GB2027707A - Heterocyclic compounds - Google Patents

Abstract

Compound of general formula I, <IMAGE> 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

SPECIFICATION Heterocyclic compounds 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 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.

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 pentyi radical. X may, for example, represent a hydrogen atom or a methoxy, ethoxy, propoxy, butoxy or pentoxy 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 I 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 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 represent 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[ 1 ,2-ajquinoxaline-2-carboxylic acid, ethyl 7,8-dichloroimidazo[1 ,2-a]quinoxaline-2-carboxylate, 7,8-dichloroimidazo[ 1 ,2-a]quinoxaline-2-carboxylic acid, 7-chloroimidazo[ 1 ,2-a]quinoxaline-2-ca rboxylic acid, 8-chloroimidazo[1 ,2-a]quinoxaline-2-carboxylic acid, 4-ethoxyimidazo[l ,2-a]quinoxaline-2-carboxylic acid, and 4-carbamoylimidazo[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

(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 Z are as hereinbefore defined) with a compound of formula III, Hal-CH2-CCOOR' (III) (wherein Hal dnd R' 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 of formula I as hereinbefore defined (wherein R represents an alkyl radical). 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 I, 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 nitrogeneous base addition salts thereof by reaction with an appropriate metal compound or organic or inorganic base.

The compounds of general formulae II and Ill useful as starting materials in the preparation of compounds of general formula I according to the invention are known from the literature. Compounds of general formula I 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) sensitization with antiserum followed three days later by systemic challenge with antigen. Evans blue dye injected with the antigen is used as a marker two 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 1 20 grams Al(OH)3 gel in 140 mls saline (use of a macerater facilitates 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 of Antiserum (i.e. anti-ovalbumen).

1. 1 ml of the alum precipitated ova lbu men 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-200C 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 (4060 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 intravenously with the drug immediately prior to intravenous challenge via the superficial penile vein with 1 mi 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 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 4X 2. Mean value of X for each group 3. zit =fortest group Ac = X for control group 4. % inhibition = 100 "Xc 5. ED50-- dose of drug giving 50% inhibition.

EDso values for compounds tested in the passive cutaneous anaphylaxis screen (in rats):

EDsc Compound of Example mg/kgi.v. /keg i-v- mg/kgp.o.

1 0.073 0.73 3 0.20 4 0.12 0.71 5 0.83 6 3.13 7 0.073 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, coated tablets, gelatin capsules, granuies, 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. Suitabie dosage units for adults contain from 0.25 to 100 mg, preferably from 1 to 25 mg 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 Imidazo-[t,2-a]-quinoxaline-2-carboxylic acid Step A: 1 -carbethoxycarbonylmethyl-2-aminoquinoxalinium 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 giving the quaternary salt as a pale yellow crystalline solid (1.58 g).

Step B: ethyl imidazo-[ 1 ,2-aj-quinoxaline-2-ca rboxylate A suspension of 1-carbethoxycarbonylmethyl-2-aminoquinoxalinium bromide (0.4 g) in ethanol (1 5 mls) was refluxed for 2 hours giving a clear orange solution. Concentration of the solution to half its volume gave ethyl imidazo-[1 ,2-a]-quinoxaline-2-carboxylate as a pale yellow crystalline solid (0.25 g).

Recrystallisation from ether/methanol gives soft white needles (MP 1 8470 (sealed tube)).

Analysis C13H11N3O2 Found : 64.80% C 4.66% 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 imidazo-[l ,2-a]-quinoxaline-2-carboxylate (0.63 g) in water (30 mls) and ethanol (10 mls) was treated with 1N sodium hydroxide solution (10 mls), and the reaction mixture refluxed for 1 hour, giving a clear yellow solution.The ethanol was removed "in vacuo", and the aqueous solution 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 0) Analysis CatH,N302 Found : 61.82% C 3.33% H 19.71% N Calculated 61.97% C 3.31% H 19.71% N EXAMPLE 2 ethyl 7,8-dichloro im idazo-[ 1 ,2-a]-qu inoxa line-2-carboxylate Step A: 1 -carbethoxycarbonylmethyl-2-a mino-6 ,7-dichloroquinoxa linium bromide A solution of the dichloroaminoquinoxaline and ethyl bromopyruvate (0.2 g) in dry tetrahydrofuran (1 5 mls) 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 = 0.1 65 g.

Step B: Preparation of ethyl 7,8-dichloroimidazo-[1,2-a]-qu inoxa iine-2-carboxylate A suspension of 1 -carbethoxycarbonylmethyl-2-amino-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 mls when the ethyl 7,8-dichloroimidazo-[1,2-a]-quinoxaline-2-carboxylate separated as a soft pink crystalline solid (0.22 g, MP = 297-96j. The product was recrystallised from ethanol as pale pink/white soft needles.

Analysis C3HgN302C12 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% CI The dichloro aminoquinoxaline may be prepared according to the following methods: a) Preparation of 7,8-dichloroalloxazine A solution of 4,5-dichloro-o-phenylenediamine (1 0 g) alloxan hydrate (9 g) and boric acid (1.5 g) in glaciai 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 > 3700).

b) Preparation of 2-amino-6,7-dicbloroquinoxaline A solution of dichloroalloxazine (2 g) in concentrated sulphuric acid (10 mls) was gradually heated with stirring to 2400 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 = 2200).

Analysis CsHsNaCl2 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-[ 1 ,2-aj-quinoxaline-2-carboxylic acid A suspension of ethyl 7,8-dichloroimidazo-[1 ,2-a]-quinoxaline-2-carboxylate (0.5 g) in water (60 mls), ethanol (20 mls) and 1 N sodium hydroxide solution (20 mls) was stirred for 3 days. The solid dissolved slowly and was replaced by the insoluble sodium salt, which was acidified in suspension (500 mls water), giving the imidazoquinoxalinecarboxylic acid as a white crystalline solid (0.4 g).IR Spectrum (KBr) - OH = 3450 cms-l CH = 3140 cms-' (imidazole CH), CO = 1695 cm~'.

EXAMPLE 4 7 and 8 chloroimidazo-[1 ,2-a]-quinoxaline-2-carboxylic acids Step A: 1-ca rbethoxyca rbonylmethyl-2-amino-6-and 7-ch loroq uinoxal iniu m bromides A solution of 6 and 7-chloro-2-amino-quinoxalines (3 g) and ethyl bromopyruvate (3.5 g) in dimethoxyethane (100 mls) 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 0.28 g). 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 -carbethoxyearbonylmethyl-2-amino-6-chloroquinoxalinium and 1 carbethoxycarbonylmethyl-2-amino-7-chloroquinoxalinium quaternary salts (3.1 g) in ethanol (250 mis) was stirred under refluxfor 1 hr. and a half giving a clear orange solution from which separated on concentration and cooling, a soft pale pink/white crystalline solid which was a mixture of 7- and 8 chloroimdazoquinoxalines (2.0 g, MP 220--2270). 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. 2 3 1--243 0 ) after chromatography.

Analysis C13H,oN302CI 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-chloroimidazo-[1 ,2-a]-quinoxaline-2-carboxylic acids A suspension of the mixed ethyl 7- and ethyl 8-chloroimidazo-[1 ,2-a]-quinoxaline-2-carboxylates (0.6 g) in water (60 mls), ethanol (20 mls) and 1 N sodium hydroxide solution (10 mls) 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 mls) 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 (1 1 g), alloxan hydrate (10 g) and boric acid (0.64 g) 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-chloro-2-aminoquinoxalines A solution of the 8-chloro and 7-chloro-alloxazines (10 g) in concentrated sulphuric acid (50 mls) was gradually heated to 2400 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 7-chloro-2-aminoquinoxalines as a yellow crystalline solid (5 g, MP 1 97--203 0 after recrystallised ethanol). Attempts to separate the isomers by crystallisation or chromatography failed.

EXAMPLE 5 4-ethoxyim idazo-[1 ,2-a]-qu inoxa line-2-ca rboxylic acid Step A: 1 -carbethoxycarbonylmethyl-2-amino-3-chloroquinoxalinium bromide.

Asolution of 2-amino-3-chloroquinoxaline (9 g) and ethyl bromopyruvate (12 g) in dimethoxyethane (180 mls) was stirred overnight giving the quaternary salt as a pale yellow crystalline solid (5.33 g). 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]-quinoxal ine-2-carboxylate A suspension of 1-carbethoxycarbonylmethyl-2-amino-3-chloroquinoxalinium bromide (3.5 g) in ethanol (250 mls) 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-[1 ,2-a]-quinoxaline-2 carboxylate as a white crystalline solid (1.0 g). The filtrate was concentrated further giving a white crystalline solid (1.04 g) which was a mixture of the oxoimidazoquinoxaline and O-ethyl imidazoquinoxaline. The products were separated on a silica gel column eluting with ethyl acetate giving the O-ethyl compound as a white crystalline solid (0.55 g).

Step C: 4-ethoxyimidazo[ 1 ,2-a]quinoxa Iine-2-ca rboxylic acid A suspension of O-ethyl imidazoquinoxaline (0.5 g) in water (50 mls), ethanol (1 5 mls) and 1 N sodium hydroxide solution (8 mls) 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: 2202 ).

Analysis C,3H1,N3o3f1/2H2o Found : 59.04% C 4.54% H 15.749/0 N Calculated : 58.64goo C 4.54% H 15.78% N EXAMPLE 6 4-carbamoylimidazo[1 ,2-a]quinoxaline-2-carboxylic acid Step A: 1 -carbethoxyca rbonylmethyl-2-a mino-3-ca rba moyl-qu inoxa lin ium bromide A solution of 2-amino-3-carbamoylquinoxaline (prepared from 2-chloro-3-carbethoxyquinoxaline by the method of A. H. Gowenlock, G. T. Newbold s F. S. Spring -- JCS (1945) 622-5) (1 g) in dimethoxyethane (50 mls) was stirred for two days with ethyl bromopyruvate quaternary salt as a yellow crystalline solid (1.44 g).

Step B: Ethyl 4-carba moyli midazo-[ 1 ,2-a]-qu inoxa line-2-carboxylate A suspension of the quaternary salt (1.0 g) in ethanol (100 mls) 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--40) Analysis C,4H,2N403 Found 58.78% C 4.35% H 19.51% N Calculated 59.15% C 4.25% H 19.71% N Step C: 4-carbamoylimidazo[1 ,2-a]quinoxa line-2-ca rboxylic acid A suspension of the ester (0.315 g) in water (35 mls), ethanol (12 mls) and 1 N sodium hydroxide solution (6 mls) 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.

298300C).

Analysis C12H6N4O3,H2O Found 52.12% C 3.61% H 20.02% N Calculated 52.56% C 3.68% H 20.43% N EXAMPLE 7 Tri-(hydroxymethyl)methylam moniu m imidazo[ 1 ,2-a] quinoxaline-2-carboxylate A suspension of imidazo[1 ,2-a]quinoxaline-2-carboxylic acid (2.5 g) and tri (hydroxymethyl)methylamine (1.5 g) in methanol (2 I) 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 imidazol[1,2-a]quinoxaline-2-carboxylate (2.9 g 72%) m.p. 2424 (ll2O:EtOH).

Analysis C,5Hr8N405.+H2t Found : 53.13% C 5.43% H 16.51% N Calculated 53.17% C 5.51% H 16.53% N EXAMPLE 8 Sodium imidazo[1 ,2-a]quinoxaline-2-carboxylate Aqueous sodium hydroxide (2N) was added dropwise to a stirred suspension of imldazo[1 2- a]quinoxaline-2-carboxylic 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. 3000.

Analysis : C,5H,8N405, Na Found : 56.27% C 2.68% H 17.95% N Calculated 56.17% C 2.58% H 17.8% N EXAMPLE 9 Tablets were prepared, containing - imidazo-[l ,2-a]-quinoxaline-2-carboxyiic 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-2- carboxylic acid 2 mg - excipient (lactose, talc, starch, magnesium stearate) q.s. for a tablet of 1 00 mg EXAMPLE 11 Tablets were prepared, containing - 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 (41)

1. Compounds 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.

2. Compounds as claimed in claim 1 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.

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

4. Compounds as claimed in claim 3 wherein X and Z each represents a hydrogen atom.

5. lmidazo[1 ,2-a]quinoxaline-2-carboxylic acid and salts thereof.

6. Ethyl 7,8-dichloroimidazo[1 ,2-a]quinoxaline-2-carboxylate and salts thereof.

7. 7,8-Dichloroimidazo[1 ,2-a]quinoxaline-2-carboxylic acid and salts thereof.

8. 7-Chloroimidazo[1 ,2-a]quinoxaline-2-carboxylic acid and salts thereof.

9. 8-Chloroimidazo[1 ,2-a]quinoxaline-2-carboxylic acid and salts thereof.

1 0. 4-Ethoxyimidazo[ 1 ,2-a]qu inoxa Iine-2-ca rboxylic 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,

(wherein X, Y and Z are as defined in claim 1, R' represents an alkyl radical containing from 1 to 5 carbon atoms and Hal represents a halogen atom) whereby a compound of formula I (wherein R represents an alkyl group with 1 to 5 carbon atoms) is obtained.

14. A process as claimed in claim 1 3 wherein, in the compound of formula IV, Hal represents a chlorine or bromine atom.

1 5. A process as claimed in claim 1 3 or claim 14 wherein cyclisation is effected by heating at the reflux temperature of the reaction mixture.

1 6. A process as claimed in any one of claims 13 to 1 5 wherein the cyclisation is effected in the presence of an alcohol with 1 to 5 carbon atoms as solvent.

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,

(wherein X, Y and Z are as defined in claim 1) with a compound of formula III, HaI-CH2-CO-COOFl' (wherein R' and Hal are as defined in claim 13).

18. A process as claimed in claim 1 7 wherein the reaction of the compound of formula II with the compound of formula III is effected in the presence of an organic solvent.

1 9. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R represents a hydrogen atom which comprises hydrolysing a compound of formula I as defined in claim 1 (wherein R represents an alkyl radical).

20. A process as claimed in claim 1 9 wherein a compound of formula I wherein R represents an alkyl radical containing from 1 to 5 carbon atoms is hydrolysed.

21. A process as claimed in claim 1 9 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 forthe preparation of acid addition salts of compounds of general formula las 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. 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.

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 in any one of Examples 1 to 6.

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 by a process as claimed in any one of claims 13 to 25 and 27.

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 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 suitable for oral, rectal or parenteral administration.

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

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 as claimed in any one of claims 5 to 11.

38. Pharmaceutical compositions as claimed in claim 1 substantially as herein described.

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

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

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