THIADIAZINE DERIVATIVES, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Heterocyclic compounds 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 -CR¹R²- and Y is -O-, -S- or NR³-, wherein R¹, R² and R³, which may be the same or different, each is hydrogen or alkyl of up to 4 carbon atoms; or X is-O-, -S- or-NH- and Y is -CR¹R²- wherein R¹ and R² 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 as set out in claim 1, provided that when X is -CR¹R²- and A is a direct link, Het is not unsubstituted 2-furyl; and salts thereof where appropri­ ate; processes for their manufacture and pharmaceutical compositions containing them. The compounds possess cardiotonic and/or antihypertensive activity.

Description: This invention relates to new heterocyclic compounds, some of which possess cardiotonic properties, some of which possess antihypertensive properties and some of which possess both said properties. Many 6-aryl-dihydropyridazin-3-one derivatives are known which possess pharmaceutical properties affecting the cardiovascular system. These are described in the Journal of Medicinal Chemistry, 1974, 17, 273-286 and in the Journal of Heterocyclic Chemistry, 1974, 11, 755-761, and there is much related patent literature. When an additional hetero-atom is inserted into the pyridazine nucleus, most of the simple structures have been described in the academic chemical literature. Thus, for example:- 5-phenyl-3H,6H-l,3,4-thiadiazin-2-one and its 6-methyl analogue are known from Leibig's Annalen der Chemie, 1977, 791 and from this article are also known the corresponding p -bromophenyl and 4-biphenylyl analogues. The only disclosure of thiadiazinone, derivatives which bear a heterocyclic substituent occurs in Receuil des Travaux chimiques des Pays Bas, 1964, 83, 1047 wherein there is described 5-(2-furyl)-3H,6H-l,3,4-thiadiazin-2-one. These compounds are said to have been prepared so that their bacteriostatic activity could be evaluated, but no details of this activity are given. None of the abovementioned references discloses any pharmacological utility for any of the compounds described. A compound of considerable interest at present as a cardiotonic agent is a pyridone derivative known by the name AMRINONE, which has the structure : Various phenyl-substituted thiadiazinone derivatives having cardiotonic properties are known from our earlier EP-A-52442 which was published on 26 May 1982, after the priority date of the present application. Various heterocyclic-substituted triazinone derivatives having antihypertensive activity are known from EP-A-77983 which was published on 4 May 1983. Various heterocyclic-substituted pyridazinone derivatives having cardiotonic properties are known from EP-A-34743, and US-A-4298609 and Chemical Abstracts, 1979, Volume 91, 39511W. The last two documents in particular disclose the compound 4,5-dihydro-6-(4-pyridinyl)pyridazin-3-one and its 5-methyl analogue to have antihypertensive activity. We have now found that various thiadiazinone derivatives which are linked, directly or through a hydrocarbon chain, to a heterocyclic nucleus possess valuable cardiotonic and/or antihypertensive properties. According to the invention there is provided a heterocyclic compound of the formula:- wherein R¹ and R², which may be the same or different, each is hydrogen or alkyl of up to 4 carbon atoms; 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, trifluoro; 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 -CZOR⁶ -CZNR⁷R⁸ -SO₂R⁷R⁸ wherein Z is oxygen or sulphur and wherein R⁶, R⁷ and R⁸, which may be the same or different, each is hydrogen, alkyl, alkenyl or cycloalkyl each of up to 6 carbon atoms, or aryl or arylalkyl each of up to 12 carbon atoms, or wherein R⁷ and R⁸ 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 Het is not unsubstituted 2-furyl; or a salt thereof where appropriate. A suitable value for R¹ or R² when it is alkyl is, for example, methyl or ethyl. A suitable halogen substituent in the heterocyclic ring Het is, for example, fluoro, chloro or bromo. A suitable alkylamino or dialkylamino substituent in the heterocyclic ring Het is, for example, ethylamino or dimethylamino. A suitable alkyl or alkoxy substituent in the heterocyclic ring Het is, for example, methyl, ethyl, methoxy or ethoxy. A suitable value for R⁶, R⁷ or R⁸ when it is alkyl, alkenyl or cycloalkyl is, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, allyl, cyclopentyl or cyclohexyl, A suitable value for R⁶, R⁷ or R⁸ when it is aryl or aralkyl is, for example, phenyl, tolyl, chlorophenyl, trichlorophenyl, benzyl or phenylethyl. A suitable value for the heterocyclic ring formed by R⁷, R⁸ and the adjacent nitrogen atom is, for example, the pyrrolidino, piperidino or morpholino ring. Specific values for Het are, for example, pyridyl, thienyl, furyl, pyrrolyl, pyrimidinyl, thiazoly, imidazolyl, indolyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl or quinoxalinyl, for example 2-, 3- or 4-pyridyl, l-oxy-4-pyridyl, 2-thienyl, 3-thienyl, 3-furyl, 2-pyrrolyl, 2-pyrimidinyl, 4-thiazolyl, 4-imidazolyl, 3-indolyl, 3-benzothienyl, 2-benzo[b]thienyl, 2-benzo[b]furyl, 3-benzo[b]furyl, 2-, 3-or 4-quinolyl, l-isoquinolyl or 2-quinoxalinyl, any of which may bear one or two chloro, bromo, cyano, carbamoy, nitro or methyl substituents. An appropriate salt is an acid-addition salt, for example a hydrochloride, hydrobromide, acetate, oxalate, tartrate or citrate, of a compound wherein the group Het- is sufficiently basic to form an acid-addition salt; or a base-addition salt, for example a sodium, potassium, ammonium or benzylamine salt, of an acidic compound wherein R⁶ is hydroxy. A preferred heterocyclic compound of the invention has the formula stated above wherein wherein -CR¹R²- is -CH₂- or -CH(CH₃)- 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. A particularly preferred heterocyclic compound which possesses cardiotonic activity has the formula stated above wherein -CR¹R²-is -CH₂- and Het is 2-, 3- or 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. A particularly preferred heterocyclic compound which possesses antihypertensive activity has the formula stated above wherein -CR¹R²- is -CH₂-, and Het is 2-benzo[b]furyl, 3-benzo[b]thienyl, 2,5-dichlorothien-3-yl or 5-bromo- or 5-chloro-3-pyridyl. Specific heterocyclic compounds of the invention are, for example:- 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-l,3,4-thiadiazin-2-one. A preferred process for the manufacture of a compound of the invention comprises the reaction of a phenacyl halide of the formula:- Het-A-COCR¹R²-Hal wherein Het, R¹ and R² have the meanings stated above and wherein Hal is a halogen atom, for example the chlorine or bromine atom, with a thiocarbazate of the formula:- H₂N.NH.CS-O-R¹⁰ or H₂N.NH.CSO ⁻- M + wherein R¹⁰ is alkyl of up to 4 carbon atoms, for example methyl or ethyl, and wherein M + is an alkali metal or ammonium ion. The reaction may be carried out in an organic diluent or solvent, for example acetonitrile or ethanol, at laboratory temperature or at an elevated temperature, for example at the boiling point of the diluent or solvent. As stated above, some of the heterocyclic compounds of the invention possess cardiotonic activity. This may be demonstrated by their ability to increase the rate of change of aortic blood pressure in the anaesthetised cat. At a dose of the compound which produces an effective increase in said rate of change, that is, greater than a 25% increase, no symptom of toxicity is apparent. As stated above, some of the heterocyclic compounds of the invention possess antihypertensive activity, as demonstrated by their ability to decrease the blood pressure of a normotensive cat or of a spontaneously hypertensive rat. The antihypertensive activity may also be demonstrated by the vasodilation effect produced by the heterocyclic compounds of the invention as shown by their ability to reduce spontaneous contraction in a rat portal vein preparation. The heterocyclic compound of the invention may be administered to warm-blooded animals, including man, in the form of a pharmaceutical composition comprising as active ingredient at least one heterocyclic compound of the invention in association with a pharmaceutically-acceptable diluent or carrier therefor. A suitable composition is, for example, a tablet, capsule, aqueous or oily solution or suspension, emulsion, injectable aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation. The pharmaceutical composition may contain, in addition to the heterocyclic compound of the invention, one or more drugs selected from sedatives, for example phenobarbitone, meprobamate, chlorpromazine and benzodiazepine sedative drugs, for example chlordiazepoxide and diazepam; vasodilators, for example hydralazine, glyceryl trinitrate, pentaerythritol tetranitrate and isosorbide dinitrate; diuretics, for example chlorothiazide, hydrochlorothiazide, amiloride, bendrofluazide or chlorthalidone; β-adrenergic blocking agents, for example propranolol or atenolol; cardiac membrane stabilising agents, for example quinidine; agents used in the treatment of Parkinson's disease and other tremors, for example benzhexol; and cardiotonic agents, for example digitalis preparations. When used for the treatment of acute or chronic heart failure or of hypertension in man, it is expected that the heterocyclic compound would be given to man at a total oral dose of between 100 mg and 2000 mg daily, at doses spaced at 6-8 hourly intervals, or at an intravenous dose of between 5 mg and 100 mg. Preferred oral dosage forms are tablets or capsules containing between 50 and 500 mg, and preferably 100 mg or 500 mg, of active ingredient. Preferred intravenous dosage forms are sterile aqueous solutions of the heterocyclic compound containing between 0.05% and 1% w/w of active ingredient, and more particularly containing 0.1% w/v of active ingredient. The invention is illustrated but not limited by the following Examples:- Example 1 A mixture of bromomethyl 4-pyridyl ketone hydrobromide (1.41 g), ethanol (10 ml) and a solution of ammonium thiocarbazate (1.64 g) in water (5 ml) was stirred at laboratory temperature for 15 hours and then evaporated to dryness under reduced pressure. The residue was stirred with water and the mixture was filtered. A mixture of the solid product, S-[2-oxo-2-(4-pyridyl)ethyl]thiocarbazate (1.0 g), ethanol (15 ml) and concentrated aqueous hydrochloric acid (0.2 ml) was heated under reflux for 15 minutes, cooled and filtered. The solid product was crystallised from methanol and there was thus obtained 5-(4-pyridyl)-3H,6H-1,3,4-thiadiazin-2-one, m.p. 227-228°C. Example 2 A mixture of bromomethyl 3-benzo[b]thienyl ketone (1.275 g), methyl thiocarbazate (0.8 g) and acetonitrile (80 ml) was heated under reflux for 2 hours, kept at laboratory temperature for 24 hours and then filtered. The solid residue was crystallised from acetonitrile and there was thus obtained 5-(3-benzo[b]thienyl)-3H,6H-l,3,4-thiadiazin-2-one, m.p. 226-228°C (with decomposition). The process described above was repeated using the appropriate bromomethyl ketone as starting material, and there were thus obtained the compounds described in the following table:- The process described above was repeated using l-bromoethyl 4-pyridyl ketone as starting material. There was thus obtained 6-methyl-5-(4-pyridyl)-3H,6H-l,3,4-thiadiazin-2-one, m.p. 172-174°C after crystallisation from methylene chloride.

Claims: A heterocyclic compound of the formula:- wherein R¹ and R² which may be the same of different, each is hydrogen or alkyl of up to 4 carbon atoms; and wherein Het is a 5- or 6- membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and 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 -CZOR⁶ -CZNR⁷R⁸ -SO₂R⁷R⁸ wherein Z is oxygen or sulphur and wherein R⁶, R⁷ and R⁸, which may be the same or different, each is hydrogen, alkyl, alkenyl or cycloalkyl each of up to 6 carbon atoms, or aryl or arylalkyl each of up to 12 carbon atoms, or wherein R⁷ and R⁸ 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 Het is not unsubstituted 2-furyl; or a salt thereof where appropriate. The compound:- 5-( 4-pyridyl-)-3H,6H-l,3,4-thiadiazin-2-one. The compound 6-methyl-5-(4-pyridyl)-3H,6H-l,3,4-thiadiazin-2-one. A process for the manufacture of a heterocyclic compound, claimed in any of claims 1 to 3, which comprises: the reaction of a phenacyl halide of the formula:- Het-COCR¹R²-Hal wherein Het, A, R¹ and R² have the meanings stated in any of claims 1 to 4 and wherein Hal is a halogen atom, with a thiocarbazate of the formula:- H₂N.NH.CS-O-R¹⁰ or H₂N.NH.CSO ⁻ M + wherein R¹⁰ is alkyl of up to 4 carbon atoms and wherein M + is an alkali metal or ammonium ion. A pharmaceutical composition comprising as active ingredient at least one heterocyclic compound, claimed in any of claims 1 to 3 in association with a pharmaceutically-acceptable diluent or carrier therefor. A composition as claimed in claim 5 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 for the following Contracting State:AT A process for the manufacture of a heterocyclic compound of the formula:- wherein R¹ and R² which may be the same of different, each is hydrogen or alkyl of up to 4 carbon atoms; 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 -CZOR⁶ -CZNR⁷R⁸ -SO₂R⁷R⁸ wherein Z is oxygen or sulphur and wherein R⁶, R⁷ and R⁸, which may be the same or different, each is hydrogen, alkyl, alkenyl or cycloalkyl each of up to 6 carbon atoms, or aryl or arylalkyl each of up to 12 carbon atoms, or wherein R⁷ and R⁸ 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 Het is not unsubstituted 2-furyl; or a salt thereof where appropriate, characterised by the reaction of a phenacyl halide of the formula:- Het -COCR¹R²-Hal wherein Het, A, R¹ and R² have the meanings stated above and wherein Hal in a halogen atom, with a thiocarbazate of the formula:- H₂N.NH.CS-O-R¹⁰ or H₂N.NH.CSO ⁻M + wherein R¹⁰ is alkyl of up to 4 carbon atoms and wherein M + is an alkali metal or ammonium ion. or Het is 3-methyl-2-quinoxalinyl. A process as claimed in claim 1 wherein in the starting materials, Het is 4-pyridyl. A process as claimed in claim 1 wherein in the starting materials, R¹ is methyl, R² is hydrogen and Het is 4-pyridyl.

Inventors: HARGREAVES, RODNEY BRIAN, MCLOUGHLIN, BERNARD JOSEPH, MILLS, STUART DENNETT
Applicants: IMPERIAL CHEMICAL INDUSTRIES PLC
Application year: 1982
Main classification: C07D417
IPC codes: C07D333, C07D213, C07D285, C07D401, C07D413, C07D405, A61K31, C07D307, C07D273, C07D253, C07D215, A61P37, A61P9, C07D417, C07D409