AU625779B2

AU625779B2 - Imidazodiazepine derivatives

Info

Publication number: AU625779B2
Application number: AU40275/89A
Authority: AU
Inventors: Walter Hunkeler; Emilio Kyburz; Marc Meier
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1988-08-31
Filing date: 1989-08-28
Publication date: 1992-07-16
Anticipated expiration: 2009-08-28
Also published as: AU4027589A; US5021411A; NO893485L; IL91440A0; NO168587C; MC2052A1; NZ230436A; EP0357043A2; NO168587B; FI894026A7; EP0357043A3; NO893485D0; JPH02111775A; HUT52509A; JPH0786108B2; DK428789A; PH26564A; PT91588A; FI894026A0; DK428789D0

Description

~r

V,

S F Ref: 104390 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATN

(ORIGINAL)

if,: FOR OFFICE USE: C14 9I Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: ft a 0 ft oa <a Name and Address of Applicant: 9* ft 9 ft F Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4002 Basle

SWITZERLAND

Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia f t Complete Specification for the invention entitled: Imidazodiazepine Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3 i i i ~clc~ RAN 4008/344 Abstract The novel imidazodiazepine derivatives of the general formula o 00 o 0 i 000 oo 00 0 0 0 0 00£ 0 00O 0 00 o oe 0 o o 0800 S3 wherein A together with the two carbon atoms denoted by a and B signifies one of the groups 0*#0 0 *r t I IC and

R

1 signifies a partially unsaturated lower hydrocarbon group which is optionally substituted by hydroxy, oxo. aryl or the group -OR, -SR or -OCOR or a lower alkyl group which is substituted by aryl or the group -SR' or -OCOR'. R and R' each signify aryl or a saturated or partially unsaturated C -18-hydrocarbon group which is optionally substituted by aryl or lower alkoxy. R 2 signifies hydrogen and R 3 -I A signifies lower alkyl or R and R 3 together signify dimethylene or trimethylene and R and R each signify hydrogen, halogen, trifluoromethyl, cyano, nitro or lower alkyl, the group -OR' having a significance different from lower alkoxy and the compounds of formula I having the or (R.S)-configuration with reference to the carbon atom 2 3 denoted by y when R and R together signify dimethylene or trimethylene, can be used in the control or prevention of convulsions, anxiety states, stress conditions, excitation states and sleep disorders and/or in the partial or complete S* selective antagonism of some or all activities which 1,4-benzodiazepines having tranquillizing activity or a other substances display via the central benzodiazepine receptors.

2O

-FW_

i _--_-IX~WYIIII d i 11 1111~-~r~ ib- RAN 4008/344 The present invention is concerned with imidazodiazepine derivatives. In particular, it is concerned with imidazodiazepine derivatives of the general formula 0 43 o o 0Q O 0 oa o «I

I

0

I

3 wherein A together with the two carbon atoms denoted by a and B signifies one of the groups

S

and :a

R

1 signifies a partially unsaturated lower hydrocarbon group which is optionally substituted by hydroxy. oxo. aryl or the group -OR, -SR or -OCOR or a lower alkyl group which is substituted by aryl or the group -SR' or -OCOR'. R and R' each signify aryl or a saturated or partially unsaturated C 1 18 -hydrocarbon group which is optionally substituted by aryl or lower alkoxy. R 2 signifies hydrogen and R 3 2 3 signifies lower alkyl or R and R together Nt/20.6.89

L-

2 4 signify dimethylene or trimethylene and R and R each signify hydrogen, halogen, trifluoromethyl, cyano, nitro or lower alkyl, the group -OR' having a significance different from lower alkoxy and the compounds of formula I having the or (R.S)-configuration with reference to the carbon atom 2 3 denoted by y when R and R together signify dimethylene or trimethylene.

These compounds are novel and are distinguished by valuable pharmacodynamic properties.

Objects of the'present invention are the compounds of °o formula I above per se and as therapeutically active 1'o substances, a process for their manufacture, medicaments containing a compound of formula I and a therapeutically 0* inert carrier, the manufacture of such medicaments and the 0 use of compounds of formula I in the control or prevention of illnesses (especially in the control or prevention of convulsions, anxiety states, stress conditions, excitation states and sleep disorders and/or in the partial or complete selective antagonism of some or all activities 0 0 which 1,4-benzodiazepines having tranquillizing activity or other substances display via the central benzodiazepine receptors) and, respectively, the use of compounds of formula I fo'r the manufacture of medicaments, especially of medicaments for use in the just-mentioned indications.

The term "lower" is used to denote residues and -0 compounds with up to 7. preferably up to 4, carbon atoms.

The term "alkyl" denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-propyl. isopropyl. n-butyl. isobutyl, s-butyl, t-butyl and the like. The term "alkoxy" denotes alkyl residues in the sense of the previous definition of the term "alkyl" which are attached via an oxygen atom. The term "alkenyl" denotes straight-chain or branched hydrocarbon residues i I L, I i

U

3 which contain at least one olefinic double bond such as cis- and trans-2-buten-2-yl and 1-buten-3-yl. The term "aryl" preferably denotes monocyclic aromatic hydrocarbon residues which are preferably unsubstituted or substituted by lower alkyl, lower alkoxy and/or halogen. Unless indicated otherwise, the term "halogen" denotes the four halogens fluorine, chlorine, bromine and iodine.

The term "hydrocarbon group" denotes open-chain and cyclic groups and combinations thereof. The open-chain groups can be straight-chain or branched. Examples of saturated lower hydrocarbon groups are: methyl, ethyl, i-propyl, t-butyl, 3-pentyl, 1-nonyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl and 1-cyclopropylethyl. Examples of unsaturated hydrocarbon groups are, for example, the above-mentioned alkenyl groups, especially lower alkenyl groups, or hydrocarbon residues which contain at least one acetylenic 2 triple bond, i.e. alkynyl, especially lower alkynyl, groups such as l-propyn-3-yl.

a

R

1 preferably signifies a lower alkenyl group which S. is optionally substituted by hydroxy, oxo, aryl or the group -OR, -SR or -OCOR or a lower alkyl group which is l substituted by aryl or the group -SR' or -OCOR', especially a lower alkenyl group which is substituted by hydroxy or the group -OR, -SR or -OCOR or a lower alkyl group which is substituted by the group -SR' or S -OCOR'. Preferably, R and R' each signify aryl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkyl, C3- 7 -cycloalkyl or C3_ 7 -cycloalkyl-lower alkyl.

When R 2 signifies hydrogen and R 3 signifies lower 3 alkyl, then R 3 preferably stands for methyl. When R 2 and R together signify dimethylene or trimethylene, then the carbon atom denoted by y preferably has the (S)-configuration.

Li :i -4- When A signifies a residue of formula then 4 5 preferably one of R and R signifies hydrogen and the other signifies hydrogen or halogen; thus, for example.

Rand R 5 both signify hydrogen or Rsignifies hydrogen and R 5signifies fluorine or R 4signifies chlorine or bromine and R signifies hydrogen.

Preferred compounds of formula I in the scope of the present invention are: 7-Chloro-3-[3-(cyclopropylmethoxy)-l-.propynyl]-4,5- -dihydro-5-methyl-6H-imidazo[ls-a]r1,4]benzodiazepin- -6-one, 3-(7-chloro-5.6-dihydro-5-methyl-6-oxo4Himidazo V,5-a][1.4lbenzodiazepin-3-yl)-2-propynyl acetate, 7-chloro-3-[3-(cyclopropylmethoxy)-3-methyl-l-butynyl].

-5-methyl-6H-imidazo1,sa[1,4benzodiazepin6-one, 0 7-chloro-4. 5-dihydro-3-[ (Z)-5-hydroxy-3-methyl-3- -penten-1-ynyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzo.

diazepin-6-one, 7-chloro-4,5-dihydro-3- (3-hydroxy-3-methyl-4-penten-l- -ynyl)-5-methyl-6H-imidazo[l.5-a][14benzodiazepin6one and 7 -chloro-3-[E)-5-hydroxy3methyl3penten-1ynyl]s..

-methyl-6H-imidazo[1.s-a]r1.4]benzodiazepin6one.

The compounds of formula I can be manufactured in accordance with the invention by a) reacting a compound of the general formula 5 0 R wherein A. R and R have the above significance and X signifies bromine or iodine, with the proviso that where A signifies a residue of formula and

R

4 and/or R 5 signifies halogen, this halogen is fluorine or chlorine when X signifies bromine or is fluorine, chlorine or bromine when X signifies iodine, with a compound of the general formula 0 OQ as o wherein R 1 has the above significance; or b) etherifying or acylating a compound of formula I in which R 1 signifies a partially unsaturated lower hydrocarbon group which is substituted by hydroxy or a compound i 30 t of the general formula o CmC-E-OH 35 2 b)ehrfigo clt acmon ffruaIi 1I

-C

i iii r i 6 2 3 wherein E signifies lower alkylene and R R and A have the above significance, with an agent yielding the group -OR or -OCOR or the group -OR' or -OCOR'.

The reaction of compounds of formulae II and III in accordance with aspect a) of the process in accordance S with the invention is effected in the presence of a palladium(II) salt such as palladium chloride or palladium acetate, of an organophosphine such as triphenylphosphine.

of copper(I) iodide and of a secondary or tertiary amine such as diethylamine or triethylamine. In place of a palladium(II) salt and an organophosphine there can also be used a suitable corresponding complex such as e.g.

bis(triphenylphosphine)palladium(II) dichloride. As the So solvent there can be used the aforementioned secondary or 8 tertiary amine itself, a halogenated hydrocarbon such as methylene chloride, N.N-dimethylformamide or a mixture S 20 thereof. The reaction is effected at temperatures in a range between about room temperature and about 120C., with the reflux temperature being preferred. Depending on the remaining reaction parameters, the reaction time can amount to about 1 to about 70 hours. The starting materials of formula II are known or can be prepared readily according to methods which are known per se and which are familiar to any person skilled in the art.

In accordance with aspect b) of the process in accordance with the invention a hydroxy group is etherified or acylated. This is thus an etherification or acylation of a hydroxy group and methods for carrying out Ssuch an etherification are known per se and are familiar to any person skilled in the art. A corresponding halide, especially a chloride or bromide, is conveniently used as the etherifying or acylating agent. In the case of the etherification, this is conveniently carried out in the I I j 7 presence of a base, for example an alkali metal hydroxide such as potassium hydroxide, and in the presence of an organic solvent which is inert under the reaction conditions, for example in N.N-dimethylformamide, dimethyl sulphoxide, toluene or the like. In the case of the acylation, this is conveniently carried out in the presence of an acid-binding agent, for example a tertiary amine such as pyridine, which can simultaneously serve as the solvent. The reaction temperature conveniently lies in a range of about -100C to about 50 0

C.

o The compounds of formula IV which are used as starting S materials can be prepared in analogy to process variant a) So 15 from compounds of formula II and compounds of the formula o HCEC-E-OH in which E has the above significance.

o 0 As mentioned earlier, the compounds of formula I are novel. They possess valuable pharmacodynamic properties and have only a low toxicity. They have as a common characteristic a pronounced affinity to the central O*D benzodiazepine receptors and have either pronounced .O anxiolytic, anticonvulsant, muscle relaxant and seditive- -hypnotic properties and/or they partially or completely 2, selectively antagonize some or all activities which 1,4-benzodiazepines having tranquillizing activity or other substances display via the central benzodiazepine receptors.

affinity of compounds of general formula I to the central benzodiazepine receptors was determined according to the method described in Life Science 20. 2101-2110 (1977) and Science 198, 849-851 (1977). According to this method, the inhibition of the binding of tritiated diazepam at the specific benzodiazepine receptors in the cerebral cortex by the respective test substances is ascertained. The IC 50 inhibiting concentration") I g

I

L,.

V

-8is that concentration of the respective test substance which brings about a 50 percent inhibition of the specific binding of the tritiated diazepam at the specific benzodiazepine receptors in the cerebral cortex.

The results which have been obtained with representative members of the class of compound defined by general formula I are compiled in the following Table.

CC I o i o Cb C CP COa Coc Compound Affinity to benzodiazepine receptors IC 50. nnol/1 i d

B

1.4 2.6 1.4 3.7 2.2 a0ao C a a Ca1 a o ii A 7-Chloro-3-[3-(cyclopropylmetoxy)-l-propynyl-4'- -dihydro-5-methyl-6H-imidazo[l.5-a[1,.4]benzodiazepin- -6-one B 3-(7-Chloro-5.6-dihydro-5-methyl-6-oxo-4H-imidazo- [l.5-a][l.4]benzodiazepin-3-yl)-2-propynyl acetate C 7-Chloro-3-[3-(cyclopropylmethoxy)3methyl-l-butynyl> -4.5-dihydro-5-methyl-6H-imidazo[1.5-aJ]j.4benzo diazepin-6-one

L-

i~Y 9 *n C #0 *C 0 040 0t

COO

C.e

II

D 7-Chloro-4.5-dihydro-3-[(Z)-5-hydroxy-3-methyl-3- -penten-i-ynyl]-5-methyl-6H-imidazo[l,5-a][1,4]benzodiazepine-6-one E 7-Chloro-4.5-dihydro-3-(3-hydroxy-3-methyl-4-penten-l- -ynyl)-5-methyl-6H-imidazo[l,5-a][l,4]benzodiazepin- -6-one F 7-Chloro-4.5-dihydro-3-[(E)-5-hydroxy-3-methyl-3- -penten-l-ynyl]-5-methyl-6H-imidazo[l,5-a][l,4]benzodiazepin-6-one.

The compounds of formula I can be used as medicaments, 15 1 e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be 20 carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the manufacture of pharmaceutical preparations the compounds of formula I can be processed with pharma- 2 ceutically inert, inorganic or organic carriers. Lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like. Suitable carriers for injection solutions are, for example, water.

U

:4V 10 alcohols. polyols. glycerol, vegetable oils and the like.

Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.

0 4 a o 15 As mentioned earlier, medicaments containing a S*o compound of formula I and a therapeutically inert excipient are also an object of the present invention, as o"o is a process for the manufacture of such medicaments which comprises bringing one or more compounds of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

*0 I As mentioned earlier, the compounds of formula I can be used in accordance with the invention in the control or prevention of illnesses, especially in the control of convulsions and anxiety states and/or in the partial or complete antagonism of some or all activities which 1,4-benzodiazepines having tranquillizing activity or other substances display via the central benzodiazepine receptors. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 100 mg should be sufficient.

B 11 11 Finally, as mentioned earlier, the use of compounds of formula I for the manufacture of medicaments, especially of medicaments for use in the control or prevention of convulsions, anxiety states, stress conditions, excitation states and sleep disorders and/or in the partial or complete selective antagonism of some or all activities which 1,4-benzodiazepines having tranquillizing activity or other substances display via the central benzodiazepine receptors, is also an object of the invention.

The following Examples are intended to illustrate the present invention in more detail, but are not intended to limit its extent in any manner. All temperatures are given 1 in degrees Celsius.

o Example 1 a) 5.20 g (14 mmol) of 7-chloro-4,5-dihydro-3-iodo-5- -methyl-6H-imidazo[l.5-a][1,4]benzodiazepin-6-one are heated to boiling under reflux for 4 hours with 1.04 g I (18.5 mmol) of propargyl alcohol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) oiodide in 35 ml of diethylamine. The reaction mixture is 25 evaporated and the residue is suspended in methylene chloride. The suspension is suction filtered and the suction filter cake is washed with ethyl acetate. After Stwo successive recrystallizations from ethanol and, respectively, N,N-dimethylformamide there is obtained 3 7-chloro-4.5-dihydro-3-(3-hydroxy-l-propynyl)-5-methyl-6H- -imidazo[l.5-a][1,4]benzodiazepin-6-one of melting point 250-252°.

b) 4.5 g (15 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy- -l-propynyl)-5-methyl-6H-imidazo[l,5-a][l,4]benzodiazepin- -6-one are suspended in 30 ml of pyridine and treated dropwise at 0 to 5°C within 15 minutes with 4.1 ml I- i 112 mmol) of capryl chloride. The cooling bath is removed and the mixture is left to stir at room temperature for hours. The reaction mixture is then poured into 300 ml of water and acidified to pH 1 with 30 ml of concentrated hydrochloric acid. The mixture is extracted three times with methylene chloride. the combined organic extracts are dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate/methylene chloride and crystallization from methylene chloride, petroleum ether and hexane there are obtained 1.55 g of 3-(7-chloro-5.6-dihydro-5- -methyl-6-oxo-4H-imidazo[l.5-a][1.4]benzodiazepin-3-yl)- -2--propynyl decanoate of melting point 70-720.

9 9 In an analogous manner, from 7-chloro-4.5-dihydro-3- 4 -(3-hydroxy-l-propynyl)-5-methyl-6H-imidazo[l.5--a][1,4jbenzodiazepin-6-one c) with pivaloyl chloride there was manufactured 3-(7- 6-dihydro-5-methyl-6-oxo-4H-imidazo benzodiazepin-3-yl)-2-propynyl pivalate of melting point 6 143-1450 (from ethyl acetate); d) with acetyl chloride there was manufactured 3-(7- -chloro-5.6-dihydro-5--methyl-6-oxo-4H-imidazo[1,5-aj[1,4]benzodiazepin-3-yl)-2-propynyl acetate of melting point 194-1950 (from methylene chloride and ethyl acetate); a 30 e) with cyclohexanecarbonyl chloride there was manufactured 3-(7-chloro-5.6-dihydro-5-methyl-6-oxo-4H- -imidazo(1,5-a][1,4]benzodiazepin-3-yl)-2-propynyl cyclohexanecarboxylate of melting point 143-1440 (from ethyl acetate and hexane): f) with benzoyl chloride there was manufactur-ed 3-(7- -chloro-5.6-dihydro--methyl-6-oxo-4H-imidazo,...a][1,4]- 13 benzodiazepin-3-yl)-2-propynyl benzoate of melting point 152-1540 (from ethyl acetate); g) with cyclopropanecarbonyl chloride there was manufactured 3-(7-chloro-5.6-dihydro-5-methyl-6-oxo-4H- -imidazo[1.5-a][1,4]benzodiazepin-3-yl)-2-propynyl cyclopropanecarboxylate of melting point 120-1210 (from ethyl acetate).

Example 2 a) 3.34 g (59 mmol) of freshly powdered potassium hydroxide are suspended in 25 ml of N,N-dimethylformamide and treated with 4.0 g (13.2 mmol) of 7-chloro-4,5- 000 -dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo- (1,5-aJ[1,4benzodiazepin-6-one. After stirring at room 000*) 0 0 temperature for 5 minutes the mixture is cooled to C*lio whereupon 4.95 g (31.1 mmol) of bromomethylcyclopropane are added thereto. The reaction mixture is stirred at room temperature for 1 hour and then poured into water. The mixture is extracted three times with methylene chloride, 0040 o0 the combined organic extracts are washed with water, dried 0 t over magnesium sulphate and evaporated. By crystallization of the residue from ethyl acetate and ether there are obtained 4.0 g of 7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4.5-dihydro-5-methyl-6H-imidazo- 11.5-a[1.4]benzodiazepin-6-one of melting point 124-1260 In an analogous manner, from 7-chloro-4.5-dihydro-3- -(3-hydroxy-1-propynyl)-5-methyl-6H-imidazol,5-a][1,4]benzodiazepin-6-one b) with 3-methoxybenzyl chloride there was manufactured 7-chloro-4,5-dihydro-3-13-(3-methoxybenzyloxy)-1-propynyl]- -5-methyl-6H-imidazo[1,5-a][1.4]benzodiazepin-6-one of melting point 104-1060 (from methylene chloride and hexane); ::i 141 14c) with 4-methoxybenzyl chloride there was manufactured 7-chloro-4.5-dihydro-3-[3-(4-methoxybenzyloxy)-l-propynylj- -5-methyl-6H-imidazo[1.5-aJ[1.4]benzodiazepin-6-one of melting point 108-1100 (from ethyl acetate and hexane); d) with benzyl bromide there was manufactured 3-[3- -(benzyloxy)-l-propynyl]-7-chloro-4.5-dihydro-5-methyl-6H- -imidazo[1.5-a]VL.4]benzodiazepin-6-one of melting point 108-1090 (from methanol and ether); e) with bromomethylcyclohexane there was manufactured 7-chloro-3-[3-(cyclohexylmethoxy)--propynyl]-4.5-dihydro- -5-methyl-6H-imidazorl.5-a ,4]benodiazepin-6-one of mo melting point 68-710 (from ethyl acetate/hexane); *0 0s f) with propargyl bromide there was manufactured *900 7-chloro-4,5-dihydro-5-methyl-3-[3-(3-propynyloxy)-1- -propynyl]-6H-imidazofl.5-aj[1,l4benzodiazepin-6-one of melting point 133-1340 (from methanol and ether); g) with 2-chloroethyl methyl ether there was manufactured 7-chloro-4.5-dihydro-3-[3-(2-methoxyethoxy)--propynyl)-5- -methyl-6H-imidazo[1.5-a]fl.4benzodiazepine-6-one of 0°25 melting point 105-1060 (from methanol and ether).

Example 3 a) 3.73 g (10 mmol) of 7-chloro-45-dihydro--3-iodo-5- -methyl-6H-imidazo[1.5-aJ[1.4Jbenzodiazepin- 6one are mixed with 1.10 g (12 mmol) of 2-methyl-3-butyn-2-ol and ml of diethylamine. Then. 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide are added thereto and the mixture is stirred at room temperature for 60 hours. The reaction mixture is evaporated and the residue is dissolved in methylene chloride. The solution is washed twice with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there is obtained 7-chloro-4.5-dihydro-3-(3--hydroxy-3-methyl.-1- -butynyl)-5-methyl-6H-imidazo~l.5-a][l.4jbenzodiazepin-6- -one of melting point 193-1940.

In analogy to Example 2. from 7-chloro-4,5-dihydro-3- -(3-hydroxy-3-methyl-l-butynyl)-5-methyl-6H-imidazo[l. [1.4]benzodiazepin-6-one b) with 2-chlorobenzyl chloride there was manufactured 7-chloro-3-[3-(2-chlorobenzyloxy)-3-methyl-l-butynyl]-4.5too" 1 -dihydro-.5-methyl-6H-imidazo[l.5-ajf1,4.]benzodiazepin-6-one of melting point 142-1430 (from ethyl acetate and hexane); 00 a0 0 0 c) with 4-chlorobenzyl chloride there was obtained 7-chloro-3- (4-chlorobenzyloxy) -3-methyl-1-butynyl]J-4,*5- -dihydro-5-methyl-6H-imidazo[l. 5-a] 4.benzodiazepin-6-one of melting point 107-1080 (from ethyl acetate and hexane); d) with 3-chlorobenzyl bromide there was manufactured 7-chloro-3-[3-(3-chlorobenzyloxy)-3-methyl-l-butynyl]-4.5- -dihydro-5-methyl--6H-imidazo[1,5-a][1.4]benzodiazepin-6-one of melting point 161-1630 (from ethyl acetate and hexane); K e) with benzyl bromide there was manufactured 3-[3- -(benzyloxy)-3-methyl-l-butynylj-7-chloro-4, if -methyl-6H-imidazo(l.5-a](l.4Jbenzodiazepin-6-one of melting point 143-1440 (from ethyl acetate and ether); f) with bromomethylcyclopropane there wvas obtained 7-chloro-3-[3-(cyclopropylmethoxy)-3-methyl-l-butynyl]- -4.5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin- -6-one of melting point 138-1400 (from ethyl acetate).

16 g) In analogy to Example lb). from 7-chloro-4,5-dihydro- -3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo- [1.5-a](l1.4]benzodiazepin-6-one there was manufactured 3-(7-chloro-5.6-dihydro-5-methyl-6-oxo-4H-imidazoll.5-a]- [1.4]benzodiazepin-3-yl)-1.1-dimethyl-2-propynyl cyclopropanecarboxylate of melting point 139-1410 (from ethyl acetate and hexane).

Example 4 a) 3.30 g (10 mmol) of 7-chloro-45-dihydro-3-(3-hydroxy- -3-methyl-1-butynyl)-5-methyl-6H-imidazo[l.5-a][1,4]benzo- S diazepin-6-one are dissolved in 20 ml of pyridine and o treated at room temperature with 1.57 g (13 mmol) of pivaloyl chloride. The reaction mixture is stirred at 650 for 24 hours and then evaporated. The residue is taken up 004 06 in methylene chloride, the solution is washed once with IN S hydrochloric acid and twice with water, dried over magnesium sulphate and evaporated. By chromatography on silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate and hexane there is obtained 0.96 g of 3-(7-chloro-5.6-dihydro-5-methyl- -6-oxo-4H-imidazo[1,5-a] [1.4]benzodiazepin-3-yl)-1. 1- 25 -dimethyl-2-propynyl pivalate of melting point 132-1330.

In an analogous manner, from 7-chloro-4,5-dihydro-3- -(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[l.5-a[l.4]- S benzodiazepin-6-one: b) with acetyl chloride between 40 and room temperature during 2.5 hours there was manufactured 3-(7-chloro-5,6- -dihydro-5-methyl-6-oxo-4H-imidazo[l.5-a][1.4]benzodiazepin-3-yl)-1-methyl-2-propynyl acetate of melting point 144-1450 (from ethyl acetate and hexane). Yield: 2.86 g p

IIMFM

V

-17 c) with cyclopropanecarbonyl chloride between 40 and room temperature overnight there was manufactured 3-(7-chloro- -5.6-dihydro-5-methyl-6-oxo-4H-imidazo[1.5-a][1.4]benzodiazepin-3-yl)-l-methyi-2-propynyl cyclopropanecarboxylate of melting point 158-1600 (from ethyl acetate and hexane).

Yield: 2.75 g d) with pivaloyl chloride at 55-600 during 4 hours there was manufactured 3-(7-chloro-5,6-dihydro-5-methyl-6-oxo- -4H-imidazo~l.5a][.4Jbenzodiazepin-3-yl)-l-methyl-2- -propynyl pivalate of melting point 138-1400 (from ethyl acetate and hexane). Yield: 2.75 g Example a) 7.47 g (20 mmol) of 7-chloro-4,5-dihydro--3-iodo-5- -methyl-6H-imidazo[l',5-a][1,4]benzudiazepine-6-one are heated to boiling under reflux for 4 hours with 1.75 g (25 mmol) of 3-butyn-2-ol. 70 mg of bis-(triphenyl- 00 phosphine)-palladium(Il) dichloride and 10 mg of copper(I) iodide in 50 ml of diethylamine and 20 ml of ethylene chloride. After evaporation of the solvent the residue is taken up in methylene chloride and the thus-obtained 25 suspension is suction filtered. The material obtained is washed with methylene chloride and, after recrystallization from ethyl acetate, there is obtained 7-chloro- -4.5-dihydro-3-(3-hydroxy-l-butynyl)-5-methyl-6H-imidazo- [l.5-all.4]benzodiazepin-6-one of melting point 251-252-C.

In analogy to Example 2. from 7-chloro-4,5-dihydro-3- -(3-hydroxy-l-butynyl)-5-methyl-6H-imidazo[l.5-a][1,4]benzodiazepin-6-one b) with benzyl bromide there was manufactured 3-[3- -(benzyloxy)-l-butynyl]-7-chloro-4. 5-dihydro-5-methyl-6H- -imidazo[1.5-a][1.4]benzodiazepin-6-one of melting point -18 150-1510 (from methylene chloride and hexane). Yield 0.82 g c) with bromomethylcyclopropane at 50 to room temperature during 2.5 hours there was manufactured 7-chloro-3-[3- (cyclopropylmethoxy)--butinyl]-4. 5-dihydro-5-methyl-6H- -imidazo(1.5-a](.4]benzodiazepin-6-one of melting point r 138-1390 (from methanol and ether). Yield: 2.17 g Example 6 a) 25 g (85 mmol) of ethyl 5.6-dihydro-5,,7-dimethyl-6- -oxo-4H--imidazo[l.5-a]rl.4]benzodiazepine-3-carboxylate are heated to boiling under reflux for 1 hour with 3.40 g mmol) of sodium hydroxide in 200 ml of ethanol and ml of water. After evaporation of the ethanol the *Ott mixture is diluted with water and acidified with 21 ml of 4 normal hydrochloric acid. The suspension obtained is suction filtered and washed with water. After drying the suction filter cake there is obtained 5.6-dihydro-5.7- -dimethyl-6-oxo-4H-imidazo[1,5-a][1.4]benzodiazepine-3- -carboxylic acid of decomposition point 274-2750.

b) 22.20 g (81.8 mmol) of-5.6-dihydro-57-dimethyl-6-oxo- -4H-imidazo~l.5-a][1.4]benzodiazepine--3-carboxylic acid are heated to 290-3000 in a metal bath until the CO 2 cleavage has finished. The melt is dissolved in methylene chloride and ethanol and the solution is concentrated until methylene chloride no longer distils over.

4.5-Dihydro-5.7-dimethyl-6H-imidazo[l.5-aJ(1,4]benzodiazepin-6-one of melting point 224-2250 crystallizes from this solution.

c) 15.85 g (69.7 mmol) of 4.5-dihydro-5.7-dimethyl-6H- *-imidazo[l.5--a][1.4]benzodiazepin-6-one are heated to 9350 for 2.5 hours with 67 g (264 mmol) of iodine in 100 ml of 19 N.N-dimethylformamide. The reaction mixture is then poured into 450 ml of water, treated with methylene chloride, decolorized with sodium thiosuiphate and neutralized with sodium bicarbonate. The aqueous phase is separated and extracted six times with methylene chloride. The combined organic phases are washed three times with water. dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate and hexane there is obtained 4.5-dihydro-3-iodo-5,7--dimethyl- -6H-imidazo[1.5-.a]ll.4]benzodiazepin-6-one of melting point 106-1080.

d) 5 g (14.2 mmol) of 4.5-dihydro-3-iodo-5,7-dimethyl-6H- -imidazo[l.5-ajI[l.4]benzodiazepin-6-one are heated to boiling under reflux for 4.5 hours with 1.50 g (17.8 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(l) iodide in 40 ml of diethylamine. The reaction mixture is then evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained -3-C 3-hydroxy-3-methyl-1-butynyl 7-dimethyl-6H- imidazo- [1.5-al,4]benzodiazepin-6-one of melting point 165-1670.

e) In analogy to Example 2. from 4.5-dihydro-3-(3- -hydroxy-3-methyl-1-butynyl 7-dimethyl-6H-imidazo- [1.5-aJ[1.4)benzodiazepin-6-one and benzyl chloride there was manufactured 3-(3-benzyloxy-3-methyl-l-butynyl)-4,5- -dihydro-5.7-dimethyl-6H-imidazojl. 5-a] (1,4]benzodiazepin- -6-one of melting point 1340 (from ethyl acetate and hexane).

Example 7 a) 27.3 g (100 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo1.5-apyrrolo2.1cj1.4..benzodiazepin-

Y

V -9-one are stirred at 1000 for 3 hours with 88 g (350 mmol) of iodine in 200 ml of NN-dimethylformamide.

The reaction mixture is cooled, the separated product is filtered off, rinsed with ethyl acetate and, after drying, there is obtained (S)-8-chloro-11,12,13.13a-tetrahydro-l- -ioo-H-imidaoo.-aprrl[21r]1.]enoiaein9 -one of melting point 298-3000.

b) 3.99 g (10 mmol) of (S)-8-chloro-11.1213.13a-tetrahydro-l-iodo-9H-imidazoll.5-pyrl[,c14]ez diazepin-9-one are stirred at 1000 overnight with 0.88 g 9$ 1.

(10.5 mmol) of 2-methyl-3-butyn-2-ol, 25 mg of i 15 palladium(II) acetate. 100 mg of triphenylphsphine and 10 mg of copper1l) iodide in 40 ml of triethylamine and 20 ml of N.N-dimethylformamide. The mixture is then 4 44 evaporated to dryness and the residue is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there is obtained (S)-8-chloro-11.12,13,13a-tetrahydro--(3-hydroxy-3-methylbu tynyl -9H- imida z oI l,5- a 1pyrrrolo[2 21'1-c 1, 4] be nzodiazepin-9-one of melting point 234-2350.

It c) In analogy to Example 2, from (S)-8-chloro- -11,12.13,13a-tetrahydro-l-(3-hydroxy-3-ehll-uyy) -9H-imidazo[1.5-a~pyrrolo[2.1-c][1.4Jbenzodiazepin-9-one and benzyl bromide there was manufactured (S)-1-C3- -benzyloxy-3-methyl-l-butynyl)-8-chloro-11,12,13.13a-tetrahydro-9H-imidazo[1.5-apyrrolo[2.1-c][1.4]benzodiazepin-9- -one of melting point 146-1480 (from ethyl acetate and hexane).

Example 8 a) 7.47 g (20 mmol) of 7-chloro-45-dihydro-3-iodo-5- -methyl-6H-imidazo[l.5-aJ[1,4]benzodiazepin-6-one, 2.88 g mmol) of 3-methyl-1-penten-4-yn-3-ol. 110 mg of 1'

L

V -21 bis~triphenylphosphine)-palladium(II) dichloride and 35 mg of copper(I) iodide are heated to boiling under reflux for V12 hours in 60 ml of triethylamine and 30 ml of dimethylformamide. The reaction mixture is evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the residue from acetonitrile there are obtained 4.34 g of 7-chloro-4. 5-dihydro-3-(3-hydroxy-3-methyl-4-penten-- -ynyl)-5-methyl-6H-imidazo[l.5-a][1,4-]benzodiazepin-6-one of melting point 185-187-.

In an analogous manner, from 7-chloro-4.5--dihydro-3- 15-iodo-5-methyl-6H-imidazo[1.5-a][1.4]benzodiazepin-6-one 154 I411 b) with cis-3-methyl-2-penten-4-yn-l-ol there was manufactured 7-chloro-4,5--dihydro-3-[(Z)-5-hydroxy-3- -methyl-3-penten--1-ynyl]-5-methyl-6H-imidazo[l,5-a][1,4]- 20benzodiazepin-6-one of melting point 193-1940 (from methylene chloride and ethyl acetate); c) with trans-3-methyl-2-penten-4-yn-1--ol there was manufactured 7-chloro-4.5-dihydro-3-[(E)-5-hydroxy-3- -methyl-3-penten-1-ynyl-5-methyl-6H-imidazo[.5-a][,4benzodiazepin-6-one of melting point 186-1880 (from ethyl acetate and acetonitrile); d) with methyl propargyl sulphide and diethylamine in place of triethylamine there was manufactured 7-chloro- 5-dihydro-5-methyl-3-[3-(methylthio)-l-propynyl]-6H- -imidazo[l.5-a]l1.4.lbenzodiazepin-6-one of melting point 165-1660 (from ethyl acetate); e) with 3-butynyl methyl sulphide and diethylamine in place of triethylamine there was manufactured 7-chloro- -4.5--dihydro-5-methyl-3-[4- (methylthio)-1-butynyl]-6H- -imidazo~l.5-aJ[1,4]benzodiazepin-6-one of melting point 143-1450 (from ethyl acetate); 22 f) with 2-phenylethyl propargyl ether and diethylamine in place of triethylamine there was manufactured 7-chloro- -4.5-dihydro-5-methyl-3-[3-(phenethyloxy)-1-propynyl-6H- -imidazo[l.5-aj[1.4]benzodiazepin-6-one of melting point 76-780 (from ethyl acetate and hexane).

Example 9 a) 2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H- -imidazoll,5-a][l.4]benzodiazepin-6-one are stirred at 950 Sfor 1.5 hours with 8.88 g (35 mmol) of iodine in 25 ml of NN-dimethylformamide. The reaction mixture is then poured 600 V 0 into 300 ml of water, decolorized with sodium thiosulphate a 15 solution and extracted four times with methylene chloride.

00.

~The organic extracts are washed three times with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there is obtained 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H- -imidazo[l,5-a][1.4]benzodiazepin-6-one of melting point 0 i mid a zo ll, 5 1,4] be nzod ia ze pi n- 6 ne o f mel1t ing p o int 187-1880 b) In analogy to Example 8a), from 8-fluoro-4,5-dihydro- I -3-iodo-5-methyl-6H-imidazo[l1,5-a][1.4]benzodiazepin-6-one, benzyl propargyl ether and diethylamine in place of triethylamine there was manufactured 3 [3-(benzyloxy)-l- -propynylJ-4,5-dihydro-8-fluoro-5-methyl-6H-imidazol.5-a]- [1.4]benzodiazepin-6-one of melting point 90-910 (from ethyl acetate and hexane).

Example a) 19.1 g (56.8 mmol) of 7-bromo-5.6-dihydro-5-methyl-6- -oxo-4H-imidazo[1,5-a]l(1.4]benzodiazepine-3-carboxylic acid are decarboxylated at 290-300o. The melt is taken up in methylene chloride, the solution is diluted with ethyl acetate and ethanol and decolorized with animal charcoal.

;f*0 Li_ -23 After evaporation and recrystallization from ethyl acetate and ethanol there is obtained 7-bromo-4.5-dihydro-5- -methyl-6H-imidazo[1.5-a][1,4]benzodiazepin-.6-one of Smelting point 196-1970.

b) 12.80 g (44 mmol) of 7-bromo-4.5-dihydro-5--methyl-6H- -imidazo[1.5-a][1.4]benzodiazepin-6-one are stirred at 950 for 3.5 hours with 39 g (154 mmol) of iodine in 80 ml of N.N-dimethylformamide. The reaction mixture is evaporated, the residue is taken up in methylene chloride and water and decolorized by the addition of sodium thiosulphate.

The mixture is filtered. the organic phase is separated, 41 dried over magnesium sulphate and evaporated. After of the residue on silica gel while eluting fool4 with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 7-bromo-4,5- -dihydro--3-iodo-5-methyl-6Tj-imidazo benzodiazepin-6-one of melting point 203-2040.

c) In analogy to Example 8a), from 7-bromo-4.5-dihydro-3- -iodo-5-methyl-6H-imidazo[1,s.a][1.4]benzodiazepin-6-one, benzyl propargyl ether and diethylamine in place of triethylamine there was manufactured 3-[3--(benzyloxy)--- -propynyl-7-bromo4.-dihydro5methyl6H-imidazo[1,5-a]- [1.4]benzodiazepin-6-one of melting point 106-1070 (from methanol and ether).

Example 11 In analogy to Example 8a), from 4.5-dihydro-3-iodo-5- -methyl-6H-imidazo1.5-a][1,4]benzodiazepin6-one benzyl propargyl ether and diethylamine in place of triethylamine there was obtained 3-[3-(benzyloxy)-1-propynyl4.5of melting point 61-630 (from ethanol and ether).

-24 Example A Tablets of the following composition are manufactured in the usual manner: mg/tablet 7-Chloro-3-[3-(cyclopropylmethoxy)-l- S -propynylj-4.5-dihydro-5-methyl-6H-imidazo- [1.5-al~l.4]benzodiazepin-6-one 0.2 Lactose 140 Maize starch 50.8 Polyvinylpyrrolidine 8 415 Magnesium stearate 1 Tablet weight 200 VExample B Capsules of the following composition are manufactured in the usual manner: mg/cap sule 7-Chloro-3-[3-(cyclopropylmethoxy)-1- -propynyl]-4.5--dihydro-5-methyl-6H-imidazo- [L.5-aJ[1.4]benzodiazepin-6-one Lactose Maize starch 8 Talc 1 Magnesium stearate Capsule fill weight Example C Injection solutions of the following composition are manufactured: 25 7-Chloro-3- (cyclopropylmethoxy) -1- -propynyll-4. 5-dihydro-5-methyl--6H-imidazo- [1.5-al[1.4jbenzodiazepin-6-one 0.1 mg Sodium chloride 45.0 mg SESQUESTREN Na 2 0.5 mg Acetic acid p.a. 0.5 mg NaCH 1N ad pH 4.5 q.s.

Water for injection q.s ad 5.0 ml 4 0

Claims

1. Compounds of the general formula 00) 00 f o 0 *000 0000~ 000 wherein A together with the two carbon atoms denoted by a and 8 signifies one of the groups and o0 0 S4 I *r 0 R 1 signifies a partially unsaturated lower hydro- carbon group which is optionally substituted by hydroxy. oxo, aryl or the group -OR, -SR or -OCOR or a lower alkyl group which is substituted by aryl or the group -SR' or -OCOR'. R and R' each signify aryl or a saturated or partially unsaturated C 1-18-hydro- carbon group which is optionally substituted by aryl or lower alkoxy, R 2 signifies hydrogen and R 3 -ignifies lower alkyl or R 2 and R 3 together signify dimethylene or trimethylene and R 4 and R each signify hydrogen, halogen, trifluoromethyl, cyano, nitro or lower alkyl, the group -OR' having a significance different from lower alkoxy and the :AP D J -27- compounds of formula I having the or (RS)-configuration with reference to the carbon atom denoted by y when R 2 and R together signify dimethylene or trimethylene.

2. Compounds according to claim 1, wherein R and R' each signify aryl or a saturated or partially unsaturated 1 C hydrocarbon group which is optionally substituted 1-18 by aryl.

3. Compounds according to claim 1 or 2, wherein R otso signifies a lower alkenyl group which is optionally on substituted by hydroxy, oxo, aryl or the group -OR, -SR or -OCOR or a lower alkyl group which is substituted by aryl or the group -SR' or -OCOR'. 0 S4. Compounds according to claim 3, wherein R signifies a lower alkenyl group which is substituted by hydroxy or the group -OR, -SR or -OCOR or a lower alkyl group which is substituted by the group -SR' or o -OCOR'. Compounds according to any one of claims 1-4, 25 wherein R and R' each signify aryl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkyl, C -cycloalkyl 3-7 or C -cycloalkyl-lower alkyl.

6. Compounds according to any one of claims Aim 30 wherein R 2 signifies hydrogen and R 3 signifies methyl 2 3 or wherein R and R together signify dimethylene or trimethylene and the carbon atom denoted by y has thp (S)-configuration.

7. Compounds according to any one of claims 1-6, wherein A signifies a residue of formula and one of 4 5 R and R signifies hydrogen and the other signifies hydrogen or halogen. -28 4

8. Compounds according to claim 7. wherein R and 5 4. R both signify hydrogen or R signifies hydrogen and 4 R signifies fluorine or R signifies chlorine or bromine and R signifies hydrogen.

9. 7-Chloro-3-[3-(cyclopropylmethoxy)-1-propynyli- -45dhdo5mty-Hiiaz[,-]14bnoizpn -6-one. 3-(7-Chloro-5,6-dihydro-5-methyl-6--oxo-4H-imidazo- [1.5-aJ[1.4]benzodiazepin-3-yl)-2--propyny1 acetate.

11. 7-Chloro.-3-[3-(cyclopropylmethoxy)-3-methyl-- butynyl]-4.5-dihydro-5-methyl-6H-imidazo~l15-a]H1,4]benzo- diazepin-6-one. -penten-1-ynyl]-5-methyl-6H-imidazoL1.5-a][1,4]benzo- 20diazepin-6-one.

13. 7-Chloro-4.5-dihydro-3-(3-hydroxy-3-methyl-4- a -penten-1-ynyl)-5-methyl-6H-imidazo[l.5--a][.4]benzo- diazepin-6-one.

14. 7-Chloro-4,5-dihydro-3-[(E)-5-hydroxy-3-methyl-3- -penten-1-ynyll-5-methyl-6H-imidazo[1,5-a][1,4belzo- a, diazepin.-6-one. t15 Cu 1 "p rds n av rrda-ewth any one'-f-ctaims to 14 for use as therapeutically active substan

16. Compounds in accordance-with any one of claims 1 to 14 for use as th~ 9 er trically active substances which 3 >have anticonvu fl t. anxiolytic. muscle relaxant and sedatl ypnotic activity and/or which partially or u-1-e-e-eC--t-ve--y-a4a--g4Izes-e-o-r~i J 1~ctii1 Cc- r o 6 29 I 29 j -whh-r;4-=-bftzo&ia-phesh-a-v-ing tranqu Ii-nMiMy or other substances d lY-v" e central benzodiazepine A process for the manufacture of compounds in accordance with any one of claims 1 to 14, which process j comprises ii a) reacting a compound of the general formula I~ t 0 R2 II i 3 B O R 2 3 i 20 wherein A, R and R have the significance given Sin claim 1 and X signifies bromine or iodine, with the r proviso that where A signifies a residue of 4 formula and R and/or R signifies halogen, this halogen is fluorine or chlorine when X signifies bromine or is fluorine, chlorine or bromine when X signifies iodine, with a compound of the general formula HCEC-R 1 III wherein R has the significance given in claim 1; or b) etherifying or acylating a compound of formula I in which R signifies a partially unsaturated lower hydro- cc; OFFO i, 30 carbon group which is substituted by hydroxy or a compound of the general j formula CC-E-OH j2 i O R 2 3 wherein E signifies lower alkylene and R 2 R and A have the significance given in claim 1, with an agent yielding the group -OR or -OCOR or the group -OR' or -OCOR'. 16. Compounds according to any one of claims 1 to 4, whenever prepared according to the process claimed in claim 15 or by an obvious S" chemical equivalent thereof.

17. Imidazodiazepine derivatives substantially as hereinbefore 20 described with reference to any one of Examples 1 to 11. ~18. A process for producing an imidazodlazepine derivative substantially as hereinbefore described with reference to any one of Examples 1 to 11.

19. A pharmaceutical composition having anticonvulsant, anxiolytic, muscle relaxant and sedative-hypnotic activity and/or which partially or completely selectively antagonize some or all activities which 1,4-benzodiazepines having tranquillizing activity or other I substances display via the central benzodiazepine receptors, comprising a compound according to any one of claims 1 to 14, 16 or 17 together with a pharmaceutically acceptable carrier, diluent and/or excipient. A method of treating convulsions, anxiety states, stress conditions, excitation states and sleep disorders and/or of partially or completely selectively antagonizing some or all activities which 1,4-benzodlazepines having tranquillizing activity or other substances display via the central benzodiazepine receptors in a patient in need of such treatment, which method comprises administering to said patient an T CS/1523U I I d .II I 31 effective amount of a compound of set forth in any one of claims 1 to 14, 16 or 17, or a pharmaceutical composition according to claim 19. DATED this TNENTY-SEVENTH day of APRIL 1992 F Hoffmann-La Roche AG Patent Attorneys for the Applicant SPRUSON FERGUSON O o OR ORO o O s n 01 bI (Iba~ D I C~O 0* P B* a r rro o r r ,42 AU"d MS/1523u C