromo-or 5-chloro-3-pyridyl.

Claim 6

The compounds:- 5-(3-pyridyl-, 4-pyridyl-, 5-chloro-3-pyridyl-, 2-cyano-4-pyridyl-, 5-carbamoyl-2-pyridyl-, 6-carbamoyl-3-pyridyl-, 2-carbamoyl-4-pyridyl-, 2-benzo[b]furyl- and 3-indolyl)-3H,6H-1,3,4-thiadiazin-2- one; 2-(2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 6-methyl-2-pyridyl-, 5-bromo-3-pyridyl- and 2-quinolyl)-4H,6H-1,3,4-thiadiazin-5-one; 6,6-dimethyl-2-{4-pyridyl)-4H,6H-1,3,4-thiadiazin-5-one; 5-(2-benzo[b]furyl)-3H,6H-1,3,4-oxadiazin-2- one; 4-(4-pyridyl)-5,6-dihydro-1,2,4-triazin-6(lH)-one; and 6-(3-pyridyl-, 4-pyridyl-, 5-chloro-3-pyridyl-, 5-bromo-3-pyridyl-, 2,5-dichlorothien-3-yl-and 3-benzo[b]thienyl)-4,5-dihydro-1,2,4-triazin-3(2H)-one.

Claim 7

The compounds:- 5-(3-pyridyl-, 4-pyridyl-, 5-chloro-3-pyridyl-, 2-cyano-4-pyridyl-, 5-carbamoyl-2-pyridyl-, 6-carbamoyl-3-pyridyl-, 2-carbamoyl-4-pyridyl-, 2-benzo[b]furyl- and 3-indolyl)-3H,6H-1,3,4-thiadiazin-2- one; 2-(2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 6-methyl-2-pyridyl-, 5-bromo-3-pyridyl- and 2-quinolyl)-4H,6H-1,3,4-thiadiazin-5-one; 6,6-dimethyl-2-{4-pyridyl)-4H,6H-1,3,4-thiadiazin-5-one; 5-(2-benzo[b]furyl)-3H,6H-1,3,4-oxadiazin-2- one; 4-(4-pyridyl)-5,6-dihydro-1,2,4-triazin-6(lH)-one; and 6-(3-pyridyl-, 4-pyridyl-, 5-chloro-3-pyridyl-, 5-bromo-3-pyridyl-, 2,5-dichlorothien-3-yl-and 3-benzo[b]thienyl)-4,5-dihydro-1,2,4-triazin-3(2H)-one.

Claim 8

A process for the manufacture of a heterocyclic compound, claimed in any of claims 1 to 5, which comprises: (a) for the manufacture of a compound wherein X is oxygen or sulphur and Y is -CR l R 2_ , the reaction of a hydrazide or thiohydrazide of the formula:- wherein Het and A have the meanings stated in any of claims 1 to 4 and X is sulphur or oxygen, with an acid of the formula:- wherein R 1 and R 2 have the meanings stated in any of claims 1 to 4 and wherein Hal is a halogen atom, or with a reactive derivative thereof; or (b) for the manufacture of a compound wherein X is -C R 1 R 2- and Y is sulphur, the reaction of a phenacyl halide of the formula:- wherein Het, A, R 1 , R 2 and Hal have the meanings stated above, with a thiocarbazate of the formula:- wherein R 10 is alkyl of up to 4 carbon atoms and wherein M + is an alkali metal or ammonium ion; or (c) for the manufcture of a compound wherein X is -CR 1 R 2 - and Y is oxygen, the cyclisation of a compound of the formula:- wherein Het, A, R 1 , R 2 and R 10 have the meanings stated above and wherein R 11 is hydrogen or alkanoyl of up to 4 carbon atoms; or (d) for the manufacture of a compound wherein X is -NH- and Y is -CR 1 R 2 -, the reaction of a compound of the formula:- wherein Het, A, R l , R 2 and R 10 have the meanings stated above (the two R 10 substituents being the same or different alkyl radicals of up to 4 carbon atoms), with hydrazine; or (e) for the manufacture of a compound wherein X is -CR 1 R 2 - and Y is -NR 3 -, the reaction of a compound of the formula:- wherein Het, A, R l , R 2 , R 3 and R 10 have the meanings stated above, with hydrazine; whereafter a compound wherein R 3 is alkyl may be obtained by the alkylation of the corresponding compound wherein R 3 is hydrogen.

Claim 9

A pharmaceutical composition comprising as active ingredient at least one heterocyclic compound, claimed in any of claims 1 to 5, in association with a pharmaceutically-acceptable diluent or carrier therefor.

Claim 10

A composition as claimed in claim 7 which contains, in addition to the heterocyclic compound, one or more drugs selected from sedatives, vasodilators, diuretics,β-adrenergic blocking agents, cardiac membrane stabilising agents, agents used in the treatment of Parkinson's disease and other tremors, and cardiotonic agents.

Claim 11

10 A method for the treatment of acute or chronic heart failure, or of hypertension, in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a heterocyclic compound claimed in claim 1.

Claim 12

A process for the manufacture-of a heterocyclic compound of the formula:- wherein A is a direct link, or is alkylene of 1 to 4 carbon atoms or alkenylene of 2 to 4 carbon atoms; wherein either X is -CR l R 2 and Y is -O-, -S- or -NR 3 -, wherein R 1 , R 2 and R 3 , which may be the same of different, each is hydrogen or alkyl of up to 4 carbon atoms; or X is -O-, -S- or -NH- and Y is -CR 1 R 2 -, wherein R 1 and R 2 have the meanings stated above; and wherein Het is a 5- or 6- membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, which ring may be unsubstituted or may bear one or two substituents selected from:- halogen, cyano, nitro, trifluoromethyl; amino, alkylamino and dialkylamino wherein the one or two alkyls each is of up to 4 carbon atoms; alkyl and alkoxy each of up to 4 carbon atoms; hydroxy, oxo (if on carbon next to nitrogen) and oxy (if on nitrogen or sulphur); substituents of the formula wherein Z is oxygen or sulphur and wherein R 6 , R 7 and R 8 , which may be the same or different, each is hydrogen, alkyl, alkenyl, cycloalkyl or alkoxyalkyl each of up to 6 carbon atoms, or aryl or arylalkyl each of up to 12 carbon atoms, or wherein R 7 and R 8 together with the adjacent nitrogen atom form a 5- or 6- membered fully-saturated heterocyclic ring; and the substituent -CH=CH-CH=CH- (that'is, the substituent which forms a benzo-fused heterocyclic ring); provided that when X is -CR 1 R 2 - and A is a direct link, Het is not unsubstituted 2-furyl; or a salt thereof where appropriate, characterised by . (a) for the manufacture of a compound wherein X is oxygen or sulphur and Y is -CR 1 R 2 -, the reaction of a hydrazide or thiohydrazide of the formula:- wherein Het and A have the meanings stated above and X is sulphur or oxygen, with an acid of the formula:- wherein R 1 and R 2 have the meanings stated above and wherein Hal is a halogen atom, or with a reactive derivative thereof; or (b) for the manufacture of a compound wherein X is -CR l R 2- and Y is sulphur, the reaction of a phenacyl halide of the formula:- wherein Het, A, R 1 , R 2 and Hal have the meanings stated above, with a thiocarbazate of the formula:- wherein R 10 is alkyl of up to 4 carbon atoms and wherein M + is an alkali metal or ammonium ion; or (c) for the manufcture of a compound wherein X is -CR 1 R 2 - and Y is oxygen, the cyclisation of a compound of the formula:- wherein Het, A, R 1 , R2 and R 10 have the meanings stated above and wherein R 11 is hydrogen or alkanoyl of up to 4 carbon atoms; or (d) for the manufacture of a compound wherein X is -NH- and Y is -CR 1 R 2 -, the reaction of a compound of the formula:- wherein Het, A, R 1 , R 2 and R 10 have the meanings stated above (the two R 10 substituents being the same or different alkyl radicals of up to 4 carbon atoms), with hydrazine; or (e) for the manufacture of a compound wherein X is -CR 1 R 2 - and Y is -NR 3 -, the reaction of a compound of the formula:- wherein Het, A, R 1 , R 2 ,R 3 und R 10 have the meanings stated above, with hydrazine; whereafter a compound wherein R 3 is alkyl may be obtained by the alkylation of the corresponding compound wherein R 3 is hydrogen.

Claim 13

A process for the manufacture-of a heterocyclic compound of the formula:- wherein A is a direct link, or is alkylene of 1 to 4 carbon atoms or alkenylene of 2 to 4 carbon atoms; wherein either X is -CR l R 2 and Y is -O-, -S- or -NR 3 -, wherein R 1 , R 2 and R 3 , which may be the same of different, each is hydrogen or alkyl of up to 4 carbon atoms; or X is -O-, -S- or -NH- and Y is -CR 1 R 2 -, wherein R 1 and R 2 have the meanings stated above; and wherein Het is a 5- or 6- membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, which ring may be unsubstituted or may bear one or two substituents selected from:- halogen, cyano, nitro, trifluoromethyl; amino, alkylamino and dialkylamino wherein the one or two alkyls each is of up to 4 carbon atoms; alkyl and alkoxy each of up to 4 carbon atoms; hydroxy, oxo (if on carbon next to nitrogen) and oxy (if on nitrogen or sulphur); substituents of the formula wherein Z is oxygen or sulphur and wherein R 6 , R 7 and R 8 , which may be the same or different, each is hydrogen, alkyl, alkenyl, cycloalkyl or alkoxyalkyl each of up to 6 carbon atoms, or aryl or arylalkyl each of up to 12 carbon atoms, or wherein R 7 and R 8 together with the adjacent nitrogen atom form a 5- or 6- membered fully-saturated heterocyclic ring; and the substituent -CH=CH-CH=CH- (that'is, the substituent which forms a benzo-fused heterocyclic ring); provided that when X is -CR 1 R 2 - and A is a direct link, Het is not unsubstituted 2-furyl; or a salt thereof where appropriate, characterised by . (a) for the manufacture of a compound wherein X is oxygen or sulphur and Y is -CR 1 R 2 -, the reaction of a hydrazide or thiohydrazide of the formula:- wherein Het and A have the meanings stated above and X is sulphur or oxygen, with an acid of the formula:- wherein R 1 and R 2 have the meanings stated above and wherein Hal is a halogen atom, or with a reactive derivative thereof; or (b) for the manufacture of a compound wherein X is -CR l R 2- and Y is sulphur, the reaction of a phenacyl halide of the formula:- wherein Het, A, R 1 , R 2 and Hal have the meanings stated above, with a thiocarbazate of the formula:- wherein R 10 is alkyl of up to 4 carbon atoms and wherein M + is an alkali metal or ammonium ion; or (c) for the manufcture of a compound wherein X is -CR 1 R 2 - and Y is oxygen, the cyclisation of a compound of the formula:- wherein Het, A, R 1 , R2 and R 10 have the meanings stated above and wherein R 11 is hydrogen or alkanoyl of up to 4 carbon atoms; or (d) for the manufacture of a compound wherein X is -NH- and Y is -CR 1 R 2 -, the reaction of a compound of the formula:- wherein Het, A, R 1 , R 2 and R 10 have the meanings stated above (the two R 10 substituents being the same or different alkyl radicals of up to 4 carbon atoms), with hydrazine; or (e) for the manufacture of a compound wherein X is -CR 1 R 2 - and Y is -NR 3 -, the reaction of a compound of the formula:- wherein Het, A, R 1 , R 2 ,R 3 und R 10 have the meanings stated above, with hydrazine; whereafter a compound wherein R 3 is alkyl may be obtained by the alkylation of the corresponding compound wherein R 3 is hydrogen.

Claim 14

A process as claimed in claim 1 wherein in the starting materials A is a direct link or is methylene or vinylene; wherein either X is -CH 2 - or -CH(CH 3 )- and Y is -S-; or X is -S_ and Y is -CH 2 -, -CH(CH 3 )-; CH(CH 3 ) 2 -CH- or -C(C H 3 ) 2 - or X is -0- or -NH- and Y is -CH 2 -; and wherein Het is 2-, 3- or 4-pyridyl which is unsubstituted or bears one chloro, bromo, cyano, carbamoyl or methyl substituent; or Het is 2- or 3-thienyl which is unsubstitued or which bears one or two chloro or methyl substituents; or Het is unsubstituted benzo[b]thienyl, benzo[b]furyl, indolyl or quinolyl; or Het is 3-methyl-2-quinoxalinyl.

Claim 15

3 . A process as claimed in claim 1 wherein in the starting material, A is a direct link, one of X and Y is -S- or -NH- and the other of X and Y is -CH 2 -and Het is 2-, 3- and 4-pyridyl which is unsubstituted or which bears one chloro, bromo, cyano, carbamoyl or methyl substituent, or Het is unsubstituted 2-quinolyl or 3-indolyl.

Claim 16

4 . A process as claimed in claim 1 wherein in the starting materials, A is a direct link, X is -CH 2 -, Y is -0-, -S- or -NH- and Het is 2-benzo[b]furyl, 3-benzo[b]thienyl, 2,5-dichlorothien-3-yl or 5-bromo- or 5-chloro-3-pyridyl.