IE51200B1

IE51200B1 - Substituted tricyclic thieno compounds,process for their preparation and medicaments containing them

Info

Publication number: IE51200B1
Application number: IE997/81A
Authority: IE
Original assignee: Byk Gulden Lomberg Chem Fab
Priority date: 1980-05-07
Filing date: 1981-05-06
Publication date: 1986-10-29
Also published as: IL62792A0; EP0039519B1; NO156753C; PT72982B; HU182712B; NO156753B; DK157872B; KR830006300A; WO1981003173A1; JPS57500695A; PL139428B1; PT72982A; HK6890A; IL62792A; IE810997L; YU116181A; KR850000241B1; FI814028L; DK1582A; DK157872C

Abstract

The new compounds, defined as thieno-benzodiazepinones, are represented by the general formula I, (FORMULA) wherein R<s1>s represents a hydrogen atom or an alkyl residue from C<u1>u to C<u4>u, R<s2>s represents a halogen atom or has the same representation as R<s1>s, and R<s3>s represents a halogen atom or a group-N (R<s4>s)R<s5>s, wherein R<s4>s represents an alkyl residue from C<u1>u to C<u4>u or an alkenyl residue from C<u3>u to C<u5>u and wherein R<s5>s has one of the representations of R<s4>s or represents a group having the partial formula -(CH<u2>u)<um>u-N (R<s6>s)R<s7>s, or wherein R<s4>s and R<s5>s in common, including the nitrogen atom to which they are bound, represent a morpholino, pyrrolidino, piperidino group, a hexa-hydro-azepin-1-yl group, a piperazine-1-yl group optionally substituted in position 4 by methyl or ethyl or benzyl, a 2, 4-dimethyl-piperazine-1-yl group or an hexa-hydro-1H-1, 4-diazepin-1-yl group substituted in position 4 by methyl or ethyl, the symbol R<s6>s representing an alkyl group in C<u1>u to C<u4>u and R<s7>s representing an alkyl group in C<u1>u to C<u4>u, the symbol A of the formula I represents an alkylen group with a straight or branched chain C<u1>u to C<u5>u and the symbol m hereabove is 2 or 3; their addition salts may also be formed. All these compounds exhibit a pharmacologic activity for the protection of the stomach and intestine organs and are therefore appropriate for the treatment of diseases affecting the stomach or intestine organs; these compounds may also be used as intermediary products. There are also disclosed methods for the preparation of said new compounds which exhibit an interesting pharmacological activity and also form intermediary products.

Description

The invention relates to substituted tricyclic thieno compounds, a process for their preparation, their use and medicaments containing them.

The compounds according to the invention are used 5 in the pharmaceutical industry as intermediate products and for the preparation of medicaments.

Ulcus and secretion inhibiting actions are ascribed to certain dibenzodiazepinones in German unexamined Patent Specification DE-OS 1,795,176. Substituted benzodiazepi10 nones with an antidepressant and analgesic action are known from U.S. Patent Specification US-PS 3,953,430. Substituted thienobenzodiazepines with an analgesic action are described in US-PS 4,168,269. Thienobenzodiazepinones which have new interesting pharmacological actions have now been conceived.

The invention relates to substituted thienobenzodiazepinones of the general formula I wherein R1 denotes a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R represents a halogen atom or has one of the meanings of R1, 4 5 R denotes a halogen atom or the group -N(R )R , R denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 to 5 carbon atoms, 4 R has one of the meanings of R or represents the group -(CH2)m-N(R6)R7, or 4 5 R and R together, and with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, a piperazin-1 -yl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazin-1-yl group, or a hexahydro1H-1,4-diazepin-1-yl group which is substituted in the 4-position by a methyl or ethyl group, R® denotes an alkyl group with 1 to 4 carbon atoms, R7 denotes an alkyl group with 1 to 4 carbon atoms, A denotes a straight-chain or branched alkylene group with 1 to 5 carbon atoms, m denotes 2 or 3, and their acid addition salts.

Alkyl radicals with 1 to 4 carbon atoms are the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyi, sec.-butyl and tert.-butyl radical. Of the alkyl radicals, the methyl radical and ethyl radical are preferred in the case of R1, R2, R4, R5, R® and R7.

The methyl radical is particularly preferred as the 2 alkyl radical in the case of R and R .

The allyl radical and the 2-methallyl radical may be mentioned as alkenyl radicals with 3 to 5 carbon atoms.

Halogen atoms R are the bromine atom and, in particular, the chlorine atom. Halogen atoms R^ (Hal) are the iodine atom, the bromine atom and, in particular, the chlorine atom.

Alkylene groups with 1 to 5 carbon atoms are the trimethylene, tetramethylene, pentamethylene, propylene and ethylmethylene group, preferably the ethylene group and in particular the methylene group.

Suitable salts include any acid addition salt. The 10 pharmacologically acceptable salts of the inorganic and organic acicfe customarily used galenically may be mentioned in particular. Pharmacologically unacceptable salts are converted into pharmacologically acceptable salts by processes which are known to the expert. Examples of such pharmacologically acceptable salts which may be mentioned are water-soluble or water-insoluble acid addition salts, such as the hydrobromide, hydriodide, nitrate, acetate, benzoate, hibenzate [2-(4-hydroxy-benzoyl)-benzoate], fendizoate (2-((2’-hydroxy-4-biphenylyl)-carbonylJ-benzoate), propionate, butyrate, sulphosalicylate, laurate, oxalate, amsonate (4,4'-diaminostilbene-2,2'-disulphonate), embonate (4,41-methylene-bis-(3-hydroxy-2-naphthoate)], metembonate [4,4'-methylene-bis-(3-methoxy-2-naphthoate,], stearate, 2-hydroxy-3-naphthoate and 3-hydroxy-2-naphthoate, and in particular the hydrochloride, phosphate, sulphate, citrate, gluconate, maleate, malate, fumarate, succinate, tartrate, tosylate (p-toluenesulphonate,, mesylate (methanesulphonate) and amidosulphonate.

Substituted thienobenzodiazepinones of the general formula I* wherein i * R denotes a hydrogen atom or a methyl or ethyl radical, 2* R represents a chlorine atom or has one of 1 * the meanings of R , 3* R denotes a chlorine atom, A* denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms, form an embodiment of the invention.

Preferred representatives of embodiment I* are 1 * those in which R denotes a hydrogen atom or a methyl 2* radical, R denotes a hydrogen atom or a methyl radical and A* denotes a methylene group.

Particularly preferred representatives of embodi1 * 2* ment I* are those in which R and R denotes a hydrogen atom and A* denotes a methylene group.

Substituted thienobenzodiazepinones of the general formula I** wherein ** R denotes a hydrogen atom or a methyl or ethyl radical, 2** R represents a chlorine atom or has one of 1 ** the meanings of R , 3** 4** 5** R denotes the group -N(R )R , ★★ R denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 or 4 carbon atoms, ** 4** R has the meaning of R or represents the ct* 7** group -(CH2)m**-N(R )R , or 4** ς** R and R together, with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, a pipera zin-1-yl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazin-1-yl group or a hexahydro 1H-1,4-diazepin-1-yl group which is substituted in the 4-position by a methyl or ethyl group, and s** R denotes a methyl or ethyl group, 7** R denotes a methyl or ethyl group, m** denotes 2 or 3 and A** denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms, and their acid addition salts form a further embodiment of the invention.

A group of representatives of embodiment I** are 1 ** those in which R denotes a hydrogen atom or a methyl or ethyl radical, R represents a chlorine atom or has 1** 4** one of the meanings of R ; R denotes a methyl or 5** - 4** ethyl radical and R has the meaning of R or repre£ * * A it Α ζ sfc ★ sents the group -(CH2)m**-N(R° )r' , or r* and R together, with the inclusion of the nitrogen atom, denote a pyrrolidino, piperidino or hexahydroazepin-1-yl radical, R6** and R7** denote a methyl or ethyl radical, m** denotes 2 and A** denotes a methylene group, and their pharmacologically acceptable acid addition salts.

Another group of representatives of embodiment I** ** are those in which R denotes a hydrogen atom or a 2** methyl or ethyl radical, R represents a chlorine atom or has one of the meanings of R1**, R4** and R5** together, with the inclusion of the nitrogen atom, denote a piperazin-l-yl which is substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethylpiperazin-1-yl group or a hexahydro-1H-1,4-diazepin-1-yl group which is substi25 tuted in the 4-position by a methyl or ethyl group and A** denotes a methylene group, and their pharmacologically acceptable acid addition salts.

Preferred representatives of embodiment I** are those in which R denotes a hydrogen atom or a methyl 2 * * radical, R denotes a hydrogen atom or a methyl radi4** ς** cal, R and R together, with inclusion of the nitro5 gen atom, denote a piperazin-1-yl group which is substituted in the 4-position by a methyl group and A** denotes a methylene group, and their pharmacologically acceptable acid addition salts.

Examples which may be mentioned of representatives of the compounds according to the invention are: 9,io-dihydro-4- [ 2- (di-n-propylamino )-propionyl]-4Hthieno [3,4-b ] [ 1,5 ]benzodiazepin-10-one, 4-[4- (di-nbutylamino)-butyryl]-9,10-dihydro-4H-thieno[3,4-b][1,5 3benzodiazepin-10-one, 4-[2-(diethylamino)-propionyl315 g,10-dibydr o-4H-thieno[3»4-b] [l, 5]benzodiazepin-10-one, 4—[5—(diisopropylamino)-valeryi]-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepia-10-one, 4-[diisobutylam±noacetyl]-9,10-dihydro-3-nietliyl-4H-thieno[3,4-b] [l,5]benzo diazepin-10-one, 4-[N-n-butyl-tert.-butylaminoacetyl}20 9,10-dihydro-3-methyl-4H-thieno[3,4—bj[l,5]benzodiazepin -one, 4-[4-(diallylamino)-butyryl]-9,10-dihydro-l,3dimethyl-4H-thieno[3.4-b3 [ 1,5]benzodiazepin-10-one, 4-[di-sec.-butylaminoaoetyl]-9,10-dihydro-4H-thieno[3.4-b][1,53benzodiazepin-10-one, 4-[2-(N-ethyl-a-butyl25 amino)-propionyl3-9,10-dihydro-4H-thieno[3»4-b][1,53benzodiazepin-10-one, 9,10-dihydro-3-wethyl-4-[N-methy1sec —butylaminoacetyl]-4H-thieno[3,4-b][l,5]benzodia51200 zepin-10-one, 9,10-dihydro-4-[5-(N-methyl-tert.-butylamino )-valeryl]-4H-thieno[3,4-b][l,5]benzodiazepin-10one, 9,10-dihydro-4-[2-piperidinoprcpionyl]-4Hthieno[3,4-b][l,5]benzodiazepin-10-one, 4-[4-(hexa5 hydroazepin-l-yl)-butyryl]-9 »10-dihydro-4H-thieno[3,4-b][1,5 ]benzodiazspin-10-one, 4-[3-(di-n-butylamino)propionyl]-9,10-dihydro-4H-thieno[3,4-b][l,5 ]benzodiazepin-10-one, 4-[3-(dlallylamino)-propionyl]-9,10dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 4-[3-(di-sec.-butylamino)-propionyl]-9,10-dihydro-4Hthieno[3,4-b][1,5]benzodiazepin-10-one, 4-[3-(N-n-butyltert. -buty lamino )-propionyl ]-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 4-[3-(N-ethyl-nbutylamino)-propionyl]-9,10-dihydro-4B-thieno[3,4-b][l,5l 15 benzodiazepin-10-one, 9,10-dihydro-4-[3-(N-methyl-sec.butylamino)-propionyl]-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 9,10-dihydro-4-[3-piperidinopropionyl]-4Hthieno[3,4-b][1,5]benzodiazepin-10-one and 4-[3-(hexahydroazepin-1-yl)-propionyl]-9,10-dihydro-4H-thieno20 [3,4-b][1,5]benzodiazepin-10-one and preferably 9,10dihydro-4-[(4-methylpiperazin-1-yl)-acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 9,10-dihydro-3-methyl4-[(4-methylpiperazin-1-yl)-acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 9,10-dihydro-1,3-dimethyl-4-[(425 methylpiperazin-1-yl)-acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one and their pharmacologically acceptable acid addition salts.

The substituted thieno-benzodiazepinones of the general formula I and their acid addition salts and embodiments I* and I** have valuable properties which render them commercially useful· The substituted thieno-benzodiazepinones of the general formula I in which R? denotes the group -N(R^)R^ and R4 and R^ have the above-mentioned meanings, and those of embodiment I** are characterised by an excellent protective action on the stomach and intestines of warm-blooded animals, for example they Inhibit the development of gastric ulcers. Furthermore, as a result of their low toxicity and the absence of substantial side effects, they have an advantageous therapeutic range. The substituted thienobenzodiazepinones of the general formula I in which R? denotes a halogen atom (Hal) and Hal has the above-mentioned meaning, and those of embodiment I* are valuable intermediate products in the preparation of the pharmacologically active and therapeutically useful compounds according to the invention.

The excellent activity of the pharmacologically active substituted thieno-benzodiazepinones and their pharmacologically, that is to say biologically, acceptable acid addition salts enables them to be employed in human medicine and also in veterinary medicine, where 25 they are used for the treatment and prophylaxis of illnesses based on disorders in the stomach or intestine.

For example, acute and chronic ulcus ventriculi and ulcus duodeni, gastritis or hyperacid gastric irritation in humans or animals are treated.

The compounds according to the invention thus are used in the treatment of mammals suffering from one of the abovementioned illnesses. In that treatment a therapeutically effective and pharmacologically acceptable amount of one or more compounds of the general formulae I or I**, preferred representatives thereof and/or salts thereof is administered to the sick mammal.

The invention also relates to the compounds according to the invention for use in combating the above-mentioned illnesses. The Invention furthermore comprises the use of compounds according to the invention in the preparation of medicaments which are employed for combating the illnesses mentioned.

The invention also relates to medicaments which contain one or more thieno—benzodiazepinones of the general formula la wherein R1 denotes a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, represents a halogen atom or has one of the 5 meanings of r\ R^a denotes the group -N(R^)R^ R^ denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 to 5 carbon atoms, 10 r5 οηθ of the meanings of R^ or represents the group -(CH2)m-N(R^)R7 or and R^ together, and with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydrcazepin-l-yl group, a piperazin-l-yl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethylpiperazte-1-yl group, or a hexahydro-1H-1,4-diazepin-1-yl group which is 2θ substituted in the 4-position by a methyl or ethyl group, R® denotes an alkyl group with 1 to 4 carbon atoms, R7 denotes an alkyl group with 1 to 4 carbon atoms, A denotes a straight-chain or branched alkylene 25 group with 1 to 5 carbon atoms and m denotes 2 or 3, and/or their pharmacologically acceptable acid addition salts Embodiments of the medicaments are those which contain thieno-benzodiazepinones of the formula I** or their preferred representatives and/or their pharmacologically acceptable acid addition salts.

The medicaments are prepared by processes which are known per se. As medicaments, the compounds according to the invention are employed either on their own or, preferably, in combination with suitable pharmaceutical excipients. If the new pharmaceutical formulations contain pharmaceutical excipients in addition to the compounds according to the invention, the content of active compound in these mixtures is 0.5 to 95, preferably 15 to 75, per cent by weight of the total mixture.

The medicaments are formulated, for example, for oral, rectal or parenteral (intravenous, intramuscular, subcutaneous) administration in suitable doses, e.g. in the form of a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, of a granular material, of a solution, of an emulsion or of a suspension.

In general, the daily dose of active compound or compounds, when given orally, is between 0.01 and 5, preferably 0.05 and 2.5 and in particular 0.1 and 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 3, individual administrations, in order to achieve the desired results.

The pharmaceutical formulations preferably consist of the active compounds according to the invention and non-toxic, pharmaceutically acceptable medicinal excipients, which are used as an admixture or diluent in solid, semi-solid or liquid form, or as a means of encasing, for example in the form of a capsule, a tablet coating, a sachet or some other container for the therapeutically active ingredient. An excipient can, for example, serve as a promoter of the resorption of 10 the medicament by the body, as a formulating auxiliary, as a sweetener, as a flavour correctant, as a colourant or as a preservative.

If the substituted thienobenzodiazepinones according to the invention and/or their pharmacologically acceptable acid addition salts are to be employed for treatment of the illnesses mentioned, the pharmaceutical formulations can also contain one or more pharmacologically active ingredients from other groups of medicaments, such as antacids, for example aluminium hydroxide and 20 magnesium aluminate; secretion inhibitors, such as Hg-blockers, for example cimetidine; gastric and intestinal therapeutics, for example metoolopramide, bromopride and tiapride; tranquillisers, such as benzodiazepines, for example diazepam; spasmolytic agents, for 25 example bietamiverine and camylofin; anticholinergic agents, for example oxyphenoyclimine and phencarbamide; glucocorticoids, such as prednisolone, fluocortolone and betamethasone; non-steroidal antiphlogistic agents, such as arylacetic acids and arylpropionic acids and hetero-arylacetic acids and hetero-arylpropionic acids, benzothiazinecarboxamide dioxides, pyrazolidinediones and quinazolinones, for example ibuprofen, naproxen, diclofenac, fenbufen, indomethacin, lonazolac, sudoxicam, piroxicam, phenylbutazone, calcium bumadizon and proquazone; and local anaesthetics, for example tetracaine and procaine; and optionally also, for example, enzymes, vitamins and aminoacids.

The invention furthermore relates to a process for the preparation of the substituted thienobenzodiaze15 pinones of the general formula R‘ ,2 CO-A -R3 wherein denotes a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R represents a halogen atom or has one of the meanings of R1, 5121)0 4 5 R denotes a halogen atom or the group -N(R )R and R denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 to 5 carbon atoms and has one of the meanings of R^ or represents the group -(CHg^-NiR^R? or λ 5 R and R together, and with the inclusion.of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-l-yl group, a piperazin-l-yl group which is optionally substituted in the 4-position by a methyl or ethyl group or by a benzyl group, a 2,4-dimethyl15 piperazin-l-yl group, or a hexahydro-lH-1,4diazepin-l-yl group which is substituted in the 4-position by a methyl or ethyl group, and R^ denotes an alkyl group with 1 to 4 carbon atoms, denotes an alkyl group with 1 to 4 carbon atoms, A denotes a straight-chain or branched alkylene group with 1 to 5 carbon atoms and m denotes 2 or 3, 2^nd their acid addition salts. 51800 The process ccnprises acylating and, if appropriate, then aminating thienobenzodiazepinones of the general iormula II wherein 2 R and R have the abovementioned meaning, and/or converting resulting bases into the acid addition salts, or converting resulting acid addition salts into the free base or into pharmacologically acceptable acid addition salts. io The acylation and the subsequent optional amination are carried out by methods which are known per se.

To prepare the thienobenzodiazepinones of the general formula I in which R8 denotes Hal, the starting 1 2 compounds of ~fche formula II wherein R and R have the abovementioned meanings, or their acid addition salts, are reacted with compounds of the general formulae III: Hal-A-CO-Hal’ (III) or IV: [Hal-A-C0]20 (IV), wherein Hal and Hal' denote a halogen atom and A denotes an alkylene group with 1 to 5 carbon atoms. This acylation is carried out without a solvent or, preferably, in an inert solvent at room temperature or elevated temperature, the maximum temperature being the boiling point of the sol.51200 vent, optionally in the presence of an auxiliary base and/or an acylation catalyst. -The acid halides III are preferable to the acid anhydrides IV. Chloroacetyl chloride is the preferred acid halide III and chloroacetic anhydride is the preferred acid anhydride IV. Examples of solvents which may he mentioned are aromatic hydrocarbons, such as toluene, xylene or chlorobenzene; open-chain or cyclic ethers, such as diisopropyl ether or dioxane; chlorinated hydrocarbons, suoh as dichloro10 ethane, and other solvents, such as pyridine, acetonitrile or dimethylformamide. Auxiliary bases which may be mentioned are, for example, tertiary organic bases, such as triethylamine and ethyl diisopropylamine, or pyridine; or inorganic bases, such as anhydrous alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or bicarbonates or alkaline earth metal .oxides. Examples of possible acylation catalysts are imidazole, pyridine or 4-dimethylaminopyridine.

The process for the preparation of the inter!0 mediate products of the general formula I thus comprises acylating a thienoben2odiazepinone of the general formula II with compounds of the general formulae III or IV. Appropriate starting substances are employed for the preparation of the intermediate 5 products of the general formula I*.

To prepare the substituted thienobenzodiazepinones 1 2 of the general formula I in which R , R and A have the abovementioned meaning and R denotes a group -N(R )R-S the resulting reaction product of the formula I wherein R^ denotes Hal is reacted with secondary amines of the general formula V: HN(RZ*')R^ (V), wherein , and Hal have the above meaning.

The amination is carried out in an inert solvent at temperatures between 0° and the boiling point of the solvent, either with at least 2 mols of secondary amine V or with 1 to 2 mols of secondary amine V and an auxiliary base. Examples of possible solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform or dichloroethane; open-chain or cyclic ethers, such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols, such as ethanol or isopropanol; ketones, such as acetone; acetonitrile or dimethylformamide. Exanples of auxiliary bases which may be mentioned are tertiary organic bases, such as triethylamine, N-methylpiperidine, diethylaniline or pyridine, or inorganic bases, such as alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or bicarbonates or alkaline earth metal hydroxides or oxides. If appropriate, the reaction can be accelerated by adding alkali metal iodides. The reaction times are between 15 minutes and 80 hours, depending on the amount and nature of the amine V employed. Vihen starting compounds in which . A represents an alkylene group with 2 to 5 carbon atoms, are reacted, the reaction can also proceed with H-Hal being split off; the intermediately formed alkenyl compound, which can optionally be isolated, reacts with the secondary amine V to give the same end product.

To prepare the substituted thienobenzodiazepinones 1 2 of the general formula I in which R , R and A have the 10 above-mentioned meaning and R^ denotes a group -N-'CR4)R^, thienobenzodiazepinones of the general formula II are acylated alternatively with compounds of the general formula IX Z - CO - A - N(R4)R5 (IX), wherein A, R and R have the above-mentioned meaning and Z denotes a leaving group, and, if desired, the products are then converted into 20 the acid addition salts.

The reaction of compounds II with the acid derivatives IX is carried out in a manner which is known per se. The leaving group Z is a group which, together with the carbonyl group to which it is bonded, forms a reactive carboxylic acid derivative. Examples of reactive carboxylic acid derivatives which may be mentioned are acid halides, esters and anhydrides and mixed acid anhydrides, such as are formed from salts of the corresponding acid (Z = OH) and acid chlorides, such as phosphorus oxychloride, or chloroformates. The reaction is preferably carried out with the mixed an5 hydrides of XX and strong mineral acids, in particular chlorophosphoric acid. Where relevant, the reaction is carried out in the presence of an acid-binding agent (proton acceptor). Examples of suitable proton acceptors which may be mentioned are alkali metal carbonates or bicarbonates, such as sodium carbonate or potassium bicarbonate; tertiary organic amines, such as pyridine, triethylamine or ethyldiisopropylaraine; or sodium hydride. The reaction is carried out at temperatures between -25° and 50°, in an inert solvent, preferably in dimethylforma15 mide.

To prepare the substituted thienobenzodiazepinones of 1 2 the general formula I, wherein R , R and A have the above3 4 5 mentioned meaning and R denotes a group -N(R )R in which 4 5 R and-R , including the nitrogen atom to which they are bonded, denote a piperazin-1-yl group which is substituted in the 4-position by a methyl or ethyl group, or a hexahydro- 1H-1,4-diazepin-1-yl group which is substituted in the 4-position by a methyl or ethyl group, obtained piperazinylthienobenzodiazepinones of the general formula X 512 0 0 2 wherein R , R and A have the above-mentioned meaning and n denotes 2 or 3, are alternatively methylated or ethylated.

The methylation or ethylation are carried out in a 5 manner which is known per se. Examples of methylation or ethylation agents which may be mentioned are: methyl and ethyl esters of strong acids, such as sulphuric acid, phosphoric acid or p-toluenesulphonic acid, or methyl or ethyl halides, which are reacted in a hydrous or a nonhydrous medium at temperatures between 0°C and 50°C optionally in the presence of an acid-binding agent (proton acceptor), as described e.g. in Houben-Weyl Volume XI/1 pages 24 ff. and 205 ff., Georg Thieme-Verlag, Stuttgart (1957); mixtures of formaldehyde or acetaldehyde with a reducing agent (method of re15 ductive alkylation), examples of reducing agents which may be mentioned are nascent hydrogen (e.g. from zinc and hydrochloric acid), hydrogen in the presence of a hydrogenation catalyst, such as platinum or Raney nickel, formic acid or complex metal hydrides, such as 20 sodium borohydride or sodium cyanoborohydride. Methods of reduction alkylation are described, for example, in Houben-Weyl, Volume XI/1, pages 602 ff., Georg-ThiemeVerlag, Stuttgart (1957); W.S. Emerson, Organic Reactions, Volume £, pages 174 ff., John Wiley and Sons, New York (1948); M.L. Moore, idid, Volume 5., pages 301 ff. (1949); C.A. Buehler, D.E. Pearson, Survey of Organic Synthesis, Volume pages 424-429 (1970), Volume 2, pages 403-407 (1977), John Wiley and Sons, New York; S.R. Sandler, W.

Karo, Organic Functional Group Preparations, Volume 1., pages 345 ff. (1968), Academic Press, New York. The methylation is preferably carried out as reductive methylation.

The process for the preparation of the pharmacologically active thienobenzodiazepinones of the general formula I thus comprises reacting compounds of the formula I wherein R denotes Hal with compounds of the general formula V or acylating thienobenzodiazepinones of the general formula II with acid derivatives IX or methylating or ethylating compounds X and, if appropriate, then converting the resulting base into a pharmacologically acceptable acid addition salt, or converting a resulting acid addition salt into the free base or into a pharmacologically acceptable acid addition salt.

Acid addition salts are obtained by dissolving the resulting free base in a suitable solvent, for example water, acetone, an alkanol, such as ethanol or isopropanol, or an open-chain or cyclic ether, such as diethyl ether or tetrahydrofuran , which contains the idesired acid or to which the desired acid is then added. 51300 The salts are isolated by filtration, precipitation with a non-solvent for the acid addition salt or by evaporation of the solvent. Salts can also be converted into other salts, for example pharmacologically acceptable acid addi5 tion salts, by converting them into the base and then reacting the base further with another acid.

Resulting salts can be converted, into the free base, for example by alkalisation with aqueous sodium hydroxide or potassium hydroxide, and the free base is then isolated by suitable measures, for exaaple solvent extraction with a water-immiscible solvent, such as chloroform, diethyl ether or toluene.

The preparation of the starting conpounds of the general formula II is carried-out according to or analogously to the preparation in US-PS 3,953,430, in (dimethylformamide) F o« H R' 2b N-bromosuccinimide Ila 51300 Phenylenedlamine (VI) is reacted with the tetrahydrothiophenecarboxylic acid derivatives VII, in which R·^ has the above-mentioned meaning, R^a denotes a hydrogen β atom or an alkyl group with 1 to 4 carbon atoms and R 5 denotes a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, in inert solvents, for example toluene, whilst heating, to form the tetrahydrothienobenzodiazepinones VIII. The compounds VIII are dehydrogenated with a suitable dehydrogenating agent, for example N10 bromosuccinimide in dimethylformamide, to give the dihydrothienobenzodiazepinones Ila. The represents2a tives Ila, in which R denotes a hydrogen atom, are converted into the halogen derivatives lib, in which R' denotes a chlorine or bromine atom, by chlorination or 15 bromination with suitable halogenating agents. 2b The compounds IX are known or are prepared, optionally in situ, according to known processes. The piperazinothienobenzodiazepinones X are prepared by reacting compounds of formula I, wherein R^ denotes -Hal, with appropriate amines V, i.e. piperazine or homopiperazine, according to the procedure described above for the amination.

Appropriate starting compounds II*, III* and IV*, respectively, (III*) (IV*) wherein R denotes a hydrogen atom or a methyl or ethyl radical, 2* R represents a chlorine atom or has one of the meanings * Of R , Hal* and Hal1 * denote a chlorine atom and A* denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms, and II**, III**, IV**, V**, IX** and X**, respectively, Hal**-A**-C0-Hal'** [Hal**-A**-C0]20 (III**) (IV**) (V**) 4** g** Z**_CO_A**-N(R )R (IX**) 4** g** HN(R )R wherein *★ R denotes a hydrogen atom or a methyl or ethyl radical, 2** R represents a chlorine atom or has one of 1 ** the meanings of R , Hal** and Hal'** denote a chlorine atom, R denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 or 4 carbon atoms, ς** 4** R has the meaning of R or represents the group -(CH2)m**-N(R )R , or 4** 5 it it R and R together, with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, a piperazin-lyl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazin-1-yl group or a hexahydro1H-1,4-diazepin-1-yl group which is substituted in the 4-poaition by a methyl or ethyl group, 6** R denotes a methyl or ethyl group, 7** R denotes a methyl or ethyl group, m** denotes 2 or 3, n** denotes 2 or 3, A** denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms, Z** denotes a leaving group, are employed for the preparation of the compounds I* and I**.

The following Examples serve to illustrate the invention in more detail, m. denotes melting point.

Example 1 3.5 g of 4-chloroacetyl-9,10-dihydro-4H-thieno5 [3,4-h][l,5]benzodiazepin-10-one, 8.1 g of N-methylpiperazine and 50 ml of toluene are stirred at 80°C for 2 hours, 60 ml of dilute sodium hydroxide solution are added, the layers are separated and the aqueous phase is extracted again several times hy shaking with toluene lo and concentrated to dryness in vacuo. The residue is made to crystallise with a little acetone. 4.2 g of 9,10-dihydro-4-[(4-methyl-piperazin-l-yl)acetyl]-4Hthieno[3,4-b][l,5]benzodiazepin-10-one, m. 177-178°C (acetone), are obtained. 9,10-Dihydro-3-methyl-4-[(4-methyl-piperazin-lyl)acetyl]-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, m. 263-264°C (ethanol), 3-chloro-9,10-dihydro-4-[(4methyl-piperazin-l-yl)acetyl]-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, m. 239°C, and 9,10-dihydro-1,3-dimethyl20 4-((4-methyl-piperazin-l-yl)-acetyl]-4H-thieno(3,4-b](1,5]benzodiazepin-10-one, m. 204-205°C, are obtained analogously by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4Hthieno(3,4-b](1,5]benzodiazepin-10-one, 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno(3,4-b](1,5]benzodiazepin-10-one 25 or 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one with N-methylpiperazine. wherein ι ** R denotes a hydrogen atom or a methyl or ethyl radical, 2** R represents a chlorine atom or has one of 1 ** the meanings of R , Hal** and Hal'** denote a chlorine atom, 4** R denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 or 4 carbon atoms, ** 4** R has the meaning of R or represents the group -(CH2)m**-N(R6 *)R7**, or 4** ;*» R and R together, with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, a piperazin-iyl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazin-1-yl group or a hexahydro1H-1,4-diazepin-1-yl group which is substituted in the 4-position by a methyl or ethyl group, 6** R denotes a methyl or ethyl group, 7** R denotes a methyl or ethyl group, m** denotes 2 or 3, n** denotes 2 or 3, A** denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms, Z** denotes a leaving group, are employed for the preparation of the compounds I* and I**.

Example 1 3.5 g of 4-chloroacetyl-9,10-dihydro-4H-thieno5 [3,4-b][l,5]benzodiazepin-10-one, 8.1 g of N-methylpiperazine and. 50 ml of toluene are stirred, at 80°C for 2 hours. 60 ml of dilute sodium hydroxide solution are added, the layers are separated and the aqueous phase is extracted again several times by shaking with toluene lo and concentrated to dryness in vacuo. The residue is made to crystallise with a little acetone. 4.2 g of 9,10-dihydro-4-[(4-methyl-piperazin-l-yl)acetyl]-4Hthieno[3,4-b][l,5]ben20diazepin-10-one, m. 177-178°C (acetone), are obtained. 9,10-Dihydro-3-methyl-4-[(4-methyl-piperazin-lyl)acetyl]-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, m. 263-264°C (ethanol), 3-chloro-9,10-dihydro-4-[(4methyl-piperazin-l-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, m. 239°C, and 9,10-dihydra-1,3-dimethyl20 4-£(4-methyl-piperazin-l-yl,-acetyl]-4H-thieno[3,4-b]£l,5]benzodiazepin-10-one, m. 204-205°C, are obtained analogously by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4Hthieno£3,4-b]£l,5]benzodiazepin-10-one, 3-chloro-4-chloroacetyl-9 ,10-dlhydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one or 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno£3,4-b]£1,5]benzodiazepin-10-one with N-methylpiperazine.

Example 2 14.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 21 g of N-methylpiperazine and 70 al of dioxane are stirred at 80°C for 5 1 hour and the solution is concentrated to dryness in vacuo. 150 al of isopropanol and 40 ml of water are added to the residue, 25 al of concentrated hydrochloric acid are added dropwise, the mixture is cooled in an icebath and 9,10-dihydro-4-[(4-methylpiperazin-l-yl)10 acetyl]-4H-thieno[3,4-b][l,5]benzodiazepin-10-one dihydrochloride is obtained as a mixture with N-methylpiperazine hydrochloride. The hydrochlorides are dissolved in water and chloroform, the pH is adjusted to 8.2 with 2N sodium hydroxide solution, the aqueous phase is extracted exhaustively by shaking with chloroform and the organic solution is dried and concentrated to dryness in vacuo. 16 g of 9,10-dihydro-4-[(4-methyl-piperazin1-yl) acetyl]-4H-thieno-[3,4-b][1,5]benzodiazepin-10-one, m. 177-179°c (from acetone), are obtained. 9,10-Dihydro-4-(morpholinoacetyl)-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 4-[(4-benzylpiperazin-l-yl)acetyl]-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin10-one, 4-[(4-ethylpiperazin-l-yl)-acetyl]-9,10-dihydro4H-thieno[3,4-b][l,5]benzodiazepin-10-one and 4-[(2,425 dimethyl-piperazin-l-yl)acetyl]-9,10-dihydro-4H-thieno51200 [3,4-b][l,5]benzodiazepin-10-one are obtained analogously by reaction of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-bJ[l,5]henzodiazepin-10-one with morpholine, N-benzylpiperazine, N-ethylpiperazine and 1,3-dimethyl5 piperazine, respectively.

Example 3 1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 0.55 g of pyrrolidine, 0.85 g of ground sodium carbonate and 15 ml of absolute ethanol are heated at the boil for 2 hours and the hot solution is filtered and concentrated in vacuo.

The residue is dissolved in methylene chloride, the organic solution is washed at pH 7 with water and concentrated and 1.4 g of 9,10-dihydro-4-(pyrrolidinoacetyl)15 4H-thieno[3,4-b][l,5]benzodiazepin-lO-one are obtained. Example 4 1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 3.7 g of piperidine and 15 ml of dioxane are stirred at 80°C for 1 hour, the 20 mixture is concentrated in vacuo and the residue is recrystallised from isopropanol/water. 2.0 g of 9,10dihydro-4-(piperidinoacetyl)-4H-thieno[3,4-b][1,5]benzodiazepin-10-one are obtained. 9,1O-Dihydro-3-methyl4- (piperazin-1-yl-acetyl)-4H-thieno[3,4-b][1,5]benzodia25 zepin-10-one (m. 225-228°C, dec.), 9,10-dihydro-1,3-dimethyl 4~(morpholin-4-yl-acetyl)-4H-thieno[3,4-b][1,5]benzodiazepin· 10-one (m. 188-190°C) and 9,10-dihydro-1,3-dimethyl-431 (piperidin-1-yl-acetyl)-4H-thieno[3,4-b][1, 5]benzodiazepin10-one (m. 162-164°C) are obtained analogously by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1.5] benzodiazepin-10-one with piperazine, of 4-chloro5 acetyl-9,10-dihydro-1,3-dimethyl-4H-thieno[3,4-b][1,5]benzodiazepin-10_one with morpholine and of 4-chloroacetyl9,10-dihydro-1,3-dimethyl-4H-thieno[3,4-b][1,5]benzodiazepin10-one with piperidine.

Example 5 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 6 ml of 40% strength aqueous dimethylamine solution and 10 ml of methylene chloride are stirred at 35°C for 2 hours, 0.35 g of · sodium carbonate are added and the mixture is concentrated to dryness lg vacuo. A little water is added, the solution is extracted repeatedly by shaking with chloroform and the organic solution is dried with sodium sulphate and concentrated to dryness. 1.9 g of 4(dimethylaminoacetylJ-9,10-dihydro-4H-thieno[3,4-b][1,5]20 benzodiazepin-10-one are obtained. 4-(Diethylaminoacetyl)-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5jbenzodiazepin-10-one, m. 196-197°C (toluene), and 4-(diethylaminoacetyl)-9,10-dihydro-1,3-dimethyl-4H-thieno[3,4-b][1.5] benzodiazepin-10-one, m. 186-187°C (toluene, are ob25 tained analogously by reaction of 4-chloroacetyl-9,10dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, and 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno32 [3,4-b][1,5]benzodiazepin-10-one, respectively, with diethylamine.

Example 6 9,10-Dihydro-3-methyl-4-i (pyrrolidinoacetyl)-4Hthieno[3,4-b] [l,5]benzodiazepin-10-one, 3-chloro-9,10dihydro-4-(pyrrolidinoacetyl)-4H-thieno[3,4-b][l,5]benzodiazepin-10-one and 9,10-dihydro-l,3-dimethyl-4-(pyrrolidinoacetyl)-4H-thieno[3,4-b][l,5]benzodiazepin-10-one are obtained analogously to Example 4 by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 3-chloro-4-chloroacetyl-9,10-dihydro4H-thieno[3,4~b][l,5]benzodiazepin-10-one and, respectively, 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno[3,4-b][1.5] -benzodiazepin-10-one with pyrrolidine.

Example 7 4-(Dimethylaminoacetyl)-9,10-dihydro-3-methyl4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 3-chloro-4(dimethylaminoacetyl)-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-(dimethylaminoacetyl)-9,10dihydro-l, 3-dimethyl-4H-thieno[3 , 4-b][1,5]benzodiazepin10-one are obtained analogously to Example 5 by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1.5] benzodiazepin-10-one, 3-chloro-4-chloroacetyl-9,10dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one and, respectively, 4-chloroacetyl-9,10-dihydro-l,3-dimethyl-4Hthieno[3,4-b][l,5]benzodiazepin-10-one with dimethylamine. 5120 Example β g of 9,lC-dihydro-3-methyl-4H-thieno[3,4-b][l,5]benzodiazepin-10-one and 5.6 ml of chloroacetyl chloride in 160 ml of dioxane are boiled under reflux in the presence of 8 g of ground potassium carbonate for 8 hours. The solution is concentrated to dryness, the residue is taken up in toluene, the toluene mixture is washed with sodium bicarbonate solution and then with water and the toluene solution is dried over sodium 10 sulphate. Concentration of the solution gives 4chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b] [ 1,5 ]benzodiazepin-10-one , m. 156-158°C. 3-Chloro-4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]ben2odiazepin-10-one, m. 214-216°C, and 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, m. 192-195°C, are obtained analogously by reaction of 3-ehloro9,10-dihydro-4H-thieno[3,4-b][1,5]benzodlazepin-10-one ami ,respeotively, 9,10—dihydro-1,3—dimethyl—4H-thieno[3 >4—b] 20 [l,5]benzodiazepin-10-one with chloroacetyi chloride.

Example 9 .4 ml of chloroacetyi chloride are added dropwise at roan temperature to a su^iension of 18.8 g of 9»10-dihydro-4Hthieno[3,4-h][l,5]benzodiazepin-10-one in 500 ml of dioxane, whereupon a clear solution is formed. The solution is left to stand for 3 hours and is concentrated to dryness, the residue is taken up in toluene, the toluene mixture is washed with sodium bicarbonate solution and then with water and the toluene solution is dried over sodium sulphate. Concentration of the solution gives 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one in the form of an oil, which crystallises slowly, m. 220°C. 4-Chloroacetyl-9,10-dihydro-1-methyl-4H-thieno[3,4-b][1.5] benzodiazepin-10-one and 4-chloroacety1-9,10-dihydro10 3-methyl-4H-thienoC3,4-b][1,5]benzodiazepin-10-one, m. 156-158°C, are obtained analogously by reaction of 9,10dihydro-1-methy1-4 H-thieno[3,4-b][1,5]benzodiazepin-10-one and 9,10-dihydro-3-methyl-4H-thienoC3,4-b][1,5]benzodiazepin-10-one, respectively, with chloroacetyl chloride.

Example 10 2.2 g of chloroacetyl chloride and 2 ml of triethylamine are simultaneously added dropwise to a boiling solution of 2.2 g of 9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one in 30 ml of absolute dioxane in the course of 40 minutes and the mixture is stirred for a further 3 hours. It is allowed to cool and is filtered, the filtrate is concentrated to dryness, the residue is chromatographed over a silica gel column by means of a mixture of petroleum ether/ethyl acetate A £ (1:1) and the product is recrystallised from toluene to give 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1.5] benzodiazepin-10-one as an oil, which crystallises slowly,m. 220°C.

Example 11 ml of sulfuryl chloride in 100 ml methylene chloride are added dropwise to a solution of 12 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 300 ml of methylene chloride at 20°C. The mixture is left to stand at room temperature for a further 12 hours and is then extracted by shaking it with sodium bicarbonate solution and washing it with water; the organic phase is dried and concentrated. The residue is made to crystallise with a little methanol. g of 3-chloro-4-chloroacetyl-9,10-dihydro-thieno[3,4-b][1,5]benzodiazepin-10-one is thus obtained, m. 214-216°C (acetonitrile).

Example 12 A mixture of 1-00. g of (4-methylpiperazin-1-yl)acetic acid and 0.20 g of 75 per cent sodium hydride (in paraffin oil) in 16 ml of dimethylformamide is warmed at 50-80°C until the evolution of hydrogen has ended (2 to 3 hours). 1.35 g of 9,10-dihydro -4H-thieno[3,4-b][1,5]benzodiazepin-10-one are added to the sodium salt formed from the acid, and 0.99. g of 98% pure phosphorus oxychloride are added dropwise at -10°C in the course of 10 minutes. The batch is stirred at -10°C for 4 hours, at 0°C for 4 hours and at room temperature for 20 minutes.

It is poured onto ice, adjusted to pH 3.5 with sodium hydroxide solution and extracted by shaking with methylene 513 0 0 chloride, and the aqueous phase is adjusted to pH 9 and extracted by shaking again with methylene chloride.

The organic phase is washed with water and concentrated in vacuo. 0.6 g of 9,10-dihydro-4-[(4-methyl piperazin-1-yl)-acetyl]-4H-thieno[3,4-b]Cl,5]benzodiazepin 10-one, m. 177-178°C (from acetone) are obtained. 9,10-Dihydro-3-methyl-4-[(4-methylpiperazin-1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, m. 263-264°C, and 9,10-dihydro-1,3-dimethyl-4-[(4-methyl10 piperazin-1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin10-one, m. 204-205°C, are obtained analogously by reaction of (4-methylpiperazin-1-yl)acetic acid with sodium hydride 9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin10-one, respectively, 9,10-dihydro-1,3-dimethyl-4H-thieno15 [3,4-b][1,5]benzodiazepin-10-one and phosphorous oxychloride .

Example 13 1.1 g of ethyl chloroformate are added dropwise at o°c to a suspension of 1.58, g of (4-methylpiperazin-1-yl)acetic acid in 20 ml of tetrahydrofuran. 2.18. g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin10-one are added to the suspension obtained. The mixture is stired 1 hour at O°C and further 4 hours at.room 25 temperature. It is poured onto 2 N sodium hydroxide solution and extracted with toluene. The organic phase is concentrated to dryness. The residue is chromatographed over a silica: gel column by means of a mixture of dioxane/ methanol (1:1) to give 9,10-dihydro-4-[(4-methylpiperazin1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, m. 177-179°C. 9,10-Dihydro-3-methyl-4-[(4-methylpiperazin-1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (m. 263-264°C) is obtained analogously by reaction of 9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin10-one with (4-methylpiperazin-1-yl)acetic acid and ethyl chloroformate.

Example 14 2.0 g of 9,10-dihydro-3-methyl-4-(piperazin-1-yl-acetyl)-4H-thieno[3,4-b][1,5]benzodia2epin-10-one, 1.3 g of 98 per cent formic acid and 0.3. g of 35 per cent aqueous formaldehyde solution are warmed at 100-105°C for 2 hours. The mixture liquefies under evolution of. gas. It is concentrated In vacuo, diluted with water, adjusted to pH 3,5 with diluted hydrochloric acid and extracted by shaking with dichloromethane. The aqueous phase is adjusted to pH 9 and extracted with dichlorometha'ne. The organic phase is washed, dried and concentrated. Recrystallisation of the residue from methanol yields 9,10-dihydro-3-methyl-4[(4-methylpiperazin-1-yl)acetyl]-4H-thieno[3,4-b]Cl,5]benzodiazepin-10-one, m. 263-264°C.

The starting compounds are obtained in the following manner: Example A: 13.5 g of sulphuryl chloride in 100 ml of methylene chloride are added dropwise to a solution of 21.6 g of 9,10-dihydro-4H-thieno[3,4-b][l,5]benzodiazepin-10-one in 300 ml of methylene chloride at -40°C.

The mixture is left to stand at room temperature for a further hour and is extracted by shaking with sodium bicarbonate solution and washed with water, and the organic phase is dried and concentrated. The residue is made to crystallise with a little methanol. 3Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10one is obtained.

Example B: 10 g of 1,3,9,10-tetrahydro-3-methyl-4Hthieno[3,4-b][l,5]benzodiazepin-10-one and 8.2 g of N-bromosuccinimide are dissolved in 250 ml of dimethylformamide. After one hour, the solution is poured into 2 1 of water. The precipitate is filtered off and dissolved in hot toluene and the solution is clarified with Kaisil (Tonsil is a Trade Mark). Cn cooling, 9,10-dihydio-3-irietbyl-4H thieno[3,4-b][l,5]benzodiazepin-10-one, m. 228-230°C (methanol), is obtained as a precipitate. 9,10-Dihydro-l-methyl-4H-thieno[3,4-b][l,5]benzo20 diazepin-10-one and 9,10-dihydro-l,3-dimethyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, m. 195-196°C, are obtained analogously by dehydrogenation of 1,3,9,10tetrahydro-1-methyl-4H—thieno[3,4-b][1,5]benzodiazepin10-one or 1,3,9,10-tetrahydro-1,3-dimethyl-4H-thieno25 [3,4-b][1,5]benzodiazepin-10-one with N-bromosuccinimide.

Example C: 49.9 g of ' o-phenylenediamine and 80 g of 5-methyl-tetrahydro-4-oxo-3-thiophenecarboxylic acid in 4.5 1 of toluene are boiled. The water formed is distilled off azeotropically with 2 1 of the solvent in the course of 7 hours. The solvent is removed. 1,3,9,10-Tetrahydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, m. 195-197°C (isopropanol) is obtained. 1,3,9,10-Tetrahydro-l-methyl-4H-thi eno[3,4-b][l,5] benzodiazepin-10-one and l,3,9,10-tetrahydro-l,3-dimethyl10 4H-thieno[3,4-b][1,5]benzodiazepln-10-one, m. 148-150°C, are obtained analogously by reaction of tetrahydro-2methyl-4-oxo-3-thiophenecarboxylic acid or tetrahydro2, 5-dimethyl-4-oxo-3-thiophenecarboxylic acid with o-phenylenediamine.

$ The following examples describe the formulation of a compound according to the invention to give medicaments. Example 15 ,000 tablets with an active compound content of 20 mg are prepared from the following constituents: 200 g of 9,10-dihydro-4-[(4-methyl-piperazin-l-yl)aoetyl]4H-thieno[3,4-b][l,5]benzodiazepin-10-one, 900 g of maize starch, 500 g of lactose, 30 g of amorphous silicic acid and 40 g of sodium lauryl-sulphate are mixed and the mixture is sieved. This mixture is moistened with a solution of 50 g of polyvinylpyrrolidone (average molecular weight: 25,000) in 320 ml of alcohol and is granu51200 lated through a sieve of mesh width 1.25 mm. The granules are dried'at 40° and mixed with l6o g of pectin, 100 g of talc and 20 g of magnesium stearate. This mixture is compressed to 200 mg tablets with a diameter of 8 mm.

Example 16 100,000 capsules with an active compound content of 30 mg are prepared from the following constituents: 3,000 g of 9,10-dihydro-4-[(4-methyl-piperazin-l-yl)acetyl] 10 4H-thieno[3,4-b][l,5]benzodiazepin-10-one are mixed with 5,000 g of neutral oil (Miglyol 812; Miglyol is a Trade Mark) and the mixture is filled with soft gelatin capsules.

Example 17 100,000 capsules with an active confound content 15 of 15 mg are prepared from the following constituents: 1,500 g of 9,10-dihydro-4-[(4-methyl-piperazin-l-yl)acetyl]-4H-thieno[3,4-b][l,5]benzodiazepin-10-one and 1,500 g of magnesium trisilicate are mixed with 5,000 g of neutral oil (Miglyol 812) and the mixture is filled into soft gelatin capsules.

Medicaments containing 9,10-dihydro-3-methyl-4£ (4-methylpiperazin-1-yl)acetyl]-4H-thieno£3,4-b]£l,5]benzodiazepin-10-one and, respectively, 9,10-dihydro-1,3dimethyl-4-£(4-methylpiperazin-1-yl)acetyl]-4H-thieno£3,4-b] £1,5]benzodiazepin-10-one are obtained analogously by replacing 9,10-dihydro-4-£(4-methylpiperazin-1-yl)acetyl]4H-thieno£3,4-b]£l,5]benzodiazepin-10-one in Examples 15 to by the above mentioned compounds.

Pharmacology The excellent protective action on the stomach shown hy the pharmacologically active substituted thienobenzodiazepinones can be demonstrated using as a model the so-called Shay rat .The compounds according to the invention prove to have a protective action on the stomach and a therapeutic range which are clearly superior to those of the known commercial productcarbenoxolone (l)ias can be shown, for example, by comparing (l) with 9,10-dihydro-4-[(410 methyl-piperazin-l-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (2), 3-Chloro-9,10-dihydro-4-[(4-methylpiperazin-1-yl>acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin10-one (3), 9,10-dihydro-3-methyl-4-[(4-methyl-piperazin1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (4) and 9,10-dihydro-1,3-dimethyl-4-[(4-methyl-piperazin-1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (5).

Table I: Antiulcerogenic action and toxicity of thienobenzodiazepinones Serial No. Toxicity LD5Q[og/kg], intravenous administration to mice Protective action on the stomach ED^ng/kg], per oral administration to rats TQ "5 Gastric \ secretion*J % inhibition in rats 1 290 ~70 4.1 7 2 190 2.5 76 35 3 75 A. 1 & 75 £ 28 4 130 ~ 0.3 ~433 20 5 180 1.3 139 17 ED^q = dose which reduces the ulcer index by 50% in the treated group compared with the control group LD^q = dose at which 50% of the animals die TQ = therapeutic quotient LD^q/ED^q +)% inhibition = inhibition of the gastric secretion (in %) 4 hours after administration of the anti-ulcerogenic ΕΟ-λ It should be particularly emphasised that an ED^q can indeed still he determined in the case of com10 pound 1, but the dose/action curve is then very severely flattened, so that no substantial increase in the ulcerogenic action can be achieved even at 300 mg/kg. In contrast, the action of compounds 2 to 5 is strictly dependent on the dose; inhibition effects of up to 95% can be achieved.

The anti-ulcerogenic action was tested in accordance with the method using the so-called Shay rat: Rats (female, 180 - 200 g, 4 animals per cage on a high grid) which had been fasted for 24 hours were subjected to ulcer provocation by pylorus ligature (under diethyl ether anaesthetic) and oral administration of 100 mg/10 ml/kg of acetylsalicylic acid. The substances to be tested are administered orally (10 ml/kg) 1 hour before the pylorus ligature. . The wound was closed by means of Michel clamps. 4 hours thereafter, the animals are killed under an ether anaesthetic by atlas dislocation and the stomach is removed. The stomach is opened longitudinally and fixed to a cork tile, after the amount of gastric juice secreted (volume) has been determined; the number and size (» diameter) of ulcers present are determined with a stereomicroscope with 10 fold magnification. The product of the degree of severity (according to the following rating scale) and the number of ulcers serves as the individual ulcer index.

Scale of points: no ulcers 0 ulcer diameter 0.1 - 1.4 mm 1 1.5 - 2.4 mm 2 2.5 - 3.4 mm 3 15 3.5 - 4.4 mm 4 4.5 - 5.4 mm 5 >5.5 mm 6 The reduction in the average ulcer index of each treated group compared with that of the control group (= 100%) serves as a measure of the anti-ulcerogenic effect. The EDjq designates the dose which reduces the average ulcer index by 50%.

Determination of the toxicity The toxicity investigations are carried out on 25 female NMRI mice (body weight: 22 - 26 g). The animals (5 animals per dose) receive feed and water ad libitum. 5120 0 Various doses of the substances are administered intravenously (injection time: 1 minute). The observation period is 7 days. The LD^q, that is to say the dose at which 50% of the animals die, is determined by means of linear regression.

Claims

1. CLAIMS:1. A substituted thienobenzodiazepinone of the wherein (I) R x denotes a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, o R represents a halogen atom or has one of the meanings of r\ R 8 denotes a halogen atom or the group -N(R^)R 8 denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 to 5 carbon atoms, κ A R has one of the meanings of R or represents the group -(CH 2 ) m -N(R 6 )R 7 or R^ and R 8 together, and with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-l-yl group, a piperazin-l-yl group which is optionally sub20 51300 stituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazin-1-yl group, or a hexahydro-1H-1,4diazepin-l-yl group which is substituted in the 5 4-position by a methyl or ethyl group, r6 denotes an alkyl group with 1 to 4 carbon atoms, R? denotes an alkyl group with 1 to 4 carbon atoms, lo A denotes a straight-chain or branched alkylene group with 1 to 5 carbon atoms and m denotes 2 or 3, or an acid addition salt thereof.

2. A substituted thienobenaodiazepinone according 15 to Claim 1, of the general formula I* wherein R 1 * denotes a hydrogen atom or a methyl or ethyl radical, κ represents a chlorine atom or has one of the1* meanings of R , Ir denotes a chlorine atom and A* denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms.

3. , A substituted thienobenzodiazepinone according to Claim 1, o£ the general fonnula X** wherein Ί ## R denotes a hydrogen atom or a methyl or ethyl radical, 2** R represents a chlorine atom or has one of ]## the meanings of R , 7** . k**. R** R 3 denotes the group -N(R )R 3 R^** denotes an alkyl radical with 1 to 4 carbon atoms or an alkenyl radical with 3 or 4 carbon atoms, c*·» A** R 3 has the meaning of R or represents the group -(CH2) m **-N(R 6 **)R 7 **, or A*« κ#* R and R together, with the inclusion of the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-l-yl group, 513U0 a piperazin-1-yl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazin-l-yl group or a hexahydro-lH-l,4-diazepin-l-yl group which is substituted in the 4-position by a methyl or ethyl group, R° denotes a methyl or ethyl group, R‘ denotes a methyl or ethyl group, m** denotes 2 or 3 and A** denotes a straight-chain or branched alkylene group with 1 or 2 carbon atoms, or an aoid addition salt thereof.

4. a compound according to Claim 3, in which R 15 denotes a hydrogen atom or a methyl or ethyl radical, R represents a chlorine atom or has one of ;the meanings of ι** 3** 4** 5** 4** R ; R denotes the; group -N(R )R ? R ' denotes a 5. ** a** methyl or ethyl radical and R has the meaning of R or , , . . fi** 7** 4** represents the group ~(CH 2 ) m **-N(R )R , or R and r 5** together, with the inclusion of the nitrogen atom, denote a pyrrolidino, piperidino or hexahydroazepin-1-yl 6** 7** radical, R and R denote a methyl or ethyl radical, m** denotes 2 and A** denotes a methylene group, or a pharmacologically acceptable acid addition salt thereof. „1**

5. A compound according to Claim 3, in which R denotes a hydrogen atom or a methyl or ethyl radical, R 2 ** represents a chlorine atom or has one of the meanings ι** *5** d** 5** 4** of R ; R denotes the group -N(R )R , R 5** and R together, with the inclusion of the nitrogen atom, denote a piperazin-1-yl which is substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-di5 mothyipip oraτιττ-ΐ -yl group or a hexahydro-1H-1,4-diazepin-1-yl group vhidx is substituted in the 4-posLticn by a methyl cr ethyl group and A** denotes a methylene group, or a pharmacologically acceptable acid addition salt thereof.

6. A compound according to Claim 3, 10 in which R 1 ** denotes a hydrogen atom or a methyl radical, R denotes a hydrogen atom or a methyl radi3** . . , 4**. 5** 4** 5** cai, R denotes the group -N(R )R , R and R together, with inclusion of the nitrogen atom, denote a piperazin-1-yl group wich is substituted in the 4-position 1 5 by a methyl group and A** denotes a methylene group, or a pharmacologically acceptable acid addition salt thereof.

7. A medicament which contains as active ingredient one or more thienobenzodiazepinones of the general formula la 2o wherein R 3 · denotes a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R represents a halogen atom or has one of the η meanings οϊ R , R 8a denotes the group -N(R^)R 8 · R^ denotes an alkyl radical with 1 to 4 carbon 5 atoms or an alkenyl radical, with 3 to 5 carbon atoms and 5 AR has one of the meanings of R or represents the group -(CH 2 ) m -N(R^)R 7 or R^ and R 8 together, and with the inclusion of 10 the nitrogen atom to which they are bonded, denote a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-l-yl groups a piperazin-l-yl group which is optionally substituted in the 4-position by a methyl, ethyl or benzyl 15 group, a 2,4-dimethyl-piperazin-1-yl. group, or a hexahydro-1 H-1 ,4-diazepin-1-yl. group which is substituted in the 4-position by a methyl or ethyl, group, R^ denotes an alkyl group with 1 to 4 carbon atoms, 20 R 7 denotes an alkyl group with 1 to 4 carbon atoms, A denotes a straight-chain or branched alkylene group with 1 to 5 carbon atoms and m denotes 2 or 3, and/or a pharmacologically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier or diluent therefor.

8. A process for the preparation of a substituted thienobenzodiazepinone of the general formula I given and defined in Claim 1 or an acid addition salt thereof, which comprises acylating and, if appropriate, then aminating a thienobenzodiazepinone of the general formula II R 1 (II) wherein 1 2 R and R have the meanings given in Claim 1, and/or converting the resulting base into the acid addition salt, or converting the resulting acid addition 15 salt into the free base or into a pharmacologically acceptable acid addition salt.

9. A process according to Claim 8, wherein the acylation is carried out with compounds of the general formulae Hal-A-CO-Hal' (III) or (Hal-A-CO) 2 O (IV), wherein 20 Hal and Hal' denote a halogen atom and A denotes an alkylene group with 1 to 5 carbon atoms.

10. A process according to Claim 8, wherein a compound of the general formula I wherein R represents a halogen atom, and a secondary amine of the general formula HN(R 4 )R 5 (V), wherein R 4 and R 5 have the meanings given in Claim 1, are employed in the optional subsequent amination.

11. A process according to Claim 10, wherein piperazine or homopiperazine is employed as a secondary 5 amine V in the optional subsequent amination, and the obtained product of the general formula X wherein 1 2 R , R and A have the meanings given in Claim 1 10 and n denotes 2 or 3, is methylated or ethylated.

12. A process according to Claim 8, wherein the acylation is carried out with a compound of the general 4 5 formula Z-CO-A-N(R )R (IX), wherein Z denotes a leaving 4 5 group and A, R and R have the meanings given in Claim 1. 15

13. A substituted thienobenzodiazepinone .of the general formula Ia, wherein the substituents have the meanings given in Claim 7, for use in the treatment and prophylaxis of illnesses based on disorders of the stomach or intestine. 1**

14. A compound according to Claim 3, in which R 2** 4** 20 denotes a hydrogen atom; R denotes a methyl radical; R 5** and R , and with the inclusion of the nitrogen atom, denote a piperazin-l-yl group which is substituted in the 4-position by a methyl group; and A denotes a methylene group, or a pharmacologically acceptable acid addition salt thereof.

15. A pharmaceutical preparation containing from 0.5 5 to 95% by weight of the total mixture of at least one compound according to any one of claims 1 to 6 in admixture with one or more solid or liquid pharmaceutically acceptable carriers.

16. A process for the preparation of a substituted 10 thienobenzodiazepinone of the general formula I according to Claim 1 substantially as described with reference to the specific examples hereinbefore set forth.