GB2174695A

GB2174695A - Heteroanalogs of imidazobenzodiazepines

Info

Publication number: GB2174695A
Application number: GB08511623A
Authority: GB
Inventors: Raymond Baker; John Saunders; Angus Murray Macleod
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 1985-05-08
Filing date: 1985-05-08
Publication date: 1986-11-12
Also published as: GB8511623D0

Abstract

New oxadiazolyl heteroanalogs of imidazobenzodiazepine derivatives having the general formula <IMAGE> wherein A is a 5 or 6-membered heterocycle with up to 2 heteroatoms selected from N and S, either unsubstituted or substituted with C1 3 alkyl, C1 3 alkoxy and/or halo; Q is a 5- or 3-oxadiazolyl group optionally substituted with C1 5 alkyl or C3 5 cycloalkyl, both optionally substituted with C1 3 alkoxy or phenyl which is itself optionally substituted with halo, C1 3 alkyl or C1 3 alkoxy; and either R<2> is H and R<3> is C1 6 alkyl or R<2>+R<3> form a 2-4 membered alkylene bridge, and pharmaceutically acceptable salts thereof, are useful in psychopharmaceutical preparations as anticonvulsants, anxiolytics, hypnotics and nootropics.

Description

SPECIFICATION Heteroanalogs of imidazobenzodiazepines SUMMARY OF THE INVENTION This invention relates to new oxadiazolyl heteroanalogs of imidazobenzodiazepine derivatives and to methods of preparing them. These new compounds are useful in psychopharmaceutical preparations as anticonvulsants, anxiolytics, hypnotics and nootropics and have the general formula 1:

wherein: A is a 5 or 6 membered heterocycle with up to 2 heteroatoms selected from nitrogen and sulfur; O is a 5- or 3-oxadiazolyl group of formula

respectively; R1 is C, s alkyl, either straight chain, branched chain or cyclic and either unsubstituted or substituted with C1 3 alkoxy, or phenyl; R' hydrogen; and R3 is C" alkyl or R2 and Ra together form a 2-4 membered alkylene bridge.

BACKGROUND OF THE INVENTION The most relevant prior art is to be found in European Patent application Number 109.921 in which other oxadiazolyl derivatives of imidazobenzodiazepines are disclosed. Heteroanalogs of the imidazobenzodiazepine ring system are disclosed in U.S. Patent 4,136,839.

Now with the present invention there are provided novel heteroanalogs of the imidazobenzodiazepines substituted with an oxadiazolyl group; novel processes for preparing the compounds, and novel pharmaceutical formulations thereof.

DETAILED DESCRIPTION OF THE INVENTION The novel compound of this invention has structural formula 1:

or a pharmaceutically acceptable salt thereof, wherein A is a 5 or 6 membered heterocycle with up to 2 heteroatoms selected from nitrogen and sulfur such as pyrido, pyrazino, thieno, pyrrolo, imidazo, thiazolo or the like, and either unsubstituted or substituted with C, 3 alkyl, C, 3 alkoxy and/or halo such as chloro, bromo or fluoro; Q is a group of formula

R' is C15 alkyl, either straight or branched chain, or cyclic, and either unsubstituted or substituted with: (a) C, 3 alkoxy or (b) phenyl, either unsubstituted or substituted with:: (i) halo, (ii) C, 3 alkyl, or (iii) C, 3 alkoxy; R2 is hydrogen; R3 is C16 alkyl; or R2 and R3 taken together form a 2-4 membered alkylene bridge.

It is preferred that: R' be cyclopropyl, R2 be hydrogen, Ra be methyl, and A be pyrido.

The pharmaceutically acceptable salts coming within the purview of this invention include the pharmaceutically acceptable acid-addition salts. Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, methanesulfonic, or ethane disulfonic.

A novel process for preparing the 5-oxadiazolyl compounds of this invention is illustrated as follows:

wherein: R is hydrogen or, preferably, C, 3 alkyl, especially ethyl.

The process comprises treating a compound of structure (2) with an amide oxime of structure (3) in a C, 3 lower alkanol solvent, especially ethanol in the presence of an alkali metal, especially sodium.

The reaction is conducted at about 25 to 100"C, preferably at the reflux temperature for times of about 1 to 48 hours; preferably about 1 to 5 hours.

3-Oxadiazolyl compounds according to the invention may conveniently be prepared by the reaction scheme illustrated as follows

The reaction is preferably effected in the presence of a C, 3 lower alkanol solvent, preferably under similar conditions as mentioned above for the preparation of compounds of formula (lea).

The compound of formula (4) may be conveniently obtained by reacting a compound of formula

with hydroxylamine, preferably as its hydrochloride salt in the presence of potassium carbonate.

The compound of formula (5) may itself be obtained from a compound of formula (2), most preferably wherein R is hydrogen, by dehydrating the corresponding amide produced in conventional way by forming the acid chloride followed by reaction with ammonia.

The novel compounds of this invention have strong affinity for benzodiazepine receptors; and are therefore useful in psychopharmaceutical preparations as anticonvulsants, anxiolytics, hypnotics and nootropics.

It is well known (Squires, R.F. and Braestrup, C., Nature (London), 266, (1977) 734) that specific sites in the central nervous systems of vertebrates exhibit a high specific affinity for binding 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.

The pharmacological properties of the compounds of the invention are illustrated by determining the capability for displacing radioactively labelled flunitrazepam and the imidazobenzodiazepine 3H-Ro 15-1788 from such benzodiazepine receptors. The duration of action of the pharmacological effects is determined by the capability for displacing radioactivity labelled flunitrazepam at different time intervals after incubation.

The compounds of this invention can be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, prefera bly aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is about 0.1-300 mg/day, prefera bly about 1-30 mg/day, when administered to patients, e.g. humans, as a drug.

A representative tablet which may be prepared by conventional tabletting techniques contains: Active compound 1.0 mg Lactose 67.8 mg Avicel 31.4 mg Amberlite lRP 88 1.0 mg Magnesium stearate 0.25 mg The preparation of the compounds of the invention will now be described in further detail with reference to the following examples; wherein all temperatures are Celsius.

Example 1 3- (3-Benz yI- 1 ,2,4-oxadiazol-5-yI)-5, 6-dihydro-5-methyl-4H-imidazo[ 1, 5-a]pyrido[3, 4-f]( 1, 4]diazepin- 6-one Step A: Preparation of 3, 4-Dihydro-4-methyl-2H-pyrido[4, 3-e][ 1 ,4]diazepine-2, 5(1 H)-dione The half sulphuric acid salt of 4-aminonicotinic acid (10.299, 55 mmol; prepared as described in Monatsh, 23, 239 (1902)) stirred in dry dimethylformamide (8 Oml) was treated at room temperature with triethylamine (5.569, 55 mmol). The mixture was warmed to 50 , carbonyl diimidazole (9.8 g, 60.5 mmol) added and the resulting mixture stirred at 50"C for a further 2 hours.Triethylamine (6.11 g, 60.5 mmol) and then methyl sarcosinate hydrochloride (8.44 g, 60.5 mmol) were added and the mixture stirred at 80" for 2 hours and then at the boiling point for 4 hours. After removal of the dimethylformamide in vacuo, the residue was purified by chromatography on silica in 5% methanol in dichloromethane followed by recrystallization from ethanol to afford the title compound (2.2 g), m.p. 267-269 ; R,=0.15 in methanol-dichloromethane (1:9); (Found: C, 56.5; H, 4.8; N, 22.0. CgHgN302 requires C, 56.5; H, 4.7; N, 22.0%).

Step B: Preparation of Ethyl 5,6-dEhydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[3,4-f][1,4]-dia- zepine-3-carboxylate The foregoing dione (0.95 g, 5 mmol) was added in portions to a suspension of petrolwashed sodium hydride (0.165 g of an 80% dispersion in oil; 5.5 mmol) stirred in dimethylformamide (10 ml) under nitrogen at room temperature. After a further 0.5 hour, the mixture was cooled to - 100 and diethylchlorophosphate (0.95 g, 5.5 mmol) added dropwise over 10 minutes.Stirring was continued for a further 20 minutes at which time a solution of the anion of ethyl isocyanoacetate in dimethylformamide (prepared at 400 by the addition of ethyl isocyanoacetate (0.62 g, 5.5 mmol) to a solution of potassium t-butoxide (0.62 g, 5.5 mmol) in dimethylformamide (2 ml) was added at - 100 to 300 over 5 minutes. The resulting mixture was stirred at room temperature for 1 hour and acetic acid (0.33 g, 5.5 mmol) added. The residue obtained after evaporatin of the dimethylformamide in vacuo was partitioned between dichloromethane and -water. The organic layer was washed with water, dried and evaporated and the resulting oil chromatographed on silica in 10% methanol in dichloromethane. Subsequent recrystallization from ethyl acetate yielded the desired imidazodiazepine (250 mg), m.p.

164-165 ; R,=0.45 on silica in 10% methanol in dichloromethane; (Found: C, 58.5; H, 5.0; N, 19.4. Cl4H,4N403 requires C, 58.7; H, 4.9; N, 19.6%).

Step C: Preparation of 3-(3-Benzyl- 1,2,4-oxadiazol-5-yl)-5, 6-dihydro-5-methyl-4H-imidazo[ 1,5-a]p- yrido[3,4-f][ 1,4]diazepin-6-one Activated molecular sieves (Type 3A, 4.6 g) were vigorously stirred in absolute ethanol (30 ml) for 1 hour under nitrogen. Phenethanamide oxime (458 mg, 4.32 mmol) was added to the mixture, stirring continued for a further 1 hour, and then sodium (44 mg, 1.91 X 10 3 g atm.) added. After a further 45 minutes, the ethyl ester prepared in Step B (192 mg, 0.67 mol) was added and the resulting mixture heated at reflux temperature for 2 hours. The solution obtained after filtration was evaporated in vacuo and the resulting oil chromatographed on silica in methanol-ethyl acetae (1:9).Subsquent recrystallization from dichloromethane-ether afforded the required oxadiazole (35 mg), m.p. 167 ; R,=0.57 on silica in 10% methanol in ethyl acetate; (Found: C, 64.4; H, 4.3; N, 22.6. C",H,6N602 requires C, 64.5; H, 4.3; N, 22.6%).

The phenethanamide oxime required in the above preparation was made as follows: Sodium (13.8, 0.6 g atm) was dissolved in methanol (200 ml) under nitrogen and then treated with a solution of hydroxylamine hydrochloride (40.0 g, 0.58 mol) in methanol (400 ml). Benzylcyanide (77.3 g, 0.66 mol) was added and after 2 days the mixture was filtered and the filtrate evaporated. The resulting white solid was used without further purification.

EXAMPLE 2 3-(3-Ethyl- 1,2, 4-oxadiazol-5-yI) -5, 6-Dihydro-5-methyl-4H-imidazo[ 1, 5-a]p yrido[2, 3-fff 1, 4]diazepin-6- one Step A: preparation of Ethyl-5,6-Dihydro-5-methyl-6-oxo-4-H-imidazo[1,5-a]pyrido[2,3-f][1,4-dia- zepin-3-carboxylate A suspension of 3-amino-picolinic acid (23.7 g, 0.17 mol; prepared as described in J. Chem.

Soc., 1054, (1956)) in dimethylformamide (200 ml) was treated at 50" with triethylamine (18 g, 0.17 mol) and then carbonyl diimidazole (29 g, 0.18 mol) was added in portions over 15 minutes. After 2 hours at 500, the resulting solution was treated wtih triethylamine (18 g, 0.17 mol) and methyl sarcosinate hydrochloride (18 g, 0.17 mol) and the mixture heated at 80" for 2 hours and then at the boiling point for 10 hours. The cooled mixture was filtered and the filtrate evaporated in vacuo to give an oil which crystallized upon trituration with ethanol at - 100.

Recrystallization from ethanol yielded 3 ,4-dihydro-4-methyl-2H-pyrido[3 ,2-e][ 1 ,4jdiazepin-2,5-( 1 H)- dione as a white solid (7.5 g), m.p. 273-275"; R,=0.3 on silica in methanol-dichloromethane (1:9); (Found: C, 56.4; H, 4.8; N, 21.8. CgHgN302 requies C, 56.5; H, 4.7; N, 22.0%).

To a suspension of petrol-washed sodium hydride (1.16 g of an 80% dispersion in oil; 38.5 mmol) in dimethylformamide (50 ml) stirred under nitrogen at room temperaure was added, portionwise, the foregoing dione (6.69 g, 35 mmol) and the mixture stirred for 1.5 hours.

Diethylchlorophosphate (6.64 g, 38.5 mmol) was then added dropwise and stirring continued for a further 40 minutes. Meanwhile, potassium t-butoxide (4.31 g, 38.5 mmol) in dimethylformamide (8 ml) was treated at 400 with ethyl isocyanoacetate (4.35 g, 38.5 mmol). The resulting solution was added at - 100 over 10 minutes to the mixture described above and the combined mixture stirred at room temperature for 20 minutes. After the addition of acetic acid (2.32 g, 38.5 mmol), the mixture was evaporated in vacuo and the residue partitioned between dichloromethane and water.The material isolated from the organic layer was subjected to chromatography on silica in 7.5% methano in dichloromethane and then recrystallized from ethanol to afford the required imidazodiazepine (0.43 g), m.p. 249-253 ; R,=0.45 in 10% methanol in dichloromethane; (Found: C, 58.7; H, 5.0; N, 19.5. C14H,4N403 requires C, 58.7; H, 4.9; N, 19.6%).

Step B: Preparation of 3-(3-Ethyl- 1,2,4-oxadiazol-5-yl)-5, 6-dihydro-5-methyl-4H-imidazo[ I,ti-a]py- rido[2,3-fE 1,4]diazepin-6-one Activated molecular sieves (Type 3A, 6 g) were vigorously stirred in absolute ethanol under nitrogen for 1 hour. Propionamide oxime (b.p. 60-62"C/0.2 mmHg; prepared as described above for phenethanamide oxime from propionitrile) (880 mg, 10 mmol) was added and stirring continued for a further 30 minutes. At this stage the mixture was treated with sodium (60 mg, 2.6X10 3 g atom) and then, after 1.5 hours, with ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imi dazo[1,5-a]pyrido[2,3-fj[1,4]diazepine-3-carboxylate (286 mg, 1 mmol). The resulting mixture was heated under reflux for 2 hours, cooled and filtered and the filtrate evaporated in vacuo.The residue so obtained was partitioned between dichloromethane and water. The organic layer was washed well with water and then brine, dried over sodium sulphate and evaporated to give the desired oxadiazole as a white solid (210 mgs); m.p. 301-304 ; R,=0.45 on silica in methanoldichloromethane (1:9); (Found: C, 57.2; H, 4.6; N, 26.4. C5H14N602 0.25 H20 requies C, 57.2; H, 4.6; N, 26.7%).

EXAMPLE 3 (S)- 1-(3-Ethyl- 1,2,4-oxadiazol-5-yl)- 11, 12, 13, 13a-tetrahydro-9H-imidazo[5, 1-c]pyrido[3,2-e]pyr- rolo[ 1,2-aff 1,4]diazepin-9-one Step A: Preparation of 6a, 7, B, 9- Tetrah ydro-6H-p yrido[3, 2-e]p yrrolo[ 1, 2-aff 1, 4]diazepine- 6, 1 1(5H)-dione 3-Aminopicolinic acid (10 g, 72 mmol) was stirred at room temperature with triethylamine (7.3 g, 72mmol) in dimethylformamide (50 ml) and carbonyl diimidazole (12.6 g, 79 mmoi) added in portions. After 20 minutes, the mixture was treated with triethylamine (7.3 g, 72 mmol) and methyl S-prolinate hydrochloride (11.9 g, 72 mmol) and stirred at room temperature for a further 1.5 hour. The residue after evaporation of the dimethylformamide was taken into water and extracted with dichloromethane.The material isolated from the organic extracts was heated at reflux temperature in acetic acid (200 ml) for 1 hour. Evaporation of the acetic acid gave a gum which crystallized upon trituration with ethyl acetate. Recrystallization of the resulting solid from 95% alcohol yielded the dione (4.2 g), m.p. 251-253 ; R,=0.4 on silica in methanoldichloromethane (1:9); (Found: C, 60.7; H, 5.2; N, 19.4;). CllHN307 requires C, 60.8; H, 5.1; N, 19.3%).

Step B: Preparation of ethyl 11, 12, 13, 13a-Tetrahydro-9-oxo-9H-imidazo[5, 1-c]pyrido[3,2-e]pyr- rolo[ 1, 2-aff 1, 4]diazepine- 1 -carboxylate A suspension of the foregoing dione (10.85 g, 50 mmol) in dimethylformamide (70 ml) stirred under nitrogen at 35 ws treated with sodium hydride (1.65 g of an 80% dispersion in oil; 55 mmol). As the reaction proceeded the exotherm was controlled by cooling to room temperature and the mixture stirred at this temperature for a total of 1.5 hours. Subsequently, the mixture was cooled to -30", diethyl chlorophosphate (9.49 g, 55 mmol) added and stirring continued at - 10" for 1 hour.Separately, ethyl isocyanoacetate (6.22 g, 55 mmol) was added to a solution of potassium t-butoxide (6.16 g, 55 mmol) in dimethylformamide (10 ml) stirred at 400 under nitrogen. This solution was added dropwise at -20" to the above mixture and the resulting mixture stirred at room temperature for 1.5 hours before being neutralized with acetic acid (3.3 g, 55 mmol). The residue obtained after evaporation of the dimethylformamide was partitioned between dichloromethane and water and the organic layer dried over sodium sulfate and evaporated. Chromatography of the resulting gum on silica using a gradient elution of 5% to 10% methanol in dichloromethane gave the imidazodiazepine which was further purified by recrystallization from ethyl acetate (4.4 g); m.p. 220-222"; R,=0.45 on silica in methanol-dichloromethane (1:9) (Found: C, 61.5; H, 5.2; N, 17.9. C,6H,6N403 requires C, 61.5; H, 5.1; N, 17.9%).

Step C: Preparation of (S)- 1-(3-Ethyl- 1,2,4-oxadiazol-5-yl)- 1 11, 12, 13, 13a-tetrahydro-9H-imi- dazo[5, l-c]-pyrido[3, 2-e]pyrrolo[7,2-a7 ,4]diazepin-9-one Activated molecular sieves (Type 3A, 12 g) were vigorously stirred in absolute ethanol (100 ml) for 1 hour, propionamide oxime (1.76 g, 20 mmol) added followed, after 0.5 hour, by sodium (120 mg, 5.2X10 3 9 atm.). After a further 0.5 hour, the foregoing ester (624 mg, 2 mmol) was added and the combined mixture heated at reflux temperature for 2 hours. When cool, the mixture was filtered and the material isolated from the filtrate partitioned between dichloromethane and water.The organic layer was washed (water then brine), dried over sodium sulphate and evaporated and the residue recrystallized from i-propanol to give the required oxadiazole (210 mg), m.p. 249 ; R,=0.5 on silica in methanol-dichloromethane (1:9); (Found: C, 60.6; H, 4.8; N, 24.6. C..H.NjO requires C, 60.7; H, 4.8; N, 25.8%).

EXAMPLE 4 3-(3-Ethyl- 1,2, 4-oxadiazol-5-yl) -5, 6-dTh ydro-5-me th yl-4H-imidazo[ 1,5-a]pyridof3,2-flt 1 4]diazepin -6- one Step A: Preparation of 3, 4-DThydro-4-methyl-2H-pyrido[2, 3-eff 1 ,4]diazepin-2,5(1 H)-dione To a suspension of 2-aminoicotinic acid (209, 0.145 mol) in dimethylformamide (100ml) was added carbonyldiimidazole (279, 0.166 mol) followed by triethylamine (20mls, 0.143 mol). After 1.5 hour at room temperature, further triethylamine (3ml) was added followed by methyl sarcosinate hydrochloride (20.39, 0.145 mol) and the mixture heated at 150 for 5.5 hour.Evaporation of the mixture gave a gum which was triturated with hot tetrahydrofuran (200ml) to give a white solid which was immediately collected by filtration. The organic solution deposited a black tar on cooling which was separated from the tetrahydrofuran by decantation. The solid obtained from the organic solvent was combined with that isolated above and added to saturated sodium hydrogen carbonate solution (100ml) and tetrahydrofuran (100ml). After several minutes the mixture was filtered to afford the required dione (15.39), m.p. 249-256"; R,=0.45 on silica in methanolchloroform (1:4); (Found: C, 56.0; H, 4.8; N, 22.0. C,H,N,O. requires C, 56.5; H, 4.8; N, 22.0%).

Step B: Preparation of Ethyl 5, 6-Dihydro-5-methyl-6-oxo-4H-imidazo[ 1, 5-a]p yrido[3, 2-f][ 1, 4]dia- zepine-3-carboxyla te A stirred suspension of sodium hydride (530mg of an 80% dispersion in oil, 22 mmol) in dimethylformamide (40 ml) was treated at room temperature with the dione (3.559, 18.5 mmol) prepared above. After 1 hour, diethylchlorophosphate (3.3ml, 22.8 mmol) was added and the mixture stirred for 40 minutes before cooling to -30' Meanwhile, ethyl isocyanoacetate (2.5ml, 22.8 mmol) was added at -40' to a stirred solution of potassium t-butoxide (2.579, 22.9 mmol) in dimethylformamide (20ml) and the resulting solution added to the mixture above. The combined mixture was stirred at room temperature for 2 hour, neutralised with acetic acid and the solvent removed in vacuo.The residue was partitioned between dichloromethane and water.

The organic layer was washed with water, dried over sodium sulphate and evaporated. Chromatography of the resulting oil in silica using a gradient elution of toluene to 16% methanol in toluene gave the imidazodiazepine (250mg), m.p. 157.5-158.5; R,=0.43 on silica in methanolethyl acetate (1:9); Found: C, 58.7; H, 4.9; N, 19.7. C,,H,,N,O, requires C, 58.7; H, 4.9; N, 19.6%).

Step C: Preparation of 3-(3-Ethyl- 1, 2,4-oxadiazol-5-yl)-5, 6-dmydro-5-methyl-4H-imidazoj 1, 5-a]py- rido[3,2-fff 1, 4]diazepin-6-one Activated molecular sieves (Type 3A, 209) were stirred vigorously in absolute ethanol (150ml) for 1 hour under nitrogen and propionamide oxime (2.769, 31.3 mmol) added followed by sodium (228mg, 9.91g.atm). After stirring until all the sodium had dissolved (1h), the imidazodiazepine ester from above (1.05g, 3.6 mmol) was added and the mixture heated under reflux for 2 hour. After filtering, the filtrate was evaporated in vacuo and the residue so obtained was partitioned between saturated sodium hydrogen carbonate and dichloromethane.The material isolated from the dichioromethane was chromatographed on silica in ethyl acetate-methanol (9:1) and recrystallized from dichloromethane-ether to give the desired oxadiazole (380mg), m.p.

198-202'; R,=0.6 on silica in methanol-ethyl acetate (1:9); (Found: C, 58.0; H, 4.6; N, 27.0.

C..H..N,;O} requires C, 58.0; H, 4.6; N, 27.1%).

Example 5 3-(3-Benzyl- 1,2, 4-oxadiazol-5-yl)-5, 6-dihydro-5-methyl-4H-imidazo[ 1, 5-a]pyrido[3,2-fff 7.4]diazepin- 6-one This was prepared from ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[3,2-f][1,4]di- azepine-3-carboxylate (931mg, 3.25 mmol) and phenethanamide oxide (4.179, 27.8 mmol) exactly as described in Example 4. The material isolated after chromatography was recrystallized from dichloromethane-ether to give the required benzyl oxadiazole (656mg), m.p. 187-190', R.=0.36 on silica in ethyl acetate; (Found: C, 64.3; H, 4.3; N, 22.6. C ,|H";N,80. requires C, 64.5; H, 4.3; N, 22.6%).

Example 6 3-(3-Cyclopropyl-l, 2, 4-oxadiazol-5-yl)-5, 6-dihydro-5-methyl-4H-imidazoj , 5-a]pyrido[3, 2-f][ 1, 4]dia- zepin-6-one This was prepared by the method described in Example 4 starting from cyclopropyl carboxamide oxime (1.98g, 19.8 mmol) and ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[3,2- fl[1,4]-diazepine-3-carboxylate (1.134g, 3.9 mmol) using an extended reaction time of 3.5 hour.

After chromatography, the material was recrystallised from dichloromethane-ether to afford the 3cyclopropyl oxadiazole (113mg), m.p. 222-229"; R,=0.55 on silica in methanol-ethyl acetate (1:9); (Found: C, 59.6; H, 4.4; N, 26.0. C,6H14N602 requires C, 59.6; H, 4.4; N, 26.1%).

The cyclopropyl carboxamide oxime required in the synthesis given above was prepared as follows: To a solution of sodium methoxide in methanol (from 16.19 sodium metal and methanol (200ml)) was added a solution of hydroxylamine hydrochloride (479, 0.67 mol) in methanol (400ml). After 15 minutes, the mixture was filtered and cyclopropyl cyanide (50g, 0.75 mol) added and the solution left for 3 days. The residue after evaporation of the methanol was taken into ethyl acetate (150ml) and filtered. The material isolated from the organic solvent was fractionaily distilled under reduced pressure to give the amide oxime as a colourless oil (34.29), b.p. 108 at 2mm Hg.

Example 7 3-(3-Methoxymethyl- 1,2,4-oxadiazol-5-yl)-5, 6-dihydro-5-methyl-4H-imidazo[ 1,5-a]pyrido[3,2 f][ 1,4]diazepin-6-one This was prepared exactly as described in Example 4 but using methoxyacetamide oxime (3.259, 31.25 mmol) and ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]pyrido[3,2-f][1,4]dia- zepine-3-carboxylate (1.1149, 3.89 mmol) to give the methoxymethyl oxadiazole (560mg), m.p.

173-177"; R,=0.43 on silica in methanol-ethyl acetate (1:9); (Found: C, 55.1; H, 4.3; N, 26.0.

C'5H14N603 requires C, 55.0; H, 4.3; N, 25.9%).

Example 8 (S)- 1-(3-Ethyl- 1,2,4-oxadiazol-5-yl)- 11, 12, 13, 1 3a-tetrahydro-9H-imidazo[5, 1-c]pyrido[2,3-e]pyr- rolo[ 1,2-aE1,4]diazepin-9-one Step A: Preparation of (S)-6a, 7,8,9-tetrahydro-GH-pyrido[2,3-e]pyrrolo 1,2-a 1,4]diazepin-6, 11 (5H)-dione 2-Aminonicotinic acid (3.69, 26 mmol) and carbonyl diimidazole (4.669, 29 mmol) suspended in dimethylformamide (20 ml) was treated at room temperature with triethylamine (2.639, 26 mmol) for 1 hour. Methyl (S)-prolinate hydrochloride (4.319, 26 mmol) was added and after 1.5 hour the solution was poured into water (50ml). Extraction with dichloromethane followed by evaporation of the organic solvent gave an oil which was heated under reflux for 1 hour in acetic acid.The residue obtained after evaporation of the acetic acid was partitioned between ethyl acetate and brine containing enough sodium hydrogen carbonate to neutralise any remaining acetic acid. Evaporation of the ethyl acetate to small bulk followed by cooling the remainder gave a white solid which was collected by filtration and washed with fresh ethyl acetate to give the dione (0.78g), m.p. 153-155"; R,=0.45 on silica in 9:1 ethyl acetate-methanol; (Found: C, 61.0; H, 5.2; N, 19.4. C11H11N3O2 requires C, 60.8; H, 5.1: N, 19.4%).

Step B: Preparation of (S)-Ethyl 11, 12, 13, 13a-tetrahydro-9-oxo-9H4midazo[5, 1-c]pyrido[2,3-e] pyrrolo[ 1,2-al,4]diazepin- I-carboxylate The foregoing dione (5g, 23 mmol) in dimethylformamide (20ml) was added dropwise at 20 to a stirred suspension of sodium hydride (760mg of an 80% dispersion in oil, 25 mmol) in dimethylformamide (10ml). After 2 hour at this temperature, diethylchlorophosphate (4.379, 25 mmol) was added and the reaction stirred for a further 0.5 hour.The anion of ethyl isocyanoacetate (prepared at -40" from potassium t-butoxide (2.839, 25 mmol) and ethyl isocyanoacetate (2.869, 25 mmol) in dimethylformamide (10ml) under nitrogen) was added to this solution at - 10' and the combined mixture stirred at room temperature for 1 hour. Neutralisation of the mixture with acetic acid followed by evaporation of the solvent in vacuo gave an oil which was partitioned between water and dichloromethane.Chromatography of the material isolated from the organic layer (on silica eluting with 5% ethanol in ethyl acetate) followed by recrystallisation from ethyl acetate gave the imidazodiazepine ester (0.299), m.p. 165-167"; R,=0.3 on silica in methanol-ethyl acetate (1:9). (Found: C, 61.4; H, 5.2; N, 17.8. C6H6N40, requires C, 61.5; H, 5.1; N, 17.9%).

Step C: Preparation of (S)- 1-(3-Ethyl- 1,2,4-oxadiazol-5-yI)- 11, 12, 13, 13a-tetrahydro-9H-imi- dazo[5, 1 -c]pyrido[2, 3-e]pyrrolo[ 1, 2-aff 1, 4]diazepin-9-one Propionamide oxime (1.359, 15.4 mmol) was added to a suspension of crushed molecular sieves (Type 3A, 12.59) in absolute ethanol (125ml) and stirred under nitrogen. After 1.5 hour, sodium (0.19) was dissolved in the mixture and the foregoing ethyl ester (0.89, 2.6 mmol) added. The resulting solution was heated under reflux for 1.5 hour, cooled and filtered. The material isolated from the filtrate was recrystallised from dichloromethane-petrol ether (b.p.

60-80") to afford the ethyl oxadiazole, (0.379), m.p. 190.5-192.5"; R,=0.42 on silica in methanol-ethyl acetate (1:9); (Found: C, 60,4; H, 4.8; N, 24.8. C17H16N6O2 requires C, 60.7; H, 4.8; N, 25.0%).

EXAMPLE 9 (S)- 1-(3-Ethyl- 1,2,4-oxadiazol-5-yl)- 11, 12,13,13a-tetrahydro-9H-imidazo[5, 1 -c]pyrrolo[ 1 ,2-a]thi- eno[3,2-e][1,4]diazepin-9-one Step A: Preparation of 2H-thieno[3,2-dff 1, 3]oxazine-2, 4(1 H)-dione Sodium 3-amino-2-thiophene carboxylate (8.25 g) was suspended in 250 ml tetrahydrofuran (THF) and 3 ml of concentrated sulfuric acid was added dropwise. The mixture was cooled on ice, and 90 mmol of phosgene in 50ml of toluene was added. This mixture was stirred at room temperature for 30 minutes and then at reflux for 1 hour. The mixture was left overnight at room temperature and was concentrated in vacuo to 50 ml. Water (50 ml) was added and the precipitated compound was washed with water and ether. Yield 7.49 of title compound.

Step B: Preparation of (S)-5a,6, 8-tetrahydro-5H-pyrrolo[ 1 ,2-a]thieno[3,2-e][ 1 ,4]diazepine- 5, 10(4H]-dione A mixture of 11 g of the product from Step A, 7.3g of L-proline and 75 ml dimethyl sulfoxide (DMSO) was stirred at 100-110 C for two hours. The mixture was poured into 600 ml of water. The water phase was extracted four times with 75 ml of chloroform. The chloroform phase was washed with water saturated with sodium chloride and was evaporated. The residue was boiled with glacial acetic acid and the title compound precipitated by adding ether. Yield of title compound 4.3 g; m.p. 271-5"C.

Step C: Ethyl (S)- 10, 11,12, 12a-tetrahydro-8-oxo-8H4midazo[5, 1-c]pyrrolo[1,2-a]thieno[3,2- e][1,4]diazepine- 1 -carboxylate The product from Step B (4.19) was dissolved in 20 ml of dry dimethylformamide (DMF). To this mixture 3.59 of K-t-Butoxide was added and the mixture was cooled to -300C. Then 4.4 ml of diethylchlorophosphate was added.

A mixture of 3.59 of K-t-butoxide and 3.3ml of ethyl isocyanoacetate in 20ml of dry DMF was added to above prepared mixture at - 10 to --20"C and the resulting mixture was stirred at room temperature for one hour, whereafter it was poured into 250ml of water. This mixture was extracted with chloroform. The organic phase was evaporated and the residue was then washed with ether. Yield: 0.29 of title compound. M.p. 120-130" (decomp.).

Step D: Preparation of (S)- 1-(3-ethyl- 1,2,4-oxadiazol-5-yI)- 10, 1 11, 12, l2a4etrahydro-8H-imi- dazo[5, 1 -c]pyrrolo[ 1,2-a]thieno[3, 2-eff 1,4]diaze pin -8-one Sodium (75mg) was dissolved in 25 ml dry ethanol. 1g of propionamideoxime and 5g of molecular sieves and the 1 g of ethyl (S)-10,11,12,12a-tetrahydroimidazo[5,1-c]pyrrolo[1,2-a]thi- eno[3,2-e][1 ,4]diazepine-1-carboxylate were added and the resulting mixture was refluxed for 6 hours. A further 35mg of sodum and 0.59 of propionamideoxime were added and the mixture was refluxed for 48 hours. The mixture was filtered through filteraid and was concentrated in vacuo to 10 ml.The title compound (0.5 g) was obtained by adding water, filtration and washing with water; m.p. 224.7-224.9 C.

Using the procedures substantially as described in the foregoing Examples there also were prepared the compounds described in the following table.

TABLE

Method

of A R1 R2 R3 mp(OC) Example -cyclo-C3H5 -(CH2)3- 217-219 3 CH2OCH3 -(CH2)3- 230-232 3 " -CH3 H -CH3 285-287 2 II -CH2OCH3 H -CH3 215-217 2 " -cyclo-C3H5 H -CH3 297-300 2 -CH3 H -CH3 243-245 4 'I -CH2OCH3 -(CH2)3- 175-176. 8 CH2Ph -(CH2)3- 190-191 8 -cyclo-C3H5 -(CH2)3- 202-204 8 " -CH3 -(CH2)3- 246-249 8 -C2H5 H -CH3 210-212 1* II -cyclo-C3H5 -(CH2)3- 334.5-335 1* -C2H5 -(CH2)3- 211.5-212.5 it + S -cyclo-C3H5 -(CH2)3- 207.2-208.1 9 II -C2H5 H -CH3 168-174 9 II -cyclo-C3H5 H -OH3 198.1-202.2 9 *Made as described in Example 1 but using methyl S-prolinate in place of methyl sarcosinate in Step (a) and the relevant amide oxime in Step (c).

+ (S)-enantiomer

Claims

1. A compound of structural formula:

or a pharmaceutically acceptable salt thereof, wherein: A is a 5 or 6 membered heterocycle with up to 2 heteroatoms selected from nitrogen and sulfur, either unsubstituted or substituted with C13 alkyl, C13 alkoxy and/or halo; O is a group of formula

RX is C, 5 alkyl, either straight or branched chain, or cyclic, and either unsubstituted or substituted with: (a) C13 alkoxy or (b) phenyl, either unsubstituted or substituted with: (i) halo, (ii) C13 alkyl, or (iii) Cl 3 alkoxy: R2 is hydrogen; R3 is C1-6 alkyl; or R2 and R3 taken together form a 2-4 membered alkylene bridge.

2. The compound of Claim 1 wherein Cl is a group of formula

R' is cyclopropyl, R2 is hydrogen, R3 is methyl and A is pyrido.

3. The compound of Claim 1, which is: (a) 3-(3-benzyI-1 ,2,4-oxadiazol-5-yl)-5 ,6-dihydro-5-methyl-4H-imidazo[ 1,5-a]pyrido[3 ,4-f1[1,4]dia- zepin-6-one; (b) 3-(3-ethyl- 1,2,4-oxadiazol-5-yl]-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[2,3-f][1,4]dia- zepin-6-one; (c) (S)- 1 -(3-ethyl- 1 ,2,4-oxadiazol-5-yl)- 11,12,13,1 3a-tetrahydro-9H-imidazo[5, 1 -c]pyrido[3,2-e]- pyrrolo[ 1 ,2-a][ 1 ,4]diazepin-9-one; (d) 3-(3-ethyl- 1 ,2,4-oxadiazol-5-yl)-5 ,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3,2-fj[ 1 ,4]dia- zepin-6-one; (e) 3-(3-benzyl- 1 ,2,4-oxadiazol-5-yl)-5 ,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3 ,2-fJ[ 1 ,4]di- azepin-6-one;; (f) 3-(3-cyclopropyl- 1 ,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3 ,2- f][1,4]diazepin-6-one; (g) 3-(3-methoxymethyl- 1,2-4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-im 1 ,5-a]pyrido[3,2- f][1,4]diazepin-6-one; (h) (S)- 1 -(3-ethyl-i 1,2,4-oxadiazol-5-yl)- 11,12,13, 13a-tetrahydro-9H-imidazo[5,1-c]pyrido[2,3-e]- pyrrolo[ 1 ,2-a][ 1 ,4]diazepin-9-one; (i) (S)- 1 -(3-ethyl-i ,2,4-oxadiazol-5-yl)- 11,12,13,13a-tetrahydro-9H-imidazo[5,1-c]pyrrolo[1,2- a]thieno[3,2-ej[ 1 ,4jdiazepin-9-one.

(j) (S)- 1 -(3)-cyclopropyl- 1 ,2,4-oxadiazol-5-yl- 10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyr- rolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one; (k) 3-(3-ethyi- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]ethieno[2,3-f][1,4]dia- zepin-6-one; (i) 3-(3-cyclopropyl- 1 ,2,4-oxadiazol-5-yl) -5,6-dihydro-5-methyl-4H-imidazo [1,5-a]thieno[2,3 fj[ 1 ,4jdiazepin-6-one; (m) 3-(3-cyclopropyl- ,2,4-oxadiazol-5 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[2,3- f][1,4]diazepin-6-one; (n) (3-(5-cyclopropyl- 1 ,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3,2- 8[1,4]diazepin-6-one; or (o) 3-(5-cyclopropyl- 1 ,2,4-oxadiazol-3-yl)5,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[2,3- fj[ 1 ,4]diazepin-6-one.

4. A pharmaceutical formulation comprising a pharmaceutical carrier and an effective amount of a compound of structural formula:

or a pharmaceutically acceptable salt thereof wherein A, Q, R', R2 and R3 are as defined in Claim 1.

5. The pharmaceutical formulation of Claim 4 wherein Cl is a group of formula

R' is cyclopropyl, R2 is hydrogen, R3 is methyl and A is pyrido.

6. The pharmaceutical formulation of Claim 4 wherein the compound is: (a) 3-(3-benzyl- 1 ,2,4-oxadiazol-5-yI)-5,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3 ,4-f][ 1 ,4jdia- zepin-6-one; (b) 3-(3-ethyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[2,3-f][1,4]dia- zepin-6-one; (c) (S)- 1 -(3-ethyl- 1 ,2,4-oxadiazol-5-yI)- 11,12,13,1 3a-tetrahydro-9H-imidazo[5, 1 -c]pyrido[3,2-e]- pyrrnlo[ 1 ,2-a][ 1 ,4]diazepin-9-one; (d) 3-(3-ethyl- 1 ,2,4-oxadiazol-5-yI)-5,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3,24j[ 1 ,4jdia- zepin-6-one; (e) 3-(3-benzyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyridor3,2-f][1,4]di- azepin-6-one;; (f) 3-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[3,2- f][ 1 ,4]diazepin-6-one; (g) 3-(3-methoxymethyl- 1 ,2-4-oxadiazol-5-yl)-5 ,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3 ,2- f][ 1 ,4]diazepin-6-one; (h) (S)- 1 -(3-ethyl- 1 ,2,4-oxadiazol-5-yI]- 11,12,13,13a-tetrahydro-9H-imidazo[5,1 -c]pyrido[2,3-e]- p"rrnlo[1 ,2-a][1 ,4]diazepin-9-one; (i) (S)- 1 -(3-ethyl- 1 ,2,4-oxadiazol-5-yl)- 11,12,13,13a-tetrahydro-9H-imidazo[5,1 -c]pyrrolo[1,2- a]thieno[3,2-e][1 ,4]diazepin-9-one.

(j) (S)- 1 -(3-cyclopropyl-l ,2-4-oxadiazol-5-yl]- 10,11,12,12a-tetrahydro-8H-imidazo[5,1 -c]pyr- rolo[ 1 ,2-a]thieno[3,2-e][ 1 ,4]diazepin-8-one; (k) 3-(3-ethyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]thieno[2,3-f][1,4]d ia- zepin-6-one; (i) 3-(3-cyclopropyl- 1 ,2,4-oxadiazol-5-yI)-5,6-dihydro-5-methyl-4H-imidazo[ 1, 5-a]thieno[2,3- f][ 1 ,4]diazepin-6-one; (m) 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl]-5,6-dihydro-5-methyl-4H-imidazo [1,5-a]pyrido[2,3 f][1,4]diazepin-6-one; (n) 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-4H-imidazo [1,5-a]pyrido[3,2 f][1 ,4]diazepin-6-one;; or (o) 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)5,6-dihydro-5-methyl-4H-imidazo [1,5-a]pyrido[2,3 f][ 1 ,4]diazepin-6-one.

7. A process for the preparation of a compound of structural formula:

wherein A, R', R2 and R3 are as defined in Claim 1, characterized in that a compound of structural formula:

wherein R is C,, alkyl, is treated with a compound of structural formula:

in the presence of an alkali metal.

8. The process of Claim 7 for the preparation of the compound wherein R' is cyclopropyl, R2 is hydrogen, R3 is methyl and A is pyrido.

9. The process of Claim 7 for the preparation of the compound which is: (a) 3-(3-benzyl- 1 ,2,4-oxadiazol-5-yl)-5,6-dihydrn-5-methyl-4Himidazo[ 1 ,5-a]pyrido[3,4-f][ 1 ,4]dia- zepin-6-one; (b) 3-(3-ethyl- 1 ,2,4-oxadiazol-5-yl)-5,6-dihydrn-5-methyl-4Himidazo[ 1 ,5-a]pyrido[2,3-f][ 1 ,4jdia- zepin-6-one; (c) (S)-1 -(3-ethyl- ,2,4-oxadiazol-5-yI)- 11,12,13,1 3a-tetrahydro-9H-imidazo[5, 1 -c]pyrido[3,2-e]- pyrrolo[ 1 ,2-a][ 1 ,4]diazepin-9-one; (d) 3-(3-ethyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[3,2-fl[1,4]dia- zepin-6-one; (e) 3-(3-benzyl- 1 ,2,4-oxadiazol-5-yl)-5,6-dihydrn-5-methylAH-imidazo[ 1 ,5-a]pyrido[3 ,2-fj[ 1 ,4]di- azepin-6-one;; (f) 3-(3-cyclopropyl- 1 ,2,4-oxadiazol-5-ylj-5,6-dihydro-5-methyl-4H-imidazo[ 1 ,5-a]pyrido[3 ,2- f][1,4]diazepin-6-one; (g) 3-(3-methoxymethyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[3,2- f][1,4]diazepin-6-one; (h) (S)- 1 -(3-ethyl-i ,2,4-oxadiazol-5-yl)- 11,12,13,1 3a-tetrahydro-9H-imidazo[5, 1 -cjpyrido[2,3-e]- pyrrolo[ 1 ,2-a][ 1 ,4]diazepin-9-one; (i) (S)- 1 -(3-ethyl-i ,2,4-oxadiazol-5-yl)- 11,12,13,1 3a-tetrahydro-9H-imidazo[5, 1 -c]pyrrolo[ 1,2- ajthieno[3,2-ej[ 1 ,4]diazepin-9-one.

(j) (S)- 1 -(3-cyclopropyl- 1 ,2,4-oxadiazol-5-yl)- 10,11,12,12a-tetrahydro-8H-imidazo[5,1 -c]pyr- rolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one; (k) 3-(3-ethyl- 1 2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H.imidazo[ 1 ,5-a]thieno[2,3-fl[l ,4]dia- zepin-6-one; (I) 3-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]thieno[2,3- f][1,4]diazepin-6-one; or (m) 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]pyrido[2,3- f][1,4]diazepin-6-one.

10. A process for the preparation of compounds of structural formula

wherein A, R', R2 and R3 are as defined in claim 1, which comprises reacting a compound of formula

(wherein A, R2 and R3 are as defined in claim 1) with a compound of formula (R'CO)20 (wherein R' is as defined in claim 1).

11. A process according to claim 10 for the preparation of 3-(5-Cyclopropyl-1,2,4-oxadiazol- 3-yl)- 5, 6-dihydro-5-methyl-4H-imidazo [1,5-a]pyrido[3,2-f][1,4]diazepin-6-one; or 3-(5-Cyclopropyl 1,2,4-oxadiazoí-3-yl)5,6-dihydro-5-methyl-4H-imidazo [1,5-a]pyrido[2,3-f][1,4]diazepin-6-one.