IE48611B1 - Imidazo(1,2-a)quinoxaline derivatives - Google Patents

Abstract

Compound of general formula I, wherein R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms; X represents a hydrogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a carbamoyl group; and Y and Z, which may be the same or different, each represents a hydrogen or a halogen atom, and the salts thereof which compounds possess anti-allergic activity.

Description

This invention relates to new imidazoquinoxalines and the salts thereof as well as 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 I, (wherein R represents a hydrogen atom or an alkyl radical 10 containing from 1 to 5 carbon atoms; X represents a hydrogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a carbamoyl group; and Y and Z, which may be the same or different, each 15 represents a hydrogen or a halogen atom) and the salts . thereof· It will be appreciated that the alkyl and alkoxy radicals referred to throughout the present specification, having three or more carbon atoms, may be straight or branched chain alkyl or alkoxy radicals.

Thus, for example, R may represent a hydrogen atom or a methyl, ethyl, propyl, butyl or pentyl radical. X may, for example, represent a hydrogen atom or a methoxy, ethoxy, propoxy, butoxy or pentyloxy radical.

Y and Z, which may be the same or different, may each represent, for example, a hydrogen, chlorine or bromine atom.

The compounds of general formula I may form acid addition salts with strong acids, such as, for example hydrochloric, hydrobromic, hydriodic, nitric or sulfuric acid, alkanesulphonic acids e.g. methanesulphonic acid or arylsulphonic acids e.g.benzenesulphonic acid: the esters of formula I in which R represents an alkyl radical may also form salts with weak acids such as e.g. acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxalic or aspartic acid.

The compounds of general formula I wherein R represents a hydrogen atom may form salts with metals or bases e.g. nitrogenous bases. Metal salts may, for example, be formed with alkali metals, e.g. sodium, potassium or lithium, with alkaline earth metals, e.g. calcium, or with metals such as, for example, magnesium or aluminium.

Addition salts which may be formed with nitrogenous bases include, for example, ammonium salts and salts formed with amines such as lysine, arginine, triethanolamine and tris(hydroxymethyl)aminomethane.

The compounds of general formula X and their 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 salts but other salts may find use, for example, as intermediates in the preparation of compounds of general formula I and their physiologically compatible salts.

Preferred compounds according to the invention 10 include compounds of formula I wherein R represents a hydrogen atom or an ethyl radical, X represents a hydrogen atom or an ethoxy radical and Y and Z, which may be the same or different, each represents a hydrogen or chlorine atom and the salts thereof and in particular compounds of formula I wherein R represents a hydrogen atom, X represents a hydrogen atom or an ethoxy radical and Y and Z, which may be the same or different, each represents a hydrogen or chlorine atom and the salts thereof especially those compounds of formula I wherein R, X and Z each represents a hydrogen atom and Y represents a hydrogen or chlorine atom and the salts thereof.

Particularly preferred compounds according to the invention are the following: imidazo[l,2-a]quinoxaline-2-carboxylic acid, ethyl 7,8-dichloroimidazo[l,2-a]quinoxaline-2carboxylate, 7,8-dichloroimidazo[l,2-a]quinoxaline-2-carboxylic acid, 7-chloroimidazo[l,2-a]quinoxaline-2-carboxylic acid, 8-chloroimidazo[l,2-a]quinoxaline-2-carboxylic acid, 4-ethoxyimidazo[l,2-a]quinoxaline-2-carboxylic acid, and 4-carbarooylimidazo[l,2-a]quinoxaline~2-carboxylic acid and 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. for the preparation of compounds of general formula I wherein R represents an alkyl radical containing from 1 to 5 carbon atoms, the cyclisation of a compound of the formula Θ ch7-co-coor' »1 z N.

IV (wherein X, Y and Z are as hereinbefore defined, R* represents an alkyl radical containing from 1 to 5 carbon atoms and Hal represents a halogen atom e.g. a chlorine or bromine atom) whereby a compound of formula I (wherein R represents an alkyl group with 1 to 5 carbon atoms)is obtained.

Cyclisation is conveniently effected by heating, preferably by heating at the reflux temperature of the reaction mixture, advantageously in the presence of an organic solvent such as an alcohol with, 1 to 5 carbon atoms, for example ethanol.

The compound of formula IV may, if desired, be obtained by reaction of a compound of formula: (wherein X, Y and 2 are as hereinbefore defined) with a compound of formula III, Hal - CH2 - GO - COOR' (III) (wherein Hal and R1 are as hereinbefore defined) whereby a compound of formula IV (as hereinbefore defined) is obtained.

The reaction is preferably effected in the presence of an organic solvent such as, for example, dimethoxyethane or tetrahydrofuran.

B. for the preparation of compounds of general formula I wherein R represents a hydrogen atom: Hydrolysis of a compound corresponding to a compound of formula I above (wherein X, Y and Z are as hereinbefore defined an alkyl and R may in this instance be/as hereinbefore defined or may 15 represent an alkyl radical containing more than 5 carbon atoms).

A compound of formula I is preferably used in which R represents an alkyl radical with 1 to 5 carbon atoms. Hydrolysis is preferably effected by means of an alkaline hydroxide e.g. sodium or potassium hydroxide.

It will be appreciated that a compound of formula I in which R represents a hydrogen atom may be converted, if desired, into a compound of formula I in which R represents an alkyl radical with 1 to 5 carbon atoms by esterification.

In all the above processes for the preparation of compounds of general formula X, the compound of formula I formed or a salt thereof is normally isolated from the reaction medium.

The compounds of general formula I may, if desired, be converted into acid addition salts thereof by reaction with an appropriate acid such as those set forth hereinbefore, preferably in substantially equimolar quantities.

Compounds of general formula I wherein R represents a hydrogen atom may, if desired, be converted into metal salts or base addition salts preferably nitrogenous base addition salts thereof by reaction with an appropriate metal compound or organic or inorganic base.

The compounds of general formula® II end III useful as starting materials in the preparation of compounds of general formula X according to the Invention are known from the literature. Compounds corresponding to compounds of general formula I above but wherein R represents an alkyl radical containing more than 5 carbon atoms, which may be of use In process B described above, may be obtained by a process analogous to process A above.

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

Compounds of general formula I and their physiologically compatible salts are thus of potential interest in human therapy especially 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 assess 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 AKOH)^ gel in. 140 mis saline (use of a macerator facilitates mixing). 2. Centrifuge at 3,000 r.p.m. for about 10 minutes. 3. Resuspend the precipitate with 300 mis of albumen egg powder (1.3 mg/ral) in saline and allow to stand for 30 minutes . 4. Centrifuge at 3,000 r.p.m. for 10 minutes.

. 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 of Antiserum (i.e. anti-ovalbumen). 1. 1 ml of the alum precipitated ovalbumen is injected 25 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 a 4 point scoring system.

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 immediately 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 mis saline plus 0.5 mis 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 and area of blueing, proportional to the anaphylactic reaction is assessed on a four point scoring system.

Calculations 1. Total scores for sites 1, 2, 3 and 4 «· X 2. Mean value of X for each group = X 3. X t = X for test group X c = X for control group 4. % inhibition = X c - X t ,. 100 1 ft, ' ,in' X c 1 . ED50 = dose of drug giving 50% inhibition.

EDj-θ values for compounds tested in the passive cutaneous anaphylaxis screen (in rats): COMPOUND OF EXAMPLEED50 mg/kg i.v. mg/kg p.o. 1 3 4 5 6 7 0.073 0.20 0.12 0.83 3.13 0.073 0.73 0.71 4861 1 According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising at least one compound of formula I as hereinbefore defined or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compounds of general formula I and their physiologically compatible salts may be incorporated, in either solid or liquid form, into the conventional pharmaceutical preparations, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral (including topical) administration. Preferred forms include tablets, far example coated tablets, gelatin capsules, granules,suppositories, syrups, aerosols, creams, ointments 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 100 mg, preferably from 1 to 25 mg of active ingredient. The oral daily dosage, 4861 1 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 5 illustrate the present invention.

EXAMPLE 1 : IMIDAZO [1,2-al QUINOXALINE-2CARBOXYLIC ACID Step A: l-carbethoxycarbonylmethyl-2-aminoquinoxalinium bromide A solution of 2-aminoquinoxaline (0.9 g) and ethyl bromopyruvate (1.25 g) in dimethoxyethane (25 mis) was stirred overnight at room temperature giving the quaternary salt as a pale yellow crystalline solid (1.58 g).

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

Analysis; Found : 04.80% C 4.65% H 17.47% N Calculated 64.72% C 4.60% H 17.42% N Step C; imidazo [1,2-a] quinoxaline-2-carboxylic acid A suspension of ethyl imidazc [l,2-a] quinoxaline2-carboxylate (0.63 g) in water (30 mis) and ethanol (10 mis) was treated with IN sodium hydroxide solution (10 mis), and the reaction mixture refluxed for 1 hour, giving a clear yellow solution. The ethanol was removed in vacuo, and the aqueous solution 8 611 acidified with concentrated hydrochloric acid when imidazo [1,2-a] quinoxaline-2-carboxylic acid separated as a buff crystalline solid (0.6 g, MP 274-5°) /Analysis: Found : 61.82% C 3.33% H 19.71% N Calculated: 61.97% G 3.31% H 19.71% N EXAMPLE 2 : ETHYL 7,8-DICHLORO IMIDAZO [l,2-a] QUINOXALINE-2-CARBOXYLATE Step A: l-carbethoxycarbonylmethyl-2-amino-6>7-dichloroquinoxalinium bromide A solution of the dichloroaminoquinoxaline and ethyl bromopyruvate (0.2 g) in dry tetrahydrofuran (15 mis) was stirred at room temperature for 24 hrs giving the quaternary salt as a pale yellow crystalline solid (0.1 g). On standing the filtrate for several days, a second crop of quaternary salt separated as a yellow/brown crystalline solid (0.065 g). Total yield = 0.165 g Step B: Preparation of ethyl 7,8-dichloroimidazo [1,2-aj quinoxaline-2-carboxylate A suspension of l-carbethoxycarbonylmethyl-2amino-6,7-dichloroquinoxalinium .bromide (0.3 g) in ethanol (400 mis) was stirred under reflux giving a clear solution in 1 hr and a half. The solution was concentrated to about 20 mis when the ethyl 7,8-dichloroimidazo [1,2-a] quinoxaline-2-carboxylate separated as a soft pink crystalline solid (0.22 g, MP = 297-9°).

The product was recrystallised from ethanol as pale pink/ white soft needles.

ANALYSIS : C13H9N3°2G12 Found : 50.17% C 2.93% H 13.48% N 23.30% Cl Calculated: 50.32% C 2.90% H 13.55% N 22.90% Cl The dichloro aminoquinoxaline may be prepared according to the following methods: a) Preparation of 7.8-dichioroalloxazine A solution of 4. 5-dichloro-o-phenylenediamine (10 g) alloxan hydrate (9 g) and boric acid (1.5 g) in glacial acetic acid (250 mis) was stirred overnight at room temperature. giving a brown/black solution with a yellow/buff crystalline solid separating. The alloxazine was filtered and washed well with water (15.0 g,MP / 370°), b) Preparation of 2-amino-6.7-dichloroquinoxaline A solution of dichloroalloxazine (2 g) in concentrated sulphuric acid (10 mis) was gradually heated with stirring to 240° and kept ten minutes at this temperature. The reaction mixture was cooled, poured onto ice, basified with sodium hydroxide and extracted several times with ether, giving the dichloroaminoquinoxaline as an orange crystalline solid (0.73 g,MP= 220°) ANALYSIS : CgH^C^ Found : 44.96% C 2.55% H 19.23% N Calculated : 44.89% C 2.35% H 19.63% N EXAMPLE 3 : 7.8-DICHLOROIMIDAZO fl.2-a] QUINOXALINE-2CARBOXYLIC ACID A suspension of ethyl 7,8-dichloroimidazo [1,2-a]quinoxaline-2-carboxylate (0.5 g) in water (60 mis), ethanol (20 mis) and IN sodium hydroxide solution (20 mis) 8 61 1 was stirred for 3 days. The solid dissolved slowly and was replaced by the insoluble sodium salt, which was acidified in suspension (500 mis water), giving the iraidazoquin xalinecarboxylic acid as a white crystalline solid (0.4 g).

IR Spectrum (KBr) - OH = 3450 cm CH = 3140 cm (imidazole CH) , CO = 1695 cm \ EXAMPLE 4 : 7 and 8 - CHLOROIMIDAZO [1.2-a] QU1N0XALINE2-CARBOXYLIC ACIDS STEP A : l-carbethoxycarbonylmethyl-2-amino-6-and 7-chloroquinoxalinium bromides A solution of 6-and 7-chloro-2-amino-quinoxalines (3 g) and ethyl bromopyruvate (3.5 g) in dimethoxyethane (100 mis) was stirred overnight at room temperature giving the mixed quaternary salts as a pale yellow crystalline solid (3.14 g). On standing the filtrate for several days, two further batches of the salt were obtained (1.05 g and 0.28g). Total yield of 6-and 7-chloro-2-amino-quinoxaline quaternary salts “ 4.47 g.

STEP B : ethyl 7-and ethyl 8-chloroimidazo [1.2-a] quinoxaline-2-carboxylates A suspension of the mixed 1-carbethoxycarbonyl methyl 2-amino-6-chloroquinoxalinium and 1-carbethoxycarbonyljmethyl-2-amino-7-chloroquinoxalinium quaternary salts (3.1 g) in ethanol (250 .mis) was stirred under reflux for lhr and a half giving a clear orange solution from which separated on concentration and cooling, a soft pale plnk/white crystalline solid which was a mixture of. 7-and 8-chloroimidazoquinoxalines (2.0g, MP 220-227°), Attempts to separate the isomers by column chromatography failed, but the pure mixed isomers (about 1:1 mixture) were obtained as a soft white crystalline solid (MP.231-243°) after chromatography.

ANALYSIS : C^H^N^Cl Found : 56.60% C 3.74% H 15.14% N Calculated: 56.62% C 3.63% H 15.25% N STEP C : 7-and 8-chloroimidago [1.2-a] quinoxaline -2-carboxylic acids A suspension of the mixed ethyl 7- and ethyl 8chloroimidazo [1.2-a] quinoxaline-2-carboxylates (0.6 g) in water (60 mis), ethanol (20 mis) and IN sodium hydroxide solution (10 mis) was stirred for two days giving a white granular solid (0,54 g) which was a mixture of sodium salts. The solid was suspended in water (400 mis) and acidified with concentrated hydrochloric acid when the mixed chloroimidazoquinoxaline carboxylic acids separated as a white crystalline solid (0.49 g).

The monochloroquinoxaline of step A may be prepared according to the following method: Preparation of 8-chloro-and 7-chloro-alloxazine A solution of 4-chloro-o-phenylenediamine (11 g), alloxan hydrate (10 g) and boric acid (0.64g) in glacial acetic acid (150 ml) was stirred overnight giving the chloroalloxazines as a pale yellow/brown crystalline solid. Washing with hot water and hot ethanol gave a pale yellow crystalline solid (14 g).

Preparation of 6-and 7-οΗ1οΓο-2-βιηιηοςη1ηοχ3ΐιη6Β A solution of the 8-chloro and 7-chloro-alloxazines (10 g) in concentrated sulphuric acid (50 mis) was gradually heated to 240° and kept at that temperature for ten minutes. The cooled reaction mixture was poured onto ice, basified with sodium hydroxide and extracted with ether. Evaporation of the solvent gave a mixture of 6- and 717 4861 1 chloro-2-aminoquinoxalines as a yellow crystalline solid (5 gjMP 197-203° after recrystallised ethanol). Attempts to separate the isomers by crystallisation or chromatography failed.

EXAMPLE 5 : 4 ETHOXYIMIDAZO Π,2-η] QUINOXALINE-2CARBOXYLIC ACID STEP A : l-carbethoxycarbonylmethyl-2-amino-3-chloroquinoxalinium bromide.

A solution of 2-amino-3-chloroquinoxaline (9g) and ethyl bromopyruvate (12 g) in dimethoxyethatie (180 mis) was stirred overnight giving the quaternary salt as a pale yellow crystalline solid (5.33g), On standing the filtrate in the fridge for several days, two further batches of quaternary salt were obtained (1.20 g and 3.62 g). Total yield of salt = 10.22 g.

STEP B : Ethyl 4-ethoxyimidazo [1.2-a]quinoxaline2-carboxylate A suspension of l-carbethoxycarbonylmethyl-2-amino -3-chloroquinoxalinium bromide (3,5 g) in ethanol (250 mis) was heated under reflux for one hour giving a clear pale yellow solution which was concentrated to half its volume and cooled, giving ethyl 4 (5H)-oxoimidazo [lf 2-a] quinoxaline-2-carboxylate as a white crystalline solid (l.Og). The filtrate was concentrated further giving a white crystalline solid (1.04g) which was a mixture cf the oxoimidazoquinoxaline and O-ethyl-imidazoquinoxaline. The products were separated on a silica gel column eluting with ethyl acetate giving the 0-ethyl compound as a white crystalline solid (0.55 g).

STEP G : 4-ethoxyimidazo[l.2-a]quinoxaline-2-carboxylic acid A suspension of 0-ethyl imidazoquinoxaline (0.5g) in water (50 mis), ethanol (15 mis) and IN sodium hydroxide solution (8 mis) was stirred overnight giving a clear colourless solution. Acidification with concentrated hydrochloric acid gave 4-ethoxy imidazo [1,2-a] quinoxaline- 2- carboxylic acid. (MP : 220-2°).

ANALYSIS : C13H11N3°3’ ^2^2° Found : 59.04% C 4,54% H 15.74% N Calculated: 58.64% C 4.54% H 15.78% N EXAMPLE 6 : 4-CARBAMOYLIMIDAZOn .2^-alQUINOXALINE-2CARBOXYLIC ACID STEP A : 1-carbethoxycarbonylmethyl-2-amino-3-carbamoyl -quinoxalinium bromide A solution of 2-amino-3-carbamoylquinoxaline (prepared from 2-chloro-3-carbethoxyquinoxaline by the method of A. H. Gowenlock, G. T. Newbold & F. S. Spring - JCS (1945) 622-5) (lg) in dimethoxyethane (50 mis) was stirred for two days with ethyl bromopyruvate quaternary salt as a yellow crystalline solid (1.44 g).

STEP B : Ethyl 4-carbamoylimidazo· [1.2-aj quinoxaline— 2-carboxylate A suspension of the quaternary salt (l.Og) in ethanol (100 mis) was stirred under reflux for 1 hour and a half giving a clear yellow solution. Concentration of the solution gave the carbamoylimidazoquinoxaline as a pale yellow crystalline solid (0.55 g).

The product was recrystallised from ethanol as soft white needles (M.p. 280-4°) ANALYSIS : C,,H,nN,On - 14 12 4 3 Found : 58.78% G 4.35% H Calculated: 59.15% C 4.25% H 19.51% N 19.71% N 4861 1 STEP C : 4-carbamoylimidazo [1.2-a]quinoxaline-2carboxylic acid.

A suspension of the ester (0.315 g) in water (35 mis), ethanol (12 mis) and IN sodium hydroxide solution (6 mis) was stirred overnight giving a white suspension of sodium salt. The suspension was acidified with hydrochloric acid giving the carboxylic acid as a buff crystalline solid (0.28 g) (MP. 298-300°).

ANALYSIS : C^HgN^O-j H20 Found : 52.12% c’ 3.61% H 20.02% N Calculated: 52.56% C 3.68% H 20.43% N EXAMPLE 7: TRI ( HYDROXYMETHYL )METHYLAMMONIUM. IMIDAZO[1,2-a] QUINOXALINE-2-CARBOXYLATE A suspension of imidazo[l,2-a]quinoxaline-2-carboxylic acid (2.5 g) and tri (hydroxymethyl)methylamine (1.5 g) in methanol (2 1) was stirred under reflux until all the solids had dissolved. The solution obtained was evaporated to ca. 70 ml, cooled and filtered to give tri (hydroxymethyl )methylammonium imidazo[1,2-a]quinoxaline-2-carboxylate (2.9 g 72%) m.p. 242-4° (H20:EtOH).

ANALYSIS: C-^H^N 05, | H20 Found : 53.1¾ C 5.43% H 16.51% N Calculated: 53.17% C 5.51% H 16.53% N EXAMPLE 8: SODIUM IMIDAZ0(1,2-a)QUINOXALINE-2-CARBOXYLATE 25 Aqueous sodium hydroxide (2N) was added dropwise to a stirred suspension of imidazo[l,2-a]quinoxaline-2carboxylic acid (2 g) in water (20 ml) until the solid had dissolved (pH at end-point 9-10). Acetone was then added thereto and the solid thus precipitated was filtered off to give sodium imidazo[1,2-a]quinoxaline-2-carboxylate (1.8 g), m.p. 300°.

ANALYSIS : C^gN^, Na Found : 56.27% C 2.68% H 17.95% N Calculated: 56.17% C 2.58% H 17.88% N EXAMPLE 9 : Tablets were prepared, containing - imidazo [l,2-a] quinoxaline-2-carboxylic acid... 2 mg - excipient (lactose,talc,starch,magnesium stearate) q.s. for a tablet of ..........................100 mg EXAMPLE 10 : Tablets were prepared, containing _ 7,8-dichloroimidazo [1,2-a] quinoxaline-2carboxylic acid ................................2 mg - excipient (lactose, talc, starch, magnesium stearate) q.s. for a tablet of................100 mg EXAMPLE 11: Tablets were prepared, containing 15 - tri (hydroxymethyl)methylammonium imidazo[1,2-a]-quinoxaline-2-carboxylate..............2 mg - excipient (lactose, talc, starch, magnesium stearate)q.s. for a tablet of ................100 mg

Claims (40)

1. Compounds of general formula I , wherein

2. Compounds as claimed in claim 1 wherein R represents a hydrogen atom or an ethyl radical, X represents a

3. Compounds as claimed in claim 2 wherein R represents a hydrogen atom.

4. 8 611 a compound of formula I (wherein R represents an alkyl group with 1 to 5 carbon atoms) is obtained. 5. As claimed in any one of claims 5 to 11. 5 in any one of Examples 1 to 6. 5 15. A process as claimed in claim 13 or claim 14 wherein cyclisation is effected by heating at the reflux temperature of the reaction mixture.

5. Imidazo[l,2-a]quinoxaline-2-carboxylic acid and salts thereof. 5 R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms; X represents a hydrogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a carbamoyl group; and IQ Y and Z, which may be the same or different, each represents a hydrogen or a halogen atom, and the salts thereof.

6. Ethyl 7,8-dichloroimidazo[l,2-a]quinoxaline-2carboxylate and salts thereof.

7. 7,8-Dichloroimidazo[l,2-a]quinoxaline-2-carboxylic acid and salts thereof.

8. 7-Chloroimidazo[l,2-a]quinoxaline-2-carboxylic acid and salts thereof.

9. 8-Chloroimidazo[l,2-a]quinoxaline-2-carboxylic acid and salts thereof. 10. Of an alcohol with 1 to 5 carbon atoms as solvent.

10. 4-Ethoxyimidazo[1,2-a]quinoxaline-2-carboxylic acid and salts thereof.

11. 4-Carbamoylimidazo[1,2-a]quinoxaline-2-carboxylic acid and salts thereof.

12. Physiologically compatible salts of compounds of general formula I as defined in any preceding claim.

13. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R represents an alkyl radical containing from 1 to 5 carbon atoms which comprises cyclising a compound of formula IV, & Hal ch -cn-cnnR 1 ' (wherein X, Y and Z are as defined in claim 1, R 1 represents an alkyl radical containing from 1 to 5 carbon atoms and Hal represents a halogen atom) whereby

14. A process as claimed in claim 13 wherein, in the compound of formula IV, Hal represents a chlorine or bromine atom.

15. (wherein X, Y and Z are as defined in claim 1) with a compound of formula III, Hal - CH 2 - CO - COOR ' (wherein R* and Hal are as defined in claim 13). 15 hydrogen atom or an ethoxy radical and Y and Z, which may be the same or different, each represents a hydrogen or chlorine atom.

16. A process as claimed in any one of claims 13 to 15 wherein the cyclisation is effected in the presence

17. A process as claimed in any one of claims 13 to 16 wherein the compound of formula IV is obtained by reaction of a compound of formula II,

18. A process as claimed in claim 17 wherein the

19. A process for the preparation of compounds of general formula X as defined in claim 1 wherein R represents a hydrogen atom which comprises hydrolysing a compound corresponding to a compound of formula I as defined in claim 1 wherein X, Y and Z are as defined in claim 1 and an alkyl R may in this instance be/as defined in claim 1 or may represent an alkyl radical containing more than 5 carbon atoms. 20. Suitable for oral, rectal or parenteral administration

20. A process as claimed in claim 19 wherein a compound of formula I wherein R represents an alkyl radical containing from 1 to 5 carbon atoms is hydrolysed. 20 reaction of the compound of formula II with the compound of formula III is effected in the presence of an organic solvent. 20 4. Compounds as claimed in claim 3 wherein X and Z each represents a hydrogen atom.

21. A process as claimed in claim 19 or claim 20 wherein hydrolysis is effected by means of an alkaline hydroxide.

22. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R represents an alkyl radical containing from 1 to 5 carbon atoms which comprises appropriately esterifying a compound of formula I as defined in claim 1 (wherein R represents a hydrogen atom).

23. 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.

24. A process as claimed in claim 23 wherein the compound of formula I and the acid are reacted in substantially equimolar quantities. 25. And 27.

25. A process for the preparation of metal or base addition salts of compounds of general formula I as defined in claim 1 wherein R represents a hydrogen atom which comprises reacting a compound of formula I as defined in claim 1 wherein R represents a hydrogen atom with an appropriate metal compound or base. . 48611

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

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

28. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in Example 7 or Example 8.

29. Compounds as claimed in claim 1 whenever prepared 10 by a process as claimed in any one of claims 13 to

30. Compounds as claimed in claim 1 whenever prepared by a process as claimed in claim 26 or claim 28.

31. Pharmaceutical compositions comprising, as 15 active ingredient, at least one compound of formula I as defined in claim 1 or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.

32. Compositions as claimed in claim 31 in a form

33. Compositions as claimed in claim 31 or claim 32 in the form of tablets, gelatin capsules, granules, suppositories, solutions, ointments, creams, gels and aerosols. 25

34. Compositions as claimed in any one of claims 31 to 33 in the form of dosage units.

35. Compositions as claimed in claim 34 wherein each dosage unit contains from 0.25 to 100 mg of active ingredient.

36. Compositions as claimed in claim 35 wherein each dosage unit contains from 1 to 25 mg of active ingredient.

37. Compositions as claimed in any one of claims 31 to 36 wherein the active ingredient comprises a compound

38. Pharmaceutical compositions as-claimed in claim31 substantially as herein described.

39. Pharmaceutical compositions substantially as herein described in Example 9 or Example 10. IQ

40. Compounds of general formula I as defined in claim 1 and their physiologically compatible salts for use as anti-allergic agents.