IE46967B1 - Triazinones - Google Patents

Description

This invention relates to certain triazinone derivatives and to a process for their preparation.

Our Patent Specification No. 46966 discloses and claims certain triazinone derivatives which have histamine H-j as well as histamine Hg antagonist activity. The compounds of this invention are useful as intermediates in the preparation of these triazinones.

Accordingly the present invention provides compounds of formula (4) where x is 1 to 5, Y is a 1- or 2-naphthyl group, a 2,3-dihydro-l,4-benzodioxinyl or a 1,3-benzodioxolyl group, a phenyl group substituted with one or more alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, tri fluoromethyl, di(lower alkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups, a 5-or 6- membered heterocyclic group for example a pyridyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, imidazolyl, pyrimidyl, pyrazinyl or pyridazinyl group 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, and Q is lower alkylthio or benzylthio.

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

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 2,3-dihydro1,4-benzodioxinyl group, a 1,3-benzodioxolyVgroup, or a 2- pyridyl, 3-pyridyl, 6-methy 1-3-pyridyl, 4-pyridyl or 2-thiazolyl group.

Specific compounds of formula (4) are :3-methylthio-6-(3-methoxybenzyl)-l,2,4-triazin-5-one and 3- methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one.

The compounds of formula (4) can be prepared by reacting a compound of formula (8) :- where x and Y are as defined with reference to formula (4) with a lower alkyl halide or sulphate under alkaline conditions or with a benzyl halide.

The compounds of formula (8) can be prepared by the following 5 general scheme :- (7) 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).

Alternatively, the compounds of formula (8) can be prepared by treating a pyruvic acid of formula YfCHg^.-j-COCOgH (which may be prepared by acid hydrolysis of an azlactone of formula (6)J 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 following Examples illustrate the invention :EXAMPLE 1 (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 15 (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°C. Hydrolysis with boiling IN 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°C in water (30 ml) for 1 hour. On cooling and acidification an oil was obtained which was chromatographed to give 6-(3-methoxybenzyl)- T,2,4-triazin-3-thio-3,5-dione as a pale yellow solid.

Recrystallization from ethylacetate/benzene afforded the pure product, m.p. 140-141°C.

(Found : C, 53.1; H, 4.6; N, 16.8; S, 12.6; 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)-l,2,4-triazin-3-thio-3,5-dione (3.5 g) added and the solution, was cooled:in tee. 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 sodium) was added. The mixture uas cooled overnight and filtered to give 3-methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (2.5 g) m.p. 185-186°C. A further quantity was obtained from the mother liquor by evaporation to dryness and treating the residue with dilute hydrochloric acid.

EXAMPLE 2 Pyridine-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. 155-160°C. 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)acry1ic acid (35 g) m.p. 191-192°C 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°C (dec.) as a pale brown solid. (iii) Sodium (1.73 g) was dissolved in ethanol (40 ml), 6-(3-pyridylmethyl)-l,2,4-triazin-3-thio-3,5-dione (6.6 g) was added and the mixture was cooled in ice. Methyl iodide (5.0 g) was added and the mixture stirred for 30 minutes at room temperature. After evaporat15 ing 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 crearny solid was removed and reerystallised from methanol to give 3-methylthio-6-(3-pyridylmethyl)-1,2,4-triazinT5-one (5.86 g) m.p. 215216°C.

Claims (9)

1. A compound of formula (4) :- where x is 1 to 5; Y is a 1- or 2-naphthyl group, a 2,3-dihydro5 1,4-benzodioxinyl ora 1,3-benzodioxolyl group, a phenyl group 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 heterocyclic group, which 10 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; and Q is lower alkylthio or benzylthio.

2. A compound as claimed in claim 1 where the optionally substituted 5- or 6- membered heterocyclic group is a pyridyl, furanyl, thienyl, 15 thiazolyl, oxazolyl, isothiazolyl, imidazolyl, pyrimidyl, pyrazinyl or pyridazinyl optionally substituted by lower alkyl, lower alkoxy or having a benzene ring fused to it.

3. A compound as claimed in claim 1 or claim 2 where x is 1.

4. A compound as claimed in any one of the claims 1 to 3 where Y is a phenyl substituted with one or two lower alkoxy groups, or a 2,3-dihydro-1,4-benzodioxinyl group.

5. A compound as claimed in claim 4 where Y is 3-methoxyphenyl, 4-methoxyphenyl, or 3,4-dimethoxyphenyl.

6. A compound as claimed in any one of claims 1 to 3 where Y is 2-pyridyl, 3-pyridyl, 5-methyl-3-pyridyl, 4-pyridyl or 2-thiazolyl group.

7. A compound as claimed in any one of claims 1 to 6 where is lower alkylthio. A compound as claimed in claim 7 where Q is methylthio. 3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one. 3-Methylthi0-6-(3-pyridyImethyl)-1,2,4-triazin-5-one. A process for preparing a compound as claimed in claim 1 which comprises reacting a compound of formula (8) :0 (cn 2 ) x Y (8) where x and Y are as defined with reference to formula (4) with a lower alkyl halide or sulphate under alkaline conditions or with a benzyl halide.

8. 12. A process as claimed in claim 11 substantially as described in Example 1 or 2 herein.

9. 13. A compound as claimed in claim 1 whenever prepared by a process as claimed in claim 11 or claim 12.