GB2249094A

GB2249094A - Hetero-imidazodiazepine derivatives

Info

Publication number: GB2249094A
Application number: GB9122149A
Authority: GB
Inventors: Charles John Robert Hedgecock; Stuart Donald Jones; Elizabeth Anne Kuo
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1990-10-19
Filing date: 1991-10-18
Publication date: 1992-04-29
Anticipated expiration: 2011-10-18
Also published as: FR2669335A1; GB9022758D0; GB2249094B; GB9122149D0; FR2669335B1

Abstract

Compounds of formula I <IMAGE> [wherein R1 is C1-3-alkyl, or the two R1 groups together represent a C2-5-alkylene group; X and Y are independently oxygen or sulphur (with the proviso that when R1 represents an alkyl group, X and Y have the same meaning); R2 is hydrogen or C1-3-alkyl; R3 is hydrogen, C1-5-alkyl, phenyl or a substituted phenyl group; W is oxygen or sulphur; and the ring A together with the two carbon atoms denoted alpha and beta in formula I above represents a group selected from: <IMAGE> in which R4 is hydrogen, C1-3-alkyl, C3-6-cycloalkyl, halogen or nitrile; and R5 is hydrogen, halogen or nitro]; and acid addition salts thereof possess benzodiazepine inverse agonist and/or tranquilising properties. Processes for preparing them and compositions containing them are also described, together with intermediates of formula VII <IMAGE>

Description

Hetero-imidazodiazepine derivatives This invention relates to hetero-imidazodiazepines and acid addition salts thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use as medicaments.

According to one aspect of the invention there are provided compounds of formula I

[wherein R represents an alkyl group containing from 1 to 3 carbon atoms, or the two R1 groups together represent an alkylene group containing from 2 to 5 carbon atoms; X and Y, which may be identical or different, each represents an oxygen or sulphur atom with the proviso that when R1 represent.s an alkyl group, X and Y have the same meaning; R2 represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; R3 represents a hydrogen atom, an alkyl group containing from 1 to 5 carbon atoms, a phenyl group or a substituted phenyl group; W represents an oxygen or sulphur atom; and the ring A together with the two carbon atoms denoted a and P in formula I above represents a group selected from:

in which R4 represents a hydrogen atom, an alkyl group containing from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, a halogen atom or a nitrile group; and 4 represents a hydrogen atom, a halogen atom or a nitro group]; and acid addition salts thereof.

The term "alkyl group containing from 1 to 3 carbon atoms" denotes a methyl, ethyl, propyl or isopropyl group.

The term "alkylene group containing from 2 to 5 carbon atoms" includes, for example, an ethylene, trimethylene, tetramethylene or pentamethylene group.

The term "alkyl group containing from 1 to 5 carbon atoms" includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or pentyl group.

The term "substituted phenyl group" includes, for example, a phenyl group substituted by a halogen atom, an alkyl group containing from 1 to 3 carbon atoms, an alkoxy group containing from 1 to 3 carbon atoms or a trifluoromethyl group.

The term 'halogen atom" as used herein includes, for example, a fluorine, chlorine or bromine atom.

The term "alkoxy group containing from 1 to 3 carbon atoms" includes, for example, a methoxy, ethoxy, propoxy or isopropoxy group.

The term "cycloalkyl group containing from 3 to 6 carbon atoms" includes, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The acid addition salts of the compounds of formula I can be salts of inorganic or organic acids, and can be, for example, salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, or aspartic acid; alkanesulphonic acids such as methanesulphonic acid; or arylsulphonic acids such as benzenesulphonic acid.

Preferred are compounds of formula I as defined above wherein W represents an oxygen atom; R2 represents a hydrogen atom; R3 represents a methyl group; the ring A together with the carbon atoms denoted a and p represents a group

(in which R4 and R5 are as defined above); and X, Y and R1 are as defined above; and acid addition salts thereof.

Particularly preferred are compounds of formula I as defined above wherein the groups R1 each represents a methyl or ethyl group, or the two R1 groups together represent an ethylene or trimethylene group; and X, Y, R2 R3 W and A are as defined above; and acid addition salts thereof.

Especially preferred are the following compounds of formula I: 5,6-dihydro-3-(1,3-dioxolan-2-yl)-5-methyl-6-oxo-4Himidazo[1,5-a]pyrido[3,4-f][1,4]diazepine; 3-diethyloxymethyl-5,6-dihydro-6-oxo-4H-imidazo[1,5 a]pyrido[3 ,4-f] [l,4]diazepine; and acid addition salts thereof.

The compounds according to the invention may, for example, be prepared according to the following processes, which processes constitute further features of the present invention: A. Compounds of formula 1A

(wherein RA represents an alkyl group containing from 1 to 3 carbon atoms; and R2, R3 W, R4. A and X are as defined above) may be prepared by reacting a compound of formula II

(wherein R2 R3, W and A are as defined above) with a compound of formula III H - X - R (III) (wherein X and RA are as defined above).

B. Compounds of formula 1e

(wherein RB represents an alkylene group containing from 2 to 5 carbon atoms; and R2 R3 W, A, X and Y are as defined above) may be prepared by reacting a compound of formula II as defined above with a compound of formula IV

(wherein X, Y and R6 are as defined above).

C. Compounds of formula 1A as defined above (in which W represents an oxygen atom, R2 represents a hydrogen atom and the remaining groups are as defined above) may alternatively be prepared by cyclisation of a compound of formula

(wherein A,B,X,R3 and RA are as defined above).

The compounds of formula 1A and Is obtained according to the above processes may, if desired, subsequently be converted by conventional methods into an acid addition salt thereof.

The compound of formula VII may, for example, be prepared by reacting a compound of formula V

(wherein A is as defined above and B represents a leaving group) or a functional derivative thereof with a compound of formula VI

(wherein X,RA and R3 are as defined above).

The reactions between the compound of formula II and the compound of formula III, and between the compounds of formula II and the compound of formula IV are preferably effected in the presence of an anhydrous organic solvent such as benzene or dichloromethane.

When a compound of formula II is reacted with a compound of formula III in which X represents an oxygen atom or with a compound of formula IV in which X and Y each represents an oxygen atom, the reaction is preferably effected in the presence of an anhydrous organic solvent such as benzene and in the presence of a catalytic quantity of paratoluenesulphonic acid at the reflux temperature of the reaction medium.

When a compound of formula II is reacted with a compound of formula III in which X represents a sulphur atom or with a compound of formula IV in which X and Y each represents a sulphur atom, the reaction is preferably effected in the presence of an anhydrous organic solvent such as dichloromethane in the presence of a catalytic quantity of boron trifluoroetherate at ambient temperature.

The cyclisation of a compound of formula VII is preferably effected in the presence of lithium hydride and in the presence of anhydrous organic solvent such as dimethylformamide at the reflux temperature of the reaction medium.

In the compounds of formula V, the leaving group B is preferably a halogen atom, more preferably a chlorine or bromine atom, or a nitro group.

Where a functional derivative of an acid of formula V is used, this is preferably an acid chloride.

The reaction of the compound of formula V or a functional derivative thereof with the compound of formula VI is preferably effected in the presence of an organic solvent such as dichloromethane and in the presence of a base selected from sodium carbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, or an amine such as trimethylamine.

The compounds of formula VI, when they are not already known, may be prepared according to the following reaction scheme as described in T. Murakami, M. Oksuka, M. Ohno, Tet. Lett.(1982), 23 (45),4729-4732:

The compounds of formula II can be prepared, for example, as described in European Patent No. 0027214.

The compounds of formula II wherein W represents an oxygen atom may alternatively be prepared by reacting a compound of formula 1A wherein W represents an oxygen atom and R2, R3, A, X and RA are as defined above with a strong acid such as hydrochloric acid in a solvent such as for example acetone at the reflux temperature of the reaction medium.

The compounds of formula I are basic in character and may therefore be subsequently converted, if desired, into their acid addition salts. The acid addition salts can be conveniently prepared by reacting, in approximately stoichiometric quantities, an inorganic or organic acid with a compound of formula I. The acid addition salts can be prepared without intermediate isolation of the corresponding base.

The compounds according to the invention possess very interesting pharmacological properties; of particular note are their benzodiazepine inverse agonist properties. Some of the compounds also possess tranquilising properties. These properties are further illustrated in the experimental section.

The compounds of formula I and the pharmaceutically acceptable acid addition salts thereof are thus of use as medicaments. Therefore, according to a further aspect of the invention there is provided the use of compounds of formula I as defined above and the pharmaceutically acceptable acid addition salts thereof as medicaments.

Preferred for use as medicaments are compounds of formula I as defined above wherein W represents an oxygen atom; R2 represents a hydrogen atom; R3 represents a methyl radical; the ring A represents a group

in which R4 and R5 are as defined above; and X , Y and R1 are as defined above; and pharmaceutically acceptable acid addition salts thereof.

Particularly preferred for use as medicaments are compounds of formula I as defined above wherein the groups R1 each represents a methyl or ethyl radical, or the two R1 groups together represent an ethylene or trimethylene group; and X, Y, R2 R3 W and A are as defined above; and pharmaceutically acceptable acid addition salts thereof.

Especially preferred for use as medicaments are the following compounds of formula I: 5, 6-dihydro-3- (1, 3-dioxolan-2-yl) -5-methyl-6-oxo-4H- imidazo [l,5-a]pyrido[3,4-f] [l,4]diazepine; 3-diethyloxymethyl-5, 6-dihydro-6-oxo-4H-imidazo [1,5- a]pyrido[3,4-f] [l,4]diazepine; and pharmaceutically acceptable acid addition salts thereof.

These medicaments are of use, for example, in the treatment of memory problems, particularly in geriatrics, and in cerebral senescence problems. Some of the compounds can also be used in the treatment of obesity and as minor tranquilisers in the treatment of certain agitated or irritated states and in some forms of epilepsy.

The usual dose varies according to the compound used, the patient treated and the illness concerned and can be, for example, from 0.1 mg to 200 mg per day by the oral route.

According to a further aspect of the present invention there are provided pharmaceutical compositions comprising, as active ingredient at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in association with one or more pharmaceutical carriers and/or excipients.

The compounds of formula I and the pharmaceutically acceptable acid addition salts thereof can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.

These pharmaceutical compositions can be, for example, solid or liquid and can be in pharmaceutical forms conventionally used in human medicine such as, plain or coated tablets, capsules including gelatine capsules, granules, suppositories, solutions e.g. for injection; they can be prepared by conventional methods.

The active ingredient(s) can be incorporated with excipients conventionally used in pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

The following intermediates useful in the preparation of the compounds of formula I are themselves new and comprise a further aspect of the invention: the compounds of formula VII

(wherein A, B, R3, X and RA are as defined above).

The following non-limiting examples serve to further illustrate the invention: PREPARATION OF STARTING MATERIALS a) Preparation of 5-diethoxvmethvl-4-hvdroxvmethyl-lH- imidazole and 4-diethoxvmethvl-5-hvdroxymethvl-lH- imidazole To a stirred solution of ethyl 5-diethoxymethyl-lHimidazole-4-carboxylate or ethyl 4-diethoxymethyl-lHimidazole-5-carboxylate (prepared by the method of T.

Murakami, M. Oksuka, M. Ohno, Tetrahedron Letters 1982 23 (45) 4729-4732) (10 g) in dry tetrahydrofuran (500 ml) at 5"C under nitrogen was added, over 1 h, lithium aluminium hydride (4 g) and the mixture stirred for a further 1 h. Saturated salt (50 ml) was added dropwise with care and the mixture stirred for 1/2 h before decanting the solvent from the inorganic phase. The inorganic phase was washed with dichloromethane (2 x 200 ml) and the combined organic phase dried with MgSO4 and evaporated to give 5-diethoxymethyl-4-hydroxymethyl-lHimidazole or 4-diethoxymethyl-5-hydroxymethyl-lHimidazole respectively (8,14 g, 98 %) as an oil.

b) Preparation of 5-diethoxymethyl-lH-imidazole-4- carboxaldehyde and 4-diethoxymethyl-lH-imidazole-5- carboxaldehvde To a solution of 5-diethoxymethyl-4-hydroxymethyl1H-imidazole or 4-diethoxymethyl-5-hydroxymethyl-lHimidazole (6,6 g) in dichloromethane (250 ml) was added activated manganese dioxide (33 g) and the mixture refluxed for 1/2 h before filtering through celite to remove the inorganics. Evaporation of solvent gave the title product (5,21 g, 84 %).

c) Preparation of ethyl 5-methylaminomethyl-lH- imidazole-4-carboxylate and ethvl 4-methvlaminoethvl- lH-imidazole-5-carboxvlate Method 1 (sodium cyanoborohydride) To a solution of ethyl 5-formyl-lH-imidazole-4carboxylate or ethyl 4-formyl-lH-imidazole-5-carboxylate (17 g) in dry ethanol (170 ml) containing 3A molecular sieves (25 g) was added a solution of methylamine (33% w/v in ethanol) (58 ml) and then sodium cyanoborohydride (4,24 g). To this mixture was added with cooling ( < 25"C), 2N hydrogen chloride in ethanol until just acid to bromocresol green and the mixture stirred for 24 h maintaining the pH by addition of HCl/ethanol as necessary.

The reaction was quenched with care by successive addition of 2N HCl in ethanol (100 ml) and water (100 ml), basified with sat.aq. potassium carbonate and extracted with dichloromethane. The organic solution was washed with water, dried with NgSO4 and evaporated to give ethyl 5-methylaminomethyl-lH-imidazole-4carboxylate or ethyl 4-methylaminomethyl-lH-imidazole-5carboxylate respectively (18,1 g) (70 % pure by hplc).

Method 2 (Catalytic reduction) To a solution of ethyl 5-formyl-lH-imidazole-4carboxylate or ethyl 4-formyl-lH-imidazole-5-carboxylate (5,05 g) in ethanol (200 ml) was added a solution of methylamine (33 % w/v in ethanol) (9,4 ml) and the mixture was stirred for 30 min. 5 % palladium on carbon (900 mg) was added and the mixture hydrogenated at 6 psi. Filtration of the mixture and evaporation of solvent gave ethyl 5-methylaminomethyl-lH-imidazole-4carboxylate or ethyl 4-methylaminmethyl-lH-imidazole-5- carboxylate respectively (5,5 g, 98 %) mp.

By a similar method, using the appropriate starting materials, the following compounds were prepared Ethyl 5- (4-methoxyanilino) -methyl-lH-imidazole-4- carboxylate; ethyl 4- (4-methoxyanilino) -methyl-lH- imidazole-5-carboxylate; 5-diethoxy-4-methylaminomethyl-lH-imidazole as an oil; 4-diethoxy-5-methylaminomethyl-lH-imidazole.

Example 1 : 3-diethoxvmethvl-5,6-dihydro-6-oxo-4H- imidazo [1,5-a]pyrido[3,4-4][1-4]diazepine Step A : 5-N-(4-chloronicotinoyl)-methylaminoethyl-4- diethoxvmethvl-lH-imidazole or 4-N-(4-chloronicotinoyl)methylaminomethyl-5-diethoxymethyl-1H-imidazole.

To a suspension of 4-chloronicotinic acid (2.67g, 17mmole) in dichloromethane (100ml) was added N,N'carbonyl diimidazole (3g, 18.5mmole), the mixture stirred for 2h at room temperature, 5-diethoxy-4methylamino-methyl-lH-imidazole or 4-diethoxy-5-methyllH-imidazole-5-carboxylate (4.2g, 19.7mmole) was added and the mixture stirred at room temperature overnight.

The organic solution was washed with aqueous sodium bicarbonate, dried and evaporated and the resultant crude product purified by passing through a short silica column (CH2Ch 5% methanol) to give the title compound as an oil (4.8g, 73%).

SteP B : 3-diethvloxvmethvl-5 6-dihvdro-6-oxo-4H-imidazo [1,5-a]pyrido[3,4-fl][1,4]-diazepine To a solution of 5-N-(4-chloronicotinoyl)-methylaminomethyl-4-diethoxy-lH-imidazole or 4-N-(4chloronicotinyl)-methylaminomethyl-5-diethoxy-lHimidazole (4.8g, 13.6mmole) in dimethylformamide (60ml) was added lithium hydride (422mg, 53.lmmole) and the mixture first sonicated for lOmin and then heated for 2h at 100 C. After cooling, excess lithium hydride was removed by filtration and the mixture partitioned between water and dichloromethane. Drying of the organic solution followed by evaporation of solvent gave the title compound as a crude oil (2.48g, 57%).

ExamPle 2 : 5,6-dihydro-3-[1,3-dioxolan-2-yl]-5-methyl- 6-oxo-4H-imidazoT1.S-alpyridor3.4 fi (l.4idiazeine Step A : 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a pyrido[3,4-f][1,4]diazepine-3-carboxaldehyde 3-diethoxymethyl-5,6-dihydro-6-oxo-4H-imidazo [1,5 a]pyrido[3,4-f][l,4]diazepine (of example 1) (2.48 g 7.8mmole) was dissolved in acetone (250ml) containing dilute hydrochloric acid (4M, 3ml) and the mixture refluxed for lh. Basification with dilute aqueous sodium bicarbonate and exhaustive extraction with dichloromethane gave, after evaporation of solvent, the title compound (l.0g, 51%). Mpt 225-227 C from dichloromethane/ether.

Step B : 5,60dihydro-3-[1,3-dioxolan-2-yl]-5-methyl-6- oxo-4H-imidazo[1,5-a]pyrido[3,4-f][1,4]-diazepine 5, 6-dihydro-5-methyl-6-oxo-4H-imdazo-[l, 5-a] pyrido[3,4-f][1,4]dizepine-3-carboxyaldehyde (300mg, 1.16mmole) was refluxed, under azeotropic conditions, in benzene (20 ml) containing ethane-1,2-diol (500mg, 8.06mmole) and p-toluenesulphonic acid (10 mg), for 8h.

After cooling and evaporation to a small volume the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution, dried with potassium carbonate and evaporated. Crystallisation from dichloromethane/ether gave the title compound (283mg, 85%). Mpt 248-249'C.

The spectroscopic and analytical data for the compounds of Examples 18, 2A and 28 are given in Table 1 below.

TABLE 1

Compound rield MP C ir cm-1 kBr disc of example Z Crystattisation solvent 1B -CH# 57% oil M/A 2A -CHO 51% 225.7 1687,1628,1587,1569,1557,1497,1413, CH2Cl2/Et2O 2B # 85% 248.9 1633,1583,1493,1480,1209,1065,947 CH2Cl2/Et2O TABLE I Continued Calculated Formula Analysis Found Compound 1Hnm@ Hol ut C H M Other of example CDCL3 relative to TMS 9.21(1H,s); 8.78(1H,d); 7,97(1H,s); 7,37(1H,d); C H H O 60.75 6.37 17.71 1B 5.67(1H,s); 4.2.5.0(bs); 3.69(4M,m); 3.25(3H,s) 16 20 4 3 M/A 1,29(6H,t) 316.362 10.06(1H,s); 9.30(1H,s); 8.87(1H,d); 8.02(1H,s); C H H O 58.41 4.29 22.70 2A 7.38(1H,d); 4.80(2H,bs); 3.27(3H,s) 12 10 4 2 58.76 4.34 22.44 9.24(1H,s); 8.80(1H,d); 7.94(1H,s); 7.32(1H,d); %H D 2 251.25 2B 5.95(1H,s); 4.52(2H,bs); 4.20(2H,m); 4.09(2H,m); C H H O 57.83 5.03 19.27 3,24(3H,s); 14 14 4 3 58.04 4.93 19.20 %H O 2 296.301 Example 3 Tablets were prepared according to the following formulation Compound of Example 1 .................... 20 mg Excipient for one tablet up to ........... 150 mg (details of the excipient : lactose, starch, talc, magnesium stearate).

Example 4 Tablets were prepared according to the following formulation Compound of Example 2 ................... 20 mg Excipient for one tablet up to .......... 150 mg (details of the excipient : lactose, starch, talc, magnesium stearate).

Biochemical Activitv Test 1 The affinity of the active ingredients for the benzodiazepine receptors was measured using a radioactively labelled (3H) compound flunitrazepam, and a modified version of the method of Squires and Braestrup (Nature, 1977, 266, 732).

The values given in Table 2 below are the concentration (mol x 10-9) of the compound under test which inhibits 50 % of the specific binding of 0.6 x 10-9 mol of 3H-labelled flunitrazepam in preparations of membranes from the rear portion of the brain in rats (IC50 values).

Test 2 Measure of in vivo binding to benzodiazepine receptors was carried out according to the method described by Goeders N E and Kuhar M J, Life Sciences(1985) 37 345.

TABLE 2

Example 1 Test 1 1 Test 2 I I I ED 50 mq/kq IP 2A 1200 1200 1 1 28 1 840 1 9.8

Claims

Claims 1. Compounds of formula I

[wherein R1 represents an alkyl group containing from 1 to 3 carbon atoms, or the two R1 groups together represent an alkylene group containing from 2 to 5 carbon atoms; X and Y, which may be identical or different, each represents an oxygen or sulphur atom with the proviso that when R1 represents an alkyl group, X and Y have the same meaning; R2 represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; R3 represents a hydrogen atom, an alkyl group containing from 1 to 5 carbon atoms, a phenyl group or a substituted phenyl group; W represents an oxygen or sulphur atom; and the ring A together with the two carbon atoms denoted a and p in formula I above represents a group selected from:

in which R4 represents a hydrogen atom, an alkyl group containing from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, a halogen atom or a nitrile group; and RA represents a hydrogen atom, a halogen atom or a nitro group]; and acid addition salts thereof.
2. Compounds of formula I as claimed in claim 1 wherein W represents an oxygen atom; R2 represents a hydrogen atom; R3 represents a methyl group; the ring A together witch the carbon atoms denoted a and p represents a group

(in which R4 and R5 are as defined above; and X, Y and R1 are as defined in claim 1); and acid addition salts thereof.
3. Compounds of formula I as claimed in claim 1 wherein the groups R1 each represents a methyl or ethyl group, or the two R1 groups together represent an ethylene or trimethylene group; and X, Y, R2, R3, W and A are as defined in clam 1; and acid addition salts thereof.
4. Compounds of formula I as claimed in claim 1 selected from: 5,6-dihydro-3-(1,3-dioxolan-2-yl)-5-methyl-6-oxo-4Himidazo[1,5-a]pyrido[3,4-f][1,4]diazepine; and 3diethyloxymethyl-5,6-dihydro-6-dihydro-6-oxo-4H-imidazo[1,5 a]pyrido[3,4-f] [l,4]diazepine; and acid addition salts thereof.
5. Compounds as claimed in any of the preceding claims as herein specifically described.
6. Compounds as claimed in any of the preceding claims as herein specifically described in the Examples.
7. A process for the preparation of a compound as claimed in claim 1, being a compound of formula 1A

(wherein RA represents an alkyl group containing from 1 to 3 carbon atoms and R2 R3, W, A and X are as defined in claim 1), which comprises reacting a compound of formula II

(wherein R2, R3, W and A are as defined above) with a compound of formula III H - X - RA (III) (wherein X and RA are as defined above); and if desired, subsequently converting the compound of formula 1A thereby obtained into an acid addition salt thereof.
8. A process for the preparation of a compound as claimed in claim 1, being a compound of formula 18

(wherein RB represents an alkylene group containing from 2 to 5 carbon atoms and R2 R3, W, A, X and Y are as defined in claim 1), which comprises reacting a compound of formula II as defined in claim 7 with a compound of formula IV

(wherein X, Y and RB are as defined above); and if desired subsequently converting the compound of formula 18 thereby obtained into an acid addition salt thereof.
9. A process as claimed in claim 7 or claim 8 wherein the reaction between the compound of formula II and the compound of formula III or between the compound of formula II and the compound of formula IV is effected in the presence of benzene or dichloromethane.
10. A process as claimed in any of claims 7 to 9 wherein in the reaction of a compound of formula II with a compound of formula III in which X represents an oxygen atom or with a compound of formula IV in which X and Y each represents an oxygen atom, the reaction is effected in the presence of benzene and additionally in the presence of a catalytic quantity of paratoluenesulphonic acid at the reflux temperature of the reaction medium.
11. A process as claimed in any of claims 7 to 9 wherein in the reaction of a compound of formula II with a compound of formula III in which X represents a sulphur atom or with a compound of formula IV in which X and Y each represents a sulphur atom, the reaction is effected in the presence of dichloromethane and additionally in the presence of a catalytic quantity of boron trifluoroetherate at ambient temperature.
12. A process for the preparation of a compound as claimed in claim 1, being a compound of formula 1A as defined in claim 7 (wherein W represents an oxygen atom, R2 represents a hydrogen atom and the remaining groups are as defined in claim 7), which comprises the cyclisation of a compound of formula VII

(wherein A,X,R3 and RA are as defined in claim 7 and B represents a leaving group); and if desired subsequently converting the compound of formula 1A thereby obtained into an acid addition salt thereof.
13. A process as claimed in claim 12 wherein the cyclisation of the compound of formula VII is effected in the presence of lithium hydride and in the presence of dimethylformamide at the reflux temperature of the reaction medium.
14. A process as claimed in claim 12 wherein the compound of formula VII is prepared by reacting a compound of formula V

(wherein A and B are as defined in claim 12) or a functional derivative thereof with a compound of formula VI

(wherein X, RA and R3 are as defined in claim 13).
15. A process as claimed in claim 14 wherein in the compound of formula V, the leaving group B is a halogen atom or a nitro group.
16. A process as claimed in claim -14 wherein the- functional derivative of an acid of formula V is an acid chloride.
17. A process as claimed in any of claims 14 to 16 wherein the reaction of the compound of formula V or a functional derivative thereof with the compound of formula VI is effected in the presence of dichloromethane and in the presence of a base selected from sodium carbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide or trimethylainine.
18. A process as claimed in any of claims 7 to 11 wherein a compound of formula II wherein W represents an oxygen atom is prepared by reacting a compound of formula 1A as obtained by the process of claim 12 (wherein W represents an oxygen atom, R2 represents a hydrogen atom and R3, A, X and RA are as defined in claim 7) with hydrochloric acid in acetone at the reflux temperature of the reaction medium.
19. A process as claimed in any of claims 7 to 18 substantially as herein described.
20. A process as claimed in any of claims 7 to 18 substantially as herein described in any one of the Examples.
21. Compounds of formula I as defined in claim 1 and acid addition salts thereof whenever prepared by a process as claimed in any one of claims 7 to 20.
22. Compounds of formula I as claimed in any of claims 1 to 6 and physiologically acceptable acid addition salts thereof for use as medicaments.
23. The use of a compound of formula I as claimed in any of claims 1 to 6 or a physiologically acceptable acid addition salt thereof for the manufacture of a medicament with benzodiazepine inverse agonist activity or tranquilising activity.
24. The use of a compund of formula I as claimed in any of claims 1 to 6 or a physiologically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of memory or cerebral senescence disorders, obesity, agitated or irritated conditions or epilepsy.
25. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof in association with one or more pharmaceutical carriers and/or excipients.
26. Compositions as claimed in claim 25 in the form of dosage units.
27. Pharmaceutical compositions as claimed in claim 25 specifically as herein described.
28. Pharmaceutical compositions as claimed in claim 25 specifically as herein described in the Examples.
29. A compound of formula VII

(wherein A, B, R3, X and RA are as defined in claim 13).