GB2029408A

GB2029408A - 4H-s-Triazolo[3,4-c]thieno[2,3-e] 1,4-diazepines

Info

Publication number: GB2029408A
Application number: GB7924357A
Authority: GB
Original assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Current assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Priority date: 1978-07-13
Filing date: 1979-07-12
Publication date: 1980-03-19
Also published as: AT370735B; GB2029408B; BG34451A3; SE7906093L; PL217029A1; JPS5513297A; FI792185A; LU81494A1; IL57776A; DK295179A; NO792319L; IL57776A0; NL7905483A; IT1188845B; HU177960B; FR2430949A1; BE877669A; PT69910A; FR2430949B1; PL120417B1

Abstract

Compounds of general formula (I> <IMAGE> (wherein R2 is hydrogen, fluorine, chlorine or bromine; R3 is chlorine, bromine or alkyl; and R4 and R5 independently are hydrogen, alkyl, or hydroxyalkyl, or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocyclic ring optionally substituted by one or two methyl groups and when a 6-membered ring, optionally containing an oxygen atom) exhibit neuroleptic activity and show tranquilizing, anxiolytic and/or tensiolytic properties.

Description

SPECIFICATION Substituted 4H-s-Triazolo[3,4-c]thieno-[2,3-e] 1 4-diazepines.

This invention relates to novel substituted 4H-s-triazolo[3,4-c]thieno[2,3-eji ,4-diazepines having interesting pharmacological properties.

According to one feature of the invention there are provided compounds of general formula

(wherein R2 represents a hydrogen, fluorine, chlorine or bromine atom; R3 represents a chlorine or bromine atom or an alkyl group having 1 to 3 carbon atoms; and R4 and F(5, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or hydroxyalkyl group having 2 or 3 carbon atoms, or R4 and R5 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring which is optionally substituted by one or two methyl groups, and which in the case of a 6membered ring may optionally contain an oxygen atom).

As stated above the compounds according to the invention exhibit interesting pharmacological properties. In particular our tests have indicated that the compounds show a neuroleptic activity, e.g., tranquillizing, anxiolytic and/or tensiolytic properties. Preferred compounds according to the invention, by virtue of their favourable pharmacological properties, are those in which R2 represents a chlorine atom, Ra represents a bromine atom, and R4 and Rs represent C, to Ca alkyl groups or in the case of one of R4 and RB represents a p-hydroxyethyl group.

Especially preferred compounds according to the invention, by virtue of their particularly favourable pharmacological properties, are the following: 1 -dimethyla m ino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo-[3 ,4-c]thieno [2,3-e] 1 ,4-diazepine: 1-diethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno [2,3-ej 1 ,4-diazepine; and 1 -[N-methyl-N-(ss-hydroxyethyl)-amino]-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4- c]thieno[2,3-e] 1 ,4-diazepine.

Compounds according to the invention may be prepared by any of the following processes, which processes constitute further features of the invention, a) by reacting a compound of formula

(wherein R2 and R3 are as hereinbefore defined, and Hal represents a halogen atom) with an amine of formula

(where R4 and R5 are as hereinbefore defined); b) by dehydrogenating a compound of formula

(wherein R2, R3, R4 and RB are as hereinbefore defined); and c) by reacting a compound of formula

(where R2 and R3 are as hereinbefore defined) with cyanogen bromide and, if desired, alkylating the product thereby obtained.

The reaction of compounds of general formula II with an amine of formula III according to process a) may be effected either with or without a solvent. A Solvents which may be used include, for example, benzene, toluene, dioxan, tetrahydrofuran and halogenated hydrocarbons (such as carbon tetrachloride or methylene chloride) and the reaction is preferably effected at the boiling point of the solvent used.

When the starting compound of formula III is a lower amine (e.g. dimethylamine or diethy!amine) the reaction is preferably effected in an autoclave. The reaction time depends upon the particular starting materials used, and may vary from a few minutes to several hours.

Dehydrogenation of compounds of general formula IV according to process b) is generally effected in the presence of a dehydrogenation agent such as, for example, a haiogen or a compound of the higher oxidation states of chromium or manganese (e.g. a chromate, dichromate or permanganate).

If the dehydrogenation is effected in the present of a halogen, a solvent is preferably present.

Solvents which may be used for this purpose include, for example, haiogenated hydrocarbons such as chloroform or methylene chloride. Dehydrogenation in the presence of the above-mentioned compounds of chromium or manganese is preferably effected in a solvent such as, for example, acetone, tetrahydrofuran or dioxan, and if desired in the presence of a phase transfer catalyst.

According to the particular type of dehydrogenation agent used, the reaction temperature generally lies between OOC and a boiling temperature of the solvent used.

The reaction of a 2-hydrazino-thieno[2,3e] 1 4-diazepine of formula V with cyanogen bromide according to process c) produces compounds of the formula I in which R4 and R5 are hydrogen atoms, i.e.

[c.f. K. T. Potts and C. Hirsch, J. Org. Chem. 33, 143 (1968)]. The reaction is preferably effected in the presence of a solvent such as, for example, an alcohol, benzene, toluene or a halogenated hydrocarbon.

If desired, the compounds of general formula I may be subsequently alkylated in a conventional way. Alkylating agents which may be used for this purpose include, for example, alkyl halides, dialkyl sulfates and esters of toluenesulfonic acids. The alkylation is preferably effected in a solvent such as tetrahydrofuran, dimethylformamide or a lower alcohol, the alkylation may however also be effected without the addition of a solvent. When it is desired to introduce a hydroxyalkyl group, the alkylating agent is preferably an alkylene oxide.

Examples of compounds of general formula I which may be readily prepared by the preceding processes, include the following: 8-bromo-6-(o-chlorophenyl)- 1 -amino-4H-s-triazolo[3,4-c]-thieno-[2,3-e] 1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)-l -methylamino-4H-s-triazolo[3,4-c]thieno[2,3-ej1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)-1 -ethylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)-1 -dimethyíamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -diethylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -(N-methyl-N-ethyla mino)-4H-s-triazolo[3 ,4-c]thieno[2,3-e] 1 ,4- diazepine, 8-bromo-6-(o-chlorophenyl) 1 -n-propyla mino-4H-s-triazolo[3,4-cjthienot2,3-ej 1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -diisopropylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4-diazepine, 8-bromo-6-(o-chlorophenyl)-1-di-n-butylamino-4H-s-triazolo[3,4-c]thieno[2,3-e]1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -[N-methyl-N-(,B-hydroxyethyl)-a minoj-4H-s-triazolot3,4- c]thieno[2,3-e] 1 ,4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -[di-(-hydrnxyethyl)-a mino]-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4 diazepine, 8-ethyl-6-i(o-chlornphenyl)- 1 -dimethylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 ,4-diazepine, 8-chloro-6-(o-chlorophenyl)- 1 -dimethylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4-diazepine, 8-bromo-6-phenyl- 1 -dimethylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4-diazepine, 8-bromo-6-(o-bromophenyl)-1 -dimethylamino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -(2',4'-dimethylpipeddino)-4H-s-tnazolot3,4-cjthieno[2,3-eJ 1,4 diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -morpholino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -(2'-methyimorpholino)-4H-s-triazolo[3,4-c] thieno[2,3-e]1,4- diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -piperidino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 4-diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -(4'-methylpiperidino)-4H-s-triazoio[3,4-c]thieno[2,3-e] 1,4diazepine, 8-bromo-6-(o-chlorophenyl)- 1 -pyrrolidino-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 ,4-diazepine.

The starting compounds of general formula II are known compounds and have been described in the literature. Starting compounds of general formula IV may be obtained by reacting a compound of formula

(whernin R2, R3 and Hal are as hereinbefore defined) with an amine of formula Ill, under similar conditions indicated for process a), and subsequently exchanging the oxygen atom of the ring by a nitrogen atom, as described in published German Patent Application No. P 25 31 678.

As stated above, compounds of general formula I exhibit interesting pharmacological properties.

In particular, our tests have indicated that the compounds exhibit tranquilizing, anxiolytic and tensiolytic properties. Thus, training tests have shown that the compounds possess a pronounced neuroleptic activity. This activity has been demonstrated according to the modified discriminated active avoidance test of Dobrin, PB., Rhyne, Arch. Pharmacodyn. 178,351-356(1969).

The tests which we have effected have in particular shown that the compounds of the invention only suppress the timely avoidance actions, but have no effect on the reaction to direct shock. Such a selective effect is considered with commercial therapeutics, such as, for example chlorpromazine, to be strong evidence for neuroleptic properties (see, for example, Cook, L., Sepinvall, J., Proceedings of the Sixth International Congress of Pharmacology. Vol. 3-Central Nervous System and Behavioral Pharmacology, Oxford: Pergamon 1976 b). Furthermore, we have found that this selection is especially pronounced for the compounds of the invention and that it supercedes that of commerical products.

Therefore, the compounds of the invention may be especially suitable for the reduction of psychomotor disturbances arising from irritation and/or anxiety, for example, with schizophrenia. This tranquilizing and tensiolytic effect of the compounds does not cause a disturbance of the degree of alertness.

According to a further feature of the invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I according to the invention in association with a pharmaceutical carrier or excipient.

Compositions according to the invention are conveniently in a form suitable for oral, rectal or parenteral administration, such as, for example, in the form of tablets, coated tablets, capsules, syrups, emulsions, suspensions, solutions, powders, suppositories and forms adapted to provide a sustained release of active ingredient. Such forms may be prepared using excipients and methods conventional to the pharmaceutical art.

The compositions are preferably administered in an amount sufficient to provide a daily dosage of from 5 to 1 50 mg of said active ingredient. The compositions are conveniently in dosage unit form, whereby each dosage unit for oral administration contains from 0.05 to 50 mg, and preferably from 0.1 to 25 mg, of said active ingredient.

If desired, the compositions according to the invention may also contain one or more further pharmacologically active ingredients such as, for example, spasmolytics and ,B-receptor blockers.

Tablets may, for example, be obtained by admixing the active ingredient(s) with known excipients, for example, inert diluants, such as calcium carbonate, calcium phosphate or lactose; disintegrants such as corn starch or alginic acid; binders such as starch or gelatin; lubricants such as magnesium stearate or talc; and/or agents for obtaining a sustained release of active ingredient(s), such as carboxypoiymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.

Coated tablets may be produced by coating tablet cores produced analogously to tablets described above, with agents conventionally used in for tablet coatings, for example, polyvinyl pyrrolidone, shellac, gum arabic, talc, titanium dioxide and sugar. In order to obtain sustained release or to avoid incompatibilities, the core may also consist of several layers. In order to obtain sustained release the tablet coating may additionally consist of several layers, whereby the excipients mentioned above for tablets may be used.

Syrups containing the active ingredient(s) according to the invention may additionally contain a sweetner such as saccharin, cyclamate, glycerin or sugar as well as an agent improving the taste, for example, flavourings such as vanillin or orange extract. They may also contain suspension auxiliaries or thickeners, such as sodium carboxymethyl cellulose; wetting agents, for example condensation products of fatty alcohols with ethylene oxide; or preservatives, such as p-hydroxybenzoates.

Injection solutions may be produced in a conventional manner, for example, with the addition of preservatives such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediamine tetraacetic acid, and thereafter filled into injection vials or ampoules.

Capsules containing the active ingredient(s) may be produced, for example, by admixing the active ingredient(s) with inert carriers, such as lactose or sorbitol and thereafter filled into gelatin capsules.

Suppositories may be produced, for example, by admixing the active ingredient(s) with carriers, such as neutral fats or polyethylene glycol andior derivatives thereof.

The following Examples serve to illustrate the preparation of compounds according to the invention and pharamaceutical compositions containing them: Example 1 1 -Dimethylamino-8-bromo-6-(o-chlorophenyl )-4H-s-triazolo [3,4-c]thieno [2,3-e]l .4-d iazepine 4.5 g (0.01 mol) of 1,8-dibromo- 6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno[2,3-e]1,4- diazepine are heated in an autoclave with 50 ml of dimethylamine in 1 50 ml of dioxan for 1 hour at 100 C. The solvent is then distillled off, and the residue is partitioned between water and methylene chloride. The methylene chloride phase is separated off, washed with water and dried over magnesium sulfate.The solution is passed through a SiO2 column and the desired substance is eluted with methylene chloride/methanol 98:2. After distilling off solvent, the title compound is obtained from ethyl acetate. Yield 2.2 g (52% of theory), m.p. 166-1 680C.

Example 2 1 -Dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo [3,4-c]thieno [2,3-e] 1 4-diazepine 4.2 (0.01 mol) of 1-dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno[2,3- e]5,6-dihydro-1 4-diazepine are dissolved in 50 ml of methylene chloride and after addition of 0.2 g of triethyl-N-benzylammonium chloride at a temperature of from 0 to 50C, the solution is admixed with a solution of 2 g of potassium permaganate in 20 ml of acetone. After 1 5 minutes, sodium bisulfite solution is added and the reaction mixture is acidified with dilute sulfuric acid. The title compound is obtained from the organic phase. Yield 3.1 g (73% of theory), m.p. 165-1 670C.

The 5,6-dihydro starting compound used in this Example was obtained as follows: a) 20 g (53 mmol) 7-bromo-(o-chlorophenyl)-thienot2,3-eJ4,1-oxazepine-2-thione (prepared analogously to the description of Belgian Patent Specification No. 844 1 70) are stirred in 600 ml of methylene chloride with 12 g of formula hydrazide and 80 ml of pyridine for 45 minutes at room temperature. 10 g of POCK, in 50 ml methylene chloride are then added dropwise at a maximum temperature of 350C and the reaction mixture is stirred under reflux for 5 hours. After cooling, the organic phase is shaken with 200 ml of 2 N hydrochloric acid and washed with water. After drying, the organic phase is evaporated and the residue is taken up in hot ethyl acetate.After cooling, 1 5 g (73% of theory) of 8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno [2,3-e]4, 1 -oxazepine are yielded, m.p. 176-1780C.

b) 28 g of the compound from a) above are admixed with 5.4 ml of bromide in 280 ml of methylene chloride and 8.9 ml of pyridine. The reaction mixture is refluxed for 3 hours. After cooling, it is shaken with water, and the organic phase is dried with magnesium sulfate. The solution is then evaporated and the residue is passed through SiO2. 19.2 g (57% of theory) of 1 ,8-dibromo-6-(o- chlorophenyl)-4H-s-triazolo[3,4-c]thieno[2,3-e]4,1 -oxazepine of m.p. 1 380C, are obtained.

c) 9.2 g (0.02 mol) of the dibromo compound from b) above are heated in an autoclave with 300 ml of dioxan and 100 ml of dimethylamine for 1 hour at 100 C. After distilling off the solvent, the residue is dissolved in methylene chloride, washed with water, and the organic phase dried over magnesium sulfate. A residue is obtained of 1-dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s triazolo[3,4-c]thieno[2,3-ej4,1-oxazepine as an oil (7.0 g, 82% of theory).

d) 8.5 g (0.02 mol) of the oxazepine obtained in c) above are stirred with 50 ml of conc.

hydrobromic acid for 1 hour at room temperature. The reaction mixture is diluted with 200 ml of water, made alkaline with ammonia and shaken with 100 ml of methylene chloride. The methylene chloride solution is separated and then stirred with 4 ml of thionyl chloride for 1 hour. Excess thionyl chloride decomposed carefully with water and dilute ammonia, and the organic phase is separated. After evaporation and addition of ether, 4.8 g (92% of theory) of 3-dimethylamino-4-[3-(o-chlorophenyl- bromomethyl)-5-bromo-thienyl-(2)]-5-chloromethyl-1 ,2-4-triazole of m.p. 203 0C are obtained.

e) 5.3 g (0.01 mol) of the triazole from d) are heated in an autoclave with 100 ml of methanol saturated with ammonia at 600C for 30 minutes. The reaction mixture is evaporated and worked up.

A yield of 2.8 g (66% of theory) of 1 -dimethylamino-8-bromo-6- (o-chlorophenyl)-4H-s-triazol[3,4- c]thieno[2,3-e]5,6-dihydro-1 ,4-diazepine of m.p. 1 55--1 57 OC, is obtained.

Example 3 1 -Amino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno[2,3-e] 1,4-diazepine 5 g (0.013 mol) of 2-hydrazino-5-(o-chlorophenyl)-7-bromo-thieno[2,3-e] 1,4-diazepine are heated with 100 ml of ethanol, 1.4 g of cyanogen bromide and 1.4 g of sodium carbonate for 30 minutes at 600C. The reaction mixture is evaporated, and the residue is dissolved in methylene chloride and chromatographed over SiO2. The title compound is obtained in a yield of 1.5 g (29% of theory), m.p. 251-2520C (from ethanol).

Example 4 1 -Dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thienot2,3-ej1 1,4-diazepine 395 mg 1-amino-8-bromo-6- (o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno[2,3-e] 1 ,4-diazepine are refluxed with 5 mml of 85% formic acid and 2 mml of 30% formalin solution for 1 5 hours. After cooling, the reaction mixture is shaken with methylene chloride. The organic phase is evaporated and the residue chromatographed over a silica gel column. From the eluates obtained, 250 mg of the title compound of m.p. 164-1 660C (60% of theory), is obtained.

Analogously to Examples 1 two 4, the following final products were obtained:

R4 R R m.p. 0C Example Y 2 3 No. 5 5 -KN-CH, C1 Br 166 - 168 6 -HN-C2H5 C1 Br 224 - 226 7 -N(C2H5)2 C1 Br 143 - 145 8 -2O Cl Br 224 - 226 9 -N 0 C1 Br 205 - 207 V, CH3 10 -N C1 Br 175 - 176 N CH2-CH2-OH 11 -CH3 C1 Br 180 12 -Na C1 Br 209 - 210 13 -N(CH3)2 C1 C2H5 130 - 132 14 -N(CH3)2 C1 C1 154 - 155 15 -N(CH3)z H Br 216 - 217 16 -N(CH3)2 Br Br 171 17 -NH-(CH2)2-CH3 C1 Br 148 - 150 Example A Coated Tablets 1 tablet core contains: Active ingredient according to the invention 1.0 mg lactose 28.5 mg corn starch 19.0 mg gelatin 1.0 mg magnesium stearate 0.5 mg 50.0 mg A mixture of the active ingredient with lactose and corn starch is granulated with a 10% aqueous gelatin solution through a screen of 1 mm mesh-size, dried at 4O0C and triturated once more through the screen.The granulate thus obtained is admixed with magnesium stearate and pressed. The cores thus obtained are covered with a coating in the usual way, the coat being applied as an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax.

Final weight of coated tablet: 100 mg.

Example B Tablets Active ingredient according to the invention 0.5 mg lactose 50.0 mg corn starch 43.5 mg soluble starch 5.0 mg magnesium stearate 1.0 mg 100.0 mg The active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granulate is dried and admixed thoroughly with lactose and corn starch. The mixture is pressed into tablets of 100 mg weight, each tablet containing 0.5 mg of active ingredient.

Example C Suppositories 1 suppository contains: Active ingredient according to the invention 5.0 mg suppository mass 1695.0 mg The final pulverised active ingredient is stirred with an immersion homogenizer into the molten suppository mass cooled to 40"C. At 350C the mass is poured into slightly precooled moulds.

Example D Ampoules (Injection Solution) Composition: parts by weight Active ingredient according to invention 0.5 sodium pyrosulfite 1.0 disodium salt of ethylenediamine tetraacetic acid 0.5 sodium chloride 8.5 double distilled water 1000.0 The active ingredient and excipients are dissolved in a sufficient quantity of water and brought to the desired concentration with the required quantity of water. The solution is filtered and filled into 1 ml ampoules under aseptic conditions. Finaily the ampoules are sterilized and sealed. Each ampoule contains 0.5 mg of active ingredient.

Claims

1. Compounds of general formula

(wherein R2 represents a hydrogen, fluorine, chlorine or bromine atom: R3 represents a chlorine or bromine atom or an alkyl group having 1 to 3 carbon atoms; and R4 and R5, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a hydroxyalkyl group having 2 or 3 carbon atoms, or R4 and R5 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring which is optionally substituted by one or two methyl groups and which in the case of a 6membered ring may optionally contain an oxygen atom).

2. Compounds as claimed in claim 1 wherein R2 represents a chlorine atom; R3 represents a bromine atom; and R4 and R5 represent alkyl groups having 1 to 3 carbon atoms or one of R4 and R5 represents a hydroxyethyl group and the remaining R4 and R5 radical is an alkyl group having 1 to 3 carbon atoms.

3. 1 -Dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-striazolo[3,4-c]thieno[2,3-ej 1 ,4-diazepine.

4. 1 -Diethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4-c]thieno[2,3-ej 1 ,4-diazepine.

5. 1 -[N-methyl-N-(-hydrnxyethyl)-aminot-8-brnmo-6- (o-chlorophenyl)-4H-s-triazoio [3,4- c]thieno[2,3-e] 1 ,4-diazepine.

6. Compounds of general formula I as defined in claim 1 as herein specifically disclosed with the exception of the compounds claimed in any one of claims 3 to 5.

7. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula

(wherein R2 and Ra are as defined in claim 1 and Hal represents a halogen atom) with an amine of formula

(wherein R4 and R6 are as defined in claim 1).

8. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises dehydrogenating a compound of formula

(wherein R2, R3, R4 and R are as hereinbefore defined).

9. A process for the preparation of compounds of general formula I as defined in claim 1, which comprises reacting a compound of formula

(wherein R2 and R3 are as defined in claim 1) with cyanogen bromide and, if desired, alkylating the product thereby obtained.

10. A process for the preparation of compounds of general formula I as defined in claim 1 substantially as herein described in any one of Examples 1 to 1 7.

11. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in any of claims 7 to 10.

1 2. Pharmaceutical compositions comprising an active ingredient at least one compound of formula I as defined in claim 1 in association with a pharmaceutical carrier or excipient.

13. Compositions as claimed in claim 12 in the form of dosage units for oral administration wherein each dosage unit contains from 0.05 to 50 mg of said active ingredient.

14. Compositions as claimed in claim 11 substantially as herein described in any one of Examples Ato D.