DK157872B - Analogy process for preparing substituted thienobenzodiazepinones, and intermediates for use in this process - Google Patents

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

DK 157872 B

The present invention relates to an analogous process for the preparation of novel substituted thienobenzodiazepinones as well as other substituted thienobenzodiazepinones for use as intermediates in the process.

The compounds prepared by the process of the invention are used in the pharmaceutical industry for the manufacture of medicaments.

In German Publication No. 1,795,176, certain dibenzodiazepinones are attributed to an anti-ulcer and secretion-inhibiting effect.

From US Patent No. 3,953,430, substituted thienobenzodiazepinones which are unsubstituted or carbohydride substituted at the 4-position are known to have antidepressant and analgesic effect. U.S. Patent No. 4,168,269 discloses substituted thienobenzodiazepinones, which are also unsubstituted or hydrocarbon substituted at the 4-position, with analgesic effect. Other novel thienobenzodiazepinones have now been found to have novel, interesting pharmacological effects.

The invention relates to an analogous process for the preparation of these substituted thienobenzodiazepinones of general formula I

20 in * 2 CO-AN (R 1) where rA represents hydrogen or alkyl of 1-4 carbon atoms, 25 R.2 represents halogen or has one of the meanings of rA, represents alkyl of 1-4 carbon atoms or alkenyl of 3-5 carbon atoms , and

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2 R- * has one of the meanings of sA or represents a group - (CH 2) m N (R 6) R 7, or R 2 and R 2 together with the nitrogen atom to which they are attached form a morpholino group, a pyrrolidino group, a piperidino group, a 5 hexahydroazepin-1-yl group, an optionally at the 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a 2,4-dimethyl-piperazin-1-yl group or a 4-position represents methyl or ethyl substituted hexahydro-1H-1,4-diazepin-1-yl group, and represents alkyl of 1-4 carbon atoms, R 5 represents alkyl of 1-4 carbon atoms, A represents straight or branched alkylene of 1- 5 carbon atoms, µm represents 2 or 3, and pharmacologically tolerable acid addition salts thereof.

Alkyl groups having 1-4 carbon atoms are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Of the alkyl groups, methyl and ethyl are preferred such as R 2 -, R 2, R 2, R 4, R 2 and R 2. As the alkyl group R 1 and R 2, methyl is especially preferred.

As alkenyl groups having 3-5 carbon atoms, mention is made of allyl and 2-methylallyl.

Halogen atoms R 1 is a bromine atom and especially a chlorine atom,

Alkylene groups having 1-5 carbon atoms are trimethylene, tetramethylene, pentamethylene, propylene, ethylmethylene, preferably ethylene and especially methylene.

As salts, any pharmacologically tolerable acid addition salts may be considered. Particular mention should be made of the pharmacologically tolerable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically intolerable salts are converted in the manner known to those skilled in the art into pharmacologically tolerable salts. As such, in particular, water-soluble or water-insoluble acid addition salts, e.g. the hydrobromide, hydroiodide, nitrate, acetate, benzoate, hibenzate [2- (4-hydroxybenzoyl) benzoate], fendizoate (2 - [(2'-hydroxy-4-biphenylyl) carbonyl] benzoate), propionate, butyrate,

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3 the sulfosalicylate, laurate, oxalate, amsonate (4,4'-diaminostilben-2,2'-disulfonate), embonate [4,4'-methylene bis (3-hydroxy-2-naphthoate)], metembonate [ 4,4'-methylene bis ((3-methoxy-2-naphthoate-et)], stearate, 2-hydroxy-3-napbthoate and 3-hydroxy-2-naphthoate, in particular the hydrochloride, phospbate, sulfate, citrate, the gluconate, maleate, malate, fumarate, succinate, tartrate, tosylate (p-toluenesulfonate), mesylate (methanesulfonate), and amidosulfonate.

A further aspect of the invention relates to substituted thienobenzodiazepinones for use as intermediates in the process 10 of the invention, which compounds have the general formula XX

N xx R2 is CO-A - R3 wherein rA represents hydrogen or alkyl of 1-4 carbon atoms, represents halogen or has one of R 1's, 15 represents halogen, and A represents straight or branched alkylene of 1-5 carbon atoms, or acid addition salts thereof.

Halogen atoms R an iodine, bromine and especially a chlorine atom.

A further aspect of the invention relates to substituted thienobenzo-diazepinones for use as intermediates in the process of the invention, which compounds have the general formula XX *

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4 "R1 * ^ i xx * 2 *

fT

C0-A * -R3 * where R4 - * represents hydrogen, methyl or ethyl, R4 * represents chlorine or have any of the meanings of R4 *, r3 * represents chloro, and A * represents straight or branched alkylene with 1 or 2 carbon atoms.

Preferred examples of compounds of formula XX * are those wherein 10 r 1 * represents hydrogen or methyl, R 2 * represents hydrogen or methyl and A * represents methylene.

Particularly preferred examples of compounds of formula XX * are those in which R 2 represents R 2

In a preferred aspect of the process of the invention, substituted thienobenzodiazepinones of general formula I are prepared

H 0 R

5 i **

l R

C0-A ** - N (RFC **) R **

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5 represents hydrogen, methyl or ethyl, R 2 ** represents chlorine or has any of the meanings of R 2 **, 5 R 2 represents alkyl of 1-4 carbon atoms or alkenyl of 3-4 car - bon atoms, R 5 ** has the same meaning as R 2 ** or represents a group - (CH 2) m 2 -N (R 6 **) R 7 **, and and R 2 ** together with the nitrogen atom to which they are attached 10 forms a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, an optionally in 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a 2,4-dimethyl -piperazin-1-yl group or a 4-position with methyl or ethyl substituted hexahydro-1H-1,4-diazepin-1-yl group, and R6 ** represents methyl or ethyl, R7 ** represents methyl or ethyl, m ** represents 2 or 3, and A ** represents straight or branched alkylene having 1 or 2 carbon atoms, or acid addition salts thereof.

A group of compounds of formula I ** are those wherein R 2 - ** represents hydrogen, methyl or ethyl, R 2 ** represents a chlorine atom or has the meaning of R 1 - **; R 2 ** denotes methyl or ethyl, R 2 ** 25 has the same meaning as R 2 ** or represents a group ^ Cl 2 2 m ** "N (R 2 **) R 7 **, or R 2 * and R 2 ** together with the nitrogen atom represent a pyrrolidino, piperidino or hexahydroazepin-1-yl group, R 2 ** and R 7 ** represent methyl or ethyl, m ** represents 2 and A ** represents methylene , as well as pharmacologically tolerable acid addition salts thereof.

Another group of compounds of formula I ** are those wherein R 2 ** represents hydrogen, methyl or ethyl, R 2 ** represents chlorine or has one of R 1 - ** 's meanings; R 2 and R 2 together with the nitrogen atom form a 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a 2,4-dimethyl-piperazin-1-yl group or a in the 4-position with methyl or ethyl substituted hexahydro-1H-1,4-

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6 diazepin-1-yl group, and A ** represents methylene, as well as pharmacologically tolerable acid addition salts thereof.

Preferred examples of compounds of formula I ** are those wherein R 1 ** represents hydrogen or methyl, represents hydrogen or 5 methyl, R 2 ** and R - *** together with the nitrogen atom form a 4-position with methyl substituted piperazine-1-yl group, and A ** represents methylene, as well as pharmacologically tolerable acid addition salts thereof.

A further preferred aspect of the invention relates to such compounds of Formula I *** 10 H 0 r1 *** III ^ J rt '. *) R 5 *** where r 1 *** represents hydrogen, methyl or ethyl, 15 r 2 *** represents chlorine or has any of the meanings of R 2 - ***, R 4 *** and R 2 *** together with the nitrogen atom to which they are attached form a 4-position with methyl or ethyl substituted piperazin-1-yl group or a 4-position with methyl or ethyl substituted hexahydro-1H-1,4-diazepine. Represents a straight or branched alkylene having 1 or 2 carbon atoms, or acid addition salts thereof.

Examples of compounds which can be prepared by the process of the invention include: 9,10-dihydro-4- [2- (di-n-propylamino) propionyl] -4H-thieno [3,4-b] - [1,5] benzodiazepine-10-one, 4 - [4- (di-n-butylamino) -butyl] - 9,10-dihydro-4H-thi eno [3,4-b] [1,5 ] -benzodiazepine-10-one,

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4- [2- (diethylamino) propionyl] -9,10-dihydro-4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one, 4- [5- (diisopropylamino) - valeryl] -9,10-dihydro-4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one, 4- [diisobutylaminoacetyl] -9,10-dihydro-3-methyl-4H- thieno [3,4-b] - [1.5] benzodiazepin-10-one, 4- [Nn-butyl-tert-butylaminoacetyl] -9,10-dihydro-3-methyl-4H-thieno- [3,4-b ] [1,5] benzodiazepin-10-one, 4- [4- (diallylamino) butyryl] -9,10-dihydro-1,3-dimethyl-4H-thieno-10 [3,4-b] [1,2] 5] benzodiazepin-10-one, 4- [di-sec-butylaminoacetyl] -9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 4- [ 2- (N-Ethyl-n-butylamino) propionyl] -9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one 9,10-dihydro-3-methyl -4- [N-methyl-sec-butylaminoacetyl] -4H-thieno- [3,4-b] [1,5] benzodiazepin-10-one, 9,10-dihydro-4- [5- (N-methyl-tert (butylamino) valeryl] -4H-thieno- [3,4-b] [1,5] benzodiazepin-10-one, 9,10-dihydro-4- [2-piperidinopropionyl] -4H-thieno [3,4-b] b] [1,5] benzodi-azepin-10-one, 4- [4- (hexahydroazepin-1-yl) butyryl] -9,10-dihydro-4H-thie no [3,4-b] - [1.5] benzodiazepin-10-one, 4- [3- (di-n-butylamino) propionyl] -9,10-dihydro-4H-thieno [3,4-b] [ 1,5] -benzodiazepin-10-one, 4- [3- (diallylamino) propionyl] -9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiaziazine-10-one one, 4- [3- (di-sec-butylamino) propionyl] -9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, 4- [3- (Nn -butyl-tert-butylamino) propionyl] -9,10-dihydro-4H-thieno-[3,4-b] [1,5] benzodiazepin-10-one, 4- [3- (N-ethyl-n -butylamino) propionyl] -9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, 9,10-dihydro-4- [3- (N-methyl-sec-butylamino) propionyl] -4H-thieno- [3,4-b] [1,5] benzodiazepin-10-one, 9,10-dihydro-4- [3-piperidinopropionyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 9,10-dihydro-1-methyl-4 - [(4-methylpiperazin-1-yl) acetyl] -4H-thieno- [3,4-b] [1, 5] benzodiazepine-10-one, and

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4- [3- (Hexahydroazepin-1-yl) propionyl] -9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, preferably 9,10-dihydro-4 - [(4-methylpiperazin-1-yl) -acetyl] -4H-thieno [3,4-b] -5 [1,5] benzodiazepin-10-one, 9,10-dihydro-1,3-dimethyl-4- [(4-methylpiperazin-1-yl) -acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 9,10-dihydro-3-methyl-4 - [(4-methylpiperazine -1-yl) -acetyl] -4H-thieno- [3,4-b] [1,5] benzodiazepin-10-one and pharmacologically tolerable acid addition salts thereof.

The substituted thienobenzodiazepinones of general formula I and their acid addition salts, respectively, and of formulas XX *, I ** and I ***, have valuable properties which make them industrially exploitable.

The substituted thienobenzodiazepinones of general formula I and the compounds of formulas I ** and I *** are distinguished by having a pronounced gastric and intestinal protective effect in warm-blooded, for example, inhibiting gastric ulcer formation. Furthermore, due to a low toxicity and lack of significant side effects, they have a favorable therapeutic breadth. The substituted thienobenzodiazepinones of the general formula XX which represent a halogen atom (Hal) and Hal have the above meaning and the compounds of the formula XX * are valuable intermediates in the preparation of the disclosed pharmacologically effective and therapeutically useful compounds.

The excellent effect of the pharmacologically active substituted 25 thienobenzodiazepinones and the pharmacologically, i.e. biologically tolerable acid addition salts thereof make it possible to use them in human and veterinary medicine where they are used to treat and prophylaxis of diseases due to stomach or intestinal disorders. Eg. For example, acute and chronic ventricular ulcer and duodenal ulcer, gastritis or hyperacid gastric irritation can be treated in humans or animals.

The subject pharmacologically active compounds are therefore used to treat mammals suffering from one or more of the above-mentioned diseases, administering to the sick mammal a therapeutically effective and pharmacologically tolerable amount of one or more

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9 more compounds of general formula I or I **, of the preferred representatives thereof and / or of the salts thereof.

Medicines containing one or more thieno-benzodiazepinones of general formula I, especially those containing the thienobenzodiazepinones of general formula I ** or I *** or the preferred representatives thereof and / or the pharmacological agents, may be prepared. tolerable acid addition salts thereof.

The drugs are prepared in a manner known per se. As pharmaceuticals, the subject pharmacologically active compounds are used either as such or preferably in combination with suitable pharmaceutical carriers. If the pharmaceutical compositions contain pharmaceutical carriers in addition to the disclosed pharmacologically active compounds, the active ingredient content of these mixtures is 0.5-95, preferably 15-75, by weight of the total mixture. For example, the drugs 15 are formulated. for oral, rectal or parenteral (intravenous, intramuscular or subcutaneous) administration at appropriate doses, e.g. such as tablets, dragees, capsules, suppositories or metered volumes of a powder, granulate, solution, emulsion or suspension.

The daily dose of oral administration is generally for mammals between 0.01 and 5, preferably between 0.05 and 2.5, especially between 0.1 and 1.5 mg / kg body weight, and optionally administered in mammals. in the form of several, preferably 1-3, single doses to achieve the desired results.

The pharmaceutical compositions preferably consist of the subject compounds and non-toxic, pharmaceutically tolerable drug carriers which are used as admixture or diluent in solid, semi-solid or liquid form or as a coating agent, e.g. in the form of a capsule, tablet coating, bag or other container, for the therapeutically active ingredient. A carrier can e.g. serve as a mediator for the body's uptake of the drug, as a formulation aid, as a sweetener, as a flavor correction, as a dye or as a preservative.

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When the substituted thienobenzodiazepinones prepared by the process of the invention and / or the pharmacologically tolerable acid addition salts thereof are used to treat the disorders disclosed, the pharmaceutical compositions may also contain one or more pharmacologically active components of other drug groups, e.g. . antacids, e.g. aluminum hydroxide or magnesium aluminate; secretion inhibitors, e.g. 1 blockers such as cimetidine; stomach and intestinal therapies, e.g. metoclopramide, bromopride and tiapride; tranquilizers such as benzodiazepines, e.g. diazepam; spasms, e.g. bietamiverin, camylophine; anticholinergics, e.g.

oxyphencyclimin and phencarbamide; glucocorticoids such as prednisolone, fluocortolone and betamethasone; non-steroidal antiflogistics such as arylic acetic acids and propionic acids, heteroaryl acetic acids and propionic acids, benzothiazine carboxamide dioxides, pyrazolidinediones, quinazolinones, e.g. ibuprofen, naproxen, diclofenac, fenbufen, indomethacin, lonazolac, sudoxicam, piroxicam, phenylbutazone, bumadizone calcium and proquazone; local anesthetics, e.g. tetracaine and procaine; and optionally fermentates, vitamins and amino acids.

The analogous procedure for preparing the substituted thienobenzodiazepinones of general formula I is characterized in that:

a) thienobenzodiazepinones of general formula XX

n R 'i R2' CO-A-R3

wherein A, rA and R.2 are as defined above and R R represents halogen, is aminated with a compound of the general formula V

HN (R4) R5 V

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11 where R4 and is as defined above, or

b) thienobenzodiazepinones of the above general formula XX are aminated with piperazine or homopiperazine and the obtained reaction product of the general formula X

H 0 R1 5 R2 10 -A-N 2 \ h where r 1, R 2 and A have the meaning given above and n represents 2 or 3, methylated or ethylated, or

c) compounds of general formula II

H 0 R1 io 11 H R2

wherein R 1 and R 2 are as defined above are acylated with compounds of general formula IX

Z-CO-A-N (R4) R5 IX

Wherein A, R4 and R4 have the meaning given above and Z represents a leaving group,

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12 and won bases if desired are converted to pharmacologically tolerable acid addition salts, or won acid addition salts are converted to the free bases or to other pharmaceutically tolerable acid addition salts.

The acylation and any subsequent amination is carried out in a manner known per se.

For the preparation of compounds of general formula I **, corresponding compounds, however, which carry -CO-A ** C1 at the 4-position, are reacted with amines of general formula V ** HN (R4 **) R5 ** V * * 10 wherein R 4 ** and R 2 ** have the meaning set forth above, whereupon, if desired, a won base is converted to an acid addition salt or a won acid addition salt is converted to the free base.

For the preparation of compounds of general formula I ***, corresponding compounds which, however, carry -CO-A *** - C1 at the 4-position, are reacted with 15 piperazine or homopiperazine and methylation or ethylation of the obtained piperazinothienobenzodiazepinones of the general formula X *** H 0 r1 *** NX *** r2 *** X \

CO-A *** - N NH

\ cH2) n *** / 20 where R · * - ***, R ^ *** and A *** have the meaning given above and n *** represents 2 or 3, after which a won base, if desired, is converted into an acid addition salt, or a won acid addition salt is converted to the free base.

For the preparation of thienobenzodiazepinones of general formula XX, the starting compound of formula II is reacted, wherein R

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above, or acid addition salts thereof with compounds of the general formula III or IV

R3-A-CO-Hal 'III [R3-A-C0] 20 IV

where Hal 'has one of R3's meanings and A and R3 have the meaning given above. This acylation is carried out without or preferably in an inert solvent at room temperature or at elevated temperature, maximum at the boiling temperature of the solvent, optionally in the presence of an auxiliary base and / or an acylation catalyst. The acid halides III are preferred over the acid anhydrides IV. As acid halide III, chloroacetyl chloride is preferred and as acid anhydride IV, chloroacetic anhydride is preferred. As solvents, e.g. are mentioned aromatic hydrocarbons, e.g. toluene, xylene or chlorobenzene; open-chain or cyclic ethers, e.g. diisopropyl ether or dioxane; chlorinated hydrocarbons, e.g. dichloroethane, and other solvents such as pyridine, acetonitrile or dimethylformamide.

As auxiliary bases, e.g. are mentioned tertiary organic bases, e.g. triethylamine and ethyl diisopropylamine or pyridine; or inorganic bases, e.g. anhydrous alkali metal or alkaline earth metal carbonates or hydrogen carbonates or alkaline earth metal oxides. As acylation catalysts, e.g. imidazole, pyridine or 4-dimethylaminopyridine are used.

As mentioned, the intermediates of general formula XX can be prepared by acylating a thienobenzodiazepinone of general formula II with compounds of general formula III or IV. In the preparation of the intermediates of the general formula XX * similar starting compounds are used.

For the preparation of substituted thienobenzodiazepinones of general formula I wherein R 1, R 2 and A are as defined above.

30, the reaction product of formula XX, wherein R 3 is -Hal, is reacted with secondary amines of general formula V

HN (R4) R5 V

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14 where R 4 and Hal have the meaning given above.

The amination can be carried out in an inert solvent at temperatures between 0 ° C and the boiling temperature of the solvent, either with at least 2 moles of secondary amine of formula V or with 1-2 moles of secondary 5 amine of formula V and an auxiliary base. As solvents, e.g. chlorinated hydrocarbons such as methylene chloride, chloroform or dichloroethane are used; 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. As auxiliary bases, e.g. are mentioned tertiary organic bases, e.g. triethylamine, N-methylpiperidine, diethylaniline or pyridine, and inorganic bases, e.g. alkali metal or soil alkali metal carbonates or hydrogen carbonates and alkaline earth metal hydroxides or oxides. Optionally, the reaction can be accelerated by the addition of alkali metal iodides. The reaction times depend on the amount and nature of the amine of formula V used between 15 minutes and 80 hours. By reacting starting compounds wherein A represents alkylene having 2-5 carbon atoms, the reaction may also proceed with the decomposition of H-R 2; the intermediately formed, optionally insulable alkenyl compound reacts with the secondary amine V to form the same final product.

For the preparation of substituted thienobenzodiazepinones of general formula I wherein R 1, R 2 and A are as defined above.

25, thienobenzodiazepinones of the general formula II, wherein R 1 and R 3 may be as defined above, can alternatively be acylated with compounds of the general formula IX

Z-C0-A-N (R4) R5 IX

wherein A, R4 and are as defined above, and Z represents a leaving group.

The reaction between the compounds II and the acid derivatives IX is carried out in a manner known per se. The divisible unit Z is a unit, 15

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which together with the carbonyl group to which it is attached form a reactive carboxylic acid derivative. As reactive carboxylic acid derivatives, e.g. mention is made of acid halides, esters, anhydrides or mixed-anhydrides formed from salts of the corresponding acid (Z = OH) 5 and acid chlorides such as phosphorus oxychloride or chloroformic acid ester.

It is preferred to carry out the reaction with the mixed anhydrides IX of strong mineral acids, especially of chlorophosphoric acid. The reaction is optionally carried out in the presence of an acid binding agent (a proton acceptor).

As suitable proton acceptors, e.g. mention is made of alkali metal carbonates or hydrogen carbonates such as sodium carbonate or potassium hydrogen carbonate; tertiary organic amines such as pyridine, triethylamine or ethyl diisopropylamine; or sodium hydride. The reaction can be carried out at temperatures between -25 ° C and + 50 ° C in an inert solvent, preferably in dimethylformamide.

For the preparation of substituted thienobenzodiazepinones of general formula X wherein R 1, R 2 and A are as defined above and R 2 and R 2 together with the nitrogen atom to which they are attached form a 4-position with methyl or ethyl substituted piperazin-1-yl group or a 4-position with methyl or ethyl substituted hexahydro-1H-1,4-diazepin-1-yl group, methylated or ethylated

alternatively obtained piperazinylthienobenzodiazepinones of the general formula X

R1 | . R2 x

CO-A-N ^^ NH

(CH 2) n where R 1, R 2 and A have the meaning given above and n represents 2 or 3.

25

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16

The methylation and ethylation are carried out in a manner known per se.

As methylating and ethylating agents for compounds of general formula X, e.g. methyl and ethyl esters of strong acids, e.g. of sulfuric acid, phosphoric acid or p-toluenesulfonic acid, or methyl or ethyl halides used at between 0 and 50 ° C, optionally in the presence of a proton acceptor in an aqueous or non-aqueous medium, e.g. as described in Houben-Weyl, Vol. XI / 1, pages 24 ff and page 205 ff, Georg-Thieme-Verlag,

Stuttgart (1957); mixtures of formaldehyde or acetaldehyde and a reducing agent (reductive alkylation method) using as the reducing agent 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 sodium borohydride or sodium cyanoborohydride. Reductive alkylation methods are e.g. detailed in Houben-Weyl, Vol. XI / 1, pages 602 et seq., Georg-Thieme-Verlag, Stuttgart (1957); W. S. Emerson, Organic Reactions, Volume 4, pages 174 ff, John Wiley and Sons, New York (1948); M.L. Moore, ibid, vol. 5, pages 301 et seq. (1949); C.A.

Buehier, D.E., Pearson, Survey of Organic Synthesis, Vol. 1, pages 20 424-429 (1970), Vol. 2, 403-407 (1977), John Wiley and Sons, New

York; S.R. Sandler, W. Karo, Organic Functional Group Preparations, Volume 1, page 345 et seq. (1968), Academic Press, New York. The methylation is preferably carried out as reductive methylation.

The process for the preparation of pharmacologically active thienobenzodiazepinones of general formula I is, as mentioned, characterized in that compounds of formula XX are reacted with compounds of general formula V or that thienobenzodiazepinones of general formula II are acylated with acid derivatives IX, or that Compounds X, prepared by reaction of XX with piperazine or homopiperazine, are methylated or ethylated, and the base obtained in each process variant is then optionally converted to another pharmacologically tolerable acid addition salt or a won acid addition salt is converted to the free base or to a pharmacological tolerable acid addition salt.

Acid addition salts can be obtained by dissolving the obtained free base in a suitable solvent, e.g. water, acetone, an alkanol such as ethanol.

17 DK 157872 B

nol or isopropanol or an open-chain or cyclic ether such as diethyl ether or tetrahydrofuran containing the desired acid or to which the desired acid is then added. The salts can be isolated by filtration, precipitation with a non-solvent for the acid addition salt or by evaporation of the solvent. Salts can also be converted to other salts by conversion to the base and further reaction with another acid, e.g. pharmacologically tolerable acid addition salts.

Wounded salts can e.g. by alkalization with aqueous sodium or potassium hydroxide is converted to the free base which is then isolated in a suitable manner, e.g. by solvent extraction with a water-immiscible solvent such as chloroform, diethyl ether or toluene.

The preparation of the starting compounds of the general formula II can be made according to or analogous to U.S. Patent No. 3,953,430 according to the following reaction scheme: OQ

R H K

VI VII VIII

NBS

(DMF) H o R1 H o R1 0 $> - 0¾ H R2b H R &

Hb Ha

Phenylenediamine VI is reacted with the tetrahydrothiophenecarboxylic acid derivatives VII, wherein R · is as defined above, R Ra represents 20 hydrogen or alkyl of 1-4 carbon atoms, and R hydrogen represents hydrogen

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18 or alkyl of 1-5 carbon atoms, in inert solvents, e.g. toluene, under heating to form the tetrahydrothienobenzodiaze pinones VIII. Compounds VIII are dehydrogenated with a suitable dehydrogenating agent, e.g. N-bromosuccinimide in dimethylformamide, to form the dihydrothienobenzodiazepinones IIa. By chlorination or bromination with suitable halogenating agents, the compounds of formula IIa, wherein R 2a represents hydrogen, are converted to form the halogen derivatives IIb, where R 2 b represents a chlorine or bromine atom.

The compounds IX are known or can be prepared in known manner, optionally in situ. Preparation of the piperazinothienobenzodiazepines X is carried out by reacting compounds of formula XX wherein R represents -Hal, with corresponding amines V, i. piperazine or homopiperazine, by the methods described above for amination.

For the preparation of compounds XX *, I ** and I ***, respectively, corresponding starting compounds II *, II **, II ***, III *, III **, III ***, iv *, IV are used. **, IV ***, V **, IX **, X ** and X *** HOR1 'H o GC, -Xs © C Gy * “H \ 2 * Γ HR H« 2 ** H o / ***

ir ***

T

If Rz ***

Cl-A * -CO-Cl III * Cl-A - ** - CO-Cl III ** C1-A *** - C0-C1 III *** 20 (C1-A * -CO2) 0 IV * ( C1-A ** - C02) 0 IV ** (C1-A *** - C02) 0 IV *** HN (R ^ **) R5 ** V ** Z ** - CO-A ** - N (R 2 **) R 5 ** IX **

DK 157872B

19 H O R1 ”U o fY '* jf ^ s *** OC> 0 **** N \' 2 ** 'r2 *** 5-v / \

»In NH CO-A *** A NH

C0-A «-H ^ J ·· ^ CH2) n« * 'where R ^ · *, R ^ ** and R ^ - *** respectively represent hydrogen, methyl or ethyl, respectively R ^ *, R ^ * * and R 2 *** represent chlorine or have one of the meanings of R 2 - *, R 2 ** and R 2 ***, respectively, A *, A 2 branched alkyl having 1 or 2 carbon atoms, R 2 ** represents alkyl of 1-4 carbon atoms or alkenyl of 3-4 carbon atoms, 10 r 5 ** bar R 2 ** means or represents a group - (CH 2) m ** - N (R6 **) R7 ** or r ^ ** and r5 ** together with the nitrogen atom to which they are attached form a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl a group, optionally in the 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a 2,4-dimethyl-piperazin-1-yl group or a 4-position with methyl or ethyl substituted hexahydro -1H-1,4-diazepin-1-yl group, R 2 and R 2, together with the nitrogen atom to which they are attached, form one at the 4-position with methyl or ethyl substitute unreacted piperazine-20-yl group, a 4-position with methyl or ethyl substituted hexahydro-1H-1,4-diazepin-1-yl group, R 6 ** represents methyl or ethyl, R 2 or ethyl, m ** represents 2 or 3, 25 n ** represents 2 or 3, and Z ** represents a leaving group.

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20

The invention is further illustrated in the Examples below: EXAMPLE 1 3.5 g of 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 8.1 g of N methylpiperazine and 50 ml of toluene are stirred for 2 hours at 580 ° C. 60 ml of dilute sodium hydroxide solution is added, the phases are separated and the aqueous phase is shaken several times with toluene and evaporated to dryness in vacuo. The residue is crystallized with a small amount of acetone. There are obtained 4.2 g of 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, M.p. 177-178 ° C (acetone).

Analogously, 9,10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one is obtained. , mp 263-264 ° C (ethanol), 3-chloro-9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 239 ° C, and 9.10-dihydro-1,3-dimethyl-4 - [(4-methyl-piperazin-1-yl) -acetyl] -4H-thieno [3 , 4-b] [1,5] benzodiazepin-10-one, m.p. 204-205 ° C, by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b ] [1,5] benzodia-zepin-10-one, 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiaze-pin-10 and 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-4Hthieno [3,4-b] [1,5] benzodiazepin-10-one, 21 g of N-methylpiperazine and 70 ml of dioxane are stirred for 1 hour at 80 ° C. ° C, after which the solution is evaporated to dryness in vacuo. To the residue are added 150 ml of isopropanol and 40 ml of water, which is added dropwise 25 ml of concentrated hydrochloric acid and cooled in an ice bath to give 9.10

DK 157872 B

21 dihydro-4 - [(4-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one dihydrochloride in admixture with N-methylpiperazine hydrochloride . The hydrochlorides are dissolved in water and chloroform and adjusted to pH 8.2 by the addition of 2N sodium hydroxide solution, the aqueous phase is extracted exhaustively with chloroform and the organic solution is dried and evaporated to dryness in vacuo. 16 g of 9,10-dihydro-4 - [(4-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 177-179 ° C (of acetone).

Analogously, there is obtained 9,10-dihydro-4- (morpholinoacetyl) -4Hthieno [3,4-b] [1, Sjbenzodiazepin-10-one, mp 154-156 ° C, 4 - [(4-benzylpiperazine-1) -yl) acetyl] -9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, m.p. 129-133 ° C, 4 - [(4-ethylpiperazine-1 -yl) -acetyl] -9,10-dihydro-4H-thieno [3,4-b] -15 [1,5] benzodiazepin-10-one, mp 184-186 ° C, 4 - [(2.4 -dimethyl-piperazin-1-yl) acetyl] -9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, by reaction of 4-chloroacetyl-9,10- dihydro-4H-thieno [3,4-b] [1,5] benzodiazepine-10-one with morpholine, N-benzylpiperazine, N-ethylpiperazine and 1,3-dimethylpiperazine respectively.

Example 3 1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiaze-pin-10-one, 0.55 g of pyrrolidine, 0.85 g of ground sodium carbonate and 25 ml of absolute ethanol are heated to boiling for 2 hours and the hot solution is filtered and evaporated in vacuo. The residue is dissolved in dichloromethane and the organic solution is washed at pH 7 with water and evaporated to give 1.4 g of 9,10-dihydro-4- (pyrrolidinoacetyl) -4H-thieno [3,4-b ] [1,5] benzodiazepine-10-one, m.p. 186-188 ° C.

EXAMPLE 4 22

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1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 3.7 g of piperidine and 15 ml of dioxane are stirred for 1 hour at 80 ° C. Evaporate in vacuo and the residue is recrystallized from isopropanol / -5 water. 2.0 g of 9,10-dihydro-4- (piperidin-1-yl-acetyl) -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 202 ° C.

Analogously, 9.10-dihydro-3-methyl-4- (piperazin-1-yl-acetyl) -4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one is obtained, m.p. 225-228 ° C (dec. ), 10 by reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one with piperazine; 9.10-dihydro-1,3-dimethyl-4- (morpholin-4-yl-acetyl) -4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, m.p. 188-190 ° C, at reaction of 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno-15 [3,4-b] [1,5] benzodiazepin-10-one with morpholine; and 9,10-dihydro-1,3-dimethyl-4- (piperidin-1-yl-acetyl) -4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, m.p. 162-164eC, by reaction of 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno- [3,4-b] fl5] benzodiazepin-10-one with piperidine.

Example 5 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 6 ml of 40% aqueous dimethylamine solution and 10 ml of dichloromethane Stir for 2 hours at 35 ° C, add 0.35 g of sodium carbonate and evaporate in vacuo to dryness. A little water is added, the solution is repeatedly shaken with chloroform, and the organic phase is dried over sodium sulfate and evaporated to dryness. 1.9 g of 4- (dimethylaminoacetyl) -9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one are obtained, m.p. 173-176 ° C.

Analogously, 4- (diethylaminoacetyl) -9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one, respectively, is obtained, m.p. 196-197 ° C (of toluene), and

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4- (diethylaminoacetyl) -9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, m.p. 186-187 ° C (of toluene), by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiaze-5-pin-10-one and 4-chloroacetyl-9,10- dihydro-1,3-dimethyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and diethylamine.

Example 6 Analogously to Example 4 is obtained respectively: 9,10-dihydro-3-methyl-4- (pyrrolidinoacetyl) -4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one, m.p. 235 -237 ° C, 3-chloro-9,10-dihydro-4- (pyrrolidinoacetyl) -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 9,10-dihydro -1,3-dimethyl-4- (pyrrolidinoacetyl) -4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one,

C

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, respectively, 10 - dihydro-4H-thieno [3,4-b] [1,5] benzodiazole pin-10-one and 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] b] [1,5] benzodiazepin-10-one with pyrrolidine.

EXAMPLE 7

Analogously to Example 5, 4- (dimethylaminoacetyl) -9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, respectively, is obtained, m.p. 212-214.5 ° C, 3-chloro-4- (dimethylaminoacetyl) -9,10-dihydro-4H-thieno [3,4-b] [1,5] -30-benzodiazepin-10-one and 4- (dimethylaminoacetyl) -9, 10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] - [1.5] benzodiazepin-10-one

DK 157872 B

24 by reaction of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiaze-pin-10-one, 3-chloro-4-chloroacetyl 9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno [ 3,4-b] [1,5] benzodiazepin-10-one with dimethylamine.

EXAMPLE 8 8 g of 9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 5.6 ml of chloroacetyl chloride in 160 ml of dioxane are boiled for 8 hours. reflux in the presence of 8 g of ground potassium carbonate. The solution is evaporated to dryness, the residue is taken up in toluene and washed with sodium bicarbonate solution and then with water, and the toluene solution is dried over sodium sulfate. Evaporation gives 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, mp 156-158 ° C.

Analogously, respectively, 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] is obtained benzodiaze-pin-10-one, mp 214-216 ° C. and 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 192-195 ° C, by reaction of 3-chloro-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 9,10-dihydro-1,3-dimethyl-4H-thieno, respectively [3 , 4-b] [1,5] benzodiazepin-10-one, with chloroacetyl chloride.

EXAMPLE 9

To a suspension of 18.8 g of 9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one in 500 ml of dioxane, at room temperature, drop 10.4 ml of chloroacetyl chloride, thereby forming a clear solution. Allow the solution to stand for 3 hours, then evaporate to dryness,

DK 157872 B

The solution is taken up in toluene and washed with sodium bicarbonate solution and then with water and the toluene solution is dried over sodium sulfate.

Evaporation gives 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one in the form of a slowly crystallizing oil, m.p. 220 ° C.

By analogy, respectively, 4-chloroacetyl-9,10-dihydro-1-methyl-4H-thieno [3,4-b] [1,5] benzodiaze-pin-10-one and 4-chloroacetyl-9,10- dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodia-10-zepin-10-one, mp 156-158 ° C, by reaction of 9.10-dihydro-1-methyl-4H, respectively -thieno [3,4-b] [1,5] benzodiazepin-10-one and 9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one with chloroacetyl chloride .

EXAMPLE 10

To a boiling solution of 2.2 g of 9,10-dihydro-4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one in 30 ml of absolute dioxane is added dropwise over 40 minutes 2, 2 g of chloroacetyl chloride and 2 ml of triethylamine are stirred for 3 hours. The mixture is allowed to cool and filtered, the filtrate is evaporated to dryness and chromatographed over a silica gel column using a mixture of petroleum ether and ethyl acetate in a 1: 1 ratio and recrystallized from toluene to give 2.0 g of 4-chloroacetyl-9 , 10-Dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one in the form of an oil which slowly crystallizes, m.p. 220 ° C.

EXAMPLE 11

A solution of 5 ml of sulfuryl chloride in 100 ml of methylene chloride is dropped into a solution of 12 g of 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one in 300 ml. ml of methylene chloride at 20 ° C. The mixture is allowed to stand for 12 hours at room temperature, then extracted with sodium bicarbonate solution and washed with water. The phase is dried and evaporated. The residue is crystallized with one

DK 157872 B

26 bit methanol. 7 g of 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one are obtained, m.p. 214-216 ° C (acetonitrile) .

EXAMPLE 12 A mixture of 1.00 g (4-methylpiperazin-1-yl) acetic acid and 0.20 g of 75% sodium hydride in paraffin oil in 16 ml of dimethylformamide is heated to 50-80 ° C until hydrogen evolution has ceased (2). -3 hours). To the sodium salt formed of the acid is added 1.35 g of 9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and added dropwise at -10 ° C. 0.99 g of 98% phosphorus oxychloride for 10 minutes. Stir for 4 hours at -10 ° C, for 4 hours at 0 ° C and for 20 hours at room temperature. The charge is poured onto ice, adjusted to pH 3.5 with sodium hydroxide solution and shaken with methylene chloride, and the aqueous phase is adjusted to pH 9 and shaken again with methylene chloride. The organic phase is washed with water and evaporated in vacuo. 0.6 g of 9.10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one, m.p. 177-178 ° C (of acetone).

Analogously, 9,10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepinone-10 is obtained, respectively. -one, mp 263-264 ° G, and 9,10-dihydro-1,3-dimethyl-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1 , 5] benzodiazepin-10-one, m.p. 204-205 ° C, by reacting (4-methylpiperazin-1-yl) acetic acid with sodium hydride and 9,10-dihydro-3-methyl-4H-thieno [3,4- b] [1,5] benzodiazepine-10-one and 9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and phosphorus oxychloride.

EXAMPLE 13

To a suspension of 1.58 g (4-methylpiperazin-1-yl) acetic acid in 20 ml of tetrahydrofuran is dropped at 0 ° C 1.1 g of chloromyric acid ethyl ester. To the resulting suspension is added 2.18 g of 9,10-dihydro-4

DK 157872 B

27 [3,4-b] [1,5] benzodiazepine-10-one, then stirred for an additional 1 hour at 0 ° C and then for 4 hours at room temperature. The mixture is poured onto 160 ml of 2N sodium hydroxide solution and extracted with toluene and the organic phase is evaporated to dryness. After purification 5 by column chromatography (silica gel; dioxane / methanol 1: 1), 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] is obtained [ 1,5] benzodiazepin-10-one, m.p. 177-179 ° C.

Analogously, 9.10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) -acetyl) -4H-thieno

[3,4-b] [1,5] benzodiazepin-10-one, m.p. 263-264 ° C

by reaction of 9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one with (4-methylpiperazin-1-yl) acetic acid and chloroformic acid ethyl ester.

Example 14 2.0 g of 9,10-dihydro-3-methyl-4- (piperazin-1-yl-acetyl) -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 1.3 g of 98% formic acid and 0.3 g of 35% aqueous formaldehyde solution are heated to 100-105 ° C for 2 hours, thereby allowing the mixture to liquefy under evolution of gas. Evaporate in vacuo, dilute with water, adjust to pH 3.5 with dilute hydrochloric acid and shake with dichloromethane. The aqueous phase is adjusted to pH 9 and extracted with dichloromethane. The organic phase is washed, dried and evaporated. Recrystallization of the residue of methanol gives 9,10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) -acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepine-10-one, m.p. 263-264 ° C.

The starting compounds are prepared as follows:

Example A: To a solution of 21.6 g of 9,10-dihydro-4H-thieno [3,4-b] - [1,5] benzodiazepin-10-one in 300 ml of dichloromethane is dripped at -40 ° C 13, 5 g of sulfuryl chloride in 100 ml of dichloromethane. The mixture is allowed to stand for an additional hour at room temperature, then shaken with sodium hydrogen carbonate solution and washed with water, and the

DK 157872B

28 organic phase is dried and evaporated. The residue is crystallized with a little methanol. 3-Chloro-9,10-dihydro-4H-thieno- [3,4-b] [1,5] benzodiazepin-10-one is obtained.

Example B: 10 g, 3,9,10-tetrahydro-3-methyl-4H-thieno [3,4-b] [1,5] -5-benzodiazepin-10-one and 8.2 g of N-bromosuccinimide are dissolved in 250 ml dime thylformamide. After 1 hour, the solution is poured onto 2 liters of water. The precipitate is aspirated, dissolved with hot toluene and cleared with Tonsil®. On cooling, 9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one is obtained, mp 228-230 ° C (methanol).

By analogy, 9,10-dihydro-1-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 9,10-dihydro-1,3-dimethyl-4H-thieno are respectively obtained [3, 4-b] [1,5] benzodiazepine-10-one, m.p. 195-196 ° C, 15 by dehydrogenation of 1,3,9,10-tetrahydro-1-methyl-4H-thieno [3,4-b] [1, 5] benzodiazepin-10-one and 1,3,9,10-tetrahydro-1,3-dimethyl-4H-thieno [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 are boiled in 4.5 liters of toluene. Over 7 hours, the water formed is distilled azeotropically with 2 liters of the solvent. The solvent is removed. 1,3,9,10-tetrahydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one is obtained, m.p. 195-197 ° C (isopropanol).

By analogy, respectively, 1,3,9,10-tetrahydro-1-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 1,3,9,10-tetrahydro-1,3-dimethyl-4H- thieno [3,4-b] [1,5] benzodiazepine-10-one, mp 148-150 ° C, by reacting tetrahydro-2-methyl-4-oxo-3-thiophenecarboxylic acid and tetrahydro-2.5, respectively -dimethyl-4-oxo-3-thiophenecarboxylic acid with o-phenylenediamine.

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29

The following examples describe the formulation of the present compound for drug preparations.

EXAMPLE 15 10,000 tablets with an active substance content of 20 mg are prepared from the following 5 ingredients: 200 g of 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4- b] [1,5] benzodiazepine-10-one, 900 g corn starch, 500 g lactose, 300 g amorphous silicic acid and 40 g sodium lauryl sulfate are mixed and sieved. This mixture is moistened with a solution of 50 g of polyvinylpyrrolidone (average molecular weight 25,000) in 320 ml of alcohol and granulated through a 1.25 mm mesh screen. The granulate is dried at 40 ° C and mixed with 160 g of pectin, 100 g of talc and 20 g of magnesium stearate. This mixture is pressed into tablets of 200 mg each with a diameter of 8 mm.

EXAMPLE 16 100,000 capsules with an active substance content of 30 mg are prepared from the following ingredients: 3,000 g of 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno- [3,4 -b] [1,5] benzodiazepine-10-one is mixed with 5,000 g of neutral oil (Miglyol®812) and filled into soft gelatin capsules.

EXAMPLE 17 100,000 capsules with an active substance content of 30 mg are prepared from the following ingredients: 1,500 g of 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno- [3,4 -b] [1,5] benzodiazepine-10-one and 1,500 g of magnesium trisilicate intermediate

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Dec 30 with 5,000 g of neutral oil (Miglyol®812) and filled in soft gelatin capsules.

Analogously to Examples 15-17, similar drugs are prepared in which 9,10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4- b] [1,5] benzodiazepin-10-one and 9,10-dihydro-1,3-dimethyl-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3, 4-b] [1,5] benzodiazepin-10-one is used in place of 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3 , 4-b] [l, 5] benzodiazepin-10-one.

PHARMACOLOGY

10 The excellent gastric protection effect of the pharmacologically active substituted thienobenzodiazepinones can be demonstrated in the so-called Shay rat model. . can be seen by comparing (1) with 9,10-dihydro-4- [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepine-10 one (2), 3-chloro-9,10-dihydro-4 - [(4-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one (3), 9,10-dihydro-3-methyl-4 - [(4-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiaze-pin-10 -one (4) and 9,10-dihydro-1,3-dimethyl-4 - [(4-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepine 10-ounce (5).

31 DK 157872 B

Table I

The antiulcerogenic action and toxicity of thienobenzodiazepinones.

+)

Compound Toxicity Stomach TQ Stomach secretion number ^ 50 effect LD ^^ / -% inhibition 5 (mg / kg) ED50 (mg / kg) ED ^ Q rat i.v. , mouse po, rat 1 290 «70 4.1 7 2 190 2.5 76 35 10 3 75 <1> 75 28 4 130« 0.3 «433 20 5 180 1.3 139 17 EDrn = the dose that decreases the ulcer index of the treated 50 'group relative to the control group by 50%.

LD50 = ^ a dose at which 50% of the animals die.

TQ = therapeutic quotient LD ^ q / ED ^ q% inhibition = inhibition of gastric secretion as a percentage 4 hours after administration of the antiulcerogenic ED.

In particular, it should be noted that for compound 1, although an ED, -q value can still be determined, the dose-effect curve then flattens very strongly, so that even at 300 mg / kg no significant increase of the antiulcerogenic effect. In contrast, the effect of compounds 2-5 is highly dose dependent; an inhibitory effect of up to 95% can be achieved.

The test of the antiulcerogenic effect is as mentioned by the so-called Shay rat method:

The ulcer provocation is performed on rats fasted for 24 hours (female rats, 180-200 g, 4 animals in each high lattice cage) by pylorus ligature

DK 157872B

32 (under diethyl ether anesthesia) and oral application of 100 mg / 10 ml / kg acetylsalicylic acid. The substances to be tested are administered orally (10 ml / kg) 1 hour before the pylorus ligator. The wound closure is done using Michel clamps. 4 hours thereafter, the animals are killed in an etherrus 5 by Atlas dislocation and the stomach is removed. The stomach is opened longitudinally and fixed on a cork plate after the amount of the secreted stomach juice (volume) is first determined; with a stereomicroscope, at 10x magnification, the number and size (= diameter) of ulcers present are determined. The severity product (according to the 10-point scale below) and the number of ulcers serve as an individual ulcer index.

Point Scale:

No ulcer 0

Ulcer diameter 0.1 - 1.4 mm 1 1.5 - 2.4 mm 2 2.5 - 3.4 mm 3 3.5 - 4.4 mm 4 4.5 - 5.4 mm 5> 5.5 mm 6

As a measure of the antiulcerogenic effect, the reduction of the mean 20 index of ulcer for each treated group, relative to the control group (= 100%), serves. The ED ^ q value denotes the dose which reduces the median ulcer index by 50%.

DETERMINATION OF TOXICITY

Toxicity studies are performed on NMRI female mice (body weight 22-25 26 g). The animals (5 animals for each dose) receive feed and water ad libitum.

Various doses of the drugs are administered intravenously (injection time 1 minute). The observation time is 7 days. ID value, ie the dose at which 50% of the animals die is determined by linear regression.

Claims (12)

1. Analogous Process for Preparing Substituted Thienobenzodiazepinones of General Formula I H 0 J »1 Process according to claim 1, variant a), characterized in that substituted thieno-benzodiazepinones of the general formula I ** 1 ** H 0 R1 2 ** *** R * are prepared. ; 0-a ** “ncr <, **) R5 ** where R1 represents hydrogen, methyl or ethyl, 9 in R ** represents chlorine or has one of the meanings of R1 **, R4 ** represents alkyl of 1-4 carbon atoms or alkenyl of 3-4 carbon atoms, DK 157872 B r5 ** has the same meaning as R4 ** or represents a group - (CH2) m ** - N (R6 **) R7 **, or R4 ** and r5 ** together with the nitrogen atom to which they are bound, forms a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, an optionally in the 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a dimethyl-piperazin-1-yl group or a 4-position with methyl or ethyl-substituted hexahydro-1H-1,4-diazepin-1-yl group, and R6 ** represents methyl or ethyl, R7 ** represents methyl or ethyl, m ** represents 2 or 3, and A ** represents straight or branched alkylene with 1 or 2 carbon atoms, 15 or acid addition salts thereof by reacting similar compounds, however, bearing -CO-A ** C 4-position, with amines with the general formula V ** HN (R4 **) R5 ** V ** wherein R4 ** and r5 ** have the meaning set forth above, whereupon a won base, if desired, is converted to an acid addition salt, or a won acid addition salt is converted to the free base. Process according to claim 2, characterized in that compounds of the general formula I ** are prepared, wherein 25 R 1 represents hydrogen, methyl or ethyl, R 2 ** represents chlorine or has one of R R4 ** means methyl or ethyl, R5 ** has the same meaning as R4 ** or represents a group - (CH2) m ** - N (R6 **) R7 **, or R 4 ** and R 2 ** together with the nitrogen atom form a pyrrolidino, piperidino or hexahydroazepin-1-yl group, R 6 ** and R 7 ** represent methyl or ethyl, m ** represents 2, and A ** denotes methylene, or pharmacologically tolerable acid addition salts thereof. DK 157872 B Process according to claim 2, characterized in that compounds of the general formula I ** are prepared, wherein rA ** represents hydrogen, methyl or ethyl, 5 r.2 ** represents chlorine or has one of rA ** 's. means, R 4 · ** and R - *** together with the nitrogen atom denote an optionally in the 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a 2,4-dimethyl-piperazine-1- yl group or a 4-position with methyl or ethyl substituted hexahydro-1H-1,4-diazepin-1-yl-10 group, and A ** represents methylene, or pharmacologically tolerable acid addition salts thereof. R 5 represents halogen, and A represents straight or branched alkylene having 1-5 carbon atoms, or acid addition salts thereof. R 2 **, R 2 **, R 2 **, R 2 ** and A ** have the meaning set forth in claim 2, when reacting thienobenzodiazepinones of the general formula II ** in * · * H 0 R 1 f jT * jT'5 ϊϊ ** «R 10 where r! ** and R2 ** have the meaning given above, with reactive acid derivatives of the general formula IX ** Z ** - C0-A ** - N- ( R 2 **) r 5 ** IX ** wherein Z ** represents a leaving group and A **, R ^ ** and R ^ ** have the meaning set forth in claim 2. Process according to claim 2, characterized in that compounds of the general formula I ** are prepared wherein rA ** represents hydrogen or methyl, r 2 ** represents hydrogen or methyl, r 2 ** and R 5 ** together with the nitrogen atom represents a 4-position with methyl substituted piperazine-1-yl group, and 20 A ** represents methylene, or pharmacologically tolerable acid addition salts thereof. 5 CX. 1 in R 2 CO-AN (R 4) R 5 wherein R 1 - represents hydrogen or alkyl of 1-4 carbon atoms, R2 represents halogen or has one of the meanings of rA, 10 represents alkyl of 1-4 carbon atoms or alkenyl of 3-5 carbon atoms and R 1 has one of R 1's meanings or represents a group - (CH 2 -N (R 6) R 7) or zm R 2 and R 2 together with the nitrogen atom to which they are attached form a morpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, an optionally at the 4-position with methyl, ethyl or benzyl substituted piperazin-1-yl group, a 2,4-dimethylpiperazin-1-yl group or a 4-membered methyl or ethyl substituted hexahydro-1H-1,4-diazepin-1-yl group, and 20 R 4 represents alkyl of 1-4 carbon atoms, R 7 represents alkyl of 1-4 carbon atoms, A represents straight chain or branched alkylene having 1 to 5 carbon atoms, and m represents 2 or 3, 25 or pharmacologically tolerable acid addition salts thereof, characterized in that a) thienobenzodiazepinones having the general formula XX DK 157872B Λ R 'R2 κ CO-A-R3 wherein A, R4 and having the meaning given above and R4 represents 5 halogen are aminated with a compound of the general formula V HN (R4) R5 V wherein R4 and R4 are as defined above, or b) thienobenzodiazepinones of the above general formula XX are aminated with piperazine or homopiperazine, and the reaction product of the general formula XH 0 R1 r2 x ΙΟ h = ch 2) / wherein R 1 -, R 2 and A have the meaning given above and n represents 2 or 3, methylated or ethylated, or C) compounds of the general formula II H 0 R 1 HR * 5 wherein R 1 - and having the meaning given above, are acylated with compounds of the general formula IX Z-CO-AN (R 4) R 5 'IX where A , R4 and R4 have the meaning given above, and Z represents a leaving group, 10 and won bases, if desired, are converted to pharmacologically tolerable acid addition salts, or won acid addition salts are converted to the free bases or to other pharmaceutically tolerable acid addition salts. Process according to claim 1, variant b), characterized in that substituted thieno-benzodiazepinones of general formula I are prepared. * C0-A *** - N (R4 ***) R5 *** where r1 *** represents hydrogen, methyl or ethyl, DK 157872B r.2 *** represents chlorine or has one of rA *** ' s and, together with the nitrogen atom to which they are attached, form a 4-position with methyl or ethyl substituted piperazin-1-yl group or a 4-position with methyl or ethyl substituted hexahydro-1H-1, 4-diazepin-1-yl group, and A *** represents straight or branched alkylene having 1 or 2 carbon atoms, or acid addition salts thereof, by reacting similar compounds, however, bearing -CO-A *** - C 4-position, with piperazine or 10 homopiperazine and methylation or ethylation of the obtained piperazine-nothienobenzodiazepinones of the general formula X *** H 0 r1 *** X *** Ir2 *** / \ CO-A *** - N NH \ CH2) n *** / 15 where r! ***, R ^ *** and A * ** has the meaning given above, and n *** represents 2 or 3, after which, if desired, a won base is converted to an acid addition salt or a won acid addition salt is converted to the free base. Process according to claim 6, 20, characterized in that compounds of the general formula I ***, wherein hydrogen or methyl, are represented by R 1 *** have the meaning of R 2 ***, R 2 ** and R 2 *** together with the nitrogen atom form a 4-position with methyl substituted piperazin-1-yl group, and A *** represents methylene, or pharmacologically tolerable acid addition salts thereof. Process according to claim 1, variant c), characterized in that substituted thieno-benzodiazepinones of the general formula I are prepared. ***) R *** where Process according to claim 1, characterized in that 9,10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] is prepared. [1,5] benzodiaze-pin-10-one or its dihydrochloride. Substituted thienobenzodiazepinones for use as intermediates in the process of claim 1, characterized in that they have the general formula XX where CO is represented by hydrogen or alkyl of 1-4 carbon atoms. halogen or has any of the meanings of R Substituted thienobenzodiazepinones according to claim 10, characterized in that they have the general formula XX * Rl * io r 'R2 *: oa * -r3 * wherein rA * represents hydrogen, methyl or ethyl, R 2 * represents chlorine or has a of R 2 * means R 2 * represents chlorine and A * represents straight or branched alkylene having 1 or 2 carbon atoms. DK 157872B Compound according to claim 11, characterized in that it is 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one.