IE46317B1 - Imidazopyridazines and their use as therapeutic agents - Google Patents

Abstract

The present invention relates to 5 -bO-pyridazines. The compounds according to the present invention correspond to the following formula: [FR2380281A1]

Description

This invention relates to novel imidazo[l,5-b] pyridazines, to a process for the production thereof, to pharmaceutical preparations containing said pyridazines and to methods of medical treatment employing them.

According to the present invention there are provided imidazo[l,5-b]pyridazines of the general formula' X: R.

(I) '2 and physiologically acceptable non-toxic salts thereof, in which Rj, Rg and R^ which may he the same or different represent a straight or branched chain alkyl or alkenyl group, 0r an aryl or aralkyl group in which the aryl group or the aryl moiety of the aralkyl group may be substituted by one or more hydroxy, alkoxy, or halogen atoms; and in which either or both of Rj and R„ may additionally represent hydrogen atoms; and in which Rj may further represent a halogen atom, preferably chlorine, or an alkoxy, hydroxy, alkylthio or thiol group or may represent a group R^R^N- in which R^ represents a hydrogen atom or an alkyl or alkenyl group and R^ represents a hydrogen, atom or an amino group or an alkyl, alkenyl, aryl or aralkyl group, in which the aryl group or the aryl moiety of the aralkyl group may optionally be substituted with one or more hydroxy or alkoxy groups; and in which the group Rj may also represent an acyl function RgCO-, in which Rg is a hydrogen atom or an alkyl or an aryl group; and in which the groups and R^ may together with the adjacent nitrogen atom form a saturated 4 to 8 membered heterocyclic ring which can contain an additional heteroatom, preferably N, S or 0, and may be substituted (on either a carbon atom or a hetero atom) by for example a methyl group.

Where reference is made herein to alkyl as a group, or part of a group such as aralkyl or alkoxy, this preferably meatis one containing from 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms. References herein to alkenyl preferably mean those groups containing 3 to 6 carbon atoms. Aryl preferably means phenyl and aralkyl preferably means benzyl or phenethyl,.

The compounds of formula I may be isolated as non-toxic physiologically acceptable salts in particular acid addition salts. Examples of such salts include salts with organic acids such as acetic acid, maleic acid and tartaric acid and with inorganic acids such as hydrochloric and sulphuric acid. The processes for the preparation of the compounds of the invention include as an optional step the isolation of the compounds of formula I as non-toxic physiologically acceptable salts.

Preferred novel compounds according to the invention^ are those in which the groups have the meanings given below: R^ is hydrogen; alkyl, preferably methyl, ethyl or n-propyl; halo, preferably chloro; alkoxy, preferably methoxy; hydroxy; or aryl, preferably phenyl; or the group NR^Rg where R^ is hydrogen or alkyl, preferably methyl; and R^ is hydrogen, amino, alkyl, preferably methyl, ethyl or isopropyl; or an acyl function RgCO in which Rg is alkyl, preferably methyl; or NR^R^ is a five or six-membered heterocyclic ring preferably a piperidino ring; R2 is alkyl, preferably propyl or isobutyl; or aryl, preferably phenyl; and R^ is hydrogen or alkyl, preferably methyl, ethyl or isopropyl.

Compounds in which R^ represents hydrogen, alkyl, alkoxy, aryl, or a group -NR^R^ in which R^ is hydrogen or alkyl and R5 is hydrogen, amino, alkyl or RgCO where Rg is alkyl, or NR^Rg represents piperidino are preferred.

Specific preferred compounds according to the invention are those, the preparation of which is described in the Examples Two particularly preferred compounds are :l-methyl-6-methylanlino-3-propylimidazo[1,5-b]pyridazine, 6-ethyl-l-methyl-3-propylimidazo[l,5-b]pyridazine, and their hydrochloride or maleate salts. -425 6 317 Tautomerism may exist in the compounds according to the invention for example when R^ represents a hydroxy, thiol, or primary or secondary amino group. The invention includes within its scope the tautomeric forms of the compounds of formula I.

The compounds of formula I and. non-toxic physiologically acceptable salts thereof have been found to have useful therapeutic activity. Thus they relax smooth muscle with concomitant stimulation of the enzyme adenylate cyclase giving enhanced intracellular levels of cyclic adenosine monophosphate (eAMP). The mechanism does not involve β-adrenoceptors. The compounds also inhibit the enzyme phosphodiesterase. Accordingly the compounds are particularly useful in the treatment of diseases of the lung such as asthma and bronchitis and in the treatment of peripheral vascular disease such as hypertension and Raynaud1s syndrome.

The compounds would also be useful in the treatment of skin diseases such as psoriasis.

The relaxant activity of these compounds on smooth muscle is demonstrated by their action (a) in reducing the tone of isolated guinea-pig tracheal strip preparations (R.F. Cobum & T. Tomita, 1973; Am. J. Physiol., 224. 1072-1080), and (h) in reducing bronchospasm induced by spasmogens such as histamine, 5-hydroxytryptamine and acetylcholine in the -54 6 317 anaesthetized guinea-pig (G.W. Lynn James, 1969; J.

Pharm. Pharmac., 21, 579-386).

The ability of compounds to inhibit the enzyme phosphodiesterase is demonstrated on an enzyme preparation from human lung on the basis of the· method described by T.R. Russell, W.L. Terasaki & M.M. Appleman (1973) J. Biol. Chem. 248, 1334-1340.

The compounds of formula I where R^ represents hydroxy may be prepared by cyclising a 3-substituted-pyridazin-6(lH)one of general formula II: in Tihich R2 and R^ have the meaning given above. Subsequent conversion of the resulting compound of formula I in which R^ is hydroxy into other compounds of the invention may be carried out as described below.

A suitable agent for carrying out the cyclisation reaction on compounds of formula II is a strong acid, for example polyphosphoric acid. The reaction is preferably carried out with heating and optionally in the presence of a suitable solvent. A compound of formula I in which R^ is hydroxy may then be converted into other Compounds according to the invention. For example where R^ is halogen reaction with a compound which -646 317 replaces the hydroxy group hy a halogen atom for example, hy refluxing with a halogen-containing phosphorus compound will yield compounds in which R^ is halogen. Thus, refluxing with phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride results in a compound of formula I in which R^ is chlorine, and likewise refluxing with phosphorus tribromide gives a compound in which R^ is bromine. In an alternative procedure the compound of formula II may be refluxed optionally in the presence of a solvent for example, ethylene dichloride, with a halogen introducing reagent such as the halogen containing phosphorus compounds recited above to give directly compounds of formula I in which R^ is halogen. This procedure is particularly applicable to the preparation of the chloro compound utilising-phosphorus oxychloride as the halogencontaining phosphorus compound.

Other compounds of general formula 1 may he prepared from the compounds of formula I in which R^ is halogen hy processes described below.

In particular the compound in which R^ is chlorine may he utilised as starting material for these other processes. Such processes may involve a nucleophilic displacement reaction.

For example, the chloro compound may he treated with ammonia or a primary or secondary amine to give compounds of formula I in which R^ is NR^R^; this reaction i,s usually carried out at elevated temperatures, and a solvent such as an alcohol e.g. -746317 ethanol may conveniently he used. This reaction is not suitable for the direct production of compounds in which R^ is RgCO. For the production of these compounds, an acylation step is necessary as described below. For compounds in which R^ (in the group NR^R^) is an amino group, the chloro compound may be refluxed with a hydrazine e.g. hydrazine hydrate in a solvent. An alcohol e.g. ethanol is again a suitable solvent.

For the production of compounds in which Rj is an alkoxy group one may conveniently treat a chloro compound of formula I with an alkoxide, conveniently a solution of an alkali metal alkoxide in the corresponding alcohol. Catalytic hydrogenation of a chloro compound of formula I using for example palladised charcoal as catalyst will give a compound according to the invention in which Rj is hydrogen. This reaction may be carried out in a solvent such as ethyl acetate, in the presence of a base e.g. triethylamine.

Further reactions may be effected to convert one compound according to the invention into another compound of the invention. Thus, for example, where Rj is amino, this group may be acylated with for example an acid anhydride in the presence of the corresponding acid e.g. acetic anhydride in the presence of acetic acid to give compounds in which Rj represents a group -NR^Rj where R^ represents RgCO-, as defined above. Other conventional acylating agents, such as an acid chloride, may also be used. -84 6 317 Compounds in which R^ represents alkyl, in particular methyl, or alkenyl or aryl or aralkyl, which may he substituted as mentioned above may be made by treating a compound of formula X in which Rj is hydrogen with an appropriate organo lithium compound (e.g. an alkyl lithium), conveniently in an ether solvent such as diethyl ether or tetrahydrofuran, to give an appropriately 6-substituted 5,6-dihydro-imidazo[l,5-b]pyridazine, which is subsequently dehydrogenated e.g. by refluxing with palladium oxide/charcoal in p-cymene, or oxidised using a suitable oxidising agent, for example, potassium ferricyanide, to yield the compound of formula I.

Compounds in which R^ is a thiol group may be prepared by treating a compound of formula I in which R^ is chlorine with potassium hydrogen sulphide. Alkylation of the thiol compounds yields compounds of formula I in which R^ is alkylthio.

In addition to the methods of preparation described above, compounds of formula I in which R^ is halogen other than chlorine may be prepared by displacement reactions on the chloro compound using an appropriate metal halide such as sodium bromide or potassium iodide in an aprotic solvent such as acetone or dimethylformamide.

Compounds of formula II above may conveniently be prepared from compounds of formula III, using a suitable oxidising agent for example bromine. -9*46317 NHC0Rn (HI) If desired the acyl group -CORg in a compound of formula II may he replaced hy an alternative acyl group prior to the cyclisation thereof, via the intermediacy of the amino derivative IV and subsequent re-acylation.

Compounds of formula XII, which constitute a further aspect of the invention, may be prepared from compounds of formula V or the corresponding acids VX by reaction with hydrazine. The reaction is carried out in a suitable solvent such as ethanol, without isolation of the intermediate hydrazone.

AlkOOCCHgCHgCOCHNHCORg HOOCCHgCHgCOCHNHCORg (V) (VI) The 3-substituted-pyridazin-6(lH)-ones XI and 3-substituted-4,5dihydro-pyridazin-6(lH)-ones III are novel compounds.

Compounds of formula V may be prepared from azlactones of formula VII by application of the Dakin-West reaction using either the acid chloride CICOCHgCHgCOgAlk or the corresponding 104 b* 3 j. 7 acid anhydride and employing triethylamine as the basic catalyst, as described hy W. Steglich and G. Hofle (Chem.

Ber. 1969, 102, 883 and Angew. Chem. Int. Ed. 1969, 8, 98l). This gives an intermediate azlactone of formula VIII which is hydrolysed hy heating in water to yield the γ-keto ester V. The corresponding γ-keto acid VI is obtained hy hydrolysis of the ester V by means of aqueous 8$ sodium bicarbonate solution The azlactone of formula VII may be prepared, optionally in situ, from the acyl α-amino acid of formula IX by conventional methods, for example reaction with dicyclohexylcarbodiimide, or reaction with an acid anhydride such as acetic anhydride, or an acid chloride conveniently the 3-chloroformylpropionic acid ester ClCOCHgCB^COgAlk referred to above.

T3 HOOCCHNHCORg (IX) For administration, the compounds of Formula I and salts thereof may be formulated in association with a non-toxic physiologically acceptable carrier or diluent, and with or without supplementary medicinal agents. -114 6 317 The invention-also provides pharmaceutical compositions which are characterised in that they contain a compound of formula I or a non-toxic physiologically acceptable salt thereof, preferably in association with a physiologically acceptable carrier or diluent. The compositions may include, for example, solid or liquid preparations for oral use, or may be in the form of suppositories, injections or in a form suitable for administration by inhalation.

Oral presentations are most conveniently in the form of tablets which may be prepared according to conventional methods, and may be coated if required. Soluble tablets suitable for sublingual administration may also be used.

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 compositions according to the invention can be in the form of a metered dose inhalation aerosol, a solution or suspension suitable for nebulisation by mechanical means, or as a cartridge from which the powdered composition may be inhaled with the aid of a suitable device.

The dosage at which the active ingredients are administered may vary within a wide range. A suitable per diem dos>age range for systemic use is generally from 0.1 to 100 mg. The pharmaceutical compositions may with advantage be formulated to -124 6 J I 7 provide a dose within this range either as a single unit or a number of units.

In the use of an aerosol for bronchodilation the dosage unit may be determined by providing a metering valve in the aerosol pack so that it delivers a metered amount on use.

Such a metered amount may be of the order of 10-1000^ug.

The compounds according to the invention may be formulated in combination with compounds that have stimulant activity at β-adrenoreceptors, for example, salbutamol and isoprenaline or in combination with compounds which have phosphodiesterase inhibitory activity, for example theophylline. -134 6 317 The following Examples illustrate the invention. Examples 13, 14 and 15 illustrate the production of intermediates.

EXAMPLE 1 l-Methyl-5-propyiimidazo[l,5-b]pyridazin-6(5H)-one (a)(i) 5-ButyTamido-4-oxohexanoic acid, ethyl ester A solution of N-butyrylalanine (1.59 g) in dry THP (10 ml) and triethylamine (2.8 ml) was treated with 4-dimethylaminopyridine (0.1 g) and then ethyl 3-chloroformylpropionate (2.8 ml) was added dropwise with rapid stirring during 5 minutes. The temperature was allowed to rise freely and it reached a peak at 43° and then cooled slowly to room temperature. The brown suspension was stirred at room temperature for 6 hours and left overnight. The reaction was then diluted with ethyl acetate (30 ml) and water (25 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 20 ml). The combined organic layers were washed with water (6 x 20 ml), dried (anhydrous magnesium sulphate) and concentrated to ca, 10 ml. The solution was then absorbed onto a column Of silica gel (65 g) and eluted with 1:1 ethyl aeetate:cyclohexane. The first 250 ml contained a mixture of impurities and were discarded. The next 5θ0 ml of eluent contained the pure product, 0.82 g.

In a similar manner was prepared (ii) 5-isovaleramido-4oxohexanoic acid, ethyl ester (4.45 g) m.p. 41-43° (from petroleum ether b.p. 30-40°) from N-isovalerylalanine (6.9 g). -14(iii) 5-benzamido-4-oxohexanoic acid, ethyl ester (18.1 g) m.p. 87-89’’ from N-henzoylalanine (17.3 g). Two recrystallisations from ethyl acetate-cyclohexane gave a sample m.p. 89°. (iv) 5-butyramido-4-oxoheptanoic acid, ethyl ester (48 g) b.p. 140-144°/0.1 mm from 2-hutyramidohutyric acid (43.3 g). (h)(i) 3-(1-Butyramidoethyl)-4,5-dihydro-pyridazin-(IH)-6-one Ethyl 5-hntyramido-4-oxohexanoate (0.24 g) was heated under reflux with hydrazine hydrate (0.06 ml) in ethanol (3 ml) for 30 minutes. The solvent was evaporated and the solid residue recrystallised directly from ethyl acetate, m.p. 148150°, 0.08 g.

In a similar manner was prepared (ii) 3-(l-isovaleramidoel,hyl)-4,5-dihydro-pyridazin-6(lH)-one (3.3 g) m.p. 176.5-178 (from ethyl acetate), from ethyl 5-isovaleramido-4-oxohexanoate (4.5 g). (iii) 3-(1-henzamidoethyl)-4,5-dihydro-pyridazin-6(lH)-one (0.9 g) m.p. 175-6° (from ethanol-ethyl acetate), from ethyl 5-henzamido-4-oxohexanoate (1.38 g). (iv) 3-(1-hutyramidopropyl)-4,5-dihydropyridazin-6(lH)-one (23.5 g) m.p. 120-122° (after trituration with isopropyl acetate), from 5-6utyramido-4-oxoheptanoic acid, ethyl ester (43 g). Reerystallisation from isopropyl .acetate raised the m.p. to 125°. (v) 3-butyramidomethyl~4,5-dihydropyriaazin-6(lH)-one (5.4 g), m.p. 131-133° (from ethyl acetate) from 5-6ntyramido-4-oxopentanoic acid, ethyl ester (13.1 g) (Example 13). -154631*? (vi) 3-(l-benzamido-2-methylpropyl)-4,5-dihydropyridazin-6(lH)one (9 g) m.p. 175-176° (from ethyl acetate) from 5-benzamido6-methyl-4-oxoheptanoie acid (9.2 g) (Example 14(ii)), (vii) 3-benzamidomethyl-4,5-dihydropyridazin-6(lH)-one (2.2 g) m.p. 365-167° (from ethyl acetate-cyclohexane) from 5-benzamido4-oxopentanoic acid, ethyl ester (3.5 g) (Example I4(i)). ( c) (i ) 3-(1-Butyramidoethyl)-pyridazin-6 (IH) -one A solution of the dihydropyridazine (1.05 g) in glacial acetic acid (10 ml) was warmed to 50° and bromine (0.88 g) was added dropwise with stirring. The reaction mixture was heated at 50 for 3 hours then the solvent was evaporated in vacuo.

The residue was basified with 8% sodium bicarbonate solution and the product extracted with ethyl acetate (5 x 20 ml), Evaporation of the solvent gave the title compound m.p. 158l6o°, 0.6 g. Two reerystallisations from ethyl acetate gave a sample m.p. 163-164°.

Tn a similar manner was prepared (ii) 3-(l-isovaleramidoethyl)-pyridazin-6(lH)-one (0.72 g) m.p. 176-178° (from ethyl acetate) from 3-0-isovaleramidoethyl)-4,5-dihydro-pyridazin6(lH)-one (0.9 g). (iii) 3-(l-benzamidoethyl)-pyridazin-6(lH)-one (2.32 g) m.p, I9O-I950 from 3-(l-benzamidoethyl)-4,5-dihydro-pyridazin-6(lH)one (2.45 g), Two reerystallisations from ethyl acetatecyclohexane gave a sample m.p, 197-9°, (iv) 3-(l-but.yramidopropyl)-pyridazin-6(lH)-one (9.13 g) m.p. -164 6 317 155-157 from 3-(l-butyramidopropyl)-4, 5-dihydropyridazin6(lH)-one (14.25 g). Recrystallisation from ethanol-ethyl acetate gave material m.p. 156-158°. (v) 3-butyramidomethylpyridazin-6(lH)-one m.p. 124° (from ethyl acetate) from 3-butyramidomethyl-4,5-dihydropyridazin6(lH)-one (0.98 g). (vi) 3-(l-benzamido-2-methylpropyl)pyridazin-6(lH)-one (2.5 g) m.p. 246-247°, (from isopropanol), from 3-(l-benzamido-2methylpropyl)-4,5-dihydro-pyridazin-6(lH)-one (2.73 g). (vii) 3-benzamidomethylpyridazin-6(lH)-one (0.38 g) m.p. 142-144° (from ethyl acetate-cyclohexane) from 3-benzamidomethyl-4,5-dihydropyridazin-6(lH)-one (0.46 g). (d)(i) l-Methyl-3-propylimidazo[l,5-b]pyridazin-6(5H)-one 3-(l-Butyramidoethyl)-pyridazin-(lIl)-6-one (0.9 g) was heated at 120° for 2 hours in polyphosphoric acid (10 g).

The resultant solution was poured into water (20 ml) and hasified with solid sodium carbonate. The product was extracted with ethyl acetate (3 x 30 ml), the extracts were dried (anhydrous magnesium sulphate) and evaporated to give the title compound, 0.66 g, m.p. 155-157°. Two recrystallisations from ethyl acetate raised the m.p. to 158-160°.

In a similar manner was prepared (ii) 1-methyl-3-(2methylpropyl)lmidazo[l,5-b]pyridazin-6(5H)-one (1.55 g) m.p. 166-168° (from ethyl acetate/petroleum ether, b.p. 60-80°) from 3-(l-isovaleramidoethyl)-pyridazin-6(lH)-one (2.0 g). (iii) l-methyl-3-phenylimidazo[l,5-b]pyridazin-6(5H)-one (0.8 g) m.p. 230-232° from 3-(l-benzamidoethyl)-pyridazin-6(lH)-one (2 g). Recrystallisation from ethyl acetate raised the m.p. to 241-243°.

EXAMPLE 2 (i) 6-Chloro-l-methyl-3-propylimidazo[1,5-¾Jpyridazine, hydrochloride Procedure A A sample of l-methyl-3-propylimidazo [l,5-b]pyridazin6(5H)-one (2.7 g) was heated with phosphorus oxychloride (40 ml) under reflux for 6 hours. The reaction was then carefully poured onto ice-water (600 ml) and basified by the addition of sodium carbonate. The product was extracted into ethyl acetate (6 xlOO ml) and the combined extracts were washed with 2N sodium hydroxide solution (2 x 20 ml), water (2 x 20 ml) and finally dried over magnesium sulphate. Evaporation of the solvent gave a yellow-brown oil which was dissolved in ethyl acetate (20 ml) and ethereal hydrogen chloride added to give the hydrochloride salt of the title compound as a buff, amorphous powder, 1.8 g, m.p. 184-186°. Recrystallisation of the product from isopropanol/ethyl acetate gave a sample, m.p. 185-186°.

Procedure B 3-(l-Butyramidoethyl)-pyridazin-(lH)-6-one (42.75 g) was added in portions to phosphorus oxychloride (425 ml) with -184 6 317 stirring. Themixture was heated gently under reflux for 4 hours, cooled and then carefully added to ice-water (5 litres). The solution was hasified with potassium carbonate and extracted with ethyl acetate until the extracts were colourless (7 x 400 ml). The solution was then filtered through silica gel (100 g) and the filtrates evaporated to dryness to give the product as a yellow solid, 29.75 g, m.p. 46.5-48°. A sample was converted into the hydrochloride salt, m.p. 185.6°.

In a similar manner was prepared (ii) 6-chloro-l-methyl3-(2-methylpropyl)imldazo[l,5-b]pyridazine (5.6 g), (the hydrochloride salt had m.p. 194-196° from ethanol-ethyl acetate), from 3-(l-isovaleramidoethyl)-pyridazin-6(lH)-one (7.75 g). (iii) 6-chloro-r3-propyIimidazo[l,5-6]pyridazine as a gum (1.3 g), from 3-butyramidomethylpyridazin-6(lH)-onc (5.7 g). (iv) 6-ehioro-l-ethyl-3-propylimidazo[l,5-b]pyridazine (0.87 g), b.p. 110°/0.1 mm, from 3-(l-butyramidopropyl)-pyridazin-6(lH)one (2 g). (v) 6-chloro-3-phenylimidazo[l,3-b]pyridazine (0.43 g), m.p. 113-114° (from cyclohexane) from 3-benzamidomethylpyridazin6(lH)-one (0.6 g). (vi) 6-ehloro-l-isopropyl-3-propylimidazo[l,5-b]pyridazine as a yellow oil (3.9 g) (the hydrochloride salt had m.p. 102-104°), from 3-(l-butyramido-2-methylpropyl)-pyridazin-6 (lH)-one (4.6 g) (Example 15). -1946317 EXAMPLE 5 (i) 6-Amino-l-methyl-3-propylimidazo[l,5-b]pyridazine, hydrochloride 6-Chloro-l-methyl-3-propylimidazo[l,5~b]pyridazine (1.3 g) was heated with a saturated solution of dry ammonia in absolute ethanol (40 ml) in a closed pressure vessel at 180° for 4 days. Diatomaceous earth (15 g) was added and the mixture was evaporated to dryness. The residue was then added to the top of a column of silica gel (150 g). The column was eluted with ethyl acetate. The first 1000 ml contained starting material. The next 2000 ml contained the required product, 0.41 g. The product was dissolved in ethyl acetate (40 ml) and ethereal hydrogen chloride added until the yellow colour disappeared.

The precipitated salt was filtered and recrystallised directly from a mixture of ethanol and ethyl acetate to give a sample m.p. 264° (decomp.). (ii) In a similar manner 6-chloro-l-methyl-3~(2-methylpropyl) imidazo[l,5-b]pyridazine, hydrochloride (4.4 g) was converted into 6-amino-l-methyl-3-(2-methylpropyl)imidazo[l,5-b]pyridazine (1.33 g) (the hydrochloride salt had. m.p. 151-153° from ethyl acetate?-ethanol).

EXAMPLE 4 (i) l-Methyl-6-methylamino-5-propylimidazo[l,5-b]pyridazine, maleate 6-Chloro-l-raethyl-3-propylimidazo[l,5-b]pyridazine (2.1 g) -204 6 y χ 7 was heated in a closed pressure vessel with a solution of methylamine in ethanol (l6 ml, w/w) at 150° for 3 days.

The reaction mixture was then evaporated to dryness and the semi-solid residue diluted with water. The mixture was extracted with ethyl acetate (3 x 40 ml) and the organic extracts washed with 2N sodium hydroxide solution (2 x 10 ml), water (2 x 10 ml) and finally dried over anhydrous sodium sulphate. Evaporation of the solvent gave a pale yellow solid, l. 95 g. The product was dissolved in hot ethyl acetate (50 ml) and a solution of maleic acid (2.5 g) in hot ethyl acetate (25 ml) was added. The maleate salt crystallised on cooling (2.9 g) m.p. 121-123° (from ethyl acetate).

A sample of the free base, isolated from another similar experiment prior to the maleic acid treatment, had m.p. 138139.5°. (ii) In a similar manner 6-chloro-l-methyl-3-(2-methylpropyl) imidazo[l,5-bJpyridazine (1.5 g) was converted into 1-methyl6-methylamino-3-(2-methylpropyl)imidazo[l,5-bjpyridazine, hydrochloride (l.3 g) m.p. 247-249° (decomp.), (from ethyl acetate-ethanol). (iii) In a similar manner 6-chloro-l-methyl-3-propyi-imidazo [l,5-b]pyridazine (1.0 g) was converted into 6-ethylamino-lmethyl-3-propylimidazo[l,5-b]pyridazine, hydrochloride (0.63 g) m. p. 208.5-211° (from ethyl acetate-ethanol). (iv) In a similar manner 6-chloro-l-methyl-3-propylimidazo-21463151 fl,5-b]pyridazine (1.31 g) was converted into l-methyl-6-(lmethylethyl)amino-3-propylimidazofl,5-b]pyridazine, hydrochloride (0.64 g) m.p. 214-219.5° (from ethyl acetate-ethanol), (v) In a similar manner was prepared 6-methylamino-5-propylimidazofl,5-b]pyridazine (0.95 g) m.p. 112-115° (the hydrochloride salt had. m.p. 119-122° from isopropanol-ethyl acetate), from 6-ehloro-3-propylimidazo[l,5-b]pyridazine (l»3 g). (vi) In a similar manner was prepared 6-methylamino-lisopropyl-3-propylimidazo[l,5-b]pyridazine (1.7 g) m.p. 159161°, from 6-ehloro-l-isopropyl-3-propylimidazo fl,5-b jpyridazine (2.0 g). Recrystallisation from cyclohexane gave material m.p. 159.5-161.5°.

EXAMPLE 5 6-Dimethylamino-l-methyl-3-propyli!nidazofl,5-b]pyridazine, dimaleate 6-Chloro-l-methyl-3-propylimidazofl,5-b]pyridazine (2.1 g) and a solution of dimethylamine in ethanol (16 ml, 33% w/w) were heated together in a closed pressure vessel at 150° for 18 hours. The mixture was then evaporated to dryness and the residue diluted with water and extracted with ethyl acetate (3 x 50 ml). The organic extracts were washed with 2N sodium hydroxide solution (3 x 10 ml), water (2 x 10 ml) and finally dried (anhydrous sodium sulphate). Evaporation of the solvent gave an amber gum, 2.0 g. The gum was dissolved in ethyl acetate (20 ml) and a solution of maleic acid (2 g) in ethyl -2246317 acetate (25 ml) added. Addition of petroleum ether, b.p. 60-80° (25 ml) gave an oil which solidified on trituration in ether. The solid (2.6 g) was recrystallised from ethyl acetate to give a sample m.p. 85-87°.

EXAMPLE 6 l-Methyl-6-piperidino-3-propylimidazo[l,5-¾ jpyridazine, hydrochloride 6-Chloro-l-methyl-3-propylimidazo[l,5~b]pyridazine (1.5 g) was heated at 140° in a closed pressure vessel with piperidine (40 ml) for 24 hours. The pressure vessel was rinsed out with ethanol and the solvents evaporated. The residue was dissolved in ethyl acetate (100 ml) and the organic solution was washed with 2N sodium hydroxide solution (3 x 20 ml), water (30 ml) and finally dried (anhydrous magnesium sulphate). It was then filtered through a column of silica gel (25 g) and the yellow filtrate concentrated to 5 ml. Excess ethereal hydrogen chloride was then added, followed by petroleum ether b.p. 60-80° (50 ml) to give the product as a buff powder, 1.7 6, m.p. 186° (from ethyl acetate-petroleum ether, b.p. 60-80°). EXAMPLE 7 (i) l-Methyl-3-propylimidazo[l,5-b]pyridazine, hydrochloride 6-Chloro-l-methyl-3-propylimidazo[l,5-b]pyridazine (1.5 g) was hydrogenated over 10$ palladium on charcoal in ethyl acetate (100 ml) containing triethylamine (2 ml). The reaction absorbed 180 ml hydrogen (theoretical 172 ml) during 25 minutes. The -234 6 317 catalyst was filtered and washed with ethanol (3 x 20 ml).

The filtrate was evaporated to dryness and anhydrous ether added. The precipitated triethylamine hydrochloride was filtered off and the filtrate was evaporated to give a gum.

This was dissolved in ethyl acetate (50 ml) and the solution washed with 2N sodium hydroxide solution (3 x 15 ml), water (20 ml) and dried (anhydrous magnesium sulphate). The ethyl acetate solution was filtered through a column of silica gel (15 g) and the filtrate was treated with excess ethereal hydrogen chloride. The salt was filtered off and recrystallised from ethyl acetate containing a few drops of ethanol, 0.93 g, m.p. 137°. (ii) In a similar manner was prepared l-ethyl-3-propylimidazo [l,5-hjpyridazine (2.6 g), b.p. 90°/0.02 mm, from 6-ehloro-lethyl-3-propylimidazo[l,5-bjpyridazine (3.6 g).

EXAMPLE 8 6-Methoxy-l-methyl-5-propylimidazo[l,5-b jpyridazine, maleate 6-Chloro-l-methyl-3-propylimidazo[l,5-bjpyridazine (2.1 g) was heated in a closed pressure vessel at 150° for 18 hours with a solution of sodium (0.6 g) in methanol (15 ml). The reaction mixture was evaporated to dryness, water (30 ml) was added and the mixture extracted with ethyl acetate (3 x 40 ml). The combined organic extracts were washed with 2N sodium hydroxide solution (3 x 20 ml), water (2 x 20 ml) and finally dried (anhydrous sodium sulphate). Evaporation of the solvent -244631 gave an amber gum, 0.35 g. The gum was dissolved in ethyl acetate (10 ml) and added to a solution of maleic acid (0.5 g) in ethyl acetate (10 ml). The crystalline salt which separated was filtered off and washed with ethyl acetate to give the product, 0.33 g, m.p. 132-133°.

EXAMPLE 9 N-(l-Methyl-3-propylimidazo fl,5-¾]pyridazin-6-yl)acetamide A solution of 6-amino-l-methyl-3-propylimidazo[1,5-bjpyridazine, hydrochloride (0.148 g) in acetic anhydride (1 ml) and glacial acetic acid (0.5 mi) was heated on a steam bath for 24 hours. The solvent was evaporated and the residue recrystallised from ethyl acetate-ethanol to give the acetamide m.p. 233-236°.

EXAMPLE 10 6-Hydrazino-l-methyl-3-propyllmidazo|l,5-b jpyridazine dihydrochloride 6-Chloro-l-methyl-3-propylimidazo[l,5-b]pyridazine, (2.1 g) was heated with hydrazine hydrate (15 ml) in ethanol (40 ml) under reflux on the steam bath for 22 hr. The solvents were then evaporated, the residue dissolved in ethyl acetate (200 ml) and the solution washed with 2N sodium hydroxide solution (3 x 20 ml), water (2 x 20 ml), dried (anhydrous magnesium sulphate) and finally filtered through silica gel (30 g). The filtrate was concentrated to ca. 50 ml and ethereal hydrogen chloride added to give the dihydrochloride salt m.p. 258-260°, -2546317 2.05 g. Two recrystallisations from ethanol/ethyl acetate gave an. analytical sample m.p. 260-262°.

EXAMPLE 11 (i) l,6-Dlmethyl-5-propylimiaazo [T, 5-b jpyridazine’, hydrochloride (a) 5,6-Pihydro-l,6-dimethyl-5-propylimidazo[l,5-b jpyridazine A solution of l-methyl-3-propylimidazo[l,5-bjpyridazine (0.7 g) in dry ether was stirred under nitrogen, cooled to -20° and treated with a solution of methyl lithium in ether (2M, 2.25 ml). The reaction was stirred at -20° for 30 minutes then allowed to warm to room temperature, stirred for a further 2 hours then left overnight.

The reaction mixture was decomposed by the addition of isopropanol (2 ml) then the mixture partitioned between water (15 ml) and ethyl acetate (25 ml). The layers were separated and the aq. layer extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with water (10 ml), dried (anhydrous magnesium sulphate), concentrated to ca. 10 ml and the solution absorbed onto a 1 column of silica gel (55 g). The column was eluted with ethyl acetate. The first 500 ml contained starting material. The next 800 ml contained the required product (0.62 g). (b) 1,6-Dimethyl-3-propylimidazo fl,5-b jpyridazine, hydrochloride The dihydro compound (0.6 g) was heated under reflux with 10°/ palladium on charcoal (0.5 g) in p-cymene (50 ml) for 2 hours with stirring. The reaction was then filtered through -2646317 diatomaceous earth, the solids washed with ethyl acetate until colourless and the filtrate stirred with 2N hydrochloric acid (50 ml). The layers were separated and the aq. layer washed with ethyl acetate. The aq. layer was hasified with potassium carbonate and extracted with ethyl acetate (3 x 50 ml). The extracts were combined, washed with water, dried (anhydrous magnesium sulphate) and the solvent evaporated to leave a yellow oil. The oil was dissolved in ethyl acetate (20 ml) and ethereal hydrogen chloride added, to give the title compound m.p. 160-2°, 0.44 g. Two recrystallisations from ethyl acetate plus a trace of ethanol gave an analytical sample, m.p. 161-3°. (ii) In a similar manner was prepared b-ethyl-l-methyl-3propylimidazo[l,5-b]pyridazine (1.02 g), (the hydrochloride salt had m.p. 148-150° from ethanol-ether) from l-methyl-3propylimidazo[l,5-b]pyridazine (1.75 g) via 5,6-dihydro-6ethyl-l-methyl-3-propylimidazo[l,5-b]pyridazine. (iii) In a similar manner was prepared 6-phenyl-l-methyl-3propylimidazo[l,5-b]pyridazine (0.58 g), m.p. 82-86° (the hydrochloride had m.p. 207-209°), from l-methyl-3-propylimidazo[l,5-b]pyridazine (0.77 g).

EXAMPLE 12 l-Methyl-3,6-dipropyIimidazo fl,5-bjpyridazine (a) 5,6-Dihydro-l-methyl-3,6-dipropylimidazo[l,5-h1pyridazine Following a similar method'to that of Example 11(a), the -2746317 title compound (4.2 g) was obtained as an oil from 1-methyl3- propylimidazo[l,5-b jpyridazine (3.5 g). (b) 6-Propyl-l-methyl-3-propylimidazo[l,5-b]pyridazine A solution of 5,6-dihydro-6-propyl-l-methyl-3-propylimidazo[l,5-b]pyridazine (4.2 g), potassium ferricyanide (15.08 g) and sodium bicarbonate (4.08 g) in water (150 ml) and acetone (100 ml) was heated under reflux for 19 hours.

An additional quantity of potassium ferricyanide (6.2 g) and sodium bicarbonate (1.63 g) were added and refluxing was continued for 6 hours. The solution was cooled and extracted with ethyl acetate. Removal of the solvent gave 6-propyl-lmethyl-3-propylimidazo[l,5-b]pyridazine (3.05 g), b.p. 135°/ x 10 mm Hg.

Intermediates EXAMPLE 15 -Butyramido-4-oxopentanoic acid, ethyl ester A solution of N-butyrylglycine (29 g) and dicyclohexylcarbodiimide (41.2 g) in methylene chloride (200 ml) was stirred for 16 hours. Dicyclohexylurea was removed by filtration and washed with methylene chloride (50 ml) which was combined with the filtrate. Triethylamine (28 ml) and 4- dimethylaminopyridine (0.5 g) were added and the solution cooled to 5° was treated with 3-chloroformyl propionic acid, ethyl ester (28 ml) added dropwise over 30 minutes. The mixture was stirred at 5° ior 30 minutes then at room temperature for -284 6 31 'Ζ hours. Water (50 ml) was added and the organic layer was separated, concentrated to dryness at 35° and the residue stirred vigorously with water (100 ml) for 18 hours. The mixture was extracted with ethyl acetate (3 x 100 ml) and the extracts were washed with 8$ sodium bicarbonate (50 ml) and dried (magnesium sulphate). The solvent was removed and the residue (57 g) was chromatographed on a column of silica gel (470 g). Elution with ethyl acetate-cyclohexane (1:1, 2.4 litres) gave a mixture of non-ketonic products, but further elution with ethyl acetate-cyclohexane (1:1, 4.8 litres) afforded the y-keto ester, 13.1 g.

EXAMPLE 14 (i) 5-Benzamido-4-oxopentanoic acid, ethyl ester A solution of 2-phenyl-5-oxazolone (l.6l g), triethylamine (1.4 ml) and 4-dimethylaminopyridine (0.1 g) in tetrahydrofuran (20 ml) was treated with ethyl-3-chloroformyl propionic acid, ethyl ester (1.4 ml) and stirred for 1 hour. The mixture was concentrated to dryness, treated with water (20 ml) and heated on a steam bath for 1 hour. The mixture was extracted with ethyl acetate (3 x 30 ml) and the extracts washed with 8$ sodium bicarbonate (5 x 25 ml), water (75 ml) and dried (magnesium sulphate). Removal of the solvent gave an oil which was chromatographed on a column of silica gel (45 g). Elution with ethyl acetate-cyclohexane afforded the y-keto ester (0.65 g) m.p. 98-100°. -294 6 317 (ii) In a similar manner 4-isopropyl-2-phenyl-5-oxazolone (101.5 g) was converted into 5-benzamido-6-methyl-4-oxoheptanoie acid (22.2 g), m.p. 126-128° (from ethanol-cyclohexane) by heating the crude ethyl ester with 8% aquaous bic&rbonate in ethanol.

EXAMPLE 15 -(l-Butyramido-2-methylpropyl)-pyridazin-6(lH)-one (a) 5-(l-Amino-2-methylpropyl)pyridazin-6(IH)-one, hydrochloride 3-(l-Benzamido-2-methylpropyl)pyridazin-6(lH)-one (Example lc(vi)) (10 g) in cone, hydrochloric acid (100 ml) was heated under reflux for 14 hours. The mixture was cooled and henzoic acid removed by filtration. The filtrate was evaporated to dryness and triturated with anhydrous ether to give the amine hydrochloride as a grey powder (7.2 g) m.p. 274-276° (from ethanol-ethyl acetate). (b) 5-(l-Butyramido-2-methylpropyl)pyridazin-6(IH)-one 3-(l-Amino-2-methylpropyl)pyridazin-6(IH)-one, hydrochloride (7.1 g) was dissolved in pyridine (100 ml). Triethylamine (3.5 ml) and butyric anhydride (6.1 g) were added and the mixture was stirred for 3i hours. The mixture was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was washed with water (25 ml) and dried. Removal of the solvent gave the butyramide as a solid (5.6 g), m.p. 160-161° (from ethyl acetate-cyclohexane). -30Pharmaceutical Compositions Example 16 To prepare 10,000 tablets each containing 1 mg active ingredient Mix together 10 g powdered active ingredient, 500 g anhydrous lactose, 988.5 g microcrystalline cellulose and 1.5 g magnesium stearate. Compress on a suitable tablet machine using 8 nun diameter punches to produce tablets weighing about 150 mg.

Tablets of other strengths of active ingredient may be prepared by substituting the active ingredient for some of the anhydrous lactose.

The tablets may be film coated with suitable film forming material such as methyl cellulose, hydroxypropyl methyl cellulose or mixtures of these materials using standard techniques. The tablets may also he sugar coated hy standard sugar coating techniques.

Example 17 To prepare 10,000 capsules each containing 10 mg active ingredient Mix together 100 g active ingredient and 1100 g microcrystalline cellulose and fill into No. 5 hard gelatin capsules so that each capsule contains about 120 mg of the mixture.

Examp1e 18 To prepare an injection containing f mg/nil active ingredient Dissolve 1 g active ingredient and 9 g sodium chloride in 950 ml water for injections. When solution is complete make -514 6 317 up to 1 litre with more water for injections. Filter and subdivide the solution into suitabla size ampoules (1 ml, ml or 10 ml), seal and sterilise by heating in an autoclave. EXAMPLE 19 To prepare a syrup containing 10mg/5ml active ingredient Dissolve 12.0 kg sucrose in 5 L. hot water, add 2 L. glycerin and allow to cool, dissolve 40 g active ingredient in the syrup, and a suitable quantity of preservative of approved colour and flavour. Subdivide into 150 ml screw capped bottles.

EXAMPLE 20 To prepare cartridges each containing 50/ug active ingredient for inhalation Mix together 0,5 g micronised active ingredient and 250 g 15 lactose in a suitable mixer and fill 25 mg into each of No. 3 hard gelatin capsules.

Claims (16)

1. CLAIMS:- 1. Imidazo[l,5-b]pyridazines of the general formula I: R, (I) and physiologically acceptable non-toxic salts thereof, in which Rp R,, and Rj which may be the same or different represent a straight or branched chain alkyl or alkenyl group, or an aryl or aralkyl group in which the aryl group or the aryl moiety of the aralkyl group may be substituted by one or more hydroxy, alkoxy, or halogen atoms; and in which either or both of Rj and Rj may additionally represent hydrogen atoms and in which Rj may further represent a halogen atom, or an alkoxy, hydroxy, alkylthio or thiol group or may represent a group R^RjN- in which R4 represents a hydrogen atom or an alkyl or alkenyl group and Rj represents a hydrogen atom or an amino group or an alkyl, alkenyl, aryl or aralkyl group, in which the aryl group or the aryl moiety of the aralkyl group may optionally be substituted with one or more hydroxy or alkoxy groups; and in which the group Rj may also represent an acyl function RgCO-, in which Rg is a hydrogen atom or an alkyl or an aryl group; and in which the groups R^ and Rj may together with the adjacent nitrogen atom form a saturated 4 to 8 membered hetero 33 46317 cyclic ring which can contain an additional heteroatom and may he substituted.

2. Compounds as claimed in claim 1 in which the groups indicated below have the meanings given 5 Rj : hydrogen, alkyl, halo, alkoxy, hydroxy, aryl; or a group -NR^R^, in which R^ is hydrogen or alkyl and R^ is hydrogen, amino or alkyl; or an acyl function RgCO in which Rg is alkyl; or the group NR^Rj which represents a five or six-membered 10 heterocyclic ring; R 2 : alkyl or aryl R^ ; hydrogen or alkyl.

3. Compounds as claimed in claim 1 in which R^ represents hydrogen, alkyl, alkoxy, aryl, or a group -NR^R^ in which R^ 15 is hydrogen or alkyl and R e is hydrogen, eunino, alkyl or R,CO b b where R g is alkyl, or NR^R g represents piperidino.

4. Compounds as claimed in claim 2 in which the groups indicated below have the meanings given Rj hydrogen, methyl, ethyl, n-propyl, methoxy, phenyl, 20 or a group -NR^R^ in which R^ is hydrogen or methyl and Rj is hydrogen, amino, methyl, ethyl or isopropyl, or a group RgCO in which Rg is methyl, or NR^R^ is piperidino, R 2 : propyl,'isobutyl or phenyl, 25 R3 ; hydrogen, methyl, ethyl or isopropyl. 4 6 3 i

5. The compound as claimed in claim 1 which is selected from l-methyl-6-methylamino-3-propylimidazo [1,5-b]pyridazine and its salts.

6. The compound as claimed in claim 1 which is selected from 6-ethyl-l-methyl-3-propylimidazo [l,5-b]pyridazine and its salts.

7. The compound as claimed in claim 1 which is selected from l-methyl-6-methylamino-3-(2-methylpropyl)imidazo [1,5-b] pyridazine and its salts.

8. Compounds as claimed in claim 1 the preparation of which is specifically described in Examples 1 to 12, other than those claimed in claims 5, 6, or 7.

9. A process for the preparation of compounds as claimed in claim 1 and physiologically acceptable non-toxic salts thereof, which comprises (a) for the production of compounds in which R.| represents hydroxy, cyclising a compound of the general formula II: in which R 2 and have the meanings given in claim 1 with a strong acid; or (b) for the production of compounds in which Rj represents halogen, reacting a compound of formula I in which R^ is hydroxy with a compound which replaces the hydroxy group by a halogen atom, if desired with subsequent displacement of one halogen atom by a different halogen atom? or (c) for the production of compounds in which R^ is halo reacting a compound of formula II with a halogen introducing 4631'? reagent whereby cyclisation and replacement of the hydroxy group at the R^ position with a halogen atom is effected simultaneously; or (d) for the production of compounds in which R^ represents 5 a group NR^R^ in which R^ and R^ have the meanings given in claim 1, except that R^ cannot represent RgCO, treating a compound of formula I in which R^ is chlorine with ammonia or an appropriate primary or secondary amine HNR^R^; or (e) for the production of compounds in which R^ represents 10 a group -NR^Rg in which R^ is an amino group, treatment of a compound of formula I in which R^ is chlorine with a hydrazine; or (f) for the preparation of compounds in which R^ represents a group -NR^Rj and R. is a group RgCO in which Rg has the meaning given in claim 1 acylating a compound in which is 15 amino with an acylating agent to introduce a group RgCO; or (g) for the production of compounds in which R^ is alkoxy reaction of a compound of formula I in which Rj is chloro with an appropriate alkoxide; or (h) for the production of compounds in which R 4 is hydrogen 20 catalytically hydrogenating a compound of formula I in which R^ is chloro; or (i) for the preparation of compounds in which R^ represents alkyl, alkenyl, aryl or aralkyl which may be^substituted as defined in claim 1 treating a compound of formula I in which R^ 25 is hydrogen with an appropriate organolithium compound - 36 4 6 3X7 to produce a 6-substituted 5,6-dihydro-imidazo[l,5-b]pyridazine which is then dehydrogenated or oxidised to produce the appropriate compound of formula I; or (j) for the preparation of compounds in which Rj represents thiol or alkylthio, reaction of the compound of formula I in which Rj represents chlorine with potassium hydrogen sulphide with if necessary subsequent alkylation; said reactions comprising one or more of the steps (a) to (j); the desired end product being isolated, if desired, as a physiologically acceptable salt.

10. A process as claimed in claim 9 substantially as herein described with reference to Examples 1-15.

11. Compounds as claimed in claim 1 when prepared by a process as claimed in claim 9 or claim 10.

12. Pharmaceutical compositions comprising a compound as claimed in claim 1 or claim 11 in association with a non-toxic physiologically acceptable carrier or diluent, said composition if desired also including supplementary medicinal agents.

13. Compositions as claimed in claim 12 adapted for oral use, or for use as suppositories, or for use by injection or for use by inhalation.

14.Compositions as claimed in claim 12 or claim 13 formulated to provide a dosage of active ingredient of from 0.1 to 100 mg, as a single unit or number of units.

15. A composition as claimed in claim 13 adapted for use by - 37 4 6 317 inhalation and dispensed from an aerosol pack providing a metered dose containing from 10-1000/ug of said active compound.

16. A method of relieving bronchospasm which comprises 5 administering to an animal other than a human suffering from such bronchospasm an effective amount of a compound as claimed in claim 1.