US3840537A

US3840537A - Imidazo(5,1-f)triazinones

Info

Publication number: US3840537A
Application number: US00300749A
Authority: US
Inventors: S Garside; D Hartley; H Lunts; A Oxford
Original assignee: Allen and Hanburys Ltd
Current assignee: Allen and Hanburys Ltd
Priority date: 1971-11-19
Filing date: 1972-10-25
Publication date: 1974-10-08
Anticipated expiration: 1991-10-08
Also published as: AU4819172A; FR2160407B1; AT321923B; NL7215646A; FR2160407A1; JPS4857993A; JPS563873B2; PH9669A; AU472127B2; SE402915B; BE791025A; IL40686A; DK138691C; IE37046L; IL40686A0; GB1400999A; CH594671A5; ZA727532B; DE2255172A1; ES408736A1

Abstract

1. A A COMPOUND OF THE FORMULA I:

2-(R1-N(-R2)-),3-R3,4-(O=),5-R4,7-R5-IMIDAZO(5,1-F)

TRIAZINE

OR A PHYSIOLOGICALLY ACCEPTABLE SALT THEREOF WHEREIN R2 AND R3 MAY BE THE SAME OR DIFFERENT AND EACH REPRESENTS A HYDROGEN ATOM OR A STRAIGHT OR BRANCHED CHAIN ALKYL OR ALKENYL RADICAL CONTAINING FROM 1 TO 6 CARBON ATOMS OR SUCH A RADICAL SUBSTITUTED BY AT LEAST ONE PHENYL GROUP, R1 IS AS DEFINED FOR R2 AND R3 OR A C1-C6 ALKANOLY GROUP, AND R4 AND R5 ARE AS DEFINED FOR R2 AND R3 OR A C3-C7 CYCLOALKYL, OR PHENYL GROUP.

Description

" United States Patent Offlce 3,840,537 Patented Oct. 8, 1974 U.S. Cl. 260-2495 21 Claims ABSTRACT OF THE DISCLOSURE Compounds of the general formula I:

and physiologically acceptable salts thereof, wherein R R R R and R may be the same or diflerent and each represent a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms, which may optionally be substituted by one or more aryl groups. R, in addition may represent an acyl (C -C group and R and R may independently represent a cycloalkyl, arylalkyl or aryl group. These compounds act as spasmolytics and phosphodiesterase inhibitors.

This invention relates to certain heterocyclic compounds having pharmacological activity and to processes for the preparation thereof as well as pharmaceutical compositions containing them.

We have found that certain imidazo [5,1-f] triazinones act as spasmolytics and phosphodiesterase inhibitors and have cardiotonic and diuretic properties. They are therefore particularly useful in the treatment of diseases involving constriction of bronchial muscle, for example asthma and bronchitis and also for the treatment of pulmonary oedema and congestive heart failure. The compounds may also be useful in the treatment of skin diseases, for example psoriasis.

The present invention therefore provides compounds of the general formula I:

and physiologically acceptable salts thereof, wherein R R R R and R may be the same or different and each represent a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms, which may optionally be substituted by one or more aryl groups. R in addition may represent an acyl (C -C group and R and R may independently represent a cycloalkyl, arylalkyl or aryl group.

Compounds of the general formulae may exist in several tautomeric forms and these are included within the scope of the invention.

Preferred compounds are those in which R represents hydrogen or acyl (C R represents hydrogen, R represents hydrogen or lower alkyl (C R represents hydrogen or lower alkyl (C and R represents lower alkyl (C cycloalkyl (C aryl or arylalkyl (C alkyl). In a particular class of compounds R R and R all represent hydrogen. Preferred compounds are those whose preparation is described in the Examples.

The activity of these compounds is demonstrated by their action in the guinea pig in reducing bronchospasm induced by spasmogens such as histamine, S-hydroxytryptamine and acetylcholine according to standard test procedures. [Konzett, H, and Rossler, R. (1940). Versuchsanordung zu Untersuchungen an der Bronchial musculatur. Arc. exp. Patho. PharmakoL, 195, 71-74]. For instance, 2-amino 5 methyl-7-propylimidazo [5,1-f]-astriazin-4(3H)one, hydrochloride is more active than standard non-adrenergic bronchodilators, such as choline theophyllinate. This effect is even more apparent in preparations of the isolated trachea of the guinea pig, in response to challenge with acetylcholine. The results of these tests are shown in the Table below:

guinea pig trachea.

The compounds of the invention are inhibitors of the enzyme phosphodiesterase. For instance, at a concentration of 5 10 M, 2 amino-5-methyl-7-propyl-imidazo [5,l-f] -as-triazin-4(3-H)-one, hydrochloride is 8 times more potent than choline theophyllinate in inhibiting the degradative action of this enzyme on cyclic adenosine monophosphate, a humoral agent important in bronchodilator mechanisms.

The compounds according to the invention may be formulated for use in human and veterinary medicine for therapeutic and prophylactic purposes. They will in general be used in the form of their physiologically acceptable salts. Preferred salts include the hydrochloride, sulphate, maleate, tartrate,. etc. Such compounds may be presented for use in the conventional manner with the aid of carriers or excipients and formulating agents as required, and with or without supplementary medicinal agents.

The compositions may include solid and liquid preparations for oral use, suppositories or injections, or forms suitable for administration by inhalation. Oral administration is most convenient in the form of tablets. Injections may be formulated with the aid of physiologically acceptable carriers and agents as solutions, suspensions or as dry products for reconstitution before use. For administration by inhalation the compounds according to the invention are conveniently delievered in the form of an aerosol spray presentation from pressurised packs or a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. A typical dose for treating asthma in humans is from 1-200 mg. depending on the age, weight and condition of the patient and the route of administration.

The compounds according to the invention may be formulated in combination with compounds such as salbutamol and isoprenaline that have stimulant activity at B adrenoreceptors. These combinations, as exemplified by Z-amino-S-methyl-7-propyl-imidazo[5,l-f] as triazin- 4(3H)-one and salbutamol, are more effective than the sum of the two active ingredients given separately and the compounds are therefore synergistic. The preceding combination was about 2.5 times more potent than pred-icted from the individual dose response curves. The provision of therapeutic compositions comprising as active ingredients, a compound according to the invention and a p-adrenoreceptor stimulant, in particular salbutamoi, represents an aspect of the present invention.

The compounds according to the invention may be prepared by a number of processes. In one of these an amino guanidine II or an appropriate salt, e.g. hydrogen carbonate, is condensed with an a-ketoester III to yield the as-triazinone ester -IV. The N-benzyl derivative V of the last mentioned compound is then converted into an amine VII, for example by Curtius degradation via the corresponding hydrazine VI or by Hofiman degradation of the amide. The amine VII may then be acylated by conventional procedures, e.g. using acid halides or anhydrides to give the intermediate VIII. This amide is then cyclised by refluxing with a cyclodehydrating agent e.g. phosphorus oxychloride, with concomitant removal of the protecting group. The sequence is shown in the chart.

CHART NH: AlkOOC R4 COOAlk RIRZN 11 In 0 R4 HMGOOAK N R R N- i 2 \N/ IV 114 I COOAlk a N1 mam-Ka dnirn v t Ijfiq CONHNHQ RlR2N dnirn VI if NHz N RrRzN \N/ damn VII 9 N LK NH :0R5

damn

HN Nnoom R RzN N vrrr VIIIa *In the Provisional Specification we had suggested that the protective benzyl group was positioned on the oxygen atom at 0-5. We now know that this is incorrect and that reaction had occurred with one of the several other tautomers of the triazinone (IV) to give the N-2 benzyl compounds (V) shown. This minor structural correction does not alter the designed function of the benzylation which is to prevent premature cyclisation on to the triazine ring. The course of the synthetic process is unaffected although the nomenclature of the intermediate in some of the examples difiers from that used in the Provision Specification.

lPPA

Alternatively the final step can be carried out in two stages in which the benzyl group is first removed e.g. b'y hydrogenolysis in the presence of noble metal catalyst, and the triazinone VIIIa is then converted into IX by heating with a cyclodehydrating compound e.g. polyphosphoric acid.

Compounds of the invention in which R /R are other than hydrogen are best prepared by a related process in which the keto ester III is first condensed with thiosemicarbazide to give the thione X. The last is converted into the alkylthioether XI with an alkyl halide and a base such as sodium hydroxide in the presence of a solvent, and the N-benzyl derivative XII is formed as before. The mercapto group can then be displaced by heating with an amine vR R NH to give the intermediate V of the general synthesis:

Hm OaAlk l IT/YKC ozAlk l CHaPh XII Compounds of the invention where R is other than hydrogen may be prepared from compounds of general formula VIII and conventional alkylating agents R X, where X may be for example, halogen or tosylate in the presence of a strong base, for example sodium hydride and in a suitable solvent e.g. N,N-dimethylformamide.

The resulting imine XIII then undergoes hydrogenolysis and cyclodehydration as before.

RzN N (iHiPh The following Examples illustrate the invention:

'EXAMPLE 1 3-Amino-2,S-dihydrQ-a-methyI-S-oxo-as-triazine-6- acetic acid, ethyl ester XIII EXAMPLE 2 3-Amino-2-benzyl-2,S-dihydro-a-methyl-5-oxo-asttriazine-6-acetic acid, ethyl ester A mixture of 3 amino 2,5-dihydro-a-methyl-5-oxo-as triazine-6-acetic acid, ethyl ester (2.0 g.), benzyl chloride (1.3 g.), potassium carbonate (1.6 g.) and sodium iodide (0.5 g.) in butanone (100 ml.) was refluxed with stirring for 2 days. The mixture was filtered, and the filtrate was evaporated under reduced pressure to yield a yellow oil which was dissolved in ethyl acetate and washed with water. The ethyl acetate solution was dried (MgSO and evaporated to give a yellow oil, which on trituration with a mixture of ether, light petroleum (b.p. 40-60") and ethyl acetate gave a white solid, m.p. 14l-143. Recrystallisation from ethyl acetate yielded white microcrystals, m.p. l51152.

By a similar procedure 3-amino-2,S-dihydro-S-oxo-astriazine-6-acetic acid, ethyl ester was converted into 3- amino-2-benzyl-2,5 dihydro 5 oxo-as-triazine-G-acetic acid, ethyl ester, m.p. 188 (from ethyl acetate) and 3-amino 2,5-dihydro 5-oxo-a-propyl as triazine-6- acetic acid, ethyl ester was converted into 3-amino-2-benzyl-2,5-dihydro 5 oxo-a-propyl-as-triazine-6-acetic acid, ethyl ester, m.p. 128129 (from ethyl acetate).

EXAMPLE 3 3-Amino-2-benzyl-2,5-dihydro-a-methyl-5-oxoas-triazine-6-acetic acid, hydrazide 3-Amino 2 benzyl 2,5-dihydro-a-methyl-5-oxo-astriazine-6-acetic acid, ethyl ester (7.5 g.) in methanol (100 ml.) and hydrazine hydrate (100 ml.) was allowed to stand for 3 days. Evaporation of the solvents under reduced pressure and crystallisation of the residue from methanol yielded white needles, m.p. 246 C.

By a similar procedure 3-amino-2-benzyl-2,S-dihydro- 5-oxo-as-triazine-6-acetic acid, ethyl ester was converted into 3-amino-2-benzyl-2,S-dihydro 5 oxo as triazine- 6-acetic acid, hydrazide, m.p. 249-251 (dec.) (from ethanol) and 3-amino-2-benzyl 2,5 dihydro 5 oxoa-propyl as triazine 6 acetic acid, ethyl ester was converted into 3-amino 2 benzyl-2,5-dihydro 5 oxo-apropyl-as-triazine 6 acetic acid, hydrazide, m.p. 238- 239.

EXAMPLE 4 3-Amino-2-benzyl-2,5-dihydro-a-methyl-5-oxo as-6-acetic acid amide A solution of 3-amino-2-benzyl-2,5-dihydro-a-methyl- 5-oxo-as-triazine-6-acetic acid, ethyl ester (5 g.) in methanol (120 ml.) and aqueous ammonia (d 0.88, 360 ml.) was allowed to stand at room temperature for 5 days. The amide separated as a white solid, m.p. 272274 (2.6 g.). Concentration of the filtrate to ca. 150 ml. afiorded a second crop, m.p. 268269 (0.75 g.). Recrystallisation from aqueous dimethylformamide (1:2) gave material m.p. 271-273".

EXAMPLE 5 3-Amino-6- l-aminoethyl -2-benzyl-as-triazine- 5(2H)-0ne Method A A solution of 3-amino 2 benzyl 2,5-dihydro-a-methyl-5-oxo as triazine 6 acetic acid, hydrazide (80 g.) in concentrated hydrochloric acid (52.8 ml.) and water (800 ml.) was cooled to 8 and a solution of sodium nitrite (20.46 g.) in water (400 ml.) was added dropwise over 20 minutes keeping the temperature below 10. The mixture was stirred below 10 for 45 minutes, concentrated hydrochloric acid (80 ml.) was added and the temperature then raised to 60 whereupon the solid dissolved. The solution was maintained at 60 for 1 hour then cooled to 10 and sodium hydroxide (53.5 g.) was added over minutes keeping the temperature below The diamine separated as a White solid, m.p. 244246 (48-54 g.).

By a similar procedure 3-amino-2-benzyl-2,S-dihydro- 5-oxo-as-triazine 6 acetic acid, hydrazide was converted into 3-amino-6-aminomethyl 2 benzyl as triazine- 5 (2H)-one, m.p. 195.5-197.5 and 3-amino-2-benzyl-2,5- dihydro 5 oxo-a-propyl-as-triazine-6-acetic acid, hydrazide was converted into 3-amino-6-(l-aminobutyl)-2- benzyl-as-triazin-S-(ZH)-one, m.p. 216-218 (from ethanol).

Method B 3-Amino 2 benzyl- 2,5 dihydro-a-metl'iyl-5-oxo-as triazine-6-acetic acid, amide (0.68 g.) was added to a stirred ice cold solution of sodium of sodium hypobromite prepared by adding bromine (0.24 ml.) to an ice cold solution of sodium hydroxide (0.72 g.) in water (6 ml.). The solid dissolved after 20 minutes and the solution was stirred for 4 hours at room temperature. Eifervescence occurred on acidification, and after basification with sodium hydroxide and cooling, the diamine crystallised out, m.p. 247248 (0.3 g.).

EXAMPLE 6 N-[ 1- (3-Amino-2-benzyl-2,S-dihydro-S-oxo-as triazin-6-yl)ethyl] butyramide Method A Butyric anhydride (57.5 ml.) was added to a stirred suspension of 3-amino-6-(l-aminoethyl)-2-benzyl as-triazin-5(2H)-one g.) in dioxan (800 ml.) at room temperature. Stirring was continued for 2 hours. The solution was then diluted with ether and the product collected m.p. 174 (103 g.). Recrystallisation from methanol (400 ml.) and water 800 ml.) gave the butyramide as white crystals, m.p. 193--194 (88 g.).

By a similar procedure 3-amino-6-(1-aminomethyl)-2- benzyl-as-triazin-S (2H) one gave N-[l-(3-amino-2- benzyl-2,5-dihydro 5-oxo-as-triazin-6-yl)methylJbutyramide m.p. -498 (from ethanol).

Method B Butyryl chloride (3.3 ml.) was added to a stirred suspension of 3-amino-6-(l-aminoethyl)-2-benzyl-as-triazin- 5(2H)-one (7.0 g.) in pyridine (70 ml.) at room temperature. The solution was stirred for 17 /2 hours and diluted with ether (400 ml.) to percipitate the butyramide. This was collected, taken up in methanol and water was added until the solution was turbid. The butyramide separated as a white solid, m.p. 189l92 (5.55 g.).

The following compounds were prepared from 3-arnino- G-(I-aminoethyU-Z benzyl as-triazin-S (2H)-one by a similar procedure. N-[1-(3-amino-2-benzyl-2,S-dihydro- 5-oxo-as-triazin-6-yl)ethyl]isovaleramide m.p. 213.6; N-[1-(3-amino 2-beuzyl 2,5-dihydro-S-oxo-as-triazin- 6-yl)ethyl]acetamide m.p. 2l6-219; N-[1-(3-amino-2- benzyl-2,5 dihydro-S-oxo as-triazin-G-yl)ethyl]valeramide m.p. 191.

Method C A solution of 3-amino-6-(l-aminoethyl)-2-benzyl-astriazin-5(2H)-one (6.0 g.) in butyric acid (30 ml.) was boiled under reflux for 4 hours. Butyric acid was removed by distillation under reduced pressure and the residual black oil was triturated with dry ether to give a buflf solid. This material was absorbed onto silica gel, and eluted with methanol ethyl acetate (1:9) to give the butyramide (2.2 g.), m.p. 192-l94.

EXAMPLE 7 N-[ 1- (3-Amino-2,5-dihydro-5-oxo-as-triazin-6- yl) ethyl] butyramide N-[l-(3-Amino 2 benzyl-2,S-dihydro-S-oxo-as-triazin-6-yl)ethyl]butyramide (40 g.) in 2N hydrochloric acid (200 ml.) was hydrogenated over 10% palladium on charcoal (4 g.) at room temperature. Hydrogen uptake was complete after 1.75 hours. The catalyst was removed by filtration through Hyflo and the filtrate was neutralised with sodium carbonate to precipitate the triazinone as a white solid, m.p. 312 (dec.) (23.1 g.).'Recrystallisation from dimethylformamide gave material m.p. 316.5 (dec.).

By a similar procedure N-[l-(3-amino-2-benzyl-2,5-dihydro--oxo-as-triazin-6-yl)ethylJisovaleramide gave N- [1-(3-amino-2,5-dihydro 5 oxo-as-triazin-6-yl)ethyl] isovaleramide, m.p. 271; -N-[1-(3-amino-2-benzyl-2,5- dihydro-5-oxo-as-triazin-6-yl)methyl]butyramide gave N- [1-(3-amino-2,5-dihydro 5 oxo-as-triazin--yl)methyl] butyramide m.p. 300.

EXAMPLE 8 Z-Amino-S-methyl-7-propyl-imidazo[5,1-f] as-triazin- 4(3H)-one, hydrochloride Method A N-[1-(3-Arnino2,5-dihydro 5 oxo-as-triazin-G-yl) ethyl]butyramide g.) was stirred with polyphosphoric acid (70 g.) at 100 and the temperature was then raised to 140 for 1 hour. The hot yellow solution was poured into water (500 ml.) and neutralised with sodium carbonate to precipitate the imidazo-triazinone as a white solid, m.p. l254 (8.4 g.). The base was taken up in ethanol ml.) and 10% ethanolic hydrogen chloride (25 ml.) was added to precipitate the hydrochloride, m.p. 282-285 (8.25 g.). Recrystallisation from water. (6 ml.) and ethanol (50 ml.) gave material m.p. 285-289 (6.3 g.).

By a similar procedure N-[1-(3-amino-2,5-dihydro-5- oxo-as-triazin-6-yl)ethyl]isovaleramide gave 2-amino-7- isobutyl-S methyl-imidazo[5,1-f] -as-triazin-4(3H)-one, m.p. 25l252 (dec.) (from ethyl acetate); N-[1-(3- amino-2,5-dihydro 5-oxo-as-triazin-6 yl)methyl]butyramide gave 2 amino-7-propyl-imidazo[5,1-f1-as-triazin- 4(3H)-one hydrochloride m.p. 23l232 (from ethanolether) N- 1- 3-amino-2,5-dihydro-5-oxo-as-triazin-6-yl) valeryl]acetamide gave 2-amino-7-methyl-5-propyl-imidazo[5,l-f]-as-triazin-4(3H) one, hydrochloride, m.p. 270-274 with decomposition. N-[1-(3-amino-2,5-dihydro-S oxo-as-triazin 6- yl)ethyl]cyclopentanecarboxamide gave 2-amino-5 methyl-7-cyclopentyl-imidazo- [5,1-f]-as-triazin-4(3H)-one, m.p. 299302. N-[1-(3- amino-2,5-dihydro S-oxo-as-triazin 6-yl)ethyl]phenylacetamide gave 2-amino 7-benzyl-5-methyl-imidazo- [5,1-f]-as-triazin-4(3H)-one, m.p. 270.5-271.5 with decomposition. N-[1-(3-arnino-2,S-dihydro-S-oxo-as-triazin- 6-yl)ethyl]benzamide gave 2-amino-5-methyl-7-phenylimidazo[5,l-f]-as-triazin-4(3H)-one, hydrochloride, m.p. 315-317 with decomposition. N-[1-(3-amino-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl] -3,3 dimcthylbutyramide gave 2-amino-7-neopentyl-S-methylimidazo[5,1-f1-as-triazin-4(3H)-one, hydrochloride, m.p. 261-263". N-[1-(3- amino-2,5-dihydro 5 oxo-as-triazin-G-yl)ethyl]hydrocinnamide gave 2-amino-5-methyl7-phenethylimidazo- [5,1-f]-as-triazin-4(3H)-one, hydrochloride, m.p. 271- 274.5".

Method B N-[1-(3-amino Z-benzyl 2,5 dihydro-S-oxo-as-triazin-6-yl)ethyl]butyramide (2.2 g.) was dissolved in phosphorus oxychloride (50 ml.) and the solution boiled under reflux for 30 minutes. The solution was cooled, poured onto ice and concentrated hydrochloric acid and adjusted to 6H 7 by the addition of solid sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried and concentrated. The residue in ethyl acetate was adsorbed onto silica gel (50 g.). Elution with ethyl acetate gave the imidazo[5,1-f]-astriazine as an off-white solid, m.p. 259-261. The hydrochloride salt had m.p. 277280 (from ethanol).

By a similar procedure N-[l-(3-amino-2-benzyl-2,5-dihydro-S-oxo-as-triazin 6 yl)ethyl]acetamide gave 2- amino-5,7-dimethyl-imidazo[5,1-f] as triazin-4(3H)- one, m.p. 380-384 (dec.); N-[1-(3-amino-2-benzyl-2,5- dihydro-5-oxo-as-triazin-6-yl)ethyl]valeramide gave 2- 8 amino-7-butyl 5 methyl-imidazo[5,1-f] -as-triazin-4- (3H)-one, m.p. 214215.

EXAMPLE 9 N- 3,4-Dihydro-S-methyl-4 oxo-7-propyl-imidazo [5 l-f 1 -as-triazin-2-yl acetamide, hydrochloride Method A A solution of 2-amino-5-methyl-7-propyl-imidazo- [5,1-f]-as-triazin-4(3H)-one (1.4 g.) in glacial acetic acid (12 ml.) and acetic auhydride (12 ml.) was heated at for 4 hours then poured onto ice. The solution was neutralised with sodium carbonate and then extracted with ethyl acetate (4X ml.). Removal of the solvent gave the acetamide as a white powder m.p. 201.8 (1.59 g.). Three recrystallisations from ethyl acetate/ light petroleum (b.p. 60-80") gave material m.p. 220- 221.

The base (1.0 g.) was taken up in ethanol (15 ml.) and treated with ethereal hydrogen chloride to precipitate the hydrochloride, m.p. 248-251. Two recrystallisations from ethanol-ether gave material, m.p. 267- 269.

Method B A solution of 2-amino5-methyl-7-propyl-imidazo- [5,1-f]-as-triazin-4(3H)-one, hydrochloride (0.7 g.) and methanesulphonyl chloride (0.5 ml.) in glacial acetic acid (25 ml.) was boiled under reflux for 17 hours. Solvent was removed and the residue treated with sodium carbonate solution. The acetamide was collected (0.59 g.) and recrystallisation from ethyl acetate petroleum ether gave material, m.p. 221223.

By a similar procedure 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazin-4(3H)-one hydrochloride was converted into N-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl) butyramide, hydrochloride, m.p. 237239 (from ethanol ethyl acetate).

EXAMPLE 10 2-Amino-3,5-dimethyl-7-propyl-imidazo[5,1-f]-astriazin-4 3H) -one, hydrochloride (a) N- l- (2-Benzyl-2,5-dihydro-3-imino-4-methyl-5- oxo-astriazin-6-yl ethyl] butyramide, hydrochloride A solution of N-[1-(3-amino-2-benzyl-2,S-dihydro-5- oxo-as-triazin-6-yl)ethyl] butyramide (0.5 g.), sodium hydride (60% dispersion in oil, 0.6 g.) and methyl iodide (0.28 g.) in dimethylformamide (5 ml.) was kept at room temperature for 3 days. The solvent was removed by evaporation under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was dried and concentrated and the residue taken up in ether. Addition of ethereal hydrogen chloride then gave the butyramide hydrochloride as a lemon-yellow solid (0.4 g.). Two recrystallisations from methanol and ethyl acetate gave a white solid, m.p. 202203.

(b) N- 1- 3-amino-4,5-dihydro-4-methyl-5-oxo-astriazin-6-yl) ethyl]butyramide N[1-(2-Benzyl-2l,5-dihydro-3-imino 4 methyl-5- oxo-as-triazin-tS-yl)ethyl]butyramide, hydrochloride (2.0 g.) in ethanol (20 ml.) was hydrogenated over 10% palladium on charcoal (1.0 g.). Uptake of hydrogen was complete after 148 ml. had been absorbed. The catalyst was removed and the solution concentrated to give a white solid, m.p. 224 (1.47 g.). Two recrystallisations from methanol and ethyl acetate gave white microcrystals, m.p. 23023l.

(c) 2-Amino-3,S-dimethyl-7-propyl-imidazo [5,1-f1-astriazin-4(3H)-one, hydrochloride The N-[1-(3-amino-4,5-dihydro 4 methyl-S-oxo-mstriazin-fi-yl)ethyl]butyramide (0.85 g.) was dissolved in polyphosphoric acid (9 g.) at 150-160 and the mixture was maintained at this temperature for 2 hours, then cooled and hydrolysed with water (20 mls.). The mixture was adjusted to pH 4-5 by the addition of sodium carbonate and a white precipitate separated. This was taken up in ethyl acetate and treated with ethereal hydrogen chloride to deposit the imidazo-triazinone hydrochloride as a white powder, m.p. 198 (0.6 g.). Recrystallisation from methanol-ethyl acetate gave white microcrystals, m.p. 198-199.

EXAMPLE 11 Preparation of Intermediate of general formula V (a) Diethyloxalopropionate thiosemicarbazone Thiosemicarbazide (27.3 g.) was suspended in ethanol (600 ml.) containing formic acid (6 ml.) and diethyloxalopropionate (60.0 g.) and the mixture was boiled under reflux until all the thiosemicarbazide dissolved (2.25 hours). The yellow solution was concentrated and the residual solid washed with water and recrystallised twice from ethanol (400 ml.) and water (200 ml.) to give the thiosemicarbazone as stout needles, m.p. 113.2 (27.4 g.). Two further recrystallisations from aqueous ethanol afforded material m.p. 114.7".

(b) 2,4-Dihydro-a-methyl--oxo-3-thio-as-triazine-6- acetic acid, ethyl ester A solution of diethyloxalopropionate thiosemicarbazone (25 g.) and sodium hydroxide (3.65 g.) in ethanol (250 ml.) was boiled under reflux for 2.5 hours. The solution was filtered and concentrated to a glass. This was taken up in water (100 ml.) and the cloudy solution brought to pH 1 by the addition of cone. hydrochloric acid. The oxo-thio-as-triazine separated as a white solid and was collected and recrystallised from aqueous ethanol to give material m.p. 149-152" (11.7 g.). A further recrystallisation from aqueous ethanol afforded colourless plates, m.p. ISO-153.

(c) 2,4-Dihydro-a-methyl-3-methylthio-5-oxo-astriazine-6-acetic acid, ether ester Methyl iodide (1.4 ml.) was added to a solution of 2,4-dihydro-a-methyl-5-oxo-3-thio-as-triazine 6 acetic acid, ethyl ester (5.0 g.) and sodium hydroxide (0.9 g.) in ethanol (25 ml.) and water (100 ml.), stirred at room temperature. The mixture was stirred for 1.25 hours and the precipitated methylthio-triazinone was collected and dried, m.p. 167-170 (3.1 g.). The filtrate was concentrated to give a second crop (0.8 g.). Recrystallisation from aqueous ethanol afforded colourless plates, m.p.

(d) 2-Benzyl-2,5-dihydro-u-methyl-3-meth'yl-thio-5-oxoas-triazine-6-acetic acid, ethyl ester A mixture of 2,4-dihydro-a-methyl-3-methylthio-5-oxoas-triazine-6-acetic acid, ethyl ester (20.0 g.) benzyl chloride (11.0 g.), potassium carbonate (13.0 g.) and sodium iodide (12.0 g.) in butanone (1 l.) was refluxed with stirring for 6 hours. The yellow solution was cooled and filtered to remove inorganic material, and the filtrate was concentrated to give the benzyl derivative as an oil. This was taken up in ethyl acetate (200 ml.) and the solution was filtered and concentrated to an oil which solidified on trituration with petroleum ether. The solid m.p. 6265 (23.06 g.) was collected and dried, and then extracted with boiling cyclohexane (4X 100 ml.). The extract afforded material m.p. 72-75 (16.21 g.) on cooling. Further purification by filtration through silica gel in ethyl acetate and recrystallisation from ethyl acetate cyclohexane furnished prisms, m.p. 8284.

-(e) 2-Benzyl-2,S-dihydro-a methyl-3-methylamino-5- oxo-as-triazine-6-acetic acid, ethyl ester Methylamine (ZS/30% w./v. in water, 0.2 ml.) was added to a solution of 2-benzyl-2,5-dihydro a-methyl-3- methylthio-S-oxo-as-triazine-6-acetic acid, ethyl ester (0.5

This Example gives representative formulations containing as active ingredient 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazin-4(3H)-one referred in the Examples as AH 8883. This compound is used in the form of the hydrochloride which is referred to as AH 8883A.

Injection-containing 10 mg. AH 8883 per ml.

Formula Per ml. AH 8883A m 11.76 Sodium chloride mg 6.1 Water for Injections ml.... To 1.0

1 Equivalent to 10 mg. AH 8883 base.

Method of Manufacture Dissolve the AH 8883 and the sodium chloride in of the water for injections. When solution is complete make up to volume with further water for injections. Filter through a suitable clarifying tfilter.

The solution can then either be packed into 1 ml. neutral glass snap-ring ampoules and sterilised by heating in an autoclave or by filtration or may be prepared aseptically.

TABLETS Formula Mg [tablet Mg [tablet AH 8883 29.4 11.8 Equivalent to AH 8883 b 25 10 Lactose 146. 6 120. 2 Maize starch B.P 20. 0 15. 0 Maize starch as 5% paste. 2. 0 1. 5 Magnesium Stearate B.P 2. 0 1. 5

Final tablet Weight 200 Method of Manufacture Blend together the milled AH 8883A and Lactose. Prepare the requisite quantity of 5% Starch Paste and add to the mixed powder and mix until a uniform damp cohesive mass is formed. Granulate this mass by passing through a suitable mill or sieve to produce discrete granulates. Dry the granules in either a fluid bed drier or on trays in a hot air oven at a temperature of about 50 C. After drying pass the granules through a 30 mesh B.S. sieve to break up aggregates.

Mix together the dried granules, the Maize Starch and Magnesium Stearate and compress on a suitable tablet press. The tablets containing 30 mg. AH 8883A each weigh about 200 mg. and are 8.0 mm. in diameter, those containing 10 mg. AH 8883A each weigh about 156 mg. and are 7.0 mm. in diameter.

Inhalation Aerosol Formulation Mg./metered dose 1. AH 8883 base (micronised) 0.5 2. Sorbiton trioleate 0.5 3. Trichlorofluoromethane B.P. 23 4. Dichlorodifluoromethane B.P. 85

Method of Manufacture Disperse the micronised AH 883 base in the trichlorofluoromethane with the Sorbitan trioleate. Fill the requisite volume of this dispersion into suitable aerosol cans and seal by means of a suitable metering valve. Pressurise the containers by injecting the dichlorofluoromethane through the valve.

In an alternative formula components 1, 3 and 4 are identical to 1, 3 and 4 identified above but 2 is replaced by Emulsifier YN 0.01 mg.

Topical Preparation Percent w./v. 1.0

Formula AH 8883 base Cetomacrogol cream B.P.C. To 100.0

Method of Manufacture or a physiologically acceptable salt thereof wherein R and R may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms or such a radical substituted by at least one phenyl group, R is as defined for R and R or a C -C alkanoyl group, and R and R are as defined for R and R or a C -C cycloalkyl, or phenyl group.

2. Compounds as claimed in claim 1 in which R represents hydrogen or C -C alk-anoyl; R represents hydrogen, R represents hydrogen or C -C alkyl; R represents hydrogen, or C -C :alkyl (C and R represents C -C alkyl, C -C cycloalkyl, phenyl or phenyl C -C alkyl.

3. A compound as claimed in claim 2 in which each of R R and R represents hydrogen.

4. The compound of claim '1 which is 2-amino-5- methyl-7-propyl-imidazo 5, l-f] -as-triazin-4 (3H) -one.

5. The compound of claim '1 which is 2-amino-7-isobutyl-S-methyl-imidazo[5,l-f]-as-triazin-4 (3H)-one.

6. The compound of claim 1 which is 2-amino-7-propylimidazo 5 l-f] -as-triazin-4 3H -one.

7. The compound of claim 1 which is 2-amino-7- methyl-S-propyl-imidazo 5, l-f] -as-triazin-'4 3H -one.

8. The compound of claim 1 which is 2-amino-5- methyl-7-cyclopentyl-imidazo[5,1-f]-as-triazin 4 (3H)- one.

9. The compound of claim 1 which is 2-amino-7- benzyl-S-methyl-imidazo [5, l-f] -as-triazin-4 3H) -one.

10. The compound of claim 1 which is 2-an1ino-5- methyl-7-phenyl-imidazo [5, 1-f]-as-triazin-4- (3H) -one.

11. The compound of claim 1 which is 2-amino-7-neopentyl-S-methyl-imid azo [5, l-f -as-tri-azin-4'( 3H) -one.

12. The compound of claim 1 which is 2-amino-5- methyl-7-phenethyl-imidazo 5, l-f] -as-triazin-4( 3H) -one.

13. The compound of claim 1 which is 2-amino-5,7 dimethyl-imidazo [5,1-f]-as-triazin-4(3E-I)-one.

14. The compound of claim 1 which is 2-amino-7- butyl-S-methyl-imidazo 5, 1-f -as-triazin-4 3H) -one.

15. The compound of claim 1 which is N(3,4-dihydro S-methy1-4-oxo-7-propyl-imidazo[5,1-f]-as-triazin-2 yl) acetamide.

16. The compound of claim 1 which is N(2,4-dihydro 5-methy1-4-oxo-7-propyl-imidazo[5,1-f]-as-triazin 2 yl butyramide.

17. The compound of claim 1 which is 2-amino-3,5- dimethyl-7-propyl-imidazo 5, l-f -as-triazin-4 3H) -one.

18. A process for the preparation of a compound of the formula:

or a physiologically acceptable salt thereof wherein R and R may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms or such a radical substituted by at least one phenyl group, R is as defined for R and R or a C -C alkanoyl group and R and R are as defined for R and R or a C -C cycloalkyl, or phenyl group, which comprises, for the production of a compound in which R is hydrogen and R R R and R have the meanings given above, the cyclodehydration with phosphorous oxychloride or polyphosphoric acid of a compound of the formula 0 R4 0 R4 H 1 hi i NHCORa EN 1 NHCOR5 01 N N Rt 2NkN RiRzN N HzP 11 VIII VIIIB.

or for the production of a compound of the formula I in which R is other than hydrogen, alkylating the compound of formula I above in which R is hydrogen with an alkylating agent of the formula R X wherein X represents halogen or tosylate in the presence of a base and solvent to replace the hydrogen atom by a group R as defined above.

19. A process as claimed in claim 18 in which the cyclodehydration of the compound of formula VIII is effected with phosphorus oxychloride whereby debenzylation is also efiected.

'20. A process as claimed in claim 18 in which the cyclodehydration of the compound of formula VIIIa is carried out with polyphosphoric acid.

21. A process as claimed in claim 18 in which the compound of formula VIIIa is made by hydrogenolysis of the compound of formula VIII.

References Cited UNITED STATES PATENTS 7/1967 Fry et al. 260-249.5 8/1967 Fry et al. 260-249.5 X

JOHN M. FORD, Primary Examiner

Claims

1. A A COMPOUND OF THE FORMULA I: