GB1601132A

GB1601132A - Pharmacologically active triazinones

Info

Publication number: GB1601132A
Application number: GB11757/77A
Authority: GB
Original assignee: Smith Kline and French Laboratories Ltd
Current assignee: Smith Kline and French Laboratories Ltd
Priority date: 1977-03-19
Filing date: 1977-03-19
Publication date: 1981-10-28
Also published as: YU65278A; ZA78988B; IT1095458B; PT67687A; HU175669B; CS208746B2; NO148556C; EG13240A; GR66122B; NO148556B; PL205382A1; IT7820754A0; SU733517A3; FI780629A; AR223643A1; NO780970L; BE864992A; DK121978A; DD134522A5; BG33157A3

Description

(54) PHARMACOLOGICALLY ACTIVE TRIAZINONES (71) We, SMITH KLINE & FRENCH LABORATORIES LIMITED, Mundells, Welwyn Garden City, Hertfordshire, England, a British Company, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to pharmacologically active compounds, to methods for preparing these compounds, to pharmaceutical compositions containing these compounds and to methods of blocking histamine H2 - receptors by administering these compounds. The compounds of the invention can exist as acid addition salts but, for convenience, reference will be made throughout this specification to the parent compounds.

Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors. Histamine is such a substance and has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine, diphenhydramine and chloropheniramine are examples, are mediated through histamine H1 - receptors (Ash and Schild, Brit. J. Pharmac. Chemother., 27, 427, (1966)), and drugs with this activity are hereinafter referred to as histamine H1 - antagonists. However, other of the biological actions of histamine are not inhibited by histamine H1 - antagonists and actions of this type which are inhibited by a compound described by Black et al. (Nature, 236, 385, (1972)) and called burimamide are mediated through receptors which are defined by Black et al. as histamine H2 - receptors. Thus histamine H2 - receptors may be defined as those histamine receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine H2 - receptors are referred to as histamine H2 - antagonists.

Blockade of histamine H2 - receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by histamine H1 - antagonists. Histamine H2 - antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as antiinflammatory agents and as agents which act on the cardiovascular system, for example, as inhibitors of the effects of histamine on blood pressure. In the treatment of certain conditions, for example, inflammation and in inhibiting the actions of histamine on blood pressure, a combination of histamine Hl- and H2-antagonists is useful.

In British Patent Specification No. 1419994 we described and claimed inter alia compounds of formula (1) as histamine Hrantagonists.

In formula (1), A is a chain of three of four atoms which chain comprises at least one carbon atom and may also comprise a sulphur atom, a nitrogen atom, two nitrogen atoms or a nitrogen and a sulphur atom, said chain also comprising keto, thione or, where possible, a sulphone grouping and may be substituted by one or two lower alkyl, aryl or aralkyl groups or in such a way that the resultant structure forms with the adjacent ring carbon and nitrogen atoms shown a bicyclic system, one ring of which is a phenyl ring; R is a grouping of the structure shown in formula (2): Het-CH2Z(CH2)- (2) wherein Het is an imidazole, pyridine, thiazole, isothiazole or thiadiazole which ring is optionally substituted by lower alkyl preferably methyl, amino, hydroxy or halogen; Z is sulphur or a methylene group; and n is 2 or 3.

We have now found that a particular group of compounds some of which fall within the above definition of compounds of formula 1 possess certain advantages over the general group of compounds of formula 1. This particular group of compounds are more potent as histamine H2-antagonists than the said general group of compounds of formula (1), and this particular group of compounds have histamine H1-antagonist activity as well as histamine H2-antagonist activity.

The particular group of compounds selected because of the above-mentioned advantages is represented by formula (3):

wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl (preferably methyl), halogen (preferably chlorine or bromine), trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by one or two groups (which may be the same or different) selected from lower alkyl (preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine), amino and hydroxy, a 2-pyridyl ring with a phenyl, carbocyclic or cyclic ether ring containing 2 oxygen atoms fused to it, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5) thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino1,3,4-thiadiazolyl) ring; Z' is sulphur or a methylene group; x is 1 to 5; Y is a 1- or 2-naphthyl ring, a 2,3-dihydro-1 ,4-benzodioxinyl or a 1 ,3-benzodioxolyl ring, a phenyl ring substituted with one or more alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(lower alkyl) amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups, a 5 or 6 membered heterocycle such as a pyridine, furan, thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine ring, which ring is optionally substituted by lower alkyl, lower alkoxy or may have a benzene ring fused to it, or when x is other than 1 Y may also be phenyl; or a pharmaceutically acceptable salt thereof.

In this specification the terms lower alkyl and lower alkoxy mean such groups containing from 1 to 6 carbon atoms inclusive.

Preferably Het' is 2-thiazolyl, 5-methyl-44midazolyl, 5-bromo-4-imidazolyl, 3-bromo-2 pyridyl, 3-chloro-2-pyridyl, 3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl ring.

Preferably Z is sulphur.

Preferably x is 1.

Preferably Y is a phenyl group substituted by one or two lower alkoxy groups (particularly 3-methoxyphenyl, 4-methoxyphenyl or 3 ,4-dimethoxyphenyl), a a 2,3- dihydro,1,4-benzodioxinyl ring, a 1,3-benzodioxolyl ring, or a 2-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 4-pyridyl or 2-thiazolyl ring.

The compounds of formula (3) are described as 2H-1,2,4-triazinone derivatives and these compounds exist in equilibrium with the 4H-tautomers, and to a lesser extent as the hydroxy tautomers. The triazine ring may also exist in the following tautomeric forms:

Certain Het' may also exist in several tautomeric forms, and it will be understood that all these tautomeric forms are within the scope of the present invention. Hydrates of compounds of formula (3) and pharmaceutically acceptable hydrated salts of compounds of formula (3) are also within the scope of this invention.

Some specific compounds which fall within the scope of the present invention are: 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-methoxybenzyl)-1 ,2,4-triazin5-one 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-pyridylmethyl)-1 ,2 ,4-triazin5-one 3- 2-(2-thiazolylmethylthio ethylaminol-6-(3-methoxybenzyl)-1 ,2,4-triazin-5-one 3- 2-(2-thiazolylmethylthio ethylamino -6- ,4-triazin-5-one 3- 2-(3-bromo-2-pyridylmethylthio)ethylamino -6-(3-pyridylmethyl)-1 ,2,4-triazin-5-one 3- 2-(3-bromo-2-pyridylmethylthio)ethylamino -6- 3-methoxybenzyl)-1 ,2,4-triazin-5-one The compounds of formula (3) can be prepared by a process which comprises treating a triazinone of formula (4):

wherein x and Y are as defined in formula (3) and Q is a group which is displaceable by an amine for example lower alkylthio benzylthio with an amine of formula Het' -CH2-Z'-(CH2)2NH2 wherein Het' and Z' are as defined in formula (3). Preferably this reaction is carried out in the absence of a solvent at an elevated temperature e.g.

150-180"C, or in the presence of a solvent, for example, in refluxing pyridine.

The triazinones of formula (4) wherein Q is lower alkylthio can be prepared by the following general scheme;

wherein a carboxaldehyde of formula (5) is converted.into an azlactone of formula (6) which is partially hydrolysed to an acetamidoacrylic acid of formula (7) and this is treated with thiosemicarbazide to give a compound of formula (8), which is converted into a triazinone of formula (4) by treatment with an alkyl halide or sulphate under alkaline conditions.

The compounds of formula (4) wherein Q is benzylthio can be prepared by reacting a compound of formula (8) with a benzyl halide.

Compounds of formula (4) where Q is lower alkylthio or benzylthio are disclosed and claimed in our copending application Nos. 8029573 and 8029574. (Serial No. 1601133).

Alternatively, the compounds of formula (8) can be prepared by treating a pyruvic acid of formula Y(CH2)xiCOCO2H (which may be prepared by acid hydrolysis of an azlactone of formula (6)) or an ester thereof with thiosemicarbazide and a base.

Alternatively, the compounds of formula (8) can be prepared by treating an azlactone of formula (6) with thiosemicarbazide in water.

The compounds of formula (3) block histamine Hrreceptors, that is they inhibit the biological actions of histamine which are not inhibited by histamine H1-antagonists such as mepyramine but are inhibited by burimamide. For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane, at doses of from 0.5 to 16 micromoles per kilogram intravenously. This procedure is referred to in the abovementioned paper of Ash and Schild. The activity of these compounds as histamine H2-antagonists is also demonstrated by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine H1-receptors. For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.

In addition, the compounds of this invention show anti-inflammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume is reduced by subcutaneous injection of doses of a compound of formula (3). In a conventional test, such as the measurement of blood pressure in the anaesthetised cat, the action of the compounds of this invention at doses of from 0.5 to 256 micromoles per kilogram intravenously in inhibiting the vasodilator action of histamine can also be demonstrated. The level of activity of the compounds of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secretion in the anaesthetised rat and the dose producing 50% inhibition of histamine-induced tachycardia in the isolated guinea pig atrium (less than 10-5 Molar).

The compounds of formula (3) also block histamine H1-receptors, that is they inhibit the biological actions of histamine which are inhibited by mepyramine, diphenhydramine and chlorpheniramine. For example the compounds of this invention have been found to inhibit the action of histamine in the isolated guinea-pig ileum. For many of the compounds of formula (3) a dose of 10-5 Molar or less inhibits the histamine-stimulated contractions of the guinea pig ileum.

For therapeutic use, the pharmacologically active compounds of the present invention will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in the basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and may conveniently be formed from the corresponding bases of formula (3) by standard procedures, for example by treating the base with an acid in a lower alkanol or by the use of ion exchange resins to form the required salt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and a compound of formula (3) or a pharmaceutically acceptable acid addition salt thereof are another aspect of this invention. The pharmaceutical carrier employed may be, for example, either a solid or liquid. Examplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.

The compositions of the invention can be formulated in a variety of ways. Thus, if a solid carrier is used, the composition can be in the form of a tablet, hard gelatin capsule, powder or pellet, or in the form of a troche or lozenge. The amount of solid carrier can be varied widely but preferably will be from about 25 mg to about 300 mg. If a liquid carrier is used, the composition can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or non-aqueous liquid suspension.

The active ingredient will be present in the compositions in an effective amount to block histamine H1- and H2- receptors.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six times per day. The route of administration may be oral or parenteral, but is preferably oral. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg.

Advantageously, the composition will be made up in a dosage form appropriate to the preferred mode of administration for example, as a tablet or capsule, for oral administration.

The pharmaceutical compositions of the invention can be prepared by conventional techniques involving procedures for example, mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The invention is illustrated by the following Examples in which all temperatures are in degrees Centigrade: EXAMPLE 1 3-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-6- (3-methoxybenzyl)-1, 2, 4-triazin5-one i) m-Anisaldehyde (25.9 g), N-acetylglycine (15.2 g) and sodium acetate (7.8 g) were heated together under reflux in acetic anhydride (50 ml) for 3/4 hour. The mixture was allowed to cool, water (150 ml) was added and the mixture was filtered to give the crude azlactone (27.7 g) m.p. 145-150 . Hydrolysis with boiling 1N hydrochloric acid (450 ml) followed by cooling and ether extraction afforded 3-methoxyphenylpyruvic acid as a pale yellow oily solid (6.3 g).

ii) 3-Methoxyphenylpyruvic acid (2.1 g), thiosemicarbazide (0.98 g) and sodium hydroxide (1.5 g) were heated together at 70-75 in water (30 ml) for 1 hour. On cooling and acidification an oil was obtained which was chromatographed to give 6-(3-methoxybenzyl)1,2,4-triazin-3-thio-3,5-dione as a pale yellow solid. Recrystallisation from ethylacetatel benzene afforded the pure product, m.p. 140-41".

(Found: C, 53.1; H, 4.6; N, 16.8; S, 12.6; CllHllN302S requires: C, 53.0; H, 4.5; N, 16.9; S, 12.9%) iii) Sodium (0.34 g) was dissolved in ethanol (25 ml), 6-(3-methoxybenzyl)-1,2,4triazin-3-thio-3,5-dione (3.5 g) added and the solution was cooled in ice. Methyl iodide (2.1 g) was added and the mixture was stirred at room temperature for 1 hour after which time a further quantity of methyl iodide (0.5 g) and sodium ethoxide solution (equivalent to 0.05 g sodium) was added. The mixture was cooled overnight and filtered to give 3-methylthio-6 (3-methoxybenzyl)-l,2,4-triazin-5-one (2.5 g) m.p. 185-86". A further quantity was obtained from the mother liquor by evaporation to dryness and treating the residue with dilute hydrochloric acid.

iv) 3-Methylthio-6-(3-methoxybenzyl)-1 ,2 ,4-triazin-5-one (1.07 g) and 2-(5-methyl-4imidazolylmethylthio)ethylamine (0.77 g) were heated together on an oil bath (160-70 ) for 3h hour. The solidified mass was broken up under methanol (ca 15 ml) and boiled for 5 minutes. After cooling the white solid was filtered off and recrystallised from dimethylformamide to give the title compound as a colourless solid (0.65 g) m.p. 203-4".

(Found: C, 55.7; H, 5.7; N, 21.7; S, 8.3. Cl8H22N602S requires: C, 55.9; H, 5.7: N, 21.8; S, 8.3%) EXAMPLE 2 3-[2-Thiazolylmethylthio)ethylamino]-6-(3-methoxybenzyl)-1,2,4-triazin-5-one 3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.18 g) and 2-(2thiazolylmethylthio)ethylamine (0.87 g) were heated together on an oil bath (160400) for 3/4 hour. The resulting oil, after chromatography and crystallization from ethanol, gave the title compound is a colourless solid (0.88 g) m.p. 128-29 .

(Found: C, 52.4: H, 5.0; N, 18.0; S, 16.6; C17H19N502S2 requires: C, 52.4; H, 4.9; N, 18.0; S, 16.5%) EXAMPLE 3 3-[2-(5-Methyl-4-imidazolylmethylthio)-6-(3-pyridylmethyl)-1,2,4-triazin-5-one i) Pryidine-3-carboxaldehyde (92.6 g). N-acetylglycine (86.0 g) and sodium acetate (35.3 g) were heated together under reflux in acetic anhydride (150 ml) for 1 hour. After cooling, water (250 ml) was added and the mixture was filtered to give the crude azlactone (50.9 g) m.p. 155-60 . Partial hydrolysis of the azlactone (50 g) was achieved by heating under reflux in acetone (450 ml) and water (175 ml) for four hours. After this time the bulk of the acetone was distilled off and more water (300 ml) added. The resulting deep red solution was boiled with charcoal for 10 minutes and filtered through Celite. (The word Celite is a Registered Trade Mark). The filtrate was evaporated to dryness and the residue was triturated and washed with acetone to give 2-acetamido-3-(3-pyridyl)acrylic acid (35 g) m.p. 191-92 which was not further purified.

ii) 2-Acetamido-3-(3-pyridyl)acrylic acid (10.3 g) and thiosemicarbazide (4.55 g) were heated together under reflux in water (50 ml) for 42 hours. The mixture was cooled and filtered to give 6-(3-pyridylmethyl)-1,2,4-triazin-3-thio 3,5-dione (7.22 g) m.p. ca 280 (dec.) as a pale brown solid.

iii) Sodium (1.73 g) was dissolved in ethanol (40 ml), 6-(3-pyridylmethyl)-1,2,4-triazin3-thio-3.5-dione (6.6 g) was added and the mixture was cooled in ice. Methyl iodide (5.0 g) x as added and the mixture stirred for 30 minutes at room temperature. After evaporating to dryness the residue was taken up in water (50 ml), filtered, and the filtrate adjusted to pH 6-7 and cooled overnight. The resulting creamy solid was removed and recrystallised from methanol to give 3-methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (5.86 g) m.p.

' 1O-16 iv) 3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (2.34 g) and 2-(5-methyl-4imidazolylmethylthio)ethylamine (1.88 g) were heated together on an oil bath (160-70").

The cooled mixture was triturated with boiling methanol and the solid was recrystallised from dimethylformamide to give the title compound as a colourless solid (2.53 g) m.p.

'o'-233.

(Found: C, 53.7: H. 5.4; N, 27.3; S, 8.8, C16H19N70S requires: C, 53.8: H. 5.4; N, 27.4; S, 9.0%) EXAMPLE 4 3-[2-(2-Thiazolylmethylthio)ethylamino]-6-(3-pyridylmethyl)4,2, 4-triazi-5-one 3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (3.28 g) and 2-(2- thiazolylmethylthio)ethylamine (2.7 g) were heated together on an oil bath (160-170 ) for 1 hour. The cooled mixture was triturated with isopropanol and the solid was twice recrystallised from ethanol to give the title compound as pale yellow plates (3.1 g) m.p.

158-59".

(Found: C, 50.0; H, 4.6; N. 23.5; S, 17.6; C15N16N6520 requires: C, 50.0; H, 4.5; N, 23.3; S, 17.8%) EXAMPLE 5 3-[2- (3-Bromo-2-pvridylm ethylth io) ethylamino]-6- (3-pyridylmethyl)-1,2,4-triazin-5-one Substitution of 2-(3-bromo-2-pyridylmethylthio)ethylamine for '-(5-methyl-4 imidazolylmethylthio)ethylamine in the procedure of Example 3 (iv) gives the title product.

EXAMPLE 6 3-[2- (3-Bromo-2-pyridylmethylthio) ethylamino]-6- (3-methoxybenzyl) -1, 2, 4-triazin-5-one Substitution of 2-(3-bromo-2-pyridylmethylthio)ethylamine for 2-(5-methyl-4imidazolylmethylthio)ethylamine in the procedure of Example 1(iv) gives the title product.

EXAMPLE 7 Substitution of the following aldehydes: (a) Naphthalene-1-carboxaldehyde (b) Naphthalene-2-carboxaldehyde (c) 2,3-Dihydro-1 ,4-benzodioxin-6-carboxaldehyde (d) 1 ,3-Benzodioxole-5-carboxaldehyde (e) 3-Methylbenzaldehyde (f) 4-Methoxybenzaldehyde (g) 3,4-Dimethoxybenzaldehyde (h) 3-Chlorobenzaldehyde (i) 3-Benzyloxybenzaldehyde (j) 3-Trifluoromethylbenzaldehyde (k) 3-(Dimethylamino)benzaldehyde (1) 3-Phenoxybenzaldehyde (m) 3-(4-Chlorophenoxy)benzaldehyde (n) 3-(4-Methoxyphenoxy)benzaldehyde (o) 3-Phenylbenzaldehyde (p) 3-(4-Chlorophenyl)benzaldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of: (a) 3-J2-(5-methyl-4-imidazolylmethylthio) ethylaminoj-6-( 1-naphthylmethyl) -1,2,4- tnazin-5-one (b) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(2-naphthylmethyl)-1 ,2,4- triazin-5-one (c) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(6-(2,3-dihydro-1 ,4- benzodioxinyl)-1,2,4-triazin-5-one (d) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(5-(1 ,3-benzodioxolyl)-1 ,2 4- triazin-5-one (e) 3-[2- (5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-methylbenzyl)-1 ,2,4- triazin-5-one (f) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(4-methoxybenzyl)-1 ,2,4- triazin-5-one (g) 3- [2-(5-methyl-4-imidazolylmethylthio) ethylaminoj-6-(3 ,4-dimethoxybenzyl)- 1,2,4-triazin-5-one (h) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-chlorobenzyl)-1,2,4- triazin-5-one (i) 3-2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-benzyloxybenzyl)-1 ,2 ,4- triazin-5-one (j) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-trifluoromethylbenzyl)- 1,2,4-triazin-5-one (k) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3- (dimethylamino)benzyl)- 1,2,4-triazin-5-one (1) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6- (3-phenoxybenzyl)- 1,2,4 triazin-5-one (m) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-(4- chlorophenoxy)benzyl)-1 2 ,4-triazin-5-one (n) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-(4- methoxyphenoxy)benzyl)-1 ,2 ,4-triazin-5-one (o) 3- [2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-phenylbenzyl)-1 ,2,4- triazin-5-one (p) 3- 2- (5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-(4-chlorophenyl)benzyl)- 1,2,4-triazin-5-one EXAMPLE 8 Treatment of 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-methoxybenzyl)- 1,2,4-triazin-5-one with an excess of boron tribromide leads to the production of 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-hydroxybenzyl)-1 ,2,4-triazin-5- one.

EXAMPLE 9 Substitution of 3- (methoxymethoxy)benzaldehyde for pyridine-3-carboxaldehyde in the procedure of Example 3 leads to the production of 3-[2-(5-methyl-4- imidazolylmethylthio)ethylaminoj-6-(3-methoxymethoxybenzyl)-I ,2,triazin-5-one.

EXAMPLE 10 Substitution of a) furan-2-carboxaldehyde b) thiophene-2-carboxaldehyde c) thiazole-2-carboxaldehyde d) oxazaTe-2-carboxaldehyde (e) isothiazole-3-carboxaldehyde (f) pyrimidine-2-carboxaldehyde (g) pyrimidine-5-carboxaldehyde (h) pyrazine-2-carboxaldehyde (i) pyridazine-4-carboxaIdehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of (a) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminol-6-(2-furylmethyl)-1,2,4-triazin- 5-one (b) 3-[2-(5-methyl-4-imidazolySmethylthio)ethylaminol-6-(2-thienylmethyl)-1,2,4- triazin-5-one (c) 3- [2- (5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(2-thiazolylmethyl)-1 ,2, 4- triazin-5-one (d) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(2-oxazolylmethyl)-1 2,4- triazin-5-one (e) 3-[2-(5-methyl-4-imidazolylmethykhio)ethylaminoj-6-(3-isoxazolylmethyl)-1 ,2 ,4- triazin-5-one (f) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminol-6-(2-pyrimidylmethyl)-1,2,4- triazin-5-one (g) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino}-6-(5-pyrimidylmethyl)-1 ,2 ,4- triazin-5-one (h) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(2-pyrazylmethyl)-1 2,4- triazin-5-one (i) 3-[2- (5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(4-pyridazylmethyl) - 1,2,4- triazin-5-one EXAMPLE 11 Substitution of 1-(4-methoxybenzyl)-2-imidazole carboxaldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of 3-[2-(5-methyl-4 imidazolylmethylthio)ethylamino-6-( 1-(4-methoxybenzyl)-2-imidazolylmethyl)-1 2,4- triazin-5-one, which when treated with anisole and hydrogen bromide in acetic acid gives 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(2-imidazolylmethyl)-1,2,4-triazin-5- one EXAMPLE 12 Substitution of 2-oxo-4-phenylbutyric acid for 3-methoxyphenylpyruvic acid in the general procedure of Example 1 (ii-iv) leads to the production of 3-[2-(5-methyl-4imidazolylmethylthio)ethylamino]-6-(3-phenylpropyl)-1,2,4-triazin-5 one EXAMPLE 13 Substitution of (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-(4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)ethylamine (c) 2% {5Sb0Oto4y1f4llt%1lyth1O)thy(l}y1 (e) 2- 5-hydroxymethyl-4-imidazolylmethylthio)ethylamine (f) 2-2-pyridylm ethylthio)ethylamine (g) 2-(3-methyl-2-pyridylmethylthio)ethylamine (h) 2-(3-methoxy-2-pyridylmethylthio)ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)ethylamine (j) 2-(3-amino-2-pyridylmethylthio)ethylamine (k) 2- 3-hydroxy-2-pyridylmethylthio)ethylamine (1) 2- 3-isothiazolylmethylthio)ethylamine (m) 2- 4bromo-3-isothiazolylmethylthio)ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamine (o 2-(4-chloro 3-(1,2,5)-thiadiazolylmethylthio)ethylamine (P 2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)ethylamine for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure of Example 3 (iv) leads to the production of: (a) 3- 2-(2-imidazolylmethylthio)ethylamino -6- 3-pyridylmethyl -1,2,4-triazin-5-one (b) 3- 2-(4-imidazolylmethylthio(ethylamino]-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (c) 3- 2-(5-bromo-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-1,2,4- triazin-5-one (d) 3-[2-(5-trifluoromethyl-4-imidazolylmethylthio)ethylamino]-6-(3-pyridylmethyl)- 1,2,4-triazin-5-one (e) 3-[2-(5-hydroxymethyl-4-imidazolylmethylthio)-ethylamino]-6-(3-pryidylmethyl)- 1,2,4-triazin-5-one (f) 3-[2-(2-pyridylmethylthio)ethylamino]-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (g) 3-12-(3-methyl-2-pyridylmethylthio EXAMPLE 15 Treatment of a solution of 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3- methoxybenzyl)-1,2,4-triazin-5-one with two equivalents of (a) hydrochloric acid (b) hydrobromic acid or (c) sulphuric acid leads to the production of (a) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(3-methoxybenzyl) 1,2,4- triazinone dihydrochloride (b) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-methoxybenzyl)-1 ,2,4- triazinone dihvdrobromide.

(c) 3-[2-(5-methyl-imidazolylmethykhio) ethylaminoj-6-(3-methoxybenzyl)-1 ,2 ,4- triazinone sulphate EXAMPLE 16 Substitution of the following aldehydes: (a) 3-methoxybenzaldehyde (b) 6-methyl-3-pyridinecarboxaldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of : (a) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(3-methoxybenzyl)- 1,2,4- triazin-5-one (b) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(6-methyl-3-pyridylmethyl)- 1,2,4-triazin-5-one EXAMPLE 17 Substitution of the following aldehydes: (a) 2-(2-furyl)acetaldehyde (b) 3-(5-methyl-2-furyi)propionaldehyde (c) 2-(2-pyridyl)acetaldehyde (d) 4-(2-pyridyl)butyraldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of: (a) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(2-(2-furyl)ethyl)-1 2,4- triazin-5-one (b) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(3-(5-methyl-2-furyl)propyl)- 1 ,2,4-triazin-5-one (c) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(2-(2-pyridyl)ethyl)-1 2,4- triazin-5-one (d) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(4-(2-pyridyl)butyl)-1 ,2,4- triazin-5-one EXAMPLE 18 Substitution of the following aldehydes: (a) 2-(phenyl)propionaldehyde (b) 4-(phenyl)butyraldehyde (c) 5-(phenyl)valeraldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of: (a) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylaminoj-6-(2-phenylethyl)-l 2,4-triazin- 5-one (b) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(4-phenylbutyl)-1 2 ,4-triazin- 5-one (c) 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(5-phenylpentyl)- 1,2,4 triazin-5-one EXAMPLE 19 Reaction of (a) 3-bromo-2-hydrox methyl-4-methylpridine (b) Chydroxymethyl-(i ,3)-dioxolot4,5-Clpyridine (c) 2,3-dihydro-5-hydroxymethyl(p-dioxino-[2,3-C]pyridine) (d) 3 ,4-dimethoxy-2-hydroxymethylpyridine (e) 5,6,7,8-tetrahydro-1-(hydroxymethyl)-isoquinoline (f) 1-(hydroxymethyl)isoquinoline with cysteamine hydrobromide in hydrobromic acid gives the corresponding 2aminoethylthiomethyl derivatives which may be substituted for 2-(5-methyl-4imidazolylmethylthio)-ethylamine in the procedure of Example 1 (iv) to give: (a) 3-[2-(3-bromo-4-methyl-2-pyridylmethylthio)ethylamino]-6-(3-methoxybenzyl)- 1,2,4-triazin-5-one (b) 3-[2-(4-(1,3-dioxolo[4,5-C]pyridyl)methylthio)-ethylamino]-6-(3-methoxybenzyl)- 1,2,4-triazin-5-one (c) 3-[2-(5-(2,3-dihydro-p-dioxino[2,3-C]pyridyl)methylthio)ethylamino]-6-(3- methoxybenzyl)-1 ,2,4-triazin-5-one (d) 3-[2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamino]-6-(3-methoxybenzyl)-1,2,4- triazin-5-one (e) 3-[2-(5,6,7,8-tetrahydro-1-isoquinolylmethylthio)-ethylamino}-6-(3- methoxybenzyl)-1,2 ,2,4-triazin-5-one EXAMPLE 20 Pharmaceutical composition: Ingredients Amounts 3-[2-(5-methyl-4-imidazolylmethylthio) ethylamino]-6-(3-methoxybenzyl)1 ,2,4 triazinone 100 mg Sucrose 100 mg Starch 30 mg Talc 7 mg Stearic Acid 2 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.

EXAMPLE 21 Pharmaceutical composition: Ingredients Amounts 3-[2-(5-methyl-4-imidazolylmethylthio)- ethylamino]-6-(3-methoxybenzyl)-l ,2,4 triazinone 150 mg Lactose 100 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.

Similarly, the other compounds of Formula 3 may be formulated into pharmaceutical compositions by the procedures of Examples 20 and 21.

The pharmaceutical compositions prepared in the foregoing examples are administered to a subject within the dose ranges given hereabove to block histamine H1- and H2 - receptors.

WHAT WE CLAIM IS: 1. A triazinone derivative of the formula (3):

wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by one or two groups selected from lower alkyl, lower alkoxy, halogen, amino and hydroxy, a 2-pyridyl ring with a phenyl, carbocyclic or cyclic ether ring containing 2 oxygen atoms fused to it, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)-thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino- 1,3,4-thiadiazolyl)ring; Z' is sulphur or a methylene group; x is 1 to 5; Y is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring substituted with one or more alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(lower alkyl)amino, phenoxy, halophenoxy, alkoxyphe noxy, phenyl, halophenyl or alkoxyphenyl groups, a 5 or 6 membered aromatic heterocycle, which ring is optionally substituted by lower alkyl, lower alkoxy or has a benzene ring fused to it, or when x is other that 1, Y may also be phenyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

methoxybenzyl)-1 ,2,4-triazin-5-one (d) 3-[2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamino]-6-(3-methoxybenzyl)-1,2,4- triazin-5-one (e) 3-[2-(5,6,7,8-tetrahydro-1-isoquinolylmethylthio)-ethylamino}-6-(3- methoxybenzyl)-1,2 ,2,4-triazin-5-one EXAMPLE 20 Pharmaceutical composition: Ingredients Amounts

3-[2-(5-methyl-4-imidazolylmethylthio) ethylamino]-6-(3-methoxybenzyl)1 ,2,4 triazinone 100 mg Sucrose 100 mg Starch 30 mg Talc 7 mg Stearic Acid 2 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.

EXAMPLE 21 Pharmaceutical composition: Ingredients Amounts 3-[2-(5-methyl-4-imidazolylmethylthio)- ethylamino]-6-(3-methoxybenzyl)-l ,2,4 triazinone 150 mg Lactose 100 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.

Similarly, the other compounds of Formula 3 may be formulated into pharmaceutical compositions by the procedures of Examples 20 and 21.

The pharmaceutical compositions prepared in the foregoing examples are administered to a subject within the dose ranges given hereabove to block histamine H1- and H2 - receptors.

WHAT WE CLAIM IS: 1. A triazinone derivative of the formula (3):

wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by one or two groups selected from lower alkyl, lower alkoxy, halogen, amino and hydroxy, a 2-pyridyl ring with a phenyl, carbocyclic or cyclic ether ring containing 2 oxygen atoms fused to it, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)-thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino- 1,3,4-thiadiazolyl)ring; Z' is sulphur or a methylene group; x is 1 to 5; Y is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring substituted with one or more alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(lower alkyl)amino, phenoxy, halophenoxy, alkoxyphe noxy, phenyl, halophenyl or alkoxyphenyl groups, a 5 or 6 membered aromatic heterocycle, which ring is optionally substituted by lower alkyl, lower alkoxy or has a benzene ring fused to it, or when x is other that 1, Y may also be phenyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring

optionally substituted by lower alkyl, lower alkoxy, halogen, amino or hydroxy, a 2-thiazolyl ring, a 34soth-iazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)-thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino- 1,3,4-thiadiazolyl) ring.
3. A compound according to claim 1 or claim 2 wherein Het' is a 2-thiazolyl, S-methyl-4imidazolyl, S-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl, 3methoxy-2-pyridyl or 3-hydroxy-2-pyridyl ring.
4. A compound according to any one of claims 1 to 3 wherein Z' is sulphur.
5. A compound according to any one of claims 1 to 4 wherein x is 1.
6. A compound as claimed in any one of claims 1 to 5 wherein Y is a pyridine, furan, thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine ring, which ring is optionally substituted by lower alkyl, lower alkoxy or may have a benzene ring fused to it.
7. A compound according to any one of claims 1 to 6 wherein Y is a phenyl group substituted by one or two lower alkoxy groups, a 2,3-dihydro-1,4-benzodioxinyl ring, a 1,3-benzodioxolyl ring, or a 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-thiazolyl ring.
8. A compound according to any one of claims 1 to 7 wherein Y is 3-methoxyphenyl, 4-methoxyphenyl, 3 4-dimethoxyphenyl or 6-methyl-3-pyridyl.
9. 3-[2-(5-Methyl-4-imidazolyhnethylthioethylamino-6-(3-methoxybenzyl)-1.2.4 triazin-S-one.
10. 3-[2-(5-Methyl-4-imidazolylmethylthioethylamino]-6-(3-pyridylmethyl)-1,2,4- triazin-S-one.
11. 3-[2-(2-Thiazolylmethylthio)ethylamino-6-(3-methoxy-benzyl)-1,2,4-triazin-5-one.
3-2-2-Thiazolylmethylthio)ethylamino -6-3-pyridylmethyl)-1,2,4-triazin-5-one.
13. 3-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-6-(3-pyridylmethyl)-1,2,4-triazin5-one.
14. 3-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-6-(3-methoxybenzyl)-1,2,4-triazin- 5-one.
15. A process for preparing a compound according to any one of claims 1 to 14 which comprises reacting a triazinone of the formula (4):

wherein x and Y are as defined in claim 1 and Q is a group which is displaceable by an amine, with an amine of formula Het'-CH2-Z'-(CH2)2NH2.
16. A process according to claim 15 wherein Q is lower alkylthio.
17. A process for preparing a compound of claim 2 substantially as hereinbefore described in any of Examples 1 to 15.
18. A compound according to claim 1 whenever prepared by a process according to claim 15 or 16.
19. A compound according to claim 2 whenever prepared by a process according to claim 17.
20. A compound according to claim 1 as hereinbefore described in any one of Examples 1 to 15.
21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and 18 to 20 in combination with a pharmaceutically acceptable diluent or carrier.
22. A pharmaceutical composition according to claim 21 in dosage unit form adapted for oral administration.
23. A pharmaceutical composition according to claim 21 or claim 22 comprising a compound according to any one of claims 8 to 12, in combination with a pharmaceutically acceptable diluent or carrier.