IE44905L

IE44905L - Imidazobenzoxazines

Info

Publication number: IE44905L
Application number: IE771052A
Authority: IE
Original assignee: Roussel Uclaf
Priority date: 1976-05-21
Filing date: 1977-05-23
Publication date: 1982-05-05
Also published as: NL7705614A; BE854850A; IE44905B1; FR2351980A1; GB1538479A; FR2351980B1; DK216977A; JPS52156899A; CH623053A5; CH624118A5; JPS6045199B2; DE2722772A1; CA1100963A

Abstract

Compounds of formula: <IMAGE> in which R3 represents a C1-C5 alkyl are prepared by decarboxylation of a corresponding alkyl ester carrying a carboxyl in position 1, followed by a nitration. The compound IB can be reduced to an amino ester (IC), can be hydrolysed to the carboxylic acid (IE) or can be reduced and then hydrolysed. The amine compound IC can be converted by acylation into the acylamino compound, and the carboxylic acid IE can be esterified or converted to the amide. The compounds mentioned above and their salts have antiallergic and bronchodilatory properties; they can be used, especially, in the treatment of allergic asthma. [GB1538479A]

Description

449°^ This invention relates to new imidazobenzoxazine3, 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 X represents a hydrogen atom, a nitro or amino radical or a protected amino radical; and Z represents a group of formula: - COOR [in \fhich R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a group of formula: (in which n is 1, 2 or 3 and, either R^ and R£, which may be the same or different, each represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon (I) R atoms, or and together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring containing from 4 to 6 carbon atoms which may, if desired, be interrupted by a further hetero atom, said further hetero atom being optionally substituted by an al^cyl radical containing from 1 to 5 carbon atoms)] or a group of £ formula: 1 (in which and R2 are as defined above); and salts thereof.

When X represents a protected amine radical this may, for example, be an alkanoylamino radical containing from 1 to 5 carbon atoms e.g. an acetaniido radical or a group of formula: (in which R* represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms) When X represents an amino radical or a group of formula (in which R* is as defined above) Z preferably represents a group of formula: CO - N V 2 NH - CO - COOR NH - CO - COOR 3 - COOR (wherein R is as defined above for R*).

When, in the compounds of general formula I, R', Rx and/or R£ represent alkyl radicals containing from 1 to 5 carbon atoms, they may, for example, represent methyl, ethyl, propyl, isopropyl, butyl or pentyl radicals.

When, in the compounds of general formula I, Rx and R£, together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring containing from h to 6 carbon atoms which may, if desired, be interruptei by a further hetero atom, said further hetero atom being optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms, the heterocyclic ring may, for example, be a pyrrolidine, piperidino, morpholino, piperazinyl, N-methyl-piperazinyl, N-ethyl-piperazinyl, N-propyl-piperazinyl or N-butyl-piperazinyl ring.

The compounds of general formula I and their salts in general possess interesting pharmacological properties and in particular an anti-allergic and bronchodilatory activity. 4400s The compounds of general formula I may form acid addition salts with acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxalic or aspartic acid, alkanesulphonic acids e.g. methanesulphonic acid or arylsulphonic acids e.g. benzenesulphonic acid.

The compounds of general formula I wherein Z represents a carboxyl group and /or X represents a group containing a free carboxyl group such as, for example, a group of formula -NH-CO-COOH, may form salts with bases e.g. metal or nitrogenous base salts. Metal salts may, for example, be formed with alkali metals e.g. sodium, potassium or lithium, with alkaline earth metals e.g. calcium or magnesium, or with metals such as, for example, aluminium. Base addition salts which may be formed include, for example, ammonium salts and salts formed with amines such as lysine, arginine, triethanolamine and tris(hydroxymethyl)aminomethane.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically 90S 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 general formula I wherein X represents a hydrogen atom, a nitro, amino or acetamido radical or a group of formula -NH-CO-COOR' (in which R * represents a hydrogen atom or a methyl or ethyl radical) and Z represents a group of formula -COOR [in which R is as defined ibove for R' or represents a group of formula /R] -(CH2)n-N^ R2 (in which.Rj and R2 together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, morpholino, piperazino or D /R1 4.t methyl - piperazin - 1 - yl ring)] or a group of formula -CO-N \ Ro (in which Rj and Rj, are as defined above) and salts thereof.

More preferred are compounds of general formula I wherein X represents a hydrogen atom, a nitro or acetamido radical or a group of formula -NH-CO-COOR' (in which R:' represents a hydrogen atom or a methyl or ethyl radical) and Z represents a group of formula 44905 -COOR (in which R is as defined above for R* or represents a morpholinoethyl group) or a 4-methyl-piperazin-l-yl-carbonyl group and salts thereof.

Of the above compounds, especially preferred are the compounds of general formula I wherein X represents a hydrogen atom and Z represents a carboxyl, morpholino-ethoxycarbonyl or 4-methyl-piperazin-l-yl-carbonyl group and the salts thereof.

Particularly preferred compounds according to the invention are the following: 4H-imidazo-[2,1-c][l, 4]-h^nzoxazine-2-carboxylie acid and salts thereof, 2-morpholinoethyl 4H-imidazo-[ 2,1-c ][l,J»] -benzoxazine-2-carboxy";ate, 8-nitro-JtH-imidazo-[2, l-c][l, 4]-benzoxazine-2-car boxy lie acid and salts thereof, and 8-acetamido-^H-imidazo-[2,l-c][l, A]-benzoxazine-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: 449<>8 A. for the preparation of compounds of general formula I wherein X represents a hydrogen atom and Z represents a group of formula -COOR (in which R represents an alkyl radipal containing from 1 to 5 carbon atoms, e.g. a methyl radical): Decarboxylation of a compound of formula II, (wherein represents an alkyl radical containing from 1 to 5 carbon atoms e.g. a methyl radical). The decarboxylation is preferably effected by heating the compound of formula II. formula I wherein X represents a hydrogen atom, a nitro or a protected amino radical, for example a lower alkanoylamino radical, and Z represents a group of formula HOOC (II) B. for the preparation of compounds of general -C00-(CH2)n-N ^ (i R2 (in which n, R^ and R2 are as hereinbefore defined): 8 *4005 Reaction of a compound of formula I as hereinbefore defined (wherein Z represents a group of formula -COOH) or a reactive derivative thereof such as, for example, a compound of formula III, H .COHal w N vN (III) (wherein X represents a hydrogen atom, a nitro radical or a protected amino radical and Hal represents a halogen atom, preferably a bromine or, more preferably, a chlorine atom) with a compound of formula IV, HO - (CH_) - N (IV) 2 (wherein, n, R^ and R2 are as hereinbefore defined) with the proviso that, where the compound of formula IV contains an ^NH grouping, this grouping is protected throughout the reaction with the acid or reactive derivative thereof, any protective groups being removed subsequent to tho reaction, whereby the desired compound of formula I is obtained. The compound of formula III is preferably reacted with the compound of formula IV in the presence of an anhydrous organic solvent such as, for example, dichloromethane. 44903 C. for the preparation of compounds of general formula I wherein X represents a hydrogen atom, a nitro radical or a protected amino radical, for example an alkanoylamino radical containing from 1 to 5 carbon atoms, and Z represents a group of formula : ^R1 -CO-N (in which R. and R- are as hereinbefore >» T> * 4 2 defined): Reaction of a compound of formula I as hereinbefore defined (wherein Z represents a group of formula -C00H) or a reactive derivative thereof such as, for example, a compound of formula III as hereinbefore defined,with a compound of formula V, (wherein R^ and R^ are as hereinbefore defined) with the proviso that, where in the compound of formula V, the group ^R1 -N contains an grouping, this grouping is 2 protected throughout the reaction with the acid or reactive derivative thereof, any protective groups being removed subsequent to the reaction, whereby the desired compound of formula I is obtained.

The compound of formula III is preferably reacted with ""Sos the compound of formula V in the presence of an anhydrous organic solvent such as, for example, dichloromethane.

D. . for the preparation of compounds of general formula I wherein X represents a nitro group and Z is as hereinbefore defined, for example, a group of formula rCOOR (in which R represents an alkyl radical containing from 1 to 5 carbon atoms e.g. a methyl radical): Nitration of a compound of formula I as hereinbefore defined (wherein X represents a hydrogen atom).

The nitration may conveniently be effected by means of a mixture of nitric and concentrated sulphuric acid.

E. for the preparation of compounds of general formula I wherein X represents an amino group and Z represents a group of formula -COOR (in which R is as hereinbefore defined, for example, an alkyl radical containing from 1 to 5 carbon atoms e.g. a methyl radical): Reduction of a compound of formula I as hereinbefore defined [(wherein X represents a nitro group and Z represents a group of formula -COOR (in which R is as hereinbefore defined)] whereby the desired compound of formula I is obtained. 44905 The reduction is conveniently effected using a mild reducing agent such as, for example, stannous chloride, preferably in an acid medium.

F. for the preparation of compounds of general formula I wherein X represents a protected amino group and Z is as hereinbefore defined other than a group ^-Rl of formula -C00-(CH„) -N (in which the group -N Z I* \ T) ^T) 2 2 contains an ^NH grouping) : Reaction of a compound of formula I as hereinbefore defined [wherein X represents an amino group and Z is as hereinbefore defined other lhan a group of R fonmila-C0d-(CH,) -N<^ 1 (in which the group contains R2 Xr2 an^NH grouping)] with an amine protecting agent whereby the desired compound of formula I is obtained.

The amine group may, for example,be protected with an alkanoyl radical containing from 1 to 5 carbon atoms, e.g.an acetyl radical, by means of reaction with the appropriate alkanoyl chloride e.g.acetyl chloride as amine protecting agent. Alternatively the amine group may, for example, be protected with a group of formula -CO-COO-R* (wherein R' is as hereinbefore defined e.g. an ethyl group) in which case a suitable amine protecting agent is, for example, a compound of formula: CI - CO - COO - R' (wherein R' is as hereinbefore defined).

The reaction is conveniently effected in an organic solvent such as, for example, dimethylformaniide. G. for the preparation of compounds of general formula I wherein Z represents a group of formula -COOR (in which R represents a hydrogen atom) : Hydrolysis of a compound of formula I as hereinbefore defined [wherein Z represents a group of formula -COOR (in which R is as hereinbefore defined other than a hydrogen atom,for example an alkyl radical containing from 1 to 5 carbon atoms e.g. a methyl radical)] whereby the desired compound of formula I is obtained.

The hydrolysis is preferably effected in the presence of a base, for example, an alkali e.g. sodium hydroxide.

As will be appreciated, when, in the starting compound of formula I, X represents a protected amino 44903 group, the protecting group may also undergo hydrolysis tinder the conditions of the reaction. For example, when, in the starting compound of formula I the protecting group comprises a group of formula -C0-C00Rr (in which R ' represents an alkyl radical containing from 1 to 5 carbon atoms e.g. an ethyl radical) this group will be hydrolysed under the conditions of the reaction to a group of formula -C0-C00H.

H. for the preparation of compounds of general formula I wherein Z represents a group of formula -COOR (in which R is other tuan a hydrogen atom): Esterification of a compound of formula I as hereinbefore defined (wherein Z represents a group of formula -C00H) or a reactive derivative thereof with a compound of formula VI, R" - OH (VI) (in which R" is as hereinbefore defined for R other than a hydrogen atom) or a reactive derivative thereof.

The esterification may, for example, be carried out by reaction of a compound of formula I (wherein Z represents a group of formula -C00H) with a compound of formula VI.

- U - *4005 , As will be appreciated, when, in the starting compound of formula 1, X represents a protected amino group, the protecting group may also undergo reaction with the compound of formula VI. Thus, for example, if the protecting group comprises a group of formula -C0-C00H then this group may also undergo reaction with the compound of formula VI to form a group of formula -C0-C00R" (in which R" is as hereinbefore defined).

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

Compounds of general formula I wherein Z represents a carboxyl group and/or X represents a group containing a free carboxyl group may, if desired, be converted into the base addition salts thereof by reaction with an appropriate organic or inorganic base 44905 The compounds of general formula II, used as starting materials in the preparations of compounds of general formula I, are themselves novel compounds and constitute a still further feature of the present invention.

The compounds of general formula II may, for example, be prepared by treatment of a compound of formula VII, (wherein is as hereinbefore defined and Hal represents a halogen atom e.g.a bromine, iodine or, more preferably, a chlorine atom) with a base, for example a weak base such as sodium carbonate followed by treatment with acid, for example, concentrated hydrochloric acid.

The compounds of general formula VII may, for example, be obtained by reaction of a compound of formula VIII, NH - C0CH2Hal (VII) 16 *'003 (VHI) (wherein is as hereinbefore defined) with a haloacetyl halide, for example chloroacetyl chloride. The compound of formula VIII wherein R^ represents an ethyl group is described in the literature. However the remaining compounds of general formula VIII are not so described.

The compounds of general formula VIII may, for exanple be prepared by hydrogenation of a compound of formula IX, HO \ N 00R. 0^0 (IX) (wherein is as hereinbefore defined). The compound of formula IX wherein represents an ethyl group is described in the literature. However the remaining compounds of general formula IX are not so dcsc.ribcd. 4905 The compounds of general formula IX may, if desired, be formed by reaction of a compound of formula X, (wherein is as hereinbefore defined) with an organic nitrite, for example amyl nitrite.

The compounds of general formula III, used as starting materials in the preparation of compounds of general formula I, are also novel compounds and constitute a still further feature of the present invention. They may, for example, be obtained by reaction of a compound of formula I as hereinbefore defined (wherein X represents a hydrogen atom or a nitro or protected amino radical and. 7. represents a carboxyl group) with a halogenating agent such as, for example, thionyl chloride or a phosphorus halide e.g. phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride.

H COOR 3 (X) 18 As stated above the compounds of general formula I and their salts possess interesting pharmacological properties. Those compounds which we have tested have shown remarkable anti-allergic and bronchodilatory activity as illustrated hereinafter.

Compounds of general formula I and their physiologically compatible salts may thus be used in human therapy especially in the treatment of asthma and bronchial asthma of an allergic origin.

Pharmacological activity Passive 9"taneous_anaghylaxis_^PCA2 in_rat.s : 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. 19 4^9 0 8 I » 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; Hale rats weighing 180-220 grams are used in groups of seven.

Preparation of Antigen for Sensitisation (Alum precipitated ovalbumen). 1. Wash 120 grams A1(0H)^ gel in U0 mis 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 mis 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.

. 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 20 sensitisation programme).

Preparation of Antiserum (i.e. antl-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 a 5 point scoring system.

Method (A) SENSITISATION :- Rats are anaesthetised with Nembutal (40-60 mg/kg iip.) 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 44005 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 syrings. 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 five 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 x 100 X c 1 . EIJjq => dose of drug giving 50% inhibition.

ED 5q values for compounds tested in the passive cutaneous anaphylaxis screen (in rats) : ( Compound of ed50 I mg/Kg I.V. mg/kg P.O.) - .8 ) 1.95 2.88 } ( Example 5 1.75 .65 ) 2.2 0.073 >10 ) f Example 12 - 3.85 } 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 physiologica, ;ble salt thereof in association with a pharmaceu_ u Ler or excipient.

For pharmaceutical administration the compounds of general formula I and their physiologically compatible salts may be incorporated, in cither solid or liquid form, 4490? 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, rcctal, topical or parenteral administration. Preferred forms include tablets, 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, 1 tose, starch, magnesium stearate, cocoa butter, i.^ueous 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 0.5 to 100 , preferably from 2 to 50 mg of active ingredient. The oral - 2't - 4400 daily dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 0.5 to 100 mg per day in adults.

The following non-limiting examples serve to illustrate the present invention. 449°S Example 1 Methyl 4H-lmidazo-[2,l-clTltAl-benzoxazlne-2-carboxylate A) methyl g-oximino-2-oxo-2H-l,4-benzoxazlne-3-acetate: 82 g (0.375 mole) of methyl 2-oxo-2H-l,4-benzoxazine-A^i,H^a- acetate (Bull. Chem, Soc. Japan 1971, hk (5), p. 1311-3) was suspended in 1 1. of glacial acetic acid and 15.0 g (0.09 mole) of trichloroacetic acid were added thereto,followed by 48 g (0.38 mole) of amyl nitrite (Annalen 1963, p. 83-104). The solution became warm (about 60°C) and all the starting material dissolved.

Aft«»r two hours TLC indicates that only a small quantity of starting material remained. A further 3 g of amyl nitrite were added and the mixture was subsequently cooled for a further two hours in an ice bath. The solid product thus obtained was filtered off and washed well with ether until the filtrate was colourless. Yield 74.4 g, dried over a vacuum oven. The mother liquor was con centrated at 70°C on a rotary evaporator to a volume of about 200 mis. and a second crop of 2.3 g was obtained.

Total yield 76.7 g (83%) as buff needles. M.pt. 169-70°C.

I.R. (KBr disc) 771, 979, 1022, 1250, 1288, 1754, 3310 cm"1. 44903 B) methyl g-amino-2-oxo-2H-1.4-benzoxazine-A'^i<^g-acetate; 42.5 g (0.17 mole) of the methyl a-oximino-2-oxo-2H-l,4-benzoxazine-3-acetate obtained in the previous stage were suspended in 500 tnls of tetrahydrofuran (dried over KOH pellets) and 0.7 g of platinum oxide were added thereto. The mixture obtained was hydrogenated at up to 4 atmospheres pressure. The uptake of hydrogen was rapid and steady and ceased after one and a half hours. The dark red solution thus formed was then filtered through celite, the filter pad being washed well with chloroform. The filtrate was subsequently evaporated to dryness at 45°C on a rotary evaporator. 100 mis. of cold absolute ethanol was added to the residue with trituration. The dark red crystalline product thus obtained was then filtered off, washed with a little cold ethanol and ether and finally dried. Yield 35.5 g, 88% yield. M.pt.122-5°C.

I.R. (KBr disc) 750, 1218, 1241, 1280, 1302, 1510, 1556, 1695, 1728, 3300, 3360, 3470cm"1. 4490® C) methyl 2-chloroacetamldo-2-(2-oxo-2H-1.4-benzoxazin-3-yl)-acetate: 50.2 g (0.214 mole) of methyl a-amino-2-oxo~2H-l,4-benzox- / M II Yy azine-A -acetate obtained in the previous stage were sus-5 pended in glacial acetic acid (400 mis) and 30 g (0.266 mole) of chloroacetyl chloride were added thereto. A yellow precipitate formed which redissolved on warming. After three hours at 50°C, TLC indicated that no starting material remained. The glacial acetic acid was then re-10 moved on a rotary evaporator and 150 mis of absolute ethanol were added to the residue with trituration and cooling. The product was then filtered off and washed well with ether to give, after drying, yellow needles. Yield 52.6 g. 79%. M. pt. 129-31°C.

I.R. (KBr disc) 765, 1226, 1533, 1670, 1745, 1767, 3295 cm"1.

D) 4H-2-methoxycarbonyl-imidazo-[2,l-c]fl, 4lrbenzoxazine-1-carboxylic acid: 72 g (0.232 mole) of the methyl 2-chloroacetamido-2-(oxo-20 2H-l,4-benzoxazin - 3-yl)-acetate obtained in the previous - 28. ' - stage were suspended in a mixture of 400 mis of water and 50 mis acetone. To the solution thus obtained were added 40 g. (0.38 mole) of anhydrous sodium carbonate. The mixjture thus formed was subsequently warmed on a water bath for about fifteen minutes until a clear yellow solution was obtained. Concentrated hydrochloric acid was then dripped slowly, with stirring, into the hot solution until the pH reached 2-3. A solid product crystallised out immediately and, after cooling in an ice bath, was filtered off, washed well with water and finally dried over 1^5 to 8*-ve 43.5 g of the desired product (off white needles). 69% yield. M.pt. 160-2°C (decarboxy-lates).

I.R. (KBr disc) 750, 1243, 1276, 1508, 1554, 1722cm"1. E) methyl 4H-imidazo-[2,1-ciri,4l-benzoxazine-2-carboxylate 20 g (0.073 mole) of the 4H-2-methoxycarbony ^imidazole,l-c][l,i»]-benzoxazine-l-carboxylic acid obtained in the previous stage were added to a flask provided with a magnetic stirrer. The flask was placed in an oil bath at 175-80°C. Stirring was continued for about twenty minutes until effervescence ceased. The decarboxylated product »*9°9 thus formed was then dissolved in chloroform and the solution obtained was passed down a short silica column to remove any remaining low Rf impurities. The combined fractions containing the methyl 4F-'midazo-[2,l-c][1,4]-benzoxazine-2-carboxylate were then reduced to dryness and ether was added with trituration. The off-white product was filtered off, washed with a little ether and dried. Yield 14.0 g. 83%. M.pt. 133-4°C.

I.R. (KBr disc) 745, 1259, 1562, 1715, 3135cm"1.

Example 2 4H-Imldazo-[2. l-c] fl ,4)-benzoxazine-2-carboxylic acid 10.0 g (0.0435 mole) of methyl 4H-imidazo-[2,l-c][1, 4]-benzoxazine-2-carboxylate (prepared, for example, according to Example 1) were suspended in a mixture of 100 mis of methanol and 50 mis of water. 2N NaOH solution was added to the mixture thus obtained until the pH was 11. The mixture was warmed until the starting material had completely dissolved. TLC indicated that no starting material remained. The solution was subsequently acidified to pH 2-3 using concentrated hydrochloric acid. The desired product precipitated out and, after cooling was filtered - 30 _ off and washed well with water. The white product was dried over P2°5* Yteld 8»5 8* 91^» H.pt.256-8°C (decarboxylates).

I.R. (KBr disc) 755, 1191, 1218, 1275, 1512, 1559, 1695, 2300-3500, 3135cm"1.

Exai pie 3 Tharo salt of 4H-imidazo-[2,l-cU;l,U]- benzoxazine-2-carboxylic acid 6.0 g (0.028 mole) of 4H-iraidazo-[2,l-c][l,4]-benzoxazine-2-carboxylic acid (prepared, for example, according to Example 2)vere suspended in methanol and 3.5 g (0.029 mole) of tris(hydroxymethyl)aminometIiane (THAM)were added thereto. On warming a clear solution was obtained. Cooling and scratching yielded the desired salt as a white crystalline product. Yield 8.1 g. 85%. M.pt. 203-5®C. I.R. (KBr disc) 750, 1040, 1222, 1277, 1349, 1369, 1403, 1510-1600, 2300-3500cm"1.

Example 4 4H - 2 - Q4 - Methyl - piperazin - 1 - yl) —carbonyl] - imidazo D»1 - cjCl,4] - benzoxazine A) 4H-imidazo-[2,l-c][l,4]-benzoxazine-2-carbonyl chloride: g (0.023 mole) of 4H-imidazo-[2,l-c][l,4]-benzoxazine-2-carboxylic acid (prepared for example, according to Example 2) were suspended in 15 mis of thionyl chloride and the mixture obtained was refluxed for two hours, during which time the solid material completely dissolved. Excess thionyl chloride was removed by azeotroping with benzene on a rotary evaporator. The product was triturated with ether, filtered off and dried. Yield 4.5 g. 83%. M.pt. 240°C (decomp.) I.R. (KBr disc) 849, 1508, 1764, 3110cm"1.

B) 4H - 2 - (4 - methyl - plpsrazin - 1 - yl)carbonyl3 Imidazo - {.2,1 - c]D.4j - benzoxazine: 1.0 g (0.0043 mole) of the acid chloride obtained in the previous stageuere suspended in dry dichloromethane and 1.0 g (0.01 mole) of N-methyl-piperazine were added thereto. After three hours at room temperature TLC indicated that no starting material remained. The solution was subsequently washed with water, dried and evaporated. Trituration of the residue with ether gave the desired product. Yield 0.9g. 71%. M.pt. 215-7°C.

I.R. (KBr disc) 746, 1253, 1620, 3130cm"1. 4<*90{J Example 5 2-Morpholinoethyl 4H-lmida20-r2.l-c][l,.4l-ben20xa2lne-2-carboxylate 1.0 g (0.0043 mole) of 4H-imidazo-[2,l-c][l,4]-benzoxazine-2-carbonyl chloride (prepared, for example, according to Example 4A) was suspended In dry dichloromethane and 1.31 g (0.01 mole) of N-(2-hydroxyethyl)-morpholine was added thereto. The mixture thus obtained was warmed at 50°C for two hours. TLC then indicated only a small quantity of starting material remained. The mixture was then washed with water, dried and evaporated. The residue was chromatographed on a silica column using ethyl acetate as eluant. The product thus obtained was finally crystallized from ether. Yield 0.6 g. 43%. M.pt. 142-3°C.

I.R. (KBr di*c) 1256, 1711, 3145cm'1.

Example 6 Methyl 8-nitrb-4H-imidazo-[2,l-c j[l,.4}-ben20xazine-2-car-boxylate 8.0 g of methyl 4H-imidazo-[2,l-c][l,4]-benzoxa2ine-2-car-boxylate (prepared, for example, according to Example 1) 44-OOS were added to a stirred mixture of 25 mis of concentrated sulphuric acid and 25 mis of concentrated nitric acid at 10°C. The ester slowly went into solution, the solution turning yellow. After three hours at room temperature TLC indicated no starting material remained. 500 mis of water was then added and the yellow product thus formed was filtered off, washed well with water and then dried over P205. Yield 7.5 g. 79%. M.pt. 270-2"C.

I.R. (KBr disc) 1276, 1348, 1541, 1728, 3150cm"1.

Example 7 Methyl 8-amino-4H-imidazo-f 2, l-c][l>.4}--benzoxazine-2-car-boxylate .0 g (0.018 mole) of methyl 8-nitro-4H-imidazo-[2,l-c]-[l,4]-benzoxazine-2-carboxylate (prepared, for example, according to Example 6)were suspended in a mixture of 20 mis of acetic acid and 15 mis of concentrated hydrochloric acid. To the solution thus obtained were added 15 g (0.055 mole) of stannous chloride. The mixture obtained was stirred and warmed to 40°C. After about an hour, a crystalline product started to appear. The mixture was then cooled for two hours in an ice bath. The product (chloro- stannate salt) was filtered off and washed with ether. The salt was then dissolved in water and the pH of the solution obtained was adjusted to pH9 using dilute sodium hydroxide solution. The free amino compound was extracted with chloroform. The combined chloroform extracts were dried, filtered and evaporated. The residue was triturated with ether to give brown crystals. Yield 2.7 g. 61%. M.pt. 213-4°C.

I.R. (KBr disc) 1740, 3135, 3215, 3320, 3440cm"1.

Example 8 Methyl 8-acetamido-4H-imidazo-[2, l-c If 1,4]-benzoxazine-2-carboxylate By following the procedure of Stage (C) in Example 1, but using methyl 8-amino-4H-imidazo-[2, l-c][l,4]- benzoxazine-2-carboxylate (prepared, for example, as indicated in Example 7) and acetyl chloride in dimethylformamide as solvent. Yield 72%. M.pt. 216-9°C.

I.R. (KBr disc) 1510, 1700, 1750, 3040cm"1. - 35 Example 9 Methyl 8-(ethoxalylamino)-itH-imidazo-r2,l-cir 1,4]-benzoxazine-2-carboxylate By following the procedure of stage (C) in Example 1, but using methyl 8-amino-4H-imidazo-[2,l-c][l,4]-benzoxazine-2-carboxylate (prepared, for example, as indicated in Example 7) and ethyl oxalyl chloride (CI CO CO^ Et) in diinethylformamide as solvent. Yield 65%. M.pt. 186-8°C. I.R. (KBr disc) : 1560, 1712, 1739, 3150, 3300cm"1.

Example 10 8-Nitro-^H-imidazo-f 2, l-c]|"lt M-benzoxazine-2-carboxylic acid By following the procedure of Example 2, but using methyl 8-nitro-i4H-imidazo-[2, l-c][l,4]-benzoxazine-2-carboxylate (prepared, for example, as indicated in Example 6). Yield 83 M.pt. 310-2°C.

I.R. (KBr disc) : 1270, 1352, 1539, 1571, 1690 cm"1.

Example 11 8-Acetaraido-4H-imidazo-r2, l-ciri»4l-benzoxazine-2-carboxylic acid *400 5 By following the procedure of Example 2, but using methyl 8-acetamido- 4H-imidazo-[ 2,l-c][l,4]- benzoxazine-2- carboxylate (prepared, for example, as indicated in Example 8). Yield 75 %. M.pt. 295-6°C.

I.R. (KBr disc) : 1520, 1555, 1667, 1740, 2200, 3040, 3600 cm"1.

Example 12 8-0xalamino-4H-imldazo-r 2 ,l-c1[ 1,4]-ben«r.oxazlne-2-carboxyllc acid By following the procedure of Example 2, but using methyl 8-(ethoxyalylamino)-4H-imidazo-[2,i-c][l,4]-benzoxazine-2-carboxylate (prepared, for example, as indicated in Example 9). Yield 45%. M.pt. 240°C (decomp.) I.R. (KBr disc) : 1560, 1700-1740, 2300-3700 cm"1.

Example 13 Tablets were prepared containing: -Tham salt of 4H-imidazo-[2, l-c][ 1, V}-benzoxazine-2- carboxylic acid 5 mg ; -Excipient (lactose, talc, starch, magnesium stearate) q.s. for 1 tablet of 100 mg. <14905 Example Ik A metered dose aerosol dispenser was packed with the following ingredients per dose: -ltH-imidazo-[2,l-c][l,i»]-benzoxazine-2-carboxylic acid 5 mg -Emulsifier 0.15 mg -Propellant 50 mg " 38 ~

Claims

'o0 What we claim Is:

1. Compounds of general formula I,

(I)

wherein

X represents a hydrogen atom or a nitro, amino or protected amino radical; and

Z represents a group of formula:

-COOR

[in which R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or a group of formula:

/R1

-(CH)-N

2 n

2

(in which n is 1, 2 or 3; and Rj ana R2, which may be the same or different, each represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, or Rj and R2, together with the nitrogen atom to which

- 39 -

t 4 4003

they are attached, represent a saturated heterocyclic ring containing from 4 to 6 carbon atoms which may, if desired, be interrupted by a further hetero atom, said further hetero atom being optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms)] or a group of formula:

"R,

-CO-N

2

(in which and R2 are as defined above): and salts thereof.

10

2. Compounds as claimed in claim 1 wherein X represents an alkanoylamino radical containing from 1 to 5 carbon atoms or a group of formula:

-NH-C0-C00-R'

(in which R' represents a hydrogen atom or an alkyl 15 radical containing from 1 to 5 carbon atoms).

3. Compounds as claimed in claim 1 or claim 2 wherein X represents an amino radical or a group of formula -NH-CO-COOR* (in which R' is as defined in claim 2) and Z represents a group of formula -COOR (in which R

- hO -

represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms).

4. Compotinds as claimed in claim 1 wherein X represents a hydrogen atom, a nitro, amino or acetamido radical or a group of formula -NH-CO-COOR' (in which R1 represents a hydrogen atom or a methyl or ethyl radical) and Z represents a group of formula -COOR [in which R represents a hydrogen atom, a methyl or ethyl radical or a group of formula -(CH-) -N

" n XR„

(In which Rj and R£» together with the nitrooen atom to which they are attached, form a pyrrolidino,

piperidiho, morpholino, piperazino or 4-methyl-piperazin-l-

yl-ringj] or a group of formula _ CO-N^**1 (in which Ri and R2 are as defined above). ^1*2

5. Compounds as claimed in claim 4 wherein X represents a hydrogen atom, a nitro or acetamido radical or a group of fbrmula -NH-CO-COOR' (in which R' represents a hydrogen atom or a methyl or ethyl radical) and Z represents a group of formula -COOR (in which R represents a hydrogen atom or a methyl, ethyl or morpholinoethyl

- 41 -

radical) or a 4-methyl-piperazin-l-yl-carbonyl radical.

6. Compotinds as claimed in claim 5 wherein X represents a hydrogen atom and Z represents a carboxyl, morpholinoethoxycarbonyl or 4-methyl-piperazin-l-yl-carbonyl radical.

7. 4H-Imidazo-[2,l-c] [1,4]-bcnzoxazine-2-c;irboxylic acid and salts thereof.

8. 2-Morpholinoethyl 4H-imidazo-[2,l-c] [l,4]-benz-oxazine-2-carboxylate.

9. 8-Nitro-4H-imidazo-[2,l-c] [l,4]-benzoxazine-2-carboxylic acid arid salts thereof.

10. 8-Acetasiido-4H-itnidazo-[2f l-c] [lf4]-benzoxazine-2-carboxylic acid and salts thereof.

11. Compounds of general fornrula I as defined in claim 1 in the form of acid addition salts.

12. Compounds of general formula I as defined in claim 1 wherein Z represents a carboxyl radical ana/or X represents a group containing a free carboxyl radical in the form of base addition salts.

13. Compounds of general formula I as defined in claim

1 in the form of physiologically compatible salts. 14. Compounds as claimed in claim 1, other than those claimed in any of claims 7 to 10, as herein specifically disclosed in any of Examples 1 to 12.

5 15. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a hydrogen atom and Z represents a group of formula -COOR (in which R represents an alkyl radical containing from 1 to 5 carbon atoms) which comprises 10 decarboxylating a compound of formula II,

HOOC. , COOR-,

(II)

(wherein R^ represents an alkyl radical containing from 1 to 5 atoms).

16. A process as claimed in claim 15 wherein decarbox-15 ylation is effected by means of heating the compound of formula II.

17. A process as claimed in claim 15 or claim 16

wherein, in the compound of formula II, R^ represents a

- 43-

methyl radical.

18. A process as claimed in any of claims 15 to 17 wherein the compound of formula II is obtained by treatment of a compound of formula VII,

(wherein R^ is as defined in claim 15 and Hal represents a halogen atom) with a base, followed by treatment with an acid.

19. A process as claimed in claim IS wherein, in the

10 compound of formula VII, Hal represents a chlorine, bromine or iodine atom.

20. A process as claimed in claim 18 or claim 19 wherein the base is a weak base.

21. A process as claimed in claim 20 wherein the base 15 comprises sodium carbonate.

22. A process as claimed in any of claims 18 to 21 wherein the acid comprises concentrated hydrochloric acid.

23. A process as claimed in any of claims 18 to 22

- 44 -

*9

0,

proviso that, where the compound of formula IV contains an >NH grouping, this grouping is protected throughout the reaction with the acid or reactive derivative thereof, any protective groups being removed subsequent 5 to the reaction, whereby the desired compound of formula

I is obtained.

29. A process sis claimed in claim 28 wherein the reaction is effected in the presence of an anhydrous organic solvent.

10 30. A process as claimed in claim 29 wherein the sol vent comprises dichloromethane.

31. A process as claimed in any of claims 28 to 30 wherein the compound of formula IV is reacted with a compound of formula III,

15

(III)

>0-

(wherein X represents a hydrogen atom, a nitro radical or a protected amino radical and Hal represents a

- 47 -

a 4 9 0 3

halogen atom.

32. A process as claimed in claim 31 wherein, in the compound of formula III, Hal represents a chlorine or bromine atom.

33. A process as claimed in claim 31 or claim 32 wherein the compound of formula III is obtained by reaction of a compound of formula I as defined in claim 1 (wherein X represents a hydrogen atom or a nitro or protected amino radical and Z represents a carboxyl radical) with an appropriate haLogenating agent.' -

34. A process as claimed in claim 33 wherein the halo-genating agent is thionyl chloride or a phosphorus halide.

35. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a hydrogen atom or a nitro or protected amino radical and Z represents a group of formula

-CO-N (in which R, and R0 are as defined in claim 1)

>7) A ^

2

i which comprises reacting a compound of formula I as defined in claim 1 (wherein Z represents a group of

- 48 -

wherein the compound of formula VII is obtained by reaction of a compound of formula VIII,

(VIII)

(wherein is as defined in claim 15) with an appropriate haloacetyl halide.

24. A process as claimed In claim 23 wherein the haloacetyl halide is chloroacetyl chloride.

25. A process as claimed in claim 23 or claim 24 wherein the compound of formula VIII is obtained by hydrogendtion of a compound of formula IX,

N

^ COOR.

(IX)

0^ ^0

(wherein R^ is as defined in claim 15).

26. A process as claimed in claim 25 wherein the compound of formula IX is obtained by reaction of a compound of formula X,

- 45 -

COOR3

10

(X)

(wherein R^ is as defined in claim 15) with an organic nitrite.

27. A process as claimed in claim 26 wherein the organic nitrite comprises amyl nitrite.

28. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a hydrogen atom or a nitro or protected amino radical and Z represents a grcup of formula

/R1

-C00-(CHo) -N A (in which n R, and R- are as defined 2 n '1 2

2

in claim 1) which comprises reacting a compound of formula I as defined in claim 1 (wherein Z represents a group of formula -COOH) or a reactive derivative thereof with a compound of formula IVf

/R1

15 H°-<CH2>n-N\ (IV)

R2

(wherein n, R^and R^ are as defined in claim 1) with tte

- 46 -

4«>0«

formula -COOH) or a reactive derivative thereof with a compound of formula V,

H1 (V)

(wherein R^ and R^ are as defined in claim 1) with the 5 proviso that, where in the compound of formula V, the

/R1

group -N^ contains an >NH grouping, this grouping is protected throughout the reaction with the acid or reactive derivative thereof, any protective groups being removed subsequent to the reaction, whereby the desired 10 compound of formula I is obtained

36. A process as claimed in claim 35 wherein the reaction is effected in the presence of an anhydrous organic solvent.

37. A process as claimed in claim 36 wherein the solvent 15 comprises dichloromethane.

38. A process as claimed in any of claims 35 to 37 wherein the compound of formula V is reacted with a compound of formula III as defined in claim 31.

39. A process as claimed in claim 38 wherein, in the

- 49 -

44903

compound of formula III, Hal represents a chlorine, bromine or iodine atom.

AO. A process as claimed in claim 38 or claim 39 wherein the compound of formula III is obtained by a process as defined in claim 33 or claim 34.

41. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a nitro group which comprises nitrating a compound of formula I as defined in c1 aim 1 (wherein X represents a hydrogen atom).

42. A process as claimed in claim 41 wherein nitration is effected by means of a mixture of nitric and concentrated sulphuric acid.

43. A process as claimed in claim 41 or claim 42 wherein, in the compound of formula I, Z represents a group of formula -CCOR (in which R represents an alkyl radical containing from 1 to 5 carbon atoms).

44. A process as claimed in claim 43 wherein R represents a methyl radical.

45. A process for the preparation of compounds of compounds of general formula I as defined in claim 1

wherein X represents an amino group and Z represents a

- 50 -

«J80s group of formula -COOR (in which R is as defined in claim 1) which comprises reducing a compound of formula I as defined in claim 1 [wherein X represents a nitro group and Z represents a group of formula -COOR (in 5 which R is as defined in claim 1)] whereby the desired compound of formula I is obtained.

46. A process as claimed in claim 45 wherein reduction is effected by means of stannous chloride.

47. A process as claimed in claim 46 wherein the re-10 duction is effected in an acid medium.

48. A process as claimed in any of claims 45 to 47 wherein, in the compound of formula I, R represents an alkyl radical containing from 1 to 5 carbon atoms.

49. A process as claimed in claim 48 wherein R repre-15 sents a methyl radical.

50. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a protected amino group and Z is as defined in claim 1

^R1

other than a group of formula -COO-(CH-) -N (inwhich

2 n

2

20 n is as defined in claim 1 and the group -N" Rl contains

^R2

- 51 -

44905

an^NH grouping) which comprises reacting a compound of formula I as defined in claim 1 [wherein X represents an amino radical and Z is as defined in claim 1 other than a group of formula -COO-XC^^-N^^l (in which the

R ^

5 group -N^_l contains an>NH grouping)] with an amine

2

protecting agent whereby the desired compound of formula I is obtained.

51. A process as claimed in claim 50 for the preparation of compounds of general formula I wherein X repre-

10 sents an alkanoylamino radical containing from 1 to 5 carbon atoms.

52. A process as claimed in claim 51 wherein the amine protecting agent is an alkanoyl chloride containing from 1 to 5 carbon atoms.

15 53. A process as claimed in claim 52 wherein the amine protecting agent is acctyl chloride.

54. A process as claimed in claim 50 for the preparation of compounds of general formula I wherein X represents a group of formula -NH-CO-COOR' (in which R' is as defined

2o in claim 2).

55. A process as claimed in claim 54 wherein the amine

- 52 -

*30-

protecting agent is a compound of formula:

Cl-CO-COO-R'

(in which R' is as defined in claim 2)

56. A. process as claimed in claim 55 wherein the amine protecting agent is a compound of formula:

ci-co-coo-c2h5

57. A process as claimed in any of claims 50 to 56 wherein the reaction is effected in the presence of an organic solvent.

58. A process as claimed in claim 57 wherein the solvent comprises dimethylformamide.

59. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a group of formula -COOR (in which R represents a hydrogen atom) which comprises hydrolysing a compound of formula I as defined in claim 1 [wherein Z represents a group of formula -COOR (in which R is as defined in claim 1 other than a hydrogen atom)] whereby the desired compound of formula I is obtained.

60. A process as claimed in claim 59 which comprises hydrolysing a compound of formula I wherein Z represents

- 53 -

44900

a group of formula -COOR (in which R represents an alkyl radical containing from 1 to 5 carbon atoms). 61. A process as claimed in claim 60 wherein R represents a methyl radical.

5 62. A process as claimed in any of claims 59 to 61 wherein the hydrolysis is effected in the presence of a base.

63. A process as claimed in claim 62 wherein the base comprises an alkali.

10 64. A process as claimed in claim 63 wherein the alkali comprises sodium hydroxide.

65. A process for the preparation of compounds of general formula 1 as defined in claim 1 wherein Z represents a group of formula -COOR (in which R is as defined 15 in claim 1 other than a hydrogen atom) which comprises esterifying a compound of formula I as defined in claim 1 (wherein Z represents a group of formula -C00H) or a reactive derivative thereof with a compound of formula

VI,

20 R"-0H (VI)

(wherein R" is as defined for R in claim 1 other than a

- 54 -

*490

hydrogen atom) or a reactive derivative thereof.

66. A process as claimed in claim 65 wherein a compound of formula I (wherein Z represents a group of formula -COOH) is reacted with a compound of formula VI.

67. A process for the preparation of physiologically compatible 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 on appropriate acid.

68. A process as claimed in claim 67 wherein the acid comprises hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxalLc or aspartic acid, or an alkanesulphonic or arylsulphonic acid.

69. A process as claimed in claim 68 wherein the acid comprises methanesulphonic or benzenesulphonic acid.

70. A process as claimed in any of claims 67 to 69 wherein the acid and the compound of formula I are reacted in substantially equimolar quantities:

71. A process for the preparation of physiologically

- 55 -

449 OS

compatible base addition salts of compounds of general formula I as defined in claim 1 wherein Z represents a carboxyl group and/or X represents a group containing a free carboxyl group which comprises reacting a compound of formula I as defined in claim 1 (wherein Z represents a carboxyl group and/or X represents a group containing a free carboxyl group) with an appropriate base.

72. A process as claimed in claim 71 wherein the base comprises an amine.

73. A process as claimed in claim 72 wherein the amine comprises lysine, arginine, triethanolamine or tris-(hydroxymethyl)aminomethane.

74. A process as claimed in claim 71 for the preparation of an alkali metal, alkaline earth metal,aluminium or ammonium salt.

75. A process as claimed in claim 74 for the preparation of a sodium, potassium, lithium, calcium or magnesium salt.

76. A process for the preparation of compounds of general formula I as defined in claim 1 and physiologically compatible salts thereof substantially as herein described.

56

"*<803

77. A process for the preparation of compounds of general formula I as defined in claim 1 and physiologically compatible salts thereof substantially as herein described in any of Examples 1 to 12.

78. Compounds of general formula I as defined in claim 1 and physiologically compatible salts thereof whenever prepared by a process as claimed in any of claims 15 to 77.

- 57 -

449°°

79. 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.

80. Compositions as claimed in claim 79 in a form suitable for oral, rectal or parenteral administration.

81. Compositions as claimed in claim 79 or claim 80 in the form of tablets, coated tablets, gelatin capsules, granules, suppositories, solutions, syrups, ointments, creams, and aerosols.

82. Compositions as claimed in any of claims 79 to 81 in the form of dosage units.

83. Compositions as claimed in claim 82 wherein each dosage unit contains from 0.5 to 100 mg of active Ingredient.

84. Compositions as claimed in claim 83 wherein each dosage unit contains from 2 to 50 mg of active ingredient.

85. Compositions as claimed in any of claims 79 to 84 wherein the active ingredient comprises a compound as claimed in any of claims 7 to 10.

86. Pharmaceutical compositions as claimed in claim 79 substantially as herein described.

87. Pharmaceutical compositions substantially as herein described in Example 13 or Example 14.

- 58 -

\

440

88. Compounds of general formula II as defined in claim 15.

89. A process for the preparation of compounds of general formula II as defined in claim 15 substantially as herein described.

90. Compounds of general formula II as defined in claim 15 whenever prepared by a process as claimed in claim 89.

91. Compounds of general formula III as defined in claim 31.

92. A process for the preparation of compound of general formula III as defined in claim 31 substantially as herein described.

93. Compounds of general formula III ns defined in claim 31 whenever prepared by a process as claimed in claim 92.

Dated this 23rd day of May 1977,

(signed)

TOM

MNS & CO. , cants' Agents,

. v. —.

5 Dartmouth Road, DUBLIN 6

- 59 -