GB2043637A - Heterotricyclic derivatives - Google Patents

Abstract

Compounds of general formula I, <IMAGE> wherein A represents a nitrogen atom or a group of formula =CH-; G represents an oxygen atom -O- or a group of formula <IMAGE> (in which Z represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or, together with Y a carbon-nitrogen or carbon-carbon bond and Z' represents a hydrogen or halogen atom); Y represents a hydrogen atom or, together with Z when G represents a group of formula <IMAGE> a carbon-nitrogen or carbon-carbon bond, or, together with X, a keto group; X represents a hydrogen atom or, together with Y, a keto group; R represents a hydroxymethyl, formyl, tetrazol-5-yl, N-(tetrasol-5-yl)carbamoyl, aminomethyl or carbamoyl radical; and R1 represents a hydrogen or halogen atom or an alkoxy radical containing from 1 to 5 carbon atoms; and acid addition salts thereof having anti- allergic activity.

Description

SPECIFICATION Heterotricyclic derivatives This invention relates to new heterotricylic derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general formula

wherein A represents a nitrogen atom or a group of formula -CH-; G represents an oxygen atom -0-or a group of formula

(in which Z represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms pr, together with Y a carbon-nitrogen or carbon-carbon bond and Z' represents a hydrogen or halogen atom); Y represents a hydrogen atom or, together with Z when G represents a group of the formula

a carbon-nitrogen or carbon-carbon bond, or, together with X, a keto group: X represents a hydrogen atom or, together with Y, a keto group; R represents a hydromethyl, formyl, tetrazol-5-yl, N-(tetrazol-5-yl)carbamoyl, aminomethyl or carbamoyl radical; and R1 represents a hydrogen or halogen atom or an alkoxy radical containing from 1 to 5 carbon atoms; and acid addition salts thereof.

When G represents a group of formula

in which Z represents an alkyl radical containing from 1 to 5 carbon atoms, Z may, for example, represent a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or pentyl radical.

When G represents a group of formula

may, for example, represent a hydrogen, chlorine or bromine atom. R1 may, for example, represent a hydrogen, chlorine or bromine atom or a methoxy, ethoxy or isopropoxy radical.

The compounds of general formula I may form acid addition salts with mineral or organic acids such as, for example, hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids e.g.

methanesulphonic and ethanesulphonic acids, arylsulphonic acids e.g. benzenesulphonic and p toluenesulphonic acids and arylcarboxylic acids.

The compounds of general formula I and their acid addition salts possess interesting pharmacological properties and in particular an anti-allergic activity.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically compatible acid addition salts but other acid addition salts may find use, for example, in the preparation of the compounds of general formula I and their physiologically compatible acid addition salts.

Preferred compounds according to the invention are those wherein R represents a hydroxymethyl, formyl or tetrazol-5-yl radical, especially those wherein R represents a hydroxymethyl or tetrazol-5-yl radical and R1 represents a hydrogen atom.

Particularly preferred compounds according to the invention are the following: 2-(1 H-tetrazol-5-yl)imidazo[1 ,2-a]quinoxaline, 2-(1 H-tetrazol-5-yl)imidazo[1 ,2-a]quinoline, 8-methoxy-2-(1 H-tetrazol-5-yl)imidazo[1 ,2-a]quinoline, imidazo[1 ,2-a]quinoxaline-2-methanol, 5-ethyl-2-hydroxymethylimidazo[1 ,2-a]quinoxalin-4-(5H)-one, 5-ethyl-2-hydroxymethylpyrrolo[1 ,2-a)quinoxal in-4(5H )-one and acid addition salts thereof.

The compounds of general formula I may, for example, be prepared by the following processes, which processes constitute further features of the present invention: A. forthe preparation of compounds of general formula I wherein R represents a hydroxymethyl radical: Reduction of a compound of formula II,

(wherein A, G, Y, X and R1 are as hereinbefore defined and Alk represents an alkyl radical containing from 1 to 5 carbon atoms) whereby the desired compound of formula I is obtained.

Reduction may, for example, be effected by means of a complex metal hydride such as, for example, lithium borohydride preferably in the presence of an ether e.g. tetrahydrofuran as solvent. The reduction is preferably effected at elevated temperatures, most preferably the boiling point of the reaction mixture: Where Y and X together represent a keto group in the starting material of formula (II), this may be simultaneously reduced to give a compound of formula (I) in which Y and X are both hydrogen or, alternatively, the reduction of the group -COOAlk may be effected selectively.

Other compounds of formula (II) may be prepared by the methods described in our French patents Nos.

2387230,2378031 and 2351980 or may be obtained by analogous methods. Where in a known compound G is

and Y and Ztogetherform a carbon-nitrogen bond, reduction with lithium borohydride gives the corresponding compound in which X and Y are both hydrogen.

B. for the preparation of compounds of general formula I wherein R represents a formyl radical: Oxidation of a compound of formula las hereinbefore defined (wherein R represents a hydroxymethyl radical) whereby the desired compound of formula I is obtained.

Oxidation may, for example, be effected by means of an oxidising agent such as manganese dioxide or chromic oxide, preferably at elevated temperatures.

C. for the preparation of compounds of general formula I wherein R represents an aminomethyl radical: Catalytic hydrogenation of a compound of the formula Ill,

(wherein A, G, Y, X and R1 are as hereinbefore defined) Catalytic hydrogenation is preferably effected with hydrogen in the presence of a metal catalyst such as, for example, palladium.

D. forthe preparation of compounds of general formula i wherein R represents tetrazol-5-yl radical: Reaction of a compound of formula IV,

(wherein A, G, Y, X and R1 are as hereinbefore defined) with sodium azide.

The reaction is preferably effected at elevated temperatures and preferably in the presence of a weak acid such as e.g. ammonium chloride.

E. for the preparation of compounds of general formula I wherein R represents an N-(tetrazol-5yl)carbamoyl radical: Reaction of a compound of formula V,

(wherein A, G, Y, X and R1 are as herein before defined) or a reactive derivative thereof with 5-aminotetrazole.

The reaction is preferably effected in the presence of a carbodiimide reagent e.g. carbonyldiimidazole.

Also preferred is the use of dimethylformamide as solvent. Suitable reactive derivatives of the compound of formula V for use in the reaction include for example the acid halides e.g. the acid chloride or bromide.

F. for the preparation of compounds of general formula I wherein R represents a carbamoyl radical: Reaction of a compound of formula Il as hereinbefore defined with ammonia.

The compounds of general formula I may, if desired, be converted into acid addition salts thereof by reaction with an acid, for example, those set forth hereinbefore preferably in substantially equimolar quantities: If desired the compounds of general formula I prepared as described above may be converted directly into their acid addition salts without isolation: The compounds of general formula V, of use in process E above, may be prepared by hydrolysis of a compound of formula Il as hereinbefore defined preferably under alkaline condition e.g. using an alkali metal hydroxide.

The compounds of general formula II wherein A represents a nitrogen atom and G represents a group of formula

when they are not known, may for example be prepared by cyclisation of a compound of formula VI,

(wherein R1, Y, X, Z and Alk are as hereinbefore defined and Hal represents a chlorine or bromine atom) preferably by means of heating the reaction mixture under reflux. The compounds of general formula VI may themselves be obtained, if desired, by reaction of a compound of formula Vll, Hal-CH2-CO-COOAlk (ill) (wherein Alk and Hal are as hereinbefore defined) with a compound of formula VEIL,

(wherein R1, Y, X and Z are as herein before defined) preferably in the presence of an organic solvent.

The compound of formula VIII may be prepared by reaction of the corresponding 2,3-dichloroquinoxaline with gaseous ammonia to replace one chlorine atom by NH2 reaction with ethanol giving, where Z is hydrogen, the desired lactam. The 2,3-dichloroquinoxaline may be prepared from the corresponding quinoxaline-2,3-diol, by the method of Stevens et al JACS (1946), 68, 1035.

It will be appreciated that where R1 is a halogen atom, the 2,3-dichloroquinoxaline is asymmetrical and conversion to a compound of formula VIII will give a mixture of isomers which may be separated at that stage, for example by chromatography, or may be reacted further as a mixture followed by separation of isomers at a later stage.

The compounds of general formula IV, useful as starting materials in process D described above, may for example be obtained by reaction of a compound of formula Ill as hereinbefore defined with acetic anhydride.

Both the compounds of general formula Ill and the compounds of general formula IV are new compounds which, together with processes for their preparation and their use, constitute further features of the present invention.

The compounds of general formula III may be prepared, if desired, by reaction of a compound of formula I as hereinbefore defined wherein R represents a formyl group with hydroxylamine, preferably in the form of its hydrochloride. The reaction is preferably effected at elevated temperatures and preferably in the presence of sodium acetate.

As stated above, the compounds of general formula I and their acid addition salts possess interesting pharmacological properties. Those compounds which we have tested show remarkable anti-allergic activity.

Such compounds are thus of use in the treatment of asthma and bronchial asthma of an allergic origin.

Pharmacological activity Passive cutaneous anaphylaxis (PCA) in rats: Cutaneous anaphylaxis can be induced in the rat by intradermal (ID) sensitisation with antiserum followed three days later by systemic challenge with antigen. Evans blue dye injected with the antigen is used as a marker to asses the severity of the local response. Anti-allergic drugs inhibit this reaction. This method has been described by OVARY (1962) in 'Passive cutaneous Anaphylaxis in Allergology' 358-367 Ed. Brown: Pergamon Press: Animals Male rats weighing 180-220 grams are used in groups of seven.

Preparation of antigen for Sensitisation (Alum precipitated ovalbumen) 1. Wash 120 grams Al (OH)3 gel in 140 mls saline (use of a maceraterfacilitates mixing).

2. Centrifuge at 3,000 r.p.m. for about 10 minutes.

3. Resuspend the precipitate with 300 mls of albumen egg powder (1.3 mg/ml) in saline and allow to stand for 30 minutes.

4. Centrifuge at 3,000 r.p.m. for 10 minutes.

5. Weigh the wet precipitate and to each gram weight add 1 ml of saline. Store in fridge.

(Quantity sufficient for 60 rats for a 3 day sensitisation programme).

Preparation ofAntiserum (i.e. anti-ovalbumen) 1. 1 ml of the alum precipitated ovalbumen is injected subcutaneously into 180-200 gram rats on days 0, 2,4.

2. The rats are bled on day 14 either by cardiac puncture or via the dorsal abdominal aorta.

3. Equal quantities of serum from each animal are pooled and thoroughly mixed.

4. 2 ml aliquots are stored at -20"C in plastic tubes.

Serum Dilution for PCA The antiserum for sensitisation is diluted such that an ID injection of 0.1 ml into control animals will give an average score of a single spot of between 2.0-3.5 using a5 point scoring system (0, 1,2,3,4).

Method (A) SENSITISATION:- Rats are anaesthetised with Nembutal (40-60 mg/kg i.p.) and are then sensitised by four ID injections (0.1 ml each) on shaved backs. The animals are then left for a period of three days to develop sensitisation.

(B) CHALLENGE:- The sensitised rats are dosed orally or intraveneously with the drug immedialy prior to intraveneous challenge via the superficial penile vein with 1 ml of an antigen/Evans blue mixture (1 mg albumen egg powder in 0.5 mls saline plus 0.5 mls of 1% Evans blue). The injections are speeded up by using an automatic 1 ml self-filling glass syringe. The 'challenged' rats are killed after 30 minutes, (usually pithed) and their skin on the dorsal surface removed. The degree of area of blueing, proportional to the anaphylactic reaction is assessed on a five point scoring system.

Calculations 1. Total Scores for sites 1,2,3 and 4 = X 2. MeanValueofXforeachgroup= X 3. Xt=X for test group X c = Xforcontrol group 4. %inhibition = X c-Xt 100 Xe 1 5. ED50 = dose of drug giving 50% inhibition.

ED50 values for compounds tested in the passive cutaneous anaphylaxis screen (in rats): Compound of Example ED50 mg/kg i.v. mg/kg p.o.

2(as hydrochloide) 0.16 0.068 0.14 0.084 3(as hydrochloride) 0.012 0.089 5 - 0.36 6 - 0.09 7 0.026 0.105 8 0.11 0.98 12 0.27 0.24 13 0.12 0.40 14 0.01 0.12 15 3.39 21 - 0.062 22 0.077 24 0.045 26 0.011 0.439 30 0.33 According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula las hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compounds of general formula land their physiologically compatible acid addition salts may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example plain tablets, coated tablets, gelatin capsules, granules, suppositories and solutions e.g. for injection.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 0.25 to 50mg, preferably from 0.25 to 30mg of active ingredient. The oral daily dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 0.25 to 100 mg per day in adults.

The following non limiting examples serve to illustrate the present invention.

Example 1 4,5-Dihydroimidazo[1,2-a]quinoxaline-2-methanol A solution of ethyl imidazo[1 ,2-a]quinoxaline-2-carboxylate (10g) in dry tetrahydrofuran (230 mis) was treated with excess lithium borohydride (2.8 g) and the resultant mixture was stirred under reflux for eighteen hours to give a yellow suspension. The reaction mixture was subsequently poured into dilute hydrochloric acid to break down the boron complex, then basified with sodium carbonate and extracted into ethyl acetate. Evaporation of the solvent gave 4,5-dihydroimidazo[1,2-a]quin oxaline-2-methanol as a buff crystalline solid (5.9 g). The product was recrystallised from ethyl acetate to give a white crystalline solid (MP 172-4 ).

IR Spectrum (KBr) - VNH = 3300cm-1 Analysis: Ca,H1,N3O = 201 Calculated %C 65.66 %H 5.51 %N 20.88 Found %C 65.63 %H 5.54 %N 20.87 Example 2 Imidazo[1,2-a]quinoxaline-2-methanol and imidazo[1,2-a]-quinoxaline-2-carboxaldehyde A solution of 4,5-dihydroimidizo[1,2-a]quinoxaline-2-methanol (3 g) in chloroform (500 mls) was stirred under reflux for six hours with manganese dioxide (9 g). The resultant mixture was filtered hot and concentrated. A white crystalline solid separated out (2.68 g) which was a mixture of the hydroxymethyl compound and the aldehyde. The filtrate was evaporated to dryness giving a buff crystalline solid (0.43 g) which was pure imidazo-[1,2-a]quinoxaline-2-carboxyaldehyde. The mixture of the hydroxymethyl compound the the aldehyde was separated by column chromatography on silica gel eluting with 21/2% mothanol/971/2% chloroform.The aldehyde was eluted first from the column (0.23 g) and then pure imidazo[1,2-a]quinoxaline-2-methanol (1.42 g).

Yield of imidazo[1,2-a]quinoxaline-2-carboxaldehyde = 0.66 g.

MP 214-5".

IR Spectrum (KBr) - VCH = 3130cm-1 (imidazole CH) 2840cm-' (aldehyde CH) vCO = 1700cm-1 (aldehyde CO) Analysis: C11H7N30= 197 Calculated %C 67.00 %H 3.85 %N 21.31 Found %C 66.70 %H 3.63 %N 21.34 Yield of imidazo[1,2-a]quinoxaline-2-methanol = 1.42 g MP 217-220 .

IR Spectrum (KBr) - VOH = 3200cm-1 (primary alcohol) VCH = 3110cm-1 (imidazole CH) Analysis: C11HgN3O = 199 Calculated %C 66.32 %H 4.55 %N 21.09 Found %C 66.25 %H 4.63 %H 21.09 The yield of aldehyde may be increased by using 4 g manganese dioxidell g dihydro-hydroxymethyl compound and refluxing the reaction mixture overnight.

Example 3 2-(1H-Tetrazol-5-yl)imidazo[1,2-alquinoxaline Step A: Imidazo[1,2-a]quinoxaline-2-carboxaldohyde oxime A suspension of imidazo[1 ,2-a]quinoxaline-2-carboxaldehyde (3.10 g) in ethanol (30 mls) was treated with a solution of hydroxylamine hydrochloride (1.4 g) and sodium acetate (1.9 g) in water (5 mls). The resultant mixture was stirred for four hours at 900 and then evaporated to dryness to give a white crystalline solid which was tritu rated with water, filtered and dried in vacuo over phosphorus pentoxide.The product was pure imidazo[1,2-a]quinoxaline-2-carboxaldehyde oxime (2.83 g) MP 243-5 Analysis: C11H8N4O = 212 Calculated %C 62.26 . %H 3.80 %N 26.40 Found: %C 62.13 %H 3.84 %N 26.41 Step B : Imidazo[1,2-a]quinoxaline-2-carbonitrile A solution of imidazoquinoxaline oxime (2 g) in acetic anhydride (20 mls) was heated under reflux for 3 hours, cooled and then poured into sodium carbonate solution. Imidazol-[1,2-a]quinoxaline-2-carbonitrile separated out as a buff crystalline solid (1.8 g). The product was recrystallised from methanol/chloroform as a buff crystalline solid (MP 281-5 , dec).

IR Spectrum (KBr) - VCN = 2225cm-1 (C=N stretch).

Analysis: C11H6N4 = 194 Calculated: %C 68.04 %H 3.11 %N 28.85 Found: %C 67.64 %H 3.21 %N 28.59 Step C:2-(1H-Tetrazol-5-yl)imidazo[1,2-a]quinoxaline A solution of imidazo[1,2-a]quinoxaline-2-carbonitrile (1 g) in dimethylformamide (50 mls) was treated with ammonium chloride (0.4 g) and sodium azide (0.45 g) and the resultant mixture was stirred overnight at 100 to qive a white suspension. The reaction mixture was cooled and poured into water. 2-(1 H-tetrazol-5- yl)imidazo[1 ,2-a]quinoxaline separated out as a buff crytalline solid (0.65 g). The product was recrystallised from dimethylformamide/water to give buff crystlline solid (MP 320-2", dec).

Analysis: C11H7N7 = 237 Calculated: %C 55.69 %H 2.98 %N 41.33 Found: %C 55.47 %H 3.24 %N 40.83 Example 4 N-(1H-Tetrazol-5-yl)imidezo[1,2-a]quinoxaline-2-carboxamide A solution of imidazo[1,2-a]quinoxaline-2-carboxylic acid (0.8 g) and carbonyldiimidazole (0.7 g) in dimethylformamide (40 mls) was stirred at 900 for thirty minutes. The resultant clear orange solution was treated with anhydrous 5-aminotetrazole (0.35 g) and stirred for a further one hour at 90 . Awhite crystalline solid separated out. The resultant mixture was cooled in a fridge and N-(1 H-tetrazol-5-yl)imidazo[1 ,2- ajquinoxaline-2-carboxamide was filtered off, washed well with ethyl acetate and dried in vacuo (1.17 g).The product was recrystallised from dimethylformamide to give a white crystalline solid (MP 280-1 , dec).

IR Spectrum (Kbr) - vNH = 3100cm-1 (amide NH) vCH= 3170cm-1 (imidazole CH) vCO= 1680cm-1 (amide CO) Analysis: C,2H8N8O = 280 Calculated: %C 51.43 %H 2.88 %N 39.98 Found: %C 51.54 %H 2.54 %N 39.98 Example 5 Imidazo[1,2-a]quinoline-2-methanol Ethyl imidazo[1,2-a]quinoline-2-carboxylate (prepared as in French Patent Specification No. 2378031 (7.2 g) in dry tetrahydrofuran (140 ml) was stirred under reflux with lithium borohydride (1.0 g) for 20 hours. The mixture obtained was cooled to room temperature and treated dropwise with 2N hydrochloric acid until effervescence ceased.The clear solution obtained was stirred for one hour, basified with saturated sodium bicarbonate solution and then concentrated under reduced pressure to remove tetrahydrofuran. The resultant mixture was diluted with water (500 ml), cooled in ice and filtered to give imidazo[1,2-a]quinoline-2methanol as a colourless solid (4.9 g) which was dried under vacuum over phosphorous pentoxide. The filtrate was extracted with chloroform and the extracts were dried over magnesium sulphate then evaporated to dryness to give a further 0.60 g of the title compound, M.P. 158-9 (needles recrystallised from ethyl acetate/diethyl ether).

Analysis: C12H10N2O = 198 Calculated: %C72.71 %H 5.08 %N 14.13 %C72.70 %H5.16 %N14.13 IR Spectrum Vmox (KBr Disc): 3300-2600 (OH, 1614, 1549, 1452,1418,1343, 1041,1034,998, 802cm1 Example 6 Imidazo[1,2-a]quinoline-2-carboxaldehyde lmidazo[1,2-a]quinoline-2-methanol (4.2 g) in chloroform (11) was refluxed for 4 hours with manganese dioxide (16.0 g) and then cooled overnight. The resultant mixture was filtered through cellulose powder and the filter pad was washed with chloroform. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with diethyl ether. Imidazo[1,2-quinoline-2-carboxaldehyde (3.4 g) was obtained as needles, M.P. 184-5 (chloroform/diethyl ether).

Analysis: C11H8N2O = 196 Calculated: %C73.46 %H4.11 %N 14.28 Found: %C 73.26 %H 4.20 %N 14.28 IR Spectrum: vmax (KBr disc) 2805 (CHO) 1700 (C=0), 1620, 1453, 1423, 1219, 1196, 811, 753 cm-1.

Example 7 2-(1H-Tetrazol-5-yl)imidazo[1,2-a]quinoline Step A : Imidazo[1,2-a]quinoline-2-carboxaldehyde oxime Imidazo[1,2-a]quinoline-2-carboxaldehyde (2.40 g) in ethanol (60 ml) was treated with hydroxylamine hydrochloride (1.0 g) and sodium acetate (1.35 g) in water (20 ml). The solution obtained was stirred under reflux for 2 hours and then concentrated under reduced pressure. The resultant mixture was stirred during the addition of water (50 ml), then filtered and washed with water. The colourless solid obtained was dried under vacuum over phosphorour pentoxide to give imidazo[1 ,2-a]quinoline-2-carboxaldehyde oxime (2.55 g) as a mixture of the syn and anti isomers. The product was recrystallised from chloroform/methanol.

MP: 224.6 Analysis: C12H9N3O = 211 Calculated: %C 68.24 %H 4.29 %N 19.89 Found: %C67.94 %H4.41 %N 19.85 IR Spectrum: Vmax (KBr disc) 3180 (OH), 1610, 1539, 1468,1451, 1413,1341,1331,1293,1 182,918, 880cm1.

Step B. Imidazo[1,2-a]quinoline-2-carbonitrile Imidazo[1,2-a]quinoline-2-carboxaldehyde oxime (2.0 g) in acetic anhydride (20 ml) was stirred under reflux for 3 hrs and then cooled overnight to room temperature. The mixture obtained was poured into a saturated sodium carbonate solution and the resultant mixture was extracted with chloroform. The chloroform extract was washed with sodium carbonate solution and with water, dried over magnesium sulphate, then evaporated to dryness under reduced pressure. The residue was triturated with diethyl ether and then filtered. Imidazo[l ,2-a]quinoline-2-carbonitrile (1.3 g) was obtained as pale yellow crystals M.P.

244.6 (recrystallised from chloroform/diethyl ether).

Analysis: C12H7N3 = 193 Calculated: %C 74.60 H% 3.65 %N 21.75 Found: %C 74.50 H% 3.79 %N 21.73 IR Spectrum: Vmax (KBr disc) 2209 (CEN), 1616, 1563, 1448, 1412, 1278, 1218, 1206, 1199, 1139 cm-1.

Step C: 2-(IH- Tetrazol-5-yllimidazo[ I, a-alquinoline Imidazo[1,2-a]quinoline-2-carbonitrile (1.0 g) in dimethylformamide (50 ml) was stirred at 40 during the addition of ammonium chloride (0.40 g) and sodium azide (0.45 g). The mixture obtained was stirred at 1000 under nitrogen for 16 hrs, treated again with ammonium chloride (0.20 g) and sodium azide (0.225 g) and then stirred at 1200 for 6 hours. A final addition of ammonium chloride (0.20 g) and sodium azide (0.225 g) was made and the resultant mixture was stirred at 1000 for 16 hours, then cooled to room temperature and treated dropwise with water (50 ml).The precipitate thus obtained was filtered off, washed with water, dried under vacuum over phosphorus pentoxide and recrystallised from chloroform/methanol. 2-(1 H-Tetrazol-5 yl)imidazo[1 ,2-a]quinoline was obtained as colourless crystals, [yield 0.92 g, M.P. 300-300.5 ] Analysis: C12H8N6 = 236 Calculated: %C 61.01 %H 3.41 %N 35.58 Found: %C 60.86 %H 3.52 %N 35.85 IR Spectrum: max (KBr disc) 3150-2400, 1631, 1618, 1541, 1510, 1450, 1341, 1204, 1078, 1066,950 cm- Example 8 Imidazo[1,2-a]quinoline-2-methanamine dihydrochloride Imidazo[1,2-a]quinaline-2-carboxaldehyde oxime (1.0 g) in 0.25 N methanolic HCI (100 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium on carbon (0.100 g). After 4 hrs absorption of hydrogen had ceased (175 ml used) and a further portion of catalyst (0.200 g) was added. The mixture obtained was again hydrogenated at atmospheric pressure at 50 for 2 hrs thereby absorbing a further 62 ml hydrogen. The resultant mixture was filtered through cellulose powder and concentrated under reduced pressure. Dry diethyl ether was added to the concentrate which was subsequently cooled in ice to effect crystallisation.The colourless solid thus formed was filtered off, dried under vacuum at 50 and recrystallised from methanol/diethyl ether to give colourless hygroscopic crystals of imidazo[1,2a]quinoline-2-methanamine dihydrochloride [yield 0.85 g, M.P. 320-5 d].

Analysis: C12H13N3Cl2, al H2O = 279 Calculated: %C 51.63 %H 5.05 %N 15.05 %CI 25.40 Found: %C 51.84 %H 4.99 %N 15.37 %CI 25.20 IR Spectrum: Vmax (KBr disc) 3540,3380,3100-2300, 1641, 1618, 1560, 1487, 1427, 1368, 1210, 1138, 1173 cm-'.

Examples 9, 10 and 11 Using a similar method to that used in Examples 5,6 and 7 products were prepared as in Table 1 below.

The starting product of Example 1 (Ethyl 5,8-dichloro-imidazo[1 ,2-a]quinoline-2-carboxylate) may be prepared as described in French Patent Specification No. 2378031.

Examples 12, 13 and 14 Using a similar method to that used in Example 5,6 and 7 products were prepared as in Table 1 below. The starting product of Example 12 (Ethyl 8-methoxy-imidazo[1,2-a]quinoline-2-carboxylate) may be prepared as described in French Patent Specification No.2378031.

Example 15 Using a similar method to that used in Example 8, a product was prepared as indicated in Table 1 below.

The starting product was that obtained in Example 14 (Step A).

TABLE 1A

Example Calculated Found no. R Z' R1 Formula mol %C %H %N %Cl %C %H %N %Cl 9 CH2OH Cl Cl C12H8N2OCl2 267 53.96 3.02 10.49 26.55 54.09 3.08 10.45 26.40 10 CHO Cl Cl C12H6N2OCl2 265 54.37 2.28 10.57 26.75 54.15 2.41 10.44 26.46 11 Step A CHNOH Cl Cl C12H7N3OCl2 280 51.45 2.52 15.00 25.31 51.78 2.71 14.89 25.47 11 Step B CN Cl Cl C12H5N3Cl2 262 54.99 1.92 16.03 27.05 54.81 2.02 15.99 11 Step C # Cl Cl C12H6N6Cl2 304 * 12 CH2OH H OCH3 C13H12N2O2 228 68.41 5.30 12.27 - 68.37 5.34 12.23 13 CHO H OCH3 C13H10N2O2 226 69.02 4.46 12.38 - 68.87 4.48 12.16 14 Step A CHNOH H OCH3 C13N11N3O2 241 64.72 4.60 17.42 - 64.38 4.81 17.18 14 Step B CN H OCH3 C13H9N3O 223 69.95 4.06 18.82 - 69.97 4.15 18.96 14 Step C # H OCH3 C13H10N6O 226 58.64 3.79 31.56 - 58.37 3.93 31.32 15 CH2NH2 H OCH3 C13H13N3O2HCl.11/2 327 47.71 5.54 12.84 21.67 47.40 5.55 12.98 21.56 H2O * Sample extremely insoluble in all solvents prohibiting satisfactory recrystalisation.

mass spectrum showed M+ -304.0015#5mmu.

C12H6N6Cl2 requires M+ = 304.0031 TABLE 1B

Example Recrystallisation Infra-red spectrum cm-1 (KBr disc) no. R Z' R1 M.P C solvent 9 CH2OH Cl Cl 207-10 EtOAc/Et2O 3320(OH), 1608, 1542, 1527, 1471w, 1440, 1396w, 1357, 1330, 1097, 1068, 1030, 993 10 CHO Cl Cl 280-5d CHCl3/Et2O 3137 (CH'), 2340(CHO), 1700(C=0), 1611, 1556.

1530, 1470, 1400, 1342, 1204, 1184, 1098, 1037, 1008 11 Stage A CHNOH Cl Cl 244-6 CHCl3/Et2O 3500-2700(OH's), 1645w(C=N), 1609s, 1535, 1440, 1390w, 1354, 1327, 1277, 1190, 1179, 1098s, 1020 11 Stage B CN Cl Cl 286-8 CHCl3 3130(CH')2211(C=N), 1608, 1551, 1528, 1431, 1342, 1325, 1300, 1183, 1094, 950 11 Stage C # Cl Cl 322-4 - 3140-3200, 1609, 1529, 1435, 1268, 1161, 1097, 1082, 1073, 1022, 951, 942 12 CH2OH H OCH3 173-5 EtOAc/Et2O 3105br(OH), 1630, 1550, 1490, 1441, 1408, 1372, 1347, 1286, 1246, 1170, 1150, 1036, 1013, 997 13 CHO H OCH3 190-3 CHCl3/Et2O 3100, 2840 (CHO), 1697, 1683, 1618, 1550, 1491, 1450, 1381, 1358, 1330, 1242, 1219, 1180, 1152, 1030, 992 14 Stage A CHNOH H OCH3 202-6 CHCl3/Et2O 3450(OH), 1627s, 1614, 1548, 1377, 1331, 1292, 1240s, 1218, 1187, 1132 14 Stage B CN H OCH3 212-4 CHCl3/Et2O 3150(CH), 2220(C=N), 1631, 1618, 1549, 1484, 1331, 1308, 1241, 1220, 1177, 1155, 1028

Example Recrystallisation Infra-red spectrum cm-1 (KBr disc) no. R Z' R1 M.P C solvent 14 Stage C # H OCH3 305-6 (CH3)2S=O 3000-2300, 1630, 1618, 1548, 1540, 1490, 1369, 1340, 1239, 1223, 1149, 1072, 1017, 951, 823 15 CH2NH2 H OCH3 CHl CH3OH/Et2O 3600-2400, 1650, 1624, 1612, 1503, 1480, 1384, salt 1248, 1228, 1106, 1019, 839 247-7 Example 16 N-( 1K- Tetrazol-5-y/)imidazo[ 1,2-aiquin oline-2-carboxamide Imidazo[1,2-a]quinoline-2-carboxylic acid (prepared as in French Patent Specification No. 2378031(0.85 g 4mmole) was heated under vacuum at 160 for 1 hr to remove water of crystallisation then dissolved in dimethylformamide (25 ml). The solution obtained was stirred at 90-100" and treated with carbonyldiimida- zole (0.72 g, 4.4mmole). The resultant mixture was stirred at 1000 for 40 minutes after which time a slight suspension had formed.Previously dried 5-aminotetrazole (0.375 g, 4.4mmole) was added thereto and the mixture obtained was stirred at 1000 for 45 minutes then allowed to cool to room temperature. The cooled mixture was treated with ethyl acetate (20 ml), cooled in ice and then filtered to give N-(1 H-tetrazol-5 yl)imidazo[1 ,2-a]quinoline-2-carboxamide as colourless crystals, (yield 1.12 g). The product was recrystallised from dimethylformamide m.pt. 266-8".

Example 17 Using a similar method to that used in Example 16 a product was prepared as indicated in Table 2 below.

The starting product (8-methoxy imidazo[1 ,2-a]quinoline-2-carboxylic acid) may be prepared as described in French Patent Specification No.2378031.

Example 18 lmidazo[1,2-a]quinolin e-2-carb oxamide Ethyl imidazo[1,2-a]quinoline-carboxylate (prepared as in French Patent Specification No. 2378031(2.0 g) was added to a solution of sodium (0.100 g) in ethanol (500 ml). The solution obtained was stirred under a slow stream of ammonia gas for 30 minutes, stoppered and allowed to stand at room temperature for 1 week. The resultant mixture was filtered to give imidazo[1,2-a]quinoline-2-carboxamide (0.60 g) as colourless plates (m.pt. 270.10). The filtrate was concentrated under reduced pressure to 50 ml and diluted with water (700 ml). The mixture thus obtained was filtered to give a further 0.50 g of the title compound.The initially precipitated product was analytically pure, the remainder was recrystallised from chloroform/ methanol/diethyl ether.

Example 19 Using a similar method to that used in Example 18, a product was prepared as indicated in Table 2 below.

The starting product (Ethyl 8-methoxyimidazo[1 ,2-a]quinoline-2-carboxylate) may be prepared as described in French Patent Specification No.2378031.

TABLE 2

ANALYSIS Example Calculated Found no. R2 R1 Formula Mol/Wt %C %H %N %C %H %N 16 # H C13H9N7O 279 55.91 3.25 35.11 55.74 3.40 34.91 17 # OCH3 C14H11N7O21/2H2O 318 52.83 3.80 30.80 53.19 3.82 31.12 18 H H C12H9N3O 211 68.24 4.29 19.89 68.00 4.33 19.87 10 H OCH3 C13H11N3O2 241 64.72 4.60 17.42 64.62 4.60 17.38 Example no. R2 R1 M.P C Recryst. solvent Infran-red cm-1 (KBr disc) 16 # H 266-8 D.M.F. 3410(NH), 3110, 1677 (C=O), 1586, 1397.

1252, 993, 800 17 # OCH3 298-301 F.M.F. 3490 (NH), 3110, 1693, 1635, 1622, 1599, 1551, 1241 18 H H 270-1 CHCl3/CH3OH/Et2O 3360(NH2), 3302(NH2), 1662b(C=0), 1616, 1580, 1540, 1391, 1358, 1335, 1318, 1278, 1200 19 H OCH3 273-6 - 3260, 3150, 1700, 1672, 1630, 1616, 1570, 1540, 1391, 1338, 1278, 1237 Example 20 5-Ethyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-methanol A solution of ethyl 5-ethyl-4,5-dihydro-4-oxo-imidazo[1,2-a]quinoxaline-2-carboxylate (3.13 g) in dry tetrahydrofuran (80mls) was stirred under reflux for twenty hours with lithium borohydride (0.5 g). The suspension obtained was then poured into dilute hydrochloric acid and the resultant mixture was stirred for ten minutes to break down the boron complex. The clear pale yellow solution thus formed was basified with sodium carbonate then extracted with ethyl acetate. The solvent was evaporated off to give the hydroxymethyldihidroimidazoquinoxaline as a buff crystalline solid (1.93 g). The product was recrystallised from ethanol to give white shiny plates (MP 160-5 , dec).

Analysis: C13H,5N3O = 229 Calculated: %C 68.10 %H 6.59 %N 18.33 Found: %C 67.85 %H 6.63 %N 18.27 Example 21 5-Ethyl-2-hydroxymethylimidazo[1,2-a]quinoxalin-4(5H)-one A solution of ethyl 5-ethyl-4,5-dihydro-4-oxoimidazo[1,2-a]quinoxaline-2-carboxylate (4 g) in dry tetrahydrofuran (105 mls) was treated with excess lithium borohydride (0.65 g), and the resultant mixture was stirred overnight just below reflux temperature. The suspension thus obtained was poured into dilute hydrochloric acid and the clear solution thus formed was stirred for a few minutes, then basified with sodium carbonate.The resultant solution was extracted with ethyl acetate and the solvent was evaporated off to give an orange/red solid (2.6 g) which was triturated with ethanol to yield the hydroxymethylquinoxalinone as a buff crystalline solid (0.9 g). The ethanol filtrate contained mainly dihydroimidazoquinoxaline. On standing the aqueous residues (after ethyl acetate extraction) for two days, a second crop of hydroxymethylquinoxalinone separated out as grey/white shiny needles (0.55 g). The combined crops of 5-ethyl-2 hydroxymethylimidazo[1,2-a]quinoxalin-4(5H)-one (1.45 g) were recrystallised from ethanol to give a white crystalline solid (MP 215-8").

IR Spectrum (KBr) - VOH = 3400cm-1 (CH20H) VCH = 311 cm (imidazole CH) vco = 1655cm-1 (amide CO) Analysis: C13H13N302 = 243 Calculated: %C 64.19 %H 5.39 %N 17.27 Found: %C64.12 %H5.49 %N17.26 Example 22 5-Ethyl-4,6-dihydro-4-oximidazo[1,2-a]quinoxaline-2-carboxaldehyde A solution of the hydroxymethylimidazoquinoxalinone of Example 21 (1.0 g) in chloroform (200 mls) was treated with manganese dioxide (3 g) and the resultant mixture was stirred under reflux for one hour. The mixture was then cooled and the manganese dioxide was filtered off through celite. The solvent was evaporated off leaving the imidazoquinoxalinonealdehyde as a white crystalline solid (0.61 g).The product was recrystallised from ethanol/chloroform to give a white crystalline solid (MP 302-6 , dec.).

Analysis: C13HllN302 = 241 Calculated: %C 64.72 %H 4.60 %N 17.42 Found: %C 64.64 %H 4.82 %N 17.20 Example 23 5-Ethyl-2-(1H-tetrazol-5-yl)imidazo-[1,2-a]quinoxalin-4-(5H-one Step A 5-Eth yl-4, 5-dihydro-4-oxoimidazo[ 1,2.a]quinoxa/ine-2-carboxa/dehyde oxime A suspension of the imidazoquinoxalinone aldehyde of Example 22 (0.5 g) in ethanol (10 mls) was treated with a solution of hydroxylamine hydrochloride (0.2 g) and sodium acetate (0.25 g) in water (2 mls), and the suspension obtained was stirred for 4 hours at 90". The white crystalline solid which separated out was filtered off, washed with water and dried in vacua. The product was pure 5-ethyl-4,5-dihydro-4-oxoimidazo [1,2-a]quinoxaline-2-carboxaldehyde oxime (0.435 g).

MP 286-8".

Step B 5-EThyl-4,5-dihydro-4-oxoimidazo[1,2-a]quinoxaline-2-carbonitrile A solution of the imidazoquinoxalinone oxime (0.4 g) in acetic anhydride (5 mls) was heated under reflux for 2- hours then cooled, when it set to a buff crystalline solid. The product was triturated with sodium carbonate solution, filtered off, washed with water and dried in vacuo to give 5-ethyl-4,5-dihydro-4 oxoimidazo[1 ,2-a]quinoxaline-2-carbonitrile as a buff crystalline solid (0.385 g). MP > 330".

IR Spectrum (KBr) -VCN = 2225cm-1 (C-N stretch).

Step C 5-Ethyl-2-(1H-tetrazol-5-yl)-imidazo[1,2-a]quinoxalin-4(5H)-one A solution of the imidazoquinoxalinone nitrile (0.35 g) in dimethylformamide (15mls) was stirred overnight at 100 with ammonium chloride (0.11 g) and sodium azide (0.12 g). The resultant suspension was cooled and poured into ice/water. 5-Ethyl-2-(1 H-tetrazol-5-yl)imidazo[1,2-a]quinoxalin-4(5H)-one separated out as a buff crystalline solid (0.29 g). The product was recrystallised from chloroform/methanol to give an off-white crystalline solid (MP 298-300 ).

Analysis: C13H11ON7 = 289 Calculated: %C 55.51 %H 3.94 %N 34.86 Found: %C 55.54 %H 3.96 %N 34.00 Example 24 5-Eth yl-2-h ydroxymeth yIp yrrolofl,2-ajquin oxalin-4-(5K)-one Ethyl 4,5-dihydro-b-ethyl-4-oxopyrrolo[1,2-a]quinoxaline-2-carboxylate prepared as in French Patent Specification No.2387230 (7.8 g, 27.5 mmole) was suspended in dry THF (500 ml) and lithium borohydride (3.5 g, 160 mmole) was added thereto. The mixture obtained was stirred at room temperature for about twelve hours, then heated under reflux for two hours. On cooling the THF was evaporated off down to a volume of 100 ml and dilute HCI was added thereto. When the evolution of gases had ceased, the mixture obtained was neutralized with sodium bicarbonate, then extracted (x3) with ethyl acetate.The combined ethyl acetate extract was dried, filtered and evaporated to dryness. Trituration from chloroform/ethyl acetate gave the product in two crops (5.90 g).

Melting point 171-3 C.

[R 1251, 1405, 1624, 3125, 3420cm-1 Analysis: C14H14N202 = 242 Calculated; %C69.41, %H5.82, %N 11.56 Found: %C69.32, %H 5.89, %N 11.60 Example 25 5-Ethyl-4,5-dihydro-4-oxopyrrolo[1,2-a]quinoxaline-2-carboxaldehyde The alcohol of Example 24 (5.0 g, 20.6 mmole) was dissolved in chloroform (500 ml) and manganese dioxide (activated) (40 9) was added thereto. The mixture was stirred vigorously for three hours, then filtered through celite and evaporated down. Trituration with ether gave the product as colourless needles, 3.9 g, 80% yield. Melting point 252-5 C.

IR 751, 1646, 1686, 3115 cm-1.

Analysis: C14H12N202 = 240 Calculated: % C 69.99, %H 5.03, %N 11.66 Found: %C69.69, %H 5.13, %N 11.60 Example 26 5-Ethyl-2-(1H-tetrazol-5-yl)pyrrolo[1,2-a]quinoxaline-4(5H)-one Step A 5-Ethyl-4,5-dihydro-4-oxopyrrolo[1,2-a]quinoxaline-2-carboxaldehyde oxime The aldehyde of Example 25 (3.4 g, 14.1 mmole) was suspended in water/ethanol (20 ml/40 ml) and sodium acetate (2 g, 24.4 mmole) and hydroxylamine hydrochloride (1.5 g, 21.6 9 mmole) were added thereto. The mixture obtained was warmed on a water bath for one hour, then reduced in volume to about 20 ml. The oxime product crystallised out as colourless needles and was collected, washed with a little water and dried over P205 under vacuum, (2.9 9). Melting Point 262-4"C.

IR 738, 1410, 1635, 3220 cm-1.

Analysis: C14H13N302 = 255 Calculated: % C65.87. %H 5.13, %N 16.46 Found : %C 65.94, %H 5.27, %N 16.29 Step B 5-Ethyl-4,5-dihydro-4-oxopyrrolo[1,2-a]quinoxaline-2-carbonitrile The oxime (2.5 g, 9.8 mmole) was heated under reflux for three hours in acetic anhydride (40 ml). The resultant mixture was then poured onto water/sodium carbonate/ethyl acetate. The ethyl acetate layer was separated, washed once with water, dried, filtered and evaporated down. Trituration with ether gave the product as buff needles (1.8 g). Melting point 237-9 C.

IR 745, 1413,1655,2220,3120 cm-1.

Analysis: C14H11N3O = 239 Calculated: %C 70.87, %H 4.67, %N 17.71 Found: %C 70.83, %H 4.76, %N 17.85 Step C 5-Ethyl-2-(1H-tetrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4(5H-one The cyanide (1.3 g, 5.5 mmole) was suspended in dimethylformamide (50 ml) and ammonium chloride (0.425 g, 8.0 mmole) and sodium azide (0.48 g, 7.4 mmole) were added thereto. The mixture obtained was stirred at 130-140 C for twelve hours, then cooled and diluted with water (200 ml). The crude product was.

filtered off and recrystallised from methanol/ethyl acetate, to give off-white crystals (0.74 g) 48% yield.

Melting Point 295-7 C. (decomp.).

IR 740, 1389, 1440, 1591, 1630, 3120 cm-1.

Analysis: Ca4H,2N6O = 280 Calculated: %C 59.99, %H 4.32, %N 29.98 Found: %C 59.39, %H, 4.36, %N 29.63 Example 27 5-Ethyl-4,5-dihydro-4-oxo-N-(1H-tetrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide 5-Ethyl-4,5-dihydro-4-oxopyrrolo[1,2-a]quinoxaline-2-carboxylic acid prepared as in French Patent Specification No. 2387230 (1.2 g, 4.7 mmole) was suspended in dry dimethylformamide (25 ml) and carbonyldiimidazole (0.81 g, 5.0 mmole) was added thereto. The resultant mixture was stirred until a clear solution was obtained. Anhydrous 5-amino tetrazole (0.425 g, 5.0 mmole) was then added thereto and after stirring at room temperature for half an hour a white crystalline precipitate was formed.The product was filtered off, washed with ethyl acetate and dried under vacuum over P2O5. Yield 1.4 g, Melting Point 315-8"C.

IR 747, 1276, 1599, 1672, 3130 cm-1.

Analysis: C15H13N702 = 331 Calculated: %C 55.72, %H 4.05, %N 30.33 Found: %C 55.57, %H 4.07, %N 30.42 Example 28 4H-Imidazo[2,1-c][1,4]benzoxazine-2-methanol Methyl 4H-imidazo[2,1-c] [1,4jbenzoxazine-2-carboxylate prepared as in French Patent Specification No.

2351980, (23 g, 0.1 mole) was stirred in dry redistilled tetrahydrofuran (250 ml) at room temperature, whilst solid lithium borohydride (6.0 g, 30% excess) was added thereto. The reaction was initially allowed to become warm (c. 70 C), then was stirred at room temperature for five hours. The resultant mixture was poured into dilute hydrochloric acid and the pH was adjusted to 1-2. The solution thus obtained was stirred until evolution of gases had ceased and then neutralised with sodium bicarbonate. The resultant solution was extracted three times with ethyl acetate and the combined ethyl acetate extract was dried, filtered and evaporated to a small volume. Ether was added and the product formed was filtered off and dried under vacuum over P205. Yield 18.3 g, melting point 167-8 C. (Colourless needles).

Analysis: C11H10N2O2 = 202 Calculated: %C 65.34 %H 4.98 %N 13.85 Found: %C65.14 %H5.11 %N13.73 IR Spectrum KBr: 736, 1238, 1445, 1541, 1606, 3000-3300cm-'.

Example 29 4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxaldehyde The alcohol of Example 28 (4.9 g, 24 mmole) was stirred at room temperature with activated manganese dioxide (30 g) in chloroform (200 ml) for three hours. The mixture obtained was filtered, the filter pad being well washed with chloroform. The combined chloroform extract was evaporated down. Trituration with ether gave the product as colourless needles.

Yield 3.9 g, melting point 180-20C.

Analysis: C11H8N3O3 = 200 Calculated: %C 66.00 %H 4.03 %N 13.99 Found: %C65.74 %H4.15 %N 13.91 IR Spectrum KBr 755, 1039, 1509, 1598, 1560 cm-1 Example 30 4H-2-(1H-Tetrazol-5-yl)imidazo[2,1-c][1,4]benzoxazine Step A 4H-lmidazo[2, 1-c][1,4]benzoxazine-2-carboxaldehyde oxime The aldehyde of Example 29 (2.0 g, 10 mmole) was suspended in ethanol (50 ml) and a solution of hydroxylamine hydrochloride (0.80 g, 11.5 mmole) and sodium acetate (1.1 g, 13.5 mmole) in water (20 ml) was added thereto. The mixture obtained was warmed on a water bath for half an hour until TLC showed no aldehyde remaining. The resultant mixture was cooled and the volume was reduced to about 20 ml.The oxime crystallised out and was collected, washed with a little water and dried under vacuum over P205. Yield 2.05 g, melting point softens 210"C, melts 232-3"C. (Colourless needles).

Analysis : C11H9H8O2 = 215 Calculated: %C 61.39 %H 4.22 %N 19.52 Found: %C 61.49 %h 4.32 %n 19.60 IR Spectrum KBr: 747, 1250, 1518, 2500-3300 cm-1 Step B 4H-Imidazo[2,1-c] [1,4] benzoxazine-2-carbonitrile The oxime prepared in Step A (1.90 g, 8.8 mmole) was heated under reflux for three hours in acetic anhydride (20 ml). The mixture obtained was poured onto water Na2/CO3/EtOAc. The ethyl acetate layer was extracted, washed once with water, dried, filtered and evaporated down. Trituration with ether gave a crystalline product as buff needles (1.45 g), melting point 226-8 C.

Analysis: C11H7N3O = 137 Calculated: %C 67.00 %H 3.58 %N 21.31 Found: %C 66.70 %H 3.69 %N 21.18 IR Spectrum KBr: 754, 1033, 1237, 1509, 1552, 2225, 3120cm-' Step C 4H-2-(1H-Tetrazol-5-yl)imidazol[2,1-c] [1,4]benzoxazine The carbonitrile prepared in Step B (1.05g) was dissolved in dimethylformamide (50ml) and sodium azide (450mg) and ammonium chloride (400mg) were added thereto. The mixture obtained was stirred at 1250C in an oil bath for 24 hours, then cooled and diluted with water (200 ml).The crude product thus formed was filtered off, dried under vacuum over P205 then recrystallized from methanol with decolourising charcoal to give off-white needles (0.55 g) melting point 282-5 C.

Example 31 5-Ethyl-2-hydroxymethylimidazo[1,2-a]quinoxalin-4(5H)-one hydrochloride 5-Ethyl-2-hydroxmethylimidazo[1,2-a] quinoxalin-4(5H)-one, prepared as described in Example 21 (2.0 g) was suspended in hot methanol (49 ml) and concentrated hydrochloric acid (1.0 ml) was added thereto. The solution obtained was filtered hot and the filtrate was treated with ethyl acetate (20 ml). The resultant mixture was cooled to 0 C and then filtered to give 5-ethyl-2-hydroxymethylimidazo[1,2-a]-quinoxalin-4(5H)one hydrochloric (2.0 g) as colourless crystals, melting point 224-6 C.

Analysis: C13H13N302 HCI. = 279.5 Calculated: %C 55.81 %H 5.05 %N 15.02 %CI 12.67 Found: %C 55.88 %H 5.11 %N 15.02 %CI 12.64 IR Spectrum KBr: OH = 3260 cm-' CO = 1678 cm-' 1579, 1547, 1380, 1370, 1077 cm-1 Example A The ethyl imidazo[1,2-a]quinoline-2-carboxylate of Example 1 and the imidazo[1,2-a]quinoline-2 carboxylic acid of Example 4 may be prepared according to the following method: Step A: 2-Amino- 1-carbethoxycarbonylmethylquinoxalinium bromide A solution of 2-aminoquinoxaline (0.9 g) and ethyl bromopyruvate (1.25 g) in dimethoxyethane (25 mls) was stirred overnight at room temperature to give the quaternary salt as a pale yellow crystalline solid (1.58 9).

Step B: Ethyl imidazo[1,2-a]quinoxaline-2-carboxylate A suspension of 1-carbethoxycarbonylmethyl-2-aminoquinoxalinium bromide (0.4g) in ethanol (15 mls) was refluxed for 2 hours to give a clear orange solution. Concentration of the solution to half its volume gave ethyl imidazo[l ,2-a]quinoxaline-2-carboxylate as a pale yellow crystalline solid (0.25 g). Recrystallisation from ether/methanol gave soft white needles (MP 184-7 (sealed tube)).

Analysis : C13H11N3O2 = 241 Calculated: %C 64.72 %H 4.60 %N 17.42 Found: %C 64.80 %H 4.66 %N 17.47 Step C: Imidazo[1,2-a]quinoline-2-carboxylic acid A suspension of ethyl imidazo[1 ,2-a]quinoline-2-carboxylate (0.63 g) in water (30 mls) and ethanol (10 mls) was treated with IN sodium hydroxide solution (10 mls). The mixture obtained was refluxed for 1 hour to give a clear yellow solution.The ethanol was removed in vacuo and the resultant aqueous solution was acidified with concentrated hydrochloric acid. lmidazo[1,2-a]quinoline-2-carboxylic acid separated out as a buff crystalline solid (0.6 g.) M.P.274-5 Analysis: C11H7N302 = 213 Calculated: %C61.97 %H3.31 %N 19.71 Found: %C 61.82 %H 3.33 %N 19.71 Example B The ethyl 5-ethyl-4,5-dihydro-4-oxoimidazo[1,2-a]quinoxaline-2-carboxylate of Example 20 may be prepared according to the following method: Step A 2-Amino-3-chloroquinoxaline From 2,3-dichloroquinoxaline and ammonia in ethanol heated under pressure by the method of Saikachi & BR< Tagami - Chem. Pharm. Bull. Tokyo (1961)9,941.

Step B 2-Amino-1-carbethoxycarbonylmethyl-3-chloroquinoxalinium bro Asolution of 2-amino-3-chloroquinoxaline (9 g) and ethyl bromopyruvate (12 g) in dimethoxyethane (180 mis) was stirred overnight to give the quatenary salt as a pale yellow crystalline solid (5.33 g). On standing the filtrate in a fridge for several days, two further batches quaternary salt were obtained (1.20 g and 3.62 g).

Total yield of salt = 10.22 g.

Step C Ethyl 4,5-dihydro-4-oxoimidazo[1,2-a]quinoxaline-2-carboxylate A suspension of the quaternary salt obtained in Step B (5 g) in ethanol (500 mls) was stirred under reflux for two hours to give a clear yellow solution which was concentrated and cooled in a fridge. The oxoimidazoquinoxaline separated out as a white crystalline solid (3.70 g). The product was recrystallised from ethanol to give white shiny crystals (MP 293-3 ).

Step D Ethyl 5-ethyl-4,5-dihydro-4-oxoimidazo[1,2-a] quinoxaline-2-carboxylate A solution of the oxoimidazoquinoxaline ester obtained in Step C (0.7 g) in dimethylformamide (30 mis) was treated with excess sodium hydride (0.1 g, 80% oil dispersion) and the solution obtained was stirred for ten minutes to give a gelatinous precipitate of the sodium salt. Excess ethyl iodide (0.6 g) was added and the resultant mixture was stirred for 3 hours to give a clear yellow solution which was poured onto ice. The N-ethyl derivative was obtained as a soft white solid (Yield: 63%). The product was recrystallised from ethanol to give white shiny micro-needles (MP 216-8 .

Analysis: C15H15N3O3 = 285 Calculated: %C63.15 %H5.30 %N 14.73 Found: %C 63.06 %H 5.26 %N 14.78 Example I Tablets were prepared corresponding to the formulation: 2-(1 H-tetrazol-5-yl)imidazo[1,2-a]quinoxaline 5 mg.

Excipient q.s. for one tablet up to .................... 100 mg (Detail of the excipient: lactose, starch, talc, magnesium stearate).

Example II Tablets were prepared corresponding to the formulation: 2-(1 H-tetrazol-5-yl)imidazo[1,2-a]quinoline ......................... 20 mg Excipient q.s. for one tablet up to ...................... 100 mg (Detail of excipient: lactose, starch, talc, magnesium stearate).

Example Ill Tablets were prepared corresponding to the formulation: imidazo[1,2-a]quinoxaline-2-methanol 25 25 mg Excipient q.s. for one tablet up to ................. 100 mg (Detail of excipient: lactose, starch, talc, magnesium stearate).

Claims (61)

1. Compounds of general formula

wherein A represents a nitrogen atom or a group of formula =CH-; G represents an oxygen atom -0- or a group of formula

(in which Z represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or, together with Y a carbon-nitrogen or carbon bond and Z' represents a hydrogen or halogen atom); Y represents a hydrogen atom or, together with Z when G represents a group of formula

a carbon-nitrogen or carbon-carbon bond, or, together with X, a keto group; X represents a hydrogen atom or, together with Y, a keto group; R represents a hyd roxymethyl, formyl, tetrzol-5-yl, N-(tetrazol-5-yl)carbamoyl, aminomethyl or carbamoyl radical; and R1 represents a hydrogen or halogen atom or an alkoxy radical containing from 1 to 5 carbon atoms; and acid addition thereof.

2. Compounds as claimed in claim 1 wherein R represents a hydroxymethyl, formyl or tetrazol-5-yl radical.

3. Compounds as claimed in claim 2 wherein R represents a hydroxymethyl ortetrazol-5-yl radical and R, represents a hydrogen atom.

4. 2-(1 H-Tetrazol-5-yl)imidazo[1,2-a]quinoxaline and acid addition salts thereof.

5. 2-(1 H-Tetrazol-5-yl)imidazo[l ,2-a]quinoline and acid addition salts thereof.

6. 8-Methoxy-2-(1 H-tetrazol-5-yl)imidazo[l ,2-a]quinoline and acid addition salts thereof.

7. Imidazo[l,2-a]quinoxaline-2-methanol and acid addition salts thereof.

8. 5-Ethyl-2-hydroxymethylimidazo[l ,2-a]quinoxalin-4(5H)-one and acid addition salts thereof.

9. 5-Ethyl-2-hydroxymethylpyrrolo[1,2-a]quinoxalin-4(5H)-one and acid addition salts thereof.

10. Physiologically compatible acid addition salts of compounds of general formula I as defined in any preceding claim.

11. Compounds as claimed in claim 1, other than those claimed in any one of claims 4 to 9, as herein specifically disclosed in any one of Examples 1 to 30.

12. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R represents a hydroxymethyl radical which comprises reducing a compound of formula II,

(wherein A, G, Y, X and R1 are as defined in claim 1 and Alk represents an alkyl radical containing from 1 to 5 carbon atoms) whereby the desired compound of formula I is obtained.

13. A process as claimed in claim 12 wherein reduction is effected by means of a complex metal hydride.

14. A process as claimed in claim 12 or claim 13 wherein the reduction is effected in the presence of an ether as solvent.

15. A process as claimed in any of claims 12 to 14 wherein the reduction is effected at the boiling point of the reaction mixture.

16. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R represents a formyl radical which comprises oxidising a compound of formula I as defined in claim 1 (wherein R represents a hydroxymethyl radical) whereby the desired compound of formula I is obtained.

17. A process as claimed in claim 16 wherein oxidation is effected by means of manganese dioxide or chromic oxide.

18. A process as claimed in claim 16 or claim 17 wherein the oxidation is effected at elevated temperatures.

19. A processforthe preparation of compounds of general formula las defined in claim 1 wherein R represents an aminomethyl radical which comprises catalyically hydrogenating a compound of formula Ill,

(wherein A, G, Y, X and R1 are as defined in claim 1).

20. A process as claimed in claim 19 wherein hydrogenation is effected with hydrogen in the presence of a metal catalyst.

21. A process as claimed in claim 20 wherein the catalyst is palladium.

22. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R represents a tetrazol-5-yl radical which comprises reacting a compound of formula IV,

(wherein A, G, Y, X and R, are as defined in claim 1) with sodium azide).

23. A process as claimed in claim 22 wherein the reaction is effected at elevated temperatures.

24. A process as claimed in claim 22 or claim 23 wherein the reaction is effected in the presence of a weak acid.

25. A process as claimed in any one of claims 22 to 24 wherein the compound of formula IV is obtained by reaction of a compound of formula Ill as defined in claim 19 with acetic anhydride.

26. A process as claimed in any one of claims 19 to 21 and 25 wherein the compound of formula Ill is obtained by reaction of a compound of formula I as defined in claim 1 (wherein R represents a formyl group) with hydroxylamine.

27. A process as claimed in claim 26 wherein the hydroxylamine is used in the form of its hydrochloride.

28. A process as claimed in claim 26 or claim 27 wherein the reaction is effected at elevated temperatures.

29. A process as claimed in any one of claims 26 to 28 wherein the reaction is effected in the presence of sodium acetate.

30. A process for the preparation of compounds of general formula i as defined in claim 1 wherein R represents a N-(tetrazol-5-yl)carbamoyl radical which comrpises reacting a compound of formula V,

(wherein A, G, Y, X and R1 are as defined in claim 1) or a reactive derivative thereof with 5-aminotetrazole.

31. A process as claimed in claim 30 wherein an acid halide of the acid of formula V is reacted with the 5-aminotetrazole.

32. A process as claimed in claim 30 or claim 31 wherein the reaction is effected in the presence of a carbodiimide reagent.

33. A process as claimed in any one of claims 30 to 32 wherein the reaction is effected in the presence of dimethylformamide as solvent.

34. A process as claimed in any one of claims 30 to 33 wherein the compound of formula V is obtained by hydrolysis of a compound of formula II as defined in claim 12.

35. A process for the preparation of compounds of general formula las defined in claim 1 wherein R represents a carbamoyl radical which comprises reacting a compound of formula II as defined in claim 12 with ammonia.

36. A process as claimed in any one of claims 12 to 15 and 35 for the preparation of compounds of general formula I wherein A represents a nitrogen atom and G represents a group of formula

wherein the compound of formula II is obtained by cyclisation of a compound of formula VI,

(wherein R, Y, X and Z are as defined in claim 1, Alk is as defined in claim 12 and Hal represents a chlorine or bromine atom.

37. A process as claimed in claim 36 wherein cyclisation is effected by means of heating the reaction mixture under reflux.

38. A process as claimed in claim 36 or claim 37 wherein the compound of formula VI is obtained by reaction of a compound offormula Vll, Hal-CH2-CO-COOAlk (Vll) (wherein Alk is as defined in claim 12 and Hal is as defined in claim 36) with a compound of formula VIII,

(wherein Rr, Y, X and Z are as defined in claim 1).

39. A process as claimed in claim 38 wherein the reaction of the compound of formula VII with the compound of formula VIII is effected in the presence of an organic solvent.

40. A process as claimed in claim 34 wherein the compound of formula II is obtained as defined in any one of claims 36 to 39.

41. A process for the preparation of acid addition salts of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula I as defined in claim 1 with an acid.

42. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

43. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 30.

44. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in Example 31.

45. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 12 to 33,35 to 39,41 and 43.

46. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 34,40,42 and 44.

47. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim 1 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

48. Compositions as claimed in claim 47 in a form suitable for oral, rectal or parenteral administration.

49. Compositions as claimed in claim 47 or claim 48 in the form of plain tablets, coated tablets, gelatin capsules, grannules, suppositories or solutions.

50. Compositions as claimed in any one of claims 47 to 49 in the form of dosage units.

51. Compositions as claimed in claim 50 wherein each dosage unit contains from 0.25 to 50 mg of active ingredient.

52. Compositions as claimed in claim 51 wherein each dosage unit contains from 0.25 to 30 mg of active ingredient.

53. Compositions as claimed in any one of claims 47 to 52 wherein the active ingredient comprises a compound as claimed in any one of claims 4 to 9.

54. Pharmaceutical compositions as claimed in claim 47 substantially as herein described.

55. Pharmaceutical compositions substantially as herein described in any one of Examples I to ill.

56. Compounds of general formula I as defined in claim 1 and their physiologically compatable acid addition salts for use as anti-allergic agents.

57. Compounds of general formula Ill as defined in claim 19.

58. A process for the preparation of compounds as claimed in claim 57 substantially as herein described.

59. Compounds of general formula IV as defined in claim 22.

60. A process for the preparation of compounds as claimed in claim 59 substantially as herein described.

61. Each and every novel method, process, compound and composition herein disclosed.