DD158902A5 - METHOD FOR PRODUCING SUBSTITUTED THIENOTRICYCLES - 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

U 542 5 $

"/ learn about the preparation of substituted Thienotricyclen

Field of application of the invention

The invention relates to a process for the preparation of substituted Thienotricyclen.

The compounds obtainable according to the invention are used in the pharmaceutical industry as intermediates and for the preparation of medicaments.

Characteristic of the known technical solutions:

In German published patent application D3-0S 17 95 176 certain dibenzodiazepions an ulcushemmende and secretion-inhibiting effect is attributed. US Pat. No. 3,953,430 discloses substituted benzodiazepines having an antidepressant and anaigetic action. Substituted thienobenzodiazepines with anagetic activity are described in US Pat. No. 4,128,292.9. Thienobenzodiazepinones have now been designed, the new interesting ones

have pharmacological effects. - 2 -

- 2 - Object of the invention:

The invention provides a process for the preparation of substituted thienobenzodiazepinones of the general formula I in which R is a hydrogen atom or an alkyl radical having 1 to 4

Carbon atoms, 2 R represents a halogen atom or one of the meanings

has from R,

Ел is a halogen atom or the group -IT (R) R and

R is an alkyl radical having 1 to 4 carbon atoms or an alkenyl radical having 3 to 5 carbon atoms, R has one of the meanings of R, or the group - (CH 2) -

-Ii (R ⁶ ) R ⁷ represents or

4 5

R and R together, including the nitrogen atom to which they are attached, a liorpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, an optionally in ι-position by a l.Iethyl-, ethyl or 3-benzyl substituted piperazin-1-yl group, a 2,4-dimethylpiperazin-1-yl group or a 4-position by a Liethy1- or ethyl group substituted hexahydro-1 Ξ-1,4-diazepin-1-yl mean group and

R is an alkyl group having 1 to 4 carbon atoms,

7 R is an alkyl group having 1 to 4 carbon atoms, A is a straight-chain or branched alkylene group having 1

to 5 carbon atoms and m is 2 or 3, as well as their acid addition salts.

Alkyl radicals having 1 to 4 carbon atoms are the LIethyl-, ethyl, propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl radical. Of the alkyl radicals R , R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} the LIethyl- and Ethyirest.

As alkenyl radicals having 3 to 5 carbon atoms, the allyl radical and the 2-bIethylallylrest be mentioned.

Halogen atoms R are the bromine atom, in particular the chlorine atom. Halogen atoms R (shark) are the iodine, the Зgst- and in particular the chlorine atom.

Alkylene groups having 1 to 5 carbon atoms are the trimethylene, tetramethylene, ethylene, propylene, ethylmethylene group, preferably the ethylene group, especially the methylene group.

Suitable salts are any acid addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically intolerable salts are converted by the method known in the Pachmann into pharmacologically acceptable salts. Examples which may be mentioned are water-soluble or water-insoluble acid addition salts, such as the hydrobromide, hydroiodide, nitrate, acetate, 3-benzoate, hibenzate / 2- (4-hydroxybenzoyl) benzoate, pendizoate (2- / 2'-hydroxy-4-biphenylyl) carbonyl, ⁷ ^ enz oat), propionate, butyrate, sulfosalicylate, laurate, oxalate, Amsonat (4,4'-diaminostilbene-2,2'-disulfonate), embonate _/> 4.4 ^{t-methylene-bis} (3-hydroxy-2 naphthoate _} _ 7j Iletembonat / 4 ", 4 ^t -bIethylen-bis- (3-methoxy-2-naphthoat27, stearate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, in particular the hydrochloride, phosphate, sulfate , Citrate, gluconate, maleate, malate, pumarate, succinate, tartrate, tosylate (p-toluenesulfonate), tesilate (methanesulfonate), amidosulfonate.

An embodiment of the substituted thienobenzodiazepinones obtainable according to the invention are those of the general formula I *. wherein

represents a hydrogen atom, a methyl or ethyl radical,

, * represents a chlorine atom or has one of the meanings of R ¹ *,

represents a chlorine atom and a straight-chain 1 or 2 carbon atoms.

A is a straight-chain or branched alkylene group with

Preferred representatives of embodiment 1 are those in which R is a hydrogen atom or a Zlethylrest, R is a hydrogen atom or a Hethylrest and A * is a methylene group.

jL ·.

Particularly preferred representatives of embodiment I are those in which R and R represent a hydrogen atom, R is a chlorine atom and A is a diethylene group.

A further embodiment of the substituted thienobenzodiazepinones obtainable according to the invention are those of the general formula I ** in which R ** denotes a hydrogen atom, a liethy1 or ethyl radical,

R represents a chlorine atom or has one of the meanings of R ¹ "**,

the group -N (R ⁴ **) R ⁵ ** and

an alkyl radical having 1 to 4 carbon atoms or an alkenyl radical having 3 to 4 carbon atoms,

the meaning of R ⁴ ** or the group - (CH ₂ ) rf

) R ⁷ ** represents or

R and R 'together include the nitrogen atom to which they are attached, a llorpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, optionally substituted in the 4-position by a methyl, ethyl or berzyl group piperazin-1-yl group,

a 2,4-dimethyl-piperazin-1-yl group or a 4-position substituted by a methyl or ethyl group hexahydro-IH-1,4-diazepin-i-yl group and

R ** is a methyl or ethyl group, R '* "* is a methyl or ethyl group, in ** 2 or 3,

A "** denotes a straight-chain or branched alkylene group having 1 or 2 carbon atoms,

and their acid addition salts.

A group of "Design I representatives are

1 ^ fct before those in which R represents a hydrogen atom, a LIethyl- or ethyl radical, R represents a chlorine atom or a

1 - ^ Hi 4 ^ ⁴ Jc has the meanings of R; R is a methyl or ethyl radical, R has the meaning of R or the group - (GH ₂ ) _m * · * - IT (R ^{6 +} ) R ⁷ * "* or R ⁴ *" * and R ^{5 <} * together with the Sticksτoffadorns an iyrrolidino-, piperidino- or hexahydroasepin-1-yl-rest ;, R

7 уСЩ Щ ^ ( ** fp * C

and R is an ethyl or ethyl radical, m 2 and A 'are a methylene group, and their pharmacologically acceptable acid addition salts.

Чей?

Sine other group of representatives of the design I

1 ** are those in which R is a hydrogen atom, a methyl or ethyl radical, R is a chlorine atom.

or has one of the meanings of R; R and R 'together with the inclusion of the nitrogen atom in a 4 -step by a LIethyl-, ethyl or benzyl-substituted piperazin-1-yl group, a 2,4-dimethyl-piperazin-1-yl group or a in 4-position by a LIethyl- or Sthylgruppe substituted hexahydro-1H-1,4-diazepin-1-yl group and A ⁺⁺ mean a LIethylengruppe, as well as their pharmacologically acceptable acid addition salts.

Preferred representatives of embodiment I are those in which R '' is a hydrogen atom or a methyl radical, a hydrogen atom or a Liethylrest, R and R 'together with the inclusion of nitrogen in a 4-position substituted by a methyl group piperazin-1-yl- group and A "mean a methylene group, as well as their pharmacologically acceptable acid addition salts.

Preferred compounds obtainable in accordance with the invention are 9,10-dihydro-4- / T "4-meth3'-piperazin-1-yl) -acetyl-7-4H-thieno ~ / 3,4-b_7 / T, _i- 57-benzodiazepine-10 on,

9, 10-dihydro-1,3-dimethyl-4 - /, r4-methylpiperazin-1-yl) -acetyl-7-4H-thieno / 3,4-b7 / T, j-7-benzodiazepin-10-one, 9,10 -D: U2-hydro-3-methyl-4-ZT4-methylpiperaz: Ln-1-yl) -acetyl7-4H-thieno / 3> 4-bJ7 / T, 57benzodiazepin-10-one, as well as their pharmacologically acceptable acid addition salts.

Presentation of the "invention of the invention:

The process according to the invention for the preparation of the substituted orthobenzodiazepinones of the general formula I and their acid addition salts is characterized in that thienobenzodiazepinones of the general formula II in which

1 2 R and R have the abovementioned meaning acylated and optionally subsequently aminated and / or converted bases into the acid addition salts or resulting acid addition salts in the free base or pharmacologically acceptable acid addition salts.

The acylation and the optionally subsequent amination is carried out by methods known per se.

For the preparation of the thienobenzodiazepinones of general formula I in which R ^{3 is} -Hai, the starting materials are

1 2 compound of formula II, wherein R and R are the above-mentioned

Ъепѳп meanings, or their acid addition salts with * compounds of the general formulas III Hal-A-CO-HaI ^! (III) or 17 / Hal -A-GOJ ₂ O (IV), wherein Hal 'has one of the meanings of shark and A and Hai have the meanings given above implemented. This acylation is carried out without or preferably in an inert solvent at room temperature or elevated temperature, at most at the boiling point 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 is chloroacetyl chloride, as acid anhydride IV chloroacetic anhydride is preferred. Examples of suitable solvents are aromatic hydrocarbons, such as toluene, xylene or chlorobenzene; open-chain or cyclic esters, such as diisopropyl ether or dioxane; chlorinated hydrocarbons, such as dichloroethane, other solvents, such as pyridine, tril or dimethylformamide,

As auxiliary bases, e.g. tertiary organic bases such as triethylamine and ethyldiisopropylamine, or pyridine; or inorganic bases such as anhydrous alkali metal or alkali earth metal carbonates or bicarbonates or 3rdalkalimetalloxide called. As acylation catalysts are, for example, imprinted in imidazole, pyridine or 4-dimethylaminopyridine.

The process for the preparation of the intermediates of all general formula I is thus characterized by acylating a thienobenzodiazepinone of the general formula II with compounds of the general formula III or IV. In the preparation of the intermediates of general formula I * corresponding starting materials are used,

For the preparation of substituted thienobenzodiazepinones

1 2

of the general formula I in which R and R have the abovementioned meaning and R represents a group -Έ (ϋ) II , the reaction product of the formula I in which R-Hal is obtained is reacted with secondary amines of the general formula V HIT ( R ⁴ ) R ⁵ (V) reacted, wherein R ⁴ , R ⁵ and Hai have the above meaning.

The amination is carried out in an inert solvent at temperatures between 0 ° and boiling temperature of the solvent either with at least 2 moles of secondary amine V or with 1 to 2 get secondary amine Y and an auxiliary base. Examples of suitable solvents are chlorinated hydrocarbons, such as, for example, methylene chloride, chloroform or dichloroethane; open-chain or cyclic ethers, such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene, toluene, ZyIöl, chlorobenzene or IPyridin; Alcohols, of ethanol or isopropanol; Ketones, such as acetone; Acetonitrile or dimethylformamide. Examples of suitable auxiliary soaps are tertiary organic bases, such as triethylamine, JT-methylpiperidine, diethylaniline or pyridine, or inorganic bases, such as alkali metal or alkaline earth metal carbonates or bicarbonates, alkaline earth metal hydroxides or oxides. Optionally, the reaction can be accelerated by the addition of alkali metal iodides. Depending on the amount and type of amine Y used, the reaction times are between 15 minutes and 80 hours. In the reaction of starting compounds in which A is an alkylene group having 2 to 5 carbon atoms, the reaction can also proceed with elimination of H-Hal; the intermediately formed, optionally isolable alkenyl compound reacts with the secondary amine V to the same end product.

For the preparation of the substituted thienobenzodiazepines

of the general formula i, in which R, R "and A have the abovementioned meaning and R denotes a group -H (R) R, are, alternatively, thienobenzodiazepinones of the general formula

1 2 new formula II, wherein R and R have the meaning given above, with compounds of general formula H, wherein

Δ. 5 A, R 'and R have the meanings given above and Z represents a leaving group (= leaving group) acylated.

The reaction of the compounds Ii with the acid derivatives K takes place in a manner known per se. The leaving group Z is a group which, together with the carbonyl group to which it is attached, forms a reactive derivative of the carboxylic acid. As reactive carboxylic acid derivatives, for example, acid halides, esters, anhydrides or mixed anhydrides, such as phosphorus chloride or Ghlorameisensäureester to be formed, called, Preferably, the reaction with the mixed anhydrides H strong Llineralsäuren, in particular chlorophosphoric acid performed. The reaction is optionally carried out in the presence of an acid-binding gown (proton acceptor). Examples of suitable proton acceptors are alkali metal carbonates or bicarbonates, such as sodium carbonate or potassium bicarbonate; tertiary organic amines such as pyridine, triethylamine, ethyldiisopropylamine; or sodium hydride. The reaction is carried out at temperatures between -25 ° and 50 ° in an inert solvent, preferably in dimethylformamide.

For the preparation of substituted thienobenzodiazepinones

1 2

of the general formula I in which R, R and A have the abovementioned meaning and R is a group -

in which R and R together, including the nitrogen atom to which they are bonded, a piper az in 1 -yl group substituted in the 4-position by a methyl or ethyl group, or a 4-position by a terminal

- 10 -

hyl- or ethyl group substituted hexahydro-1H-1,4-diazepin-1-yl group, are alternatively obtained piperazinylthienobenzodiazepinones of general formula X,

In which R, R and A have the abovementioned meaning and η is 2 or 3, methylated or ethylated.

The blethylierung and sthylation are carried out according to known methods. Thus, for example, as a methylation and ethylating agent for compounds of the general formula Σ iii considered:!.! LIethyl- and ethyl esters of strong acids, for example sulfuric acid, phosphoric acid or p-toluenesulfonic acid, or ethyl or ethylene halides, between ⁰ ° C and 5O ⁰ C are optionally used in the presence of a proton acceptor in an aqueous or non-aqueous LIedium, as for example in Houben-Weyl volume ZI / 1, page 24 et seq. and p. 205 et seq., Georg Thieme Verlag, Stuttgart (1957 ) is described; mixtures of formaldehyde or acetaldehyde with a production agent (L'Iethode of the reductive alkylation), wherein as a reducing agent nascent hydrogen (eg from zinc and hydrochloric acid), hydrogen in the presence of a hydrogenation catalyst, such as platinum or Raney ITiekel, formic acid or complex metal hydrides, such as sodium borohydride or sodium cyanoborohydride, come in mint. Methods of the reductive alkylation are described in detail, for example, in Houben-Weyl, Volume XI / 1, page 602 et seq., Georg Thieme Verlag, Stuttgart (1957); WS Emerson, Organic Reactions, 3and 4, p. 174 et seq., John Wiley and Sons, ITew York (1948); Li.L. Lloore, idiu, Volume 5, 3. 301 ff., 949); OA Buehler, DE Pearson, Survey of Organic Synthesis, Vol. 1, p. 424-429 (1970), Vol. 2, 403-407 (1977), John Wiley and Sons, Hew York; SR Sandier, W. Karo, Organic Functional Group Preparations, Vol. 1, p. 345 et seq. (1968), Academic Press, Hew York. Preferably, the methylation is carried out as a reductive methylation.

- 11 -

The process for the preparation of the pharmacologically active thienobenzodiazepinones of the general formula I is thus characterized by reacting compounds of the formula I in which R is -Hai with compounds of the general formula V or by acylating thienobenzodiazepinones of the general formula II with acid derivatives TL or "that methylated or ethylated compounds Σ and in each case optionally subsequently the base obtained in a pharmacologically acceptable Säadeadssssala or a resulting acid addition salt into the free 3ase or a pharmacologically acceptable acid addition salt.

Acid addition salts are obtained by dissolving the resulting free base in a suitable solvent, z.3. ', Tasser, acetone, an alkanol, such as 3thanol or isopropanol, an open-chain or cyclic 3ther, such as diethyl ether or! Etrahydrofuran, which contains the unnatural acid or the desired acid is then added. The salts are recovered by filtration, precipitation with an ITICirclösungsmittel for the acid addition salt or by evaporation of the solvent. Salts may also be converted to other salts by conversion to the base and further reaction with another acid, e.g. pharmacologically acceptable acid addition salts, be converted.

Obtained salts can e.g. be converted by alkalization with aqueous sodium or Kaiiumhydroxid in the free base, which then by suitable Ilaßnahmen, z.3. Solvent extraction with a non-miscible with 7 / asser solvent, such as chloroform, diethyl ether, toluene.

The preparation of the starting compounds of the general formula II is carried out according to or analogously to US Pat. No. 3,953,430 according to Reaction Scheme A:

- 12

Phenylenediamine (VI) is reacted with the Tetrahydrothiophencarbonsäurederivaten VII, in which H has the abovementioned meaning and Ra is a hydrogen atom or an alkyl group with

1 to 4 carbon atoms and R is a Yfas s st off atom or an alkyl group having 1 to 5 carbon atoms, in inert solvents, z.3. Toluene, reacted with heating to tetrahydrothienobenzodiazepinones VIII. The compounds VIII are treated with a suitable dehydrating agent, e.g. IT bromosuccinimide in dimethylformamide, dehydrated to the dihydrothienobenzodiazepinones Ha. By chlorination or bromination with suitable halogenation

mean the representatives Ha, in which R a is a hydrogen atom, to the halogen derivatives Hb, where R is a chlorine or bromine atom reacted.

The compounds IX are known or can be prepared by known processes, optionally in situ. The preparation of piperazir-L-enobenzodiazepinone Z is carried out by reacting compounds of the ormel I, wherein R-Hal means with corresponding amines V, that is, piperazine or homopiperazine, according to the methods described above for the .aminierung.

ТЦ Jj if ¹

For the preparation of the compounds I and / or I according to II * III *

II * II

II *, III,

starting starting compounds II ', IV *, IV **, V **, IZ ³ **, X ⁵ **, wherein

R 'or R ** is a hydrogen atom, a methyl or

Ethyl radical means

R * or R ^ * ³ * represents a chlorine atom or has one of the meanings of R or R **,

A or A * is a straight-chain or branched alkylene

group with 1 or 2 carbon atoms means

R is an alkyl radical having 1 to 4 carbon

atoms or an alkenyl radical having 3 to 4 carbon atoms,

the meaning of R or the group - ( ⁰¹ Vm ** -N (R ⁶ **) R ⁷ ** represents or and R " ¹ **""together, including the nitrogen atom to which they are attached, a morpholino group , a pyrrolidino group, a piperidino group, a hesahydroazepin-1-yl group, a piperazin-1-yl group optionally substituted in the 4-position by a methyl, ethyl or benzyl group, a 2,4-dimethyl-piperazine group 1-yl group or a hexahydro-IH-1,4-diazepin-1-yl group substituted in the 4-position by an ethyl or ethyl group,

R ¹ "" ¹¹ ^ represents a methyl or ethyl group,

R * represents a methyl or ethyl group,

m is 2 or 3,

n ** 2 or 3 means

2Γ * means a füluchtgruppe used.

EXAMPLES

The following examples serve to illustrate the invention. "Б ^1. " means "melting point", "Z." means "decomposition".

example 1

3.5 g of 4-chloroacetyl-9,10-dihydro-4H-thieno / J, 4-b / benzodiazepine-10-one, 8.1 g of 1-methylpiperazine and 50 ml of 'toluene are stirred at 80 ⁰ C for 2 hours. li'an is mixed with 10 ml of sodium hydroxide solution, the layers are separated, the aqueous phase is extracted several times with toluene and concentrated to dryness in vacuo. The residue is crystallized with a little acetone. This gives 4.2 g of 9,10-dihydro-4 - /, T4-methyl-piperazin-1-yl) acetyl7-4H-thieno / 3,4-b7 / T, 5jbenzodiazepin-10-one, P. 177 -178 ° C (acetone).

- 14 -

Analog obtained

9,10-dihydro-3-methyl-4-ZT4-methylpiperazin-1-yl) acetylJL7-4H-thienoZ3,4-b7zJ, i7benzodiatepin-10-one, mp 2bЗ-2b4 ° С (ethanol),

3-chloro-9,10-dihydro-4- / 4-methyl-1-piperazin-1-yl) acetyl-4H-thieno /, l, 4-b7ZT, i7benzodiazepin-10-one, P. 239 ° G, respectively 9,1O-dihydro-1,3-dimethyl-4 - / (4-ethylpiperazin-1-yl) -acetyl-7-4H-thieno / 3,4-b7Zl7benzodiazepin-10-one, P. 204-205 ° 0, by converting from

4-chloroacetyl-9,1O-dihydro-methyl-H-thienoZJ, A-bJ / J, J zodiazepine-10-one,

3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno / I, 4-b7ZT, 57-benzodiazepin-10-one

4-Chloroacetyl-9,1O-dihydro-1,3-dimethyl-4H-thieno / 3,4-b7-Z- _5- l7benzodiazepin-10-one with II-methylpiperazine.

Example 2

Ыап stirs 14.9 g of 4-chloroacetyl-9,10-dihydro-4H-thienoZ3 ' ₅ 4-b7 / T ^ Tbenzodiazepin-IO-on, 21 g of ϊΓ-methylpiperazine and 70 ml of dioxane for 1 hour at 80 ⁰ C and concentrated The solution is evaporated to dryness in vacuo. The residue is combined with 150 ml of isopropanol and 40 ml of water, 25 ml of concentrated hydrochloric acid are added dropwise, the mixture is cooled in an ice-bath and 9, 10-dihydro-Z-methylpiperazin-1-yl) acetyl are obtained , 74H-thieno / 3 »4-b_7 / T> 57benzodiazepine-10-one dihydrochloride in admixture with S ^- -ketylpiperazine hydrochloride. The hydrochlorides are dissolved in water and chloroform, adjusted to pH 8.2 with 2N sodium hydroxide solution, the aqueous phase exhaustively shaken with chloroform, the organic solution is dried and concentrated to dryness in vacuo. This gives 16 g of 9,10-dihydro-4- / 4-methylpiperazin-1-yl) acety] J ^ H-thieno / 3,4-b7 / T, _i- 7-benzodiazepine-10-one, P. 177- 179 ⁰ C (from acetone).

Analog obtained

9,10-dib-hydro-4- (morpholinoacetyl) -4H-ідіепо / _3,4-b7 / T, 5-zodiazepin-10-one,

4- / T4-benzylpiperazin-1-yl) acyl, 1.7-9, 10-dihydro-4H-thieno / 4-b7 / T, 57-benzodiazepin-10-one,

4-ZT4-butylpiperazin-1-yl) -acetyl / -9,10-dihydro-4H-thieno./3>4-b7/T, 17-benzodiazepine-10-one and 4- / 2,2-dimethylpiperazin-1-yl) acetyl 7-9,1O-dihydro-4H-thieno / 4,4-bTZ.T, 5_7-benzodiazepine-10-one by reaction of 4-chloroacetyl-9,10 -dihydro-4H-thieno / 3j4-b7 / T, 57benzodiazepin-10-one with llorpholine, U-Benzylpi perazine, Ж-ethylpiperazine or 1,3-dimethylpiperazine.

Example 3

1.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno / '3,4-b_7 / T, 57-benzodiazepine-10-one, 0.55 g of pyrrolidine, 0.85 g of ground flatrinocarbonate and 15 g 2 ml of absolute ethanol boil for 2 hours, the hot solution is filtered and concentrated in vacuo. It is dissolved in dichloromethane, the organic solution is washed with water at pH 7, concentrated and obtained, 1.4 g of 9,10-dihydro-4- (pyrrolidinoacetyl) -4H-thieno _i / '3i4-b7 / 1, jj / benzodiazepine-10-one.

Example 4

Lian stirred 1.9 Z 4-chloroacetyl-9,10-dihydro-4H-thieno / J, 4-B7 Ö ^. Tbenzodiazepin-IO-one, 3.7 g of piperidine and 15 ml of dioxane for 1 hour at ⁰ SO C, ent in a vacuum and the residue is recrystallized from isopropanol / V / asser. LiI receives 2.0 g of 9,10-dihydro-4- (piperidin-1-yl-acetyl) -4H-thieno / З ", 4-b7- [Л , S / benzodiazepine-IO-on.

- 16 -

Analog obtained

9,10-dihydro-3-methyl-4- (piperazin-1-yl-acetyl) -4H-thieno / l, 4-b7 / T, 57benzodiazepin-10-one (mp 225-228 ⁰ C, Z .) By reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno ß, 4-b7 / T, l7benzodiazepin-10-one; 9, IO-dihydro-1,3-dimethyl-4- (morpholin-4-yl-a-cetyl) -4H-thieno / 3,4-b7 / i, 5 / benzodiazepin-10-one (m. 190 ⁰ G) by reaction of 4-chloroacetyl-9, IQ-dihydro-1,3-dJjnethyl-4H-thieno / 3,4-ЬУ / Т, jj / benzodiazepin-10-one with morpholine; 9,10-dihydro-1,3-dimethyl-4- (piperidin-1-yl-acetyl) -H-thieno / J, 4-b7 _J / T, 7-benzodiazepine-10-one (B ¹ .162- 164 ⁰ C) by reaction of 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno / 3,4-b7Z7benzodiazepine-10-one with piperidine.

example 5

Lan stirs 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-1hieno / 3,4-b_7 / T, 7-benzodiazepine-10-one, 6 ml of 40% aqueous dimethylamine solution and 10 ml of dichloromethane for 2 hours at 35 ⁰ C, mixed with 0.35 g of sodium carbonate and concentrated to dryness in vacuo. Ыап mixed with a little water, the solution repeatedly shaken with chloroform, the organic solution is dried with sodium sulfate and concentrated to dryness. This gives 1.9 g of 4- (dimethylaminoacetyl) -9,10-dihydro-4H-thieno / ε, 4-b_7 / T ^ 7benzodiazepin-10-one.

Is obtained analogously to 4- (diethylaminoacetyl) -9,10-dihydro-4H-thieno / J, 4-b7 / T, £ 7benzodiazepin-10-one / ß »196-197 ⁰ C (from toluene} / or 4 - (Diethylaminoethylacetyl) -9,10-dihydro-1,3-dimethyl ^ H-thieno / J ^ -b / z ji ^ benzodiazepin-IO-on / P 186-187 ⁰ C (from toluene) by reacting. 4 Chloroacetyl-9,10-dihydro-3-methyl-4H-thieno / 3,4-b7 / T, 5.7 benzodiazepin-10-one and 4-chloroacetyl-9,10-dihydro-1,3-dimethyl 4H-thieno / 3t4-b7 ^ T, 27benzodiazepin-10-one and diethylamine.

- 17 Example 6

Analogously to Example 4 is obtained

9,10-DiJiydro-3-nietJiyl-4- (pyrrolidinoacetyl) -4H-tiiieno / 3,4-B7 / T, ^ 7benzodiazepin-10-one,

3-Chloro-9,10-dihydro-4- (pyrrolidinoacetyl) -4H-t] iieno / 3,4-b7-benzodiazepin-10-one or

9,10-dihydro-1,3-dimethyl-4- (pyrrolidinoacetyl) -4H-thieno- 13 »on 5.7benzodiazepin-10-4-Ъ_7 / Т,

through implementation of

4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno / 3,4-b7Z ~> l7-benzodiazepin-10-one,

3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno / 3,4-b7 / T, 5.7benzodiazepin-10-one or

4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno _J /3,4- b7- / T, 5,7-benzodiazepine-10-one with pyrrolidine.

Веізріеі 7

Analogously to Example 5 is obtained

4- (dimethylaminoacetyl) -9,10-dihydro-3-in.ethyl-4K-thieno / 3 "b7-4 / T, ^ 7benzodiazepin-10-one,

3-chloro-4- (dimethylaminoacetyl) -9-i0-dihydro-4H-thieno / 3,4-b7- £ T, 7-benzodiazepin-10-one or

4- (dimethylaminoacetyl) -9 ₅ 10-dihydro-1,3-dimethyl-4H-thieno- J3> 4-b7 / T, 7benzodiazepin-10-one

through implementation of

4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno / 3, 3- yss, 5j benzodiazepin-10-one,

3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno / _i 3 ", 4-ь7 / Т, 5 / benzodiazepine-10-one or

4-chloroacetyl-9, 10-dihydro-1,3-dimethyl-4H-thieno / I, 4-bJ- / Tj ^ / benzodiazepine-IO-on with dimethylamine.

- 18 -

Example 8

8 g of 9,1'-dihydro-3-methyl-4H-tertiaryiol / 3,4-b7ZI-57 ^benzodiaze pin-10-one and 5.6 ml of chloroacetyl chloride in 16 ml of dioxane are refluxed 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, washed with STa triumbicarbonatlö solution and then with water and the toluene solution is dried over sodium sulfate. By 3inengen there is obtained 4-chloroacetyl-9,10 <iib.y i ^{t r} o-3-methyl-4H-thieno / J, 4-b7 / T, £ 7benzodiazepin-10-one, mp 156-158 ⁰ C.

Analog obtained

3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno / J, 4-b7 / T, 57-benzodiazepin-10-one, m.p. 214-216 ⁰ C.

4-Chloroacetyl-9,10-dihydro-i, 3-dimethyl-4H-thieno / 3 ', 4-b7-Z "5,7-benzodiazepin-10-one, m.p. 192-195 ⁰ G, by reaction of

3-chloro-9,10-dihydro-4H-thieno / _i 3 _J 4-b_7 / ' ^! , Sjbenzodiazepine IO-ion or

9, IO-dihydro-1,3-dimethyl-4H-thieno / 3 »4-b_7 / .1, J57benzodiazepine-10-one with chloroacetyl chloride.

Example 9

To a suspension of 18.8 g of 9,10-dihydro-4H-thieno / 3,4-b7 / T, ^ Tbenzodiazepin-10-one in 500 ml of dioxane at room temperature, 10.4 ml of chloroacetyl chloride are added dropwise, with a clear solution arises. ІЯап is allowed to stand for 3 hours, the solution is concentrated to dryness, the residue is taken up in toluene, washed with sodium carbonate solution and then with water and the toluene solution is dried over sodium sulfate. By evaporation to give 4-chloroacetyl-9,10-dihydro-4H-thieno / 3 *, 4-b7 / T, 57benzodiazepin-10-one as an oil which slowly crystallized, mp 220 ⁰ C.

Analog obtained

4-Chloroacetyl-9,1O-dihydro-1-methyl-4H-3-pi / 3,4-b7 / T, 5.7-benzodiazepin-10-one and 4-chloroacetyl-9,10-dihydro-3-methyl-4H, respectively -thienoZl, 4-b7Z ~> 17benzodiazepine-10-one, P. 156-158 ⁰ C, by reaction of 9,10-dihydro-1-methyl-4H-thieno / 3 ^> , 4-b_7- / T, £ 7benzodiazepin-10-one and 9 "10-dihydro-3-methyl-4Я- -th.ieno / _i 3" b7-4 / T, 5.7benzodiazepin-10-one with chloroacetyl chloride.

Зеізріеі 10

To a boiling solution of 2.2 g of 9,10-dihydro-4H-thieno / 3,4-b_7 / T, 57benzodiazepin-10-one in 30 ml of absolute dioxane are simultaneously added in 40 minutes 2.2 g of chloroacetyl chloride and 2 ilane is allowed to cool, filtered, concentrated, the Pil entered the 2roclaie and chromatographed on a silica gel column using a mixture of petroleum ether / ethyl acetate (1: 1), crystallized from toluene to obtain 2.0 g of 4 Chloroacetyl-9,10-dihydro-4H-thieno / 3> 4-b7 / T, 5 / benzodiazepin-10-one as an oil which slowly crystallizes, P. 220 ⁰ C.

Example 11

Bine solution of 5 ml of sulfuryl chloride in 100 ml of methylene chloride v / ird to a solution of 12 g of 4-chloroacetyl-9,10-dihydro-4H-thieno / 3,4-b7 / T, 57benzodiazepin-10-one in 300 ml Added dropwise at 20 ⁰ C at room temperature. The mixture is allowed to stand for 12 hours at room temperature, then extracted with a sodium bicarbonate solution and washed with water. The phase is dried and concentrated. The residue is crystallized with a little methanol. This gives 7 g of 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno / 3,4-b7 / T, ^ 7benzodiazepine-10-or _; P. 214-216 ⁰ C (acetonitrile).

- 20

- 20 Example 12

Ыап heats a mixture of 1.00 g of (4-methylpiperazin-i-yl) acetic acid and 0.20 g of 75 percent strength. iTatriumhydrid (in paraffin oil) in 16 ml of dimethylformamide at 50-80 ⁰ G until the hydrogen evolution is complete (2 to 3 hours). To the resulting Uatriumsalz the acid is added 1.35 g of 9 »10- dihydro-4H-thieno / J, 4-b7 / T, £ 7benzodiazepin-10-one and dropwise at -10 ⁰ C 0.99 g of 98% Phosphorus chloride in 10 minutes too. The mixture is stirred for 4 hours at -10 ⁰ G, 4 hours at 0 ⁰ G and 20 hours at room temperature. It is poured to the reaction, adjusted with sodium hydroxide to pH 3> 5, shaken with Kethylenchlorid, the aqueous phase is adjusted to pH 9 and shaken out again with luethylenchlorid. Jan washes the organic phase with water and concentrates it in vacuo. This gives 0.6 g of 9,10-dihydro-4- / T4-methyl-piperazin-1-yl) acetyl7 · 4H-thieno / J, 4-b7 / T, 57benaodiazepin-10-one, E ¹ . 177-178 ⁰ G (from acetone).

Analogously to 3, 10-dihydro-3-methyl-4 - /, T4-methyl-piperazin-1-yl) acetyl / -4H-thieno / З ", 4-b7 / 7, £ 7benzodiazepinon-10-one ( i ^1, 263-264 ⁰ G) or 9,10-dihydro-1,3-dimethyl-4- / 4-methyl-piperazin-1-yl) acetyl-4H-thieno / 3,4-b7 / T , 5 / benzodiazepin-10-one (m.p. 204-205 ⁰ C) by reaction of (4-methylpiperazin-1-yl) acetic acid with IT sodium hydride, 9,10-dihydro-3-methyl-4H-thieno / 3j4 -b_7 / T, 5,7-benzodiazepine-10-one and 9,10-dihydro-1,3-dimethyl-4H-thieno / 3,4-b7ZJ, 57-benzodiazepine-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 v / ground at 0 ⁰ C 1.1 g of ethyl chloroformate was added dropwise. Add 2.18 g of 9,10-dihydro-H-thieno / J, 4-Ъ_7 / Т, 17benzodiazepine

- 21 -

10-on to the resulting suspension, stirred for a further hour at ^{0 0} G and then for 4 hours at room temperature. It is poured onto 16 ml of 2N sodium hydroxide solution, extracted with toluene and the organic phase is concentrated to dryness. After purification by column chromatography (silica gel, dioxane / methanol 1: 1), 9, 10-dihydro-4 - /, T4-methyl- piperazin-1-yl) -acetylJ ^ H-thieno / J ^ -BZ / Tjl / benzodiazepine-IO-one, m.p. 177-179 ^C

Analogously, 9-10-dihydro-3-methyl-4- / T4-methyl-piperazin-1-yl) -acetyl-7-4H-thieno / 3,4-ω / γ, 1-benzodiazepine-i 0-one (P 263-264 ⁰ C) by reaction of 9,10-dihydro-3-methyl-4H-thleno / 3,4-b7 / T, 7-benzodiazepin-10-one with (4-methylpiperazin-1-yl) - acetic and hydrofluoric acid ethyl esters.

Example 14

2.0 g of 9 _} i0-dihydro-3-methyl-4- (piperazin-1-yl-acetyl) -4H-thieno / 3 ₎ 4-b7 / T, 57-benzodiazepin-10-one, 1.3 g 98% formic acid and 0.3 g of 35 % aqueous formaldehyde solution are heated for 2 hours at 100-105 ° C, the mixture liquefies to gas evolution. It is concentrated in a vacuum, diluted with water, adjusted to pH 3j5 with dilute hydrochloric acid and extracted with dichloromethane. The aqueous phase is adjusted to pH 9 and extracted with dichloromethane. The organic phase is washed, dried and concentrated. Recrystallization of the residue from methanol affords 9,1O-dihydro-methyl-ZZ-methyl-piperazine-i-yl) -acetyl-4H-thieno /, 3,4-b7 / T, 7-benzodiazepin-10-one, F. 2бЗ-2б4 ° С.

The starting compounds are obtained in the following way:

Example A are "4-b_7 / T, 57benzodiazepin-10-one in 300 ml of dichloromethane at -40 ⁰ G 13.5 g: To a solution of 21.6 g of 9,10-dihydro-4H-thieno / J Sulfuryl chloride in 100 ml of dichloroethane added dropwise. One allows one more hour

- 22 -

Room temperature, shaken with sodium bicarbonate solution, v / washed with water, the organic phase is dried and concentrated. Ben residue is brought to crystallization with a little methanol. 3-Chloro-9,10-dihydro-4H-thieno / З ", 4-b7 / T, j57benzodiazepin-10-one is obtained.

Example B: 10 g of 1,3,9, 10-tetrahydro-methyl-H-thieno-J, 4-b-J, 5.7-benzodiazepin-10-one and 8.2 g of N-bromosuccinimite are dissolved in 250 ml Dissolved dimethylformamide. After one hour, it is poured on 2 1 v / water. The precipitation is ab-r

 n

sucks, dissolved with hot toluene and clarified with Tonsil ^x . Upon cooling is obtained as a precipitate 9,10-dihydro-3-methyl-4H-thieno / _l З, 4-b7Z _l T, 57benzodiazepin-10-one, P. 228-23O ⁰ G (methanol).

inalog you get

9,10-dihydro-1-methyl-4H-thieno / J, 4-b7 / T, ji7benzodiazepine-10-one and 9,10-dihydro-1,3-dinethyl-4H-thieno ^ 3,4- b7 £ i, 57-benzodiazepin-10-one (P. 195-196 ⁰ C) by dehydrogenation of 1,3,9,10-tetrahydro-1-methyl-4H-thieno / 3 ', 4-b_7ZT, 5.7benzodiazepin -10-one or 1,3,9, IO-tetrahydro-1,3-dimethyl-4H-thieno-Z3 ", 4-b7 / T, 27benzodiazepin-10-one with U-bromosuccinimide.

Example C: 49.9 g of о-phenylenediamine and 80 g of 5-bIethyl-tetrahydro-4-oxo-3-thiophepcarЪoπsäure be boiled in 4.5 1 of toluene, in the course of 7 hours, the resulting water with 2 1 of the solvent distilled off azeotropically. The solvent is removed. Кап receives 1,3,9,10-!-Etrahydro-3-methyl-4H-thieno / 3 »4-b7 / T, 7-benzodiazepine-10-one, m.p. 195-197 ⁰ G (isopropanol ).

inalog you get

1,3,9,10-Tetrahydro-1-methyl-4H-thieno / 3,4-b7 / T, 5.7-benzodiazepin-10-one and 1,3,9, 10-tetrahydro-1,3-dimethyl 4H-thieno-Z3,4-b7ZT, 5.7benzodiazepin-10-one (i. ¹ 148-150 ⁰ C). Reaction of tetrahydro-2-methyl-4-os: o-3-thiophenecarboxylic acid or tetrahydro-2,5-dimethyl-4-os: o-3-thiophenecarboxylic acid and 0-phenylenediamine.

Commercial usability

The substituted Thienobenzodiazepione of the general formula I and their acid addition salts or the embodiments I * and I * have valuable properties that make them commercially exploitable. The substituted thienobenzodiazepinones of the general formula I in which R is the group N (R) R and R and R have the meanings given above, or those of the embodiment I are characterized by an excellent anti-insect and intestinal protection in V / abblütlern, they inhibit z.3. the formation of gastric ulcers. Furthermore, due to low toxicity and lack of significant side effects, they have a favorable therapeutic range. The substituted

3 xhienobenzodiasepinone of the general formula I in which P.

1 2

a halogen atom (shark), R, R, A and shark have the meanings given above, or those of the embodiment I 'are valuable intermediates in the preparation of the prmrmakologisch effective and therapeutically usable inventively' / "compounds.

The excellent efficacy of the pharmacologically active substituted thienobenzodiazepinones and their pharmacologically, i. Biodegradable acid addition salts allow their use in human and in veterinary medicine, and they used for the treatment and prophylaxis of diseases based on diseases of the lamina or intestine. For example, acute and chronic ilcus ventriculi and duodenal ulcers, gastritis or hyperacid irritable stomach are treated with elk or kidney.

The compounds obtainable according to the invention therefore find application in the treatment of mammals suffering from one of the above-mentioned xercemia, in which the diseased mammal is given a therapeutically effective and pharmacologically active substance.

Macologically, tolerated bienge one or more compounds of the general formulas I, verabreicht, their preferred representatives and / or their salts administered. Likewise, the compounds obtainable according to the invention are used in the preparation of medicaments used to combat the cited diseases.

The medicaments are prepared by methods known per se. As medicaments, the compounds obtainable according to the invention (= 7 / irkstoffe) are used either as such or preferably in combination with suitable pharmaceutical excipients. If the pharmaceutical preparations contain, in addition to the compounds obtainable according to the invention, pharmaceutical carriers, the active ingredient content of these LI mixtures is 0.5 to 95, preferably 15 to 75, percent by weight of the total mixture. The medicaments are formulated, for example, for oral, rectal or parenteral (intravenous, intramuscular, subcutaneous) administration in suitable doses, for example as a tablet, dragee, capsule, suppository or measured volume of a powder, a granulate, a solution, an emulsion or a suspension.

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

The pharmaceutical preparations are preferably composed of the active compounds according to the invention and non-toxic, pharmaceutically acceptable excipients which are used as admix or diluent in solid, semisolid or liquid form or as a wrapping agent, for example in the form of a capsule, a tablet coating, a bag or other container for which therapeutically active ingredient in use. A carrier can

Z.3. serve as Termittier for the drug intake, the body, as a formulation aid, as a sweetener, as Geschmackkororrigens, as a dye or as a preservative.

If the substituted thienobenzodiazepinones obtainable according to the invention and / or their pharmacologically acceptable acid addition salts are to be used for the treatment of the indicated diseases, the pharmaceutical preparations may also contain one or more pharmacologically active constituents of other drug groups, such as antacids, for example aluminum hydroxide, magnesium aluminate; Anti-secretion agents, such as Hp-blockers, eg cimetidine; Gastrointestinal Therapeutics, z.3. Metoclopramide, bromopride, tiapride; Tranquilizers, such as benzodiazepines, for example, diazepam; Spasmolytics, z.3. Bietamiverine, Camylofine; Anticholinergica, z.3. Oxyphencyclimine, phencarbanide; Glucocorticoids, all prednisolone, fluocortclone, betanethasone; nonsteroidal antiinflammatory agents, such as arylacetic and propionic acids, heteroarylacetic and propionic acids, 3-thiazinecarboxamide dioxides, pyrazolidinediones, quinazolinones, eg, ibuprofen, haproxen, diciofenac, fenbufen, indometacin, lonazolac, sudoxicam, piroxicam, phenylbutazone, bumadizone galcium, proquazone; Local anesthetics, for example tetracaine, procaine; optionally also contain ferments, titamines, amino acids, etc.

The formulation of the compounds obtainable according to the invention into medicaments can e.g. be made on the following 7feise:

10 000 tablets with an active substance content of 20 mg are prepared from the following components: 200 g of 9,10-dihydro-4- / X4-methyl-piperazin-1-yl) acetyl-4H-thieno / 3,4-b_7 / T, 5,7-benzodiazepine-10-one, 900 g of IJais starch, 500 g of lactose, 30 g of amorphous silica and 40 g of egg

Trichloryl sulfate mixed and sieved. This Ilishun is moistened with a solution of 50 g of polyvinylpyrrolidone (weight LIoI.-weight 25 000) in 320 ml of alcohol and granulated through a sieve of 1.25 mm. The granules are dried at 40 ° and mixed with 16O g of pectin 100 g of talc and 20 g LIagnesiumstearat. This mixture is compressed into tablets a 200 mg with 8 mm diameter.

100 000 capsules with a 30 mg content are manufactured from the following components:

3000 g of 9,10-dihydro-4- / T4-methyl-piperazin-1-yl) acetyl7-4H-thieno / 3 _J 4- ^ 7 / T _J are 57benzodiazepin-10-one with 5000 g bleutralöl (Miglyol 812) and filled into soft gelatin capsules.

100,000 capsules with a 7 / irkst off content of 30 mg are made from the following ingredients:

1,500 g of 9,10-dihydro-4 - /, T4-methylpiperazin-1-yl) acetyl-4H-thieno / _i 3,4-b7 / .1 ₅ 7benzodiazepine-10-one and 1,500 g of magnesium trisilicate are mixed with 5,000 g of ITeutralöl O'iiglyol 812) and filled into soft gelatin capsules.

Claims (7)

claims: 1. A process for the preparation of substituted Shienobenzodiazepinonen of the general formula I, wherein R is a Y / ass first off atom or an alkyl radical with 1 to 4 carbon atoms, о R represents a halogen atom or has one of the meanings of R, • Э А С R is a halogen atom or the group -F (R) R and R is an alkyl radical having 1 to 4 carbon atoms or an alkenyl radical having 3 to 5 carbon atoms mean, 5 & R has one of the meanings of R 'or the group - (GH ₀ ) -Ii (R ⁶ ) R ⁷ represents or 4 * 5 R and R together include the nitrogen atom to which they are attached, a llorpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-i-yl group, an optionally in the 4-position by a LZethyl-, ethyl or benzyl-substituted piperazine - 1-yl group, a 2,4-dimethylpiperazin-1-yi group or a hexahydro-1H-1,4-diazepin-1-yl substituted in the 4-position by an I-ethyl or ethyl group mean group and R is an alkyl group having 1 to 4 carbon atoms, γ
R is an alkyl group having 1 to 4 carbon atoms, A is a straight-chain or branched alkylene group with 1 to 5 carbon atoms and m is 2 or 3, and their acid addition salts, characterized in that thienobenzodiazepinones of general formula II, wherein 1 2
R and R have the abovementioned meaning acylated and optionally subsequently aminated and / or converted bases into the acid addition salts or resulting acid addition salts in the free base or pharmacologically acceptable acid addition salts. Process according to item 1, characterized in that the acylation with compounds of the general formulas Hal-A-CO-Hal (III) or (Hal-A-CO) ₂ O (IV), in which Hal and Hal 'are a halogen atom and A is an alkylene group having 1 to 5 carbon atoms, carried out. Process according to item 1, characterized in that, in the case of the subsequent amination 3 compounds of the general formula I, wherein R represents a halogen atom, and secondary amines of the general formula HlT (R ^) R (V), wherein R and R have the meaning given in claim 1, is used. A process according to point 3, characterized in that the secondary amines V used in the optionally subsequent amination are piperazine or homopiperazine and the reaction product obtained is the 1 2 mean formula X, wherein R. ', R and A have the meaning indicated in claim 1 B _e and η is 2 or 3, methylated or ethylated. A method according to item 1, characterized in that the acylation with compounds of the general formula Z-CO-A-IT (R ^4- ) R ⁵ (IX), wherein A, R ⁴ and R ^{5 have} the meanings given in claim 1 and Z represents a fugitive group performs. Process according to items 1 and 2, characterized in that substituted 'Thienobenzodiazepinone of the general formula Γ, wherein R 'represents a hydrogen atom, an ethyl or 3thyl radical, r? represents a chlorine atom or has one of the meanings of R ', 3 · *
R is a chlorine atom and - 29 - A is a straight-chain or branched alkylene group having 1 or 2 Koiilens toff at omen mean by. Reaction of thienobenzodiazepinones of the general formula Ii in which R and R have the abovementioned meaning, with acid derivatives IIP Cl-A-CO-Gl (HI ⁺ ) or 17 * (Cl-A * -CO> ₂ O (IV *) wherein A * has the meaning given above, produces. Process according to item 1 and 3 », characterized in that substituted Ihienobenzodiazepinone of the general formula Γ, in which
R represents a hydrogen atom, a methyl or ethyl radical, Second **
R represents a chlorine atom or one of the three 1 **
gene of R, the group -IT (R ⁴ **) R ⁵ ** and
R is an alkyl radical having 1 to 4 carbon atoms or an alkenyl radical having 3 to 4 carbon atoms, the meaning of R ⁴ ** or the group - (CH ₀ ) represents or R and R together include the nitrogen atom to which they are attached, a corpholino group, a pyrrolidino group, a piperidino group, a hexahydroazepin-1-yl group, a piperazine optionally substituted in the 4-position by a methyl, ethyl or benzyl group 1-yl group, a 2,4-dimethyl-piperazin-1-yl group or a hexahydro-1H-1,4-diazepin-1-yl substituted in the 4-position by a methyl or ethyl group mean group and R "'is a methyl or ethyl group, R '' is a methyl or ethyl group, m ** 2 or 3, A is a straight-chain or branched alkylene group having 1 or 2 carbon atoms, - 30 - and their acid addition salts by reacting compounds of the general formula I "', wherein R" ³ * represents a chlorine atom, with amines of the general formula V ** HH (R ⁴ **) H ^{5 ++} (V **), where R ⁴ ** and R ⁵ ** have the abovementioned meaning, produces. 8. The method of item 7, characterized in that compounds of the general formula I **, wherein R ** is a 7 / asserstoffatom means a Hethy1- or ethyl radical, R * 'is a chlorine atom or one of the meanings of H ¹ ** Has; R ³ ** the group »IT (R ⁴ **) R ⁵ ** 4 * 4 " R represents a methyl or ethyl radical, 5 4 R has the meaning of R or the group - (CHg) ** - iI (R) R or R ^ and R together with the inclusion of the nitrogen atom, a pyrrolidino, piperidino or Hexahydroazepin-1-yl radical, R ^{o >} * and R '*' * denote an ethyl or ethyl radical, m 2 and λ denote a methylene group, and thus prepare their pharmacologically acceptable acid addition salts. The method of item 7, characterized in that compounds of the general formula Г ^ "in which ^R;!.! A hydrogen atom e.inen st off, ethyl or Ethyirest, R 'represents a chlorine atom or one of the meanings of R ¹ **, R ³ ** represents the group -H (R ⁴ ^) R ⁵ **, R and R 'together, with the inclusion of the nitrogen atom, optionally substituted in 4-position by an ethyl, ethyl or benzyl group Piperazin-1-yl group, a 2,4-dimethyl-piperazin-1-yl-group or a hexahydro-1H-1,4-diazepin-1-yl-substituted in the 4-position by a ethyl or etylyl group group and A * mean a methylene group, as well as their pharmacologically acceptable acid addition salts manufactures. - 31 - 10. The method according to item 7, characterized in that compounds of the general formula I ^ in which R represents a hydrogen atom or an ethyl radical, R represents a hydrogen atom or a methylthio radical the group -IT (R ⁴ ^) R ⁵ '**, R ⁴ ** and R together, including the nitrogen atom, a piperazin-1-yl group substituted in the 4-position by a methyl group and A ** denote a methylene group , as it produces its pharmacologically acceptable acid addition salts. 11. The method according to item 1 and 4, characterized in that substituted thienobenzodiazepinones of the general formula I **, wherein
R 'is a hydrogen atom, a!.! Ethyl or ethyl radical beaei-surmounts,
?. "represents a chloratonon or one of the of R 'has,
R- ^ due group -i \ H. and H together, including the nitrogen atom to which they are attached, a piperazin-1-yl group substituted in the 4-position by a LiethyI or ethyl group, or a 4-position by a!.! Ethyl or Bthylgruppe substituted hexahydro-1H-1H-1 "4-diazepin-i-yl group,
A 'is a straight-chain or branched alkylene group with 1 or 2 carbon atoms, and their acid addition salts by reacting compounds of general formula I ', wherein R ^ represents a chlorine atom, with piperazine or homopiperazine as amines of the general formula V ** and iJethylierung or ethylation of the obtained Piperazinothienobenzodiazepinone the general SOrmel X. ', v / orin RR "" and A "are as defined above and η is 2 or 3. 12. The method according to item 11, characterized in that compounds of the general formula I, in which a water st off atom or a LIethylrest means 2 * л 1 Hf "^ f ЗчсЧ« R '' has one of the meanings of R "; R is the group ^{45 5} R and R " ¹ " together form, together with the nitrogen atom, a piperazin-1-yl group which is substituted by an ethyl group in the 4-position and A 'denotes a methylene group and produces its pharmacologically acceptable acid addition salts, 13. The method according to item 1 and 5, characterized in that substituted Ihienobenzodiazepinone of the general formula I **, wherein R ¹ **, R ² **, R ³ ** and A ⁺ * have the meaning given in point 7, by reaction of thienobenzodiazepinones of the general formula II '', in which R * and R ^ ** have the abovementioned meaning, with reactive acid derivatives of the general formula JZi '' Z * '- CO-ri ^ -IT- (R " ¹⁴ " ) ~ Вр (IZ), v / orin 7 represents a fugitive group and A, R ⁴ * 'and R' have the meaning given in point 7, produces. For this ".j * L.Seiten formulas