FI66002B - REFERENCE FOR A FRUIT OF THERAPEUTIC SUBSTITUTE 9,10-DIHYDRO-4H-THIENO (3,4-B) (1,5) BENZODIAZEPIN-10-ONER SAMT DERAS SYRAADDITIONSSALTER - 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

1 6: 5002

The invention relates to a process for the preparation of new therapeutically useful substituted 9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-ones and their acid addition salts.

useful substituted 9,10-dihydro-1H-thieno-Z1,4-b7A / 5,7-benzodiazepin-10-ones of general formula I

HO R1

fr "yS

I r2 co-an (r4) r5 IS wherein R "* · is a hydrogen atom or an alkyl-2 radical having 1 to 4 carbon atoms, R is a halogen atom, a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R is an alkyl having 1 to 4 carbon atoms - 5 radicals, R is an alkyl radical having 1 to 4 carbon atoms, or 4 R and R together with the nitrogen tower to which they are attached denote a morpholino group, a pyrrolidino group, a piperidino group or optionally substituted in the 4-position by a methyl, ethyl or benzyl group piperazin-1-yl group and A is a straight-chain or branched alkylene group having 1 to 5 carbon atoms, and for the preparation of their acid addition salts.

The compounds according to the invention have new interesting pharmacological effects.

German application DE 1 795 176 states that certain dibenzodiazepinones have an inhibitory effect on gastric ulcer formation and gastric fluid secretion. U.S. Patent No. 3,953,430 discloses substituted benzodiazepines having antidepressant and analgesic activity. U.S. Patent No. 4,168,269 discloses substituted thienobenzodiazepines having analgesic activity.

Alkyl radicals having 1 to 4 carbon atoms include methyl, ethyl, propyl, isopropyl, n-butyl, 26: 3002 sec-butyl, tert-butyl radicals. Of the alkyl residues, 12 4 5 are preferred for R, R, R and R are methyl and 1 2 ethyl residues. As the alkyl residue R and R, a methyl residue is considered to be highly preferred.

2 5 Halogen atoms R are a bromine atom and in particular 3 chlorine atoms. Halogen atoms R are iodine, bromine and especially chlorine.

Alkylene groups having 1 to 5 carbon atoms include a trimethylene, tetramethylene, pentamethylene, propylene, ethylmethylene group, preferably an ethylene group, especially a methylene group.

Suitable salts are any acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Non-pharmacologically acceptable salts are converted to pharmacologically acceptable salts according to methods known to those skilled in the art. As such, for example, water-soluble or water-insoluble acid addition salts such as hydrobromide, hydroiodide, nitrate, acetate, benzoate, hibisate E2- (4-hydroxybenzoyl) benzoate E7 / phendizo [2 -? '(2'-hydroxy) may be mentioned. -biphenylyl) carbonyl] benzoate}, propionate, butyrate, sulfosalicylate, laurate, oxalate, ammononate (4,4'-diaminostilbene-2,21-disulfonate), embonate Z, 4'-25 methylene bis- (3-hydroxy-2 naphthoate 7, methembarbonate E 4,4'-methylene bis- (3-methoxy-2-naphthoate) -7, stearate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, especially hydrochloride , phosphate, sulfate, citrate, gluconate, maleate, malate, fumarate, succinate, tartrate, true 30-pate (p-toluenesulfonate), mesylate (methanesulfonate), amidosulfonate.

Preferred compounds of the invention are: 9,10-dihydro-4- (1,4-methylpiperazin-1-yl) acetyl] -4H-35 thieno [5,4-b] Z / 57 benzodiazepin-10-one, 9,10-dihydro-1,3-dimethyl -4- (74-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 66002 9,10-dihydro-3-methyl-4- [4-methylpiperazine 1-yl) -acetyl-4H-thieno [4,4-b] ethyl, S7-benzodiazepin-10-one and their pharmacologically acceptable acid addition salts.

The substituted thieno-5 benzodiazepinones of the general formula I and their acid addition salts have valuable properties which make them useful in the pharmaceutical industry. Substituted 9,10-dihydro-4H-thieno Z3,4-7,7benzodiazepin-10s of the general formula I have an excellent gastrointestinal protective effect in warm-blooded animals, for example by preventing the formation of gastric ulcers. In addition, due to their low toxicity and absence of substantial side effects, they have a preferred therapeutic range.

Pharmacologically active substituted thieno-15 benzodiazepinones and their pharmacologically, i. the excellent effect of biologically acceptable acid addition salts makes it possible to use them in medicine and also in veterinary medicine, whereby they are used for the treatment and prevention of diseases caused by diseases of the stomach or intestines. For example, they are used to treat acute and chronic Ulcus ventriculi (ulcer of the stomach) and Ulcus duodeni (ulcer of the lower intestine), gastritis or excessively irritable stomach in humans or animals.

The compounds of the invention are thus used in the treatment of mammals suffering from one of the aforementioned diseases, comprising administering to the mammal a therapeutically effective and pharmacologically acceptable amount of one or more compounds of general formula I and / or their salts.

In this case, the compounds according to the invention are used either as such or, preferably, in combination with suitable pharmaceutical carriers, the active ingredient content of the mixtures being from 0.5 to 95% by weight, preferably from 15 to 75% by weight, of the total mixture.

These pharmaceutical preparations may also contain 35 one or more pharmacologically active ingredients from other classes of drugs.

For oral administration, the daily dose is generally 4 66002 in mammals 0.01-5, preferably 0.05-2.5, especially 0.1-1.5 mg / kg body weight and is optionally administered in several single doses, preferably 1-3 single doses of the desired to achieve results.

5 Pharmacology

The excellent gastric protective effect of pharmacologically active substituted thieno-benzodiazepinones can be demonstrated by using the so-called Shay-rat. In this case, the compounds according to the invention clearly prove to be superior to the known commercial product Carbenoxolon (1) and the known compounds I-IV in terms of gastric protective effect and therapeutic scope, as can be shown, for example, by comparing these known compounds with the compounds according to the invention (2). (5): 15,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [5,4-b] ZT, S7b® ricodiazepin-10-one (2), 3 -Chloro-9,10-dihydro-4- [4- (4-methyl-piperazin-1-yl) -acetyl] -4H-thieno [4,4-b] N-benzodiazepin-10-one (3), 9,10-dihydro- 3-methyl-4 - [(4-methylpiperazin-1-yl) acetyl] -2H-thieno [3,4-b] [2,5] benzodiazepin-10-one (4), and 9,10-dihydro-1-yl , 3-dimethyl-4 - [(4-methyl-piperazin-1-yl) -acetyl] -4H-thieno [7,4-b] [1,5] benzodiazepin-10-one (5).

Reference compounds I-IV are: 5, H-dihydro-11- (14-methylpiperazin-1-yl) acetyl7-6H-25 pyrido [2,3-b] [1,4] benzodiazepin-6-one (EN-Publication 49 515, compound 6) (I), H-7,4-methylpiperazin-1-yl) acetyl7-1H-pyrido [1,3-b] [1,5] benzodiazepin-5 (6H) one (FR Patent 1,505,795, compound 20) (II), 30,10-dihydro-5-morpholinoacetyl-11H-dibenzo [B, e7 / T »47" diazepin-11-one (FI publication 49 509, compound D; DE publication 1 795 176 , compound C) (III), and 5,10-dihydro-10-methyl-5-morpholinoacetyl-11H-dibenzo [b] e7- / 1,47diazepin-11-one (FI publication 49 509, compound E; 35 DE- 1 795 176, compound J) (IV).

The results obtained are shown in the following table:

Table I 6 o 0 Q 2

Antiulcer effect and toxicity

Compound Toxicity Gastric TQ Gastric secretion 5 LD ^ q (mg / kg) protective effect- LD ^ q / its + ^ inhibit- intravenous injection EDcrt EDC-% in 50 50 ti mice (mg / kg) oral rat oral rat 10 1,290 ^ 70 4.1 7 2 190 2.5 76.0 35 3 75 <, 1.0>, 75.0 28 4 130 r * »0.3 r *» 433.0 20 15 5 180 1, 3,139.0 17 I 125 5.5 23.0 22 II 170 6.5 26.0 30 III 630 14.0 45.0 0 20 IV 550 23.0 24.0 12

In the table EDj-q = Dose that reduces the ulcer index by 50% in the 25 treated groups compared to the control group LD ^ q = Dose at which 50% of the animals die TQ = Therapeutic ratio LD ^ q / ED ^^ +)% inhibition = Gastric secretion inhibition (in%) four hours after administration of a dose of the anti-gastric ulcer agent.

For compound 1, although the ED 2 q was still detectable, the dose-response curve flattened out very strongly, so that even at a dose of 300 mg / kg, no significant increase in the antiulcer effect could be achieved. In contrast, the effect of compounds 2-5 was strongly dose-dependent; 65002 could achieve inhibitory effects of up to 95%.

The table also shows that compounds 2-5 prepared according to the invention have a better gastric protective effect than the known compounds I-IV. Similarly, compounds 2-5 5 have a better therapeutic range (expressed as LD50 q toxicity) than reference compounds I-IV. Compounds 2-5 prepared according to the invention thus have a much stronger antiulcer effect and a higher therapeutic ratio (LDj-q / EDj-q) than the reference compounds I-IV.

10 The experiments were performed as follows:

Investigation of the anti-ulcer effect The effect of the gastric ulcer was studied in the so-called Shay rat method.

Gastric ulceration was induced in fasted rats for 24 hours (females, 180-200 g, four animals in each cage with a high lattice), by binding the gastric port (under diethyl ether anesthesia) and by oral administration of 100 mg / 10 ml / kg acetylsalicylic acid. Test substances were administered orally (10 ml / kg) one hour before gastric ligation. Wound closure was performed using Michel wound forceps. Four hours later, the animals were killed under ether anesthesia by displacing the supporting vertebrae and removing the stomach. The stomach was opened lengthwise and fixed to the cork plate after the amount (volume) of secreted gastric fluid was first determined; the number and size (= diameter) of the ulcers at 10x magnification were determined using a stereomicroscope. The result obtained from the severity (according to the following rating scale) and the number of ulcers served as 30 individual ulcer indices.

Rating scale: no ulceration 0 ulcer diameter 0.1 - 1.4 mm 1 1.5 - 2.4 mm 2 2.5 - 3.4 mm 3 35 3.5 - 4.4 m 4 4.5 - 5.4 mm 5> 5, 5 mm 6 i 66002

The measure of the effect on the prevention of gastric ulcer is the decrease in the average ulcer index of each treated group compared to the control group (= 100%).

ED ^ q is the dose that reduces the mean ulcer index by 50%.

Determination of toxicity

Toxicity studies were performed on female NMRI mice (weight 22-26 g). Animals (5 animals / dose) were fed and water free. Different doses of 10 substances were administered intravenously (duration of injection 1 minute). The duration of observation was seven days. LD50, the dose at which 50% of the animals die, was determined by linear regression.

The process according to the invention for the preparation of substituted 9,10-dihydro-4H-thieno <0.4-7,7 / 1,57benzodiazepin-10-ones of the general formula I and their acid addition salts is characterized in that

a) haloacylthienobenzodiazepinone of general formula XI

20 1

HO R

If \, XI) ----

25 | R

CO-A-R3 12 3 wherein R and R are as defined above and R is a halogen atom are aminated with a secondary amine having

general formula V

HN (R1) R2 (V) 5 wherein R and R are as defined above, 2

b) a reaction product obtained by amination with piperazine-35 of general formula X

66002 8 h / / r1 "V ^ I 5 (X) 5 R2

CO-A-N ^ _ ^ 1 H

1 2 10 wherein R, R and A are as defined above, are methylated or ethylated, or c) a thienobenzodiazepine of general formula II h 0 D1 • cö =>, -

H R

1 2

wherein R and R are as defined above, are acylated with a compound of general formula IX

Z-CO-N (R4) R5 (IX) 4 wherein A, R and R are as defined above and Z is a leaving group, and any bases obtained are converted into acid addition salts or the resulting acid addition salts are converted into the free base or pharmacologically acceptable acid addition salts.

In process variant a), the amination is carried out in an inert solvent at a temperature between the boiling point of the solvent and 0 ° C using either at least 2 moles of secondary amine V or 1-2 moles of secondary amine V and the auxiliary base. Suitable solvents are, for example, chlorinated hydrocarbons, such as methylene chloride, chloroform or di-chloroethane; open chain or cyclic ethers such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene 9 65002 or pyridine; alcohols such as ethanol or isopropanol; ketones such as acetone; acetonitrile or dimethylformamide. Examples of auxiliary bases are tertiary organic bases, such as triethylamine, N-methylpiperidine, diethyl-lianiline or pyridine, or inorganic bases, such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, alkaline earth metal hydroxides or oxides. Optionally, the reaction can be accelerated by the addition of alkali metal iodides. Reaction times range from 15 minutes to 80 hours depending on the amount and type of amine V 10 used. In the reaction of starting materials in which A is an alkylene group having 2 to 5 carbon atoms, the reaction can also take place under the cleavage of H-Hal; the intermediate, optionally isolatable alkenyl compound formed reacts with the secondary amine V 15 to give the same final product.

In process variant b) the methylation and ethylation are carried out according to methods known per se. Thus, suitable methylating and ethylating agents for the compounds of the general formula X are, for example: methyl and ethyl esters of strong acids, for example sulfuric acid, phosphoric acid or p-toluenesulphonic acid, or methyl or ethyl halides used at 0 ° C and At a temperature between 50 ° C, possibly in the presence of a proton acceptor in an aqueous or non-aqueous medium, as described, for example, in Houben-Weyl Part XI / 1, page 24 and page 205, Georg-Thieme-Verlag, Stuttgart (1957 ) "; Mixtures of formaldehyde or acetaldehyde with a reducing agent (reductive alkylation method), the reducing agents being hydrogen in the starting state (e.g. zinc and hydrochloric acid) in the presence of a hydrogenation catalyst such as platinum or Raney nickel dihydride or sodium hydride, formic acid or complex Methods for reductive alkylation are described in detail, e.g., in "Houben-Weyl, Volume 35 XI / 1, starting on page 602, Georg-Thieme-Verlag, Stuttgart (1957)"; "W.S. Emerson, Organic Reactions, Vol. 4, starting on page 174, John Wiley and Sons, New York (1948)"; M.L. Moore, 10 60002 idid, Vol. 5, p. 301, (1949) "C.A. Buehler, D.E. Pearson, Survey of Organic Synthesis, Volume 1, pp. 424-429 (1970), Volume 2, 403-407 (1977), John Wiley and Sons, New York ";" S.R. Sandler, W. Karo, Organic Functional Group Preparations, Part 5, p. 345 (1968), Academic Press, New York.

The methylation is preferably performed as reductive methylation.

In process variant c) the reaction of the compounds of the formula II with the acid derivatives IX 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 carboxylic acid derivative. Examples of reactive carboxylic acid derivatives which may be mentioned are acid halides, esters, anhydrides or mixed anhydrides, such as those formed from the salts of the corresponding acid (Z = OH) and acid chlorides, such as phosphorus oxychloride or chloroformic acid esters. Preferably, the reaction is carried out with mixed mineral anhydrides IX, in particular chlorophosphoric acid. The reaction is optionally carried out in the presence of an acid scavenger (proton acceptor). Suitable proton acceptors include, for example, 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 a temperature of -25 to 50 ° in an inert solvent, preferably dimethylformamide.

Acid addition salts are obtained by dissolving the resulting free base in a suitable solvent, e.g. water, acetone, alcohol such as ethanol or isopropanol, a open-chain or cyclic ether such as diethyl ether or tetrahydrofuran containing the desired acid or finally adding the desired acid. The salts are obtained by filtration, precipitation with a substance which is not a solvent for the acid addition salt or evaporation of the solvent. The salts can also be converted into other salts, e.g. pharmacologically acceptable acid addition salts, by first converting them to a base and then further reacting them with another acid.

11 6 'SO 02

The resulting salts can be converted to the free base, e.g., by basification with aqueous sodium or potassium hydroxide. The base can then be isolated using appropriate measures, e.g. by extraction as a solvent, using a water-immiscible solvent such as chloroform, diethyl ether, toluene.

In process variant a) the haloacylthienobenzodiazepinones of the general formula XI used as starting materials are prepared by acylation of the thieno-10-benzodiazepinones of the formula II or their acid addition salts with the compounds of the general formulas III or IV

Hal-A-CO-Hal1 (III) (Hal-A-CO) 2 O (IV) wherein Hal * and Hal represent halogen and A represents the same as above. This acylation is carried out without solvent or, preferably, in an inert solvent at room temperature or at an elevated temperature, at most at the boiling point of the solvent, optionally in the presence of a co-base and / or an acylation catalyst. Acid halides III are considered to be preferred over acid anhydrides IV. Chloroacetyl chloride is preferred as the acid halide III, and chloroacetic anhydride is preferred as the acid anhydride IV. Examples of the solvent include aromatic hydrocarbons such as toluene, xylene or chlorobenzene; open chain or cyclic ethers such as diisopropyl ethers or dioxane; chlorinated hydrocarbons such as dichloroethane, other solvents such as pyridine, acetonitrile or dimethylformamide.

Examples of auxiliary bases are tertiary organic bases, such as triethylamine and ethyldiisopropylamine, or pyridine; or inorganic bases such as anhydrous alkali metal or alkaline earth metal carbonates or hydrogen carbonates or alkaline earth metal oxides. Suitable acylation catalysts are, for example, imidazole, pyridine or 4-dimethylaminopyridine.

In process variant c) the compounds of general formula II used as starting material are prepared according to U.S. Patent 3,953,430 or according to the following reaction scheme 66002 12, respectively; r1 f o R1 r8- ° -0C> -A toluene 5 J> -> | I \ ^^ 'vnh2 R2a! R 2a,

B

VI VII VIII

10 NBS

(DMF) N / "0¾ i R2b I R2a

B

20 Hb Ha

Phenylenediamine (VI) is reacted with tetrahydrothiophenecarboxylic acid derivatives VII in which R 2 is as defined above and R is a hydrogen atom or an alkyl group having 1 to 4 g of 25 carbon atoms and R is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, in inert solvents , e.g. in toluene, by heating to tetrahydrothienobenzodiazepinones VIII. Compounds VIII are dehydrated with a suitable dehydrating agent, e.g. N-bromosuccinimide in dimethylformamide, to the dihydrothienobenzodiazepinones Ha. By chlorination or bromination with suitable halogenating agents, the compounds of formula IIa in which R2a is a hydrogen atom are reacted into halogen derivatives Hb in which R1 is a chlorine or bromine atom.

Compounds IX are known or can be prepared according to known methods, optionally in situ. The piperazinotienobenzodiazepinones X are prepared by reacting the compounds of formula XI with the corresponding amines V, i. with piperazine or homopiperazine, according to the methods described above for amination.

Examples 1-4 concern the preparation of intermediates and Examples 5-14 relate to the preparation of final products.

Example 1 4-Chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [4,4] b] [2] benzodiazepin-10-one 10 g of 9,10-dihydro-3-methyl-4H-thieno T, 4-k [7 / T, 57-benzodiazepin-10-one and 5.6 ml of clonacetyl chloride in 160 ml of dioxane are refluxed in the presence of 8 g of ground potassium carbonate for eight hours. The solution is evaporated to dryness, the residue is dissolved in toluene, washed with sodium bicarbonate solution and finally with water and the toluene solution is dried over sodium sulfate. Concentration gives the title product, m.p. 156-158 ° C.

Correspondingly, 3-chloro-4-chloro is obtained in the form of 9,10-dihydro-4H-thieno [3 ', 4-b7,5,5-benzodiazepin-10-one, m.p. 214-216 ° C or

4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno [4,4-b] [b] [beta ],7-benzodiazepin-10-one, m.p. 192-195 ° C

by administration of 3-chloro-9,10-dihydro-4H-thieno [4,4] benzodiazepin-25-one or 9,10-dihydro-1,3-dimethyl-4H-thieno [4- React E17 benzodiazepin-10-one with chloroacetyl chloride.

The starting compounds are obtained as follows:

30 Example A

3-Chloro-9,10-dihydro-4H-thieno [1,4-b] 17,5-benzodiazepin-10-one

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 at 35 ° C is added dropwise 13.5 g of sulfuryl chloride in 100 ml. in dichloromethane. Allow to stand for a further hour at room temperature, shake with sodium bicarbonate solution, wash with water, dry the organic phase and concentrate. The residue is crystallized from a small amount of methanol. The title product is obtained.

Example B

1,3,9,10-Tetrahydro-3-methyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one 49.9 g of o-phenylenediamine and 80 g of 5-methyltetra-diamine hydro-4-oxo-3-thiophenecarboxylic acid is boiled in 4.5 liters of toluene. Within seven hours, the water formed is azeotroped with 2 liters of solvent. The solvent is removed. The title product is obtained, m.p. 195-197 ° C (crystallized from isopropanol).

Correspondingly, 1.3.9.10-tetrahydro-1,3-dimethyl-4H-thieno [3,4-b] [T, 57] benzo-15-diazepin-10-one (m.p. 148-150 ° C) is obtained by giving tetrahydro-2,5- dimethyl-4-oxo-3-thiophenecarboxylic acid to react with o-phenylenediamine.

Example C

9,10-Dihydro-3-methyl-4H-thieno [1,4-b] [1,7] benzodiazepin-10-one 10 μl, 3,9,10-tetrahydro-3-methyl-4H-thieno] R, 4-b7- [T, 57] benzodiazepin-10-one and 8.2 g of N-bromosuccinimide are dissolved in 250 ml of dimethylformamide. After one hour, pour into 2 liters of water. The precipitate is filtered off with suction, dissolved in hot toluene and clarified with Tonsil®. Upon cooling, the title product is obtained as a precipitate, m.p. 228-230 ° C (crystallized from methanol).

Correspondingly, 9,10-dihydro-1-methyl-4H-thieno [3,4-b] 1,5,5-benzodiazepin-10-one (m.p. 272-278 ° C) or 9,10-dihydro-1,3-dimethyl- 4H-thieno [4,5,4-b] ZX> 57benzodiazepin-10-one (m.p. 195-196 ° C) dehydrate 1,3,9,10-tetrahydro-1-methyl-4H-thieno [5,4,4- H7ZX, 57-benzodiazepin-10-one or 1.3.9.10-tetrahydro-1,3-dimethyl-4H-thienoZX, 4-b7ZX, E-benzo-65002 diazepin-10-one on the N-bromo succinic track.

Example 2 4-Chloroacetyl-9,10-dihydro-4H-thieno [3,4-b7β, 57-5] benzodiazepin-10-one

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 is added dropwise 10.4 ml of chloroacetyl chloride to form clear solution. Allow to stand for three to 10 hours, evaporate the solution to dryness, dissolve the residue in toluene, wash with sodium bicarbonate solution and finally with water and dry the toluene solution over sodium sulphate. Concentration gives the title product as an oil which crystallizes slowly, m.p. 220 ° C.

Correspondingly, 4- (3-chloropropionyl) -9,10-dihydro-4H-thieno63 [4- [f] 7ZJ / 57'-benzodiazepin-10-one is obtained, m.p. 208-210 ° C or 4- (3-chloropropionyl) -9,10-dihydro-3-methyl-4H-thieno-Zβ-4,7-benzodiazepin-10-one, m.p. 185-188 ° C by administration of 9.10-dihydro-4H-thieno [3,4-b] J / 57benzodiazepin-10-one or 9.10-dihydro-3-methyl-4H-thieno [1,4-thio] -β, 57benzodiazepin-10-one. react with 3-chloropropionyl chloride.

Correspondingly, 4-chloroacetyl-9,10-dihydro-1-methyl-4H-thieno [3,4-b7β, 57 ”benzodiazepin-10-one is obtained, m.p. 261-263 ° C or 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-a] L / 57-benzodiazepin-10-one, m.p. 156-158 C 30 by administration of 9.10-dihydro-1-methyl-4H-thieno73 / 4-b7β, 57benzodiazeps-10-one or 9.10-dihydro-3-methyl-4H-thieno / 3,4-fc7β-57benzodiazepine - React 10-one with chloroacetyl chloride.

16 65002

Example 3 4-Chloroacetyl-9,10-dihydro-4H-thieno [4,5-b] [1,5] benzodiazepin-10-one

To a boiling solution of 2.2 g of 9,10-dihydro-4H-5-thieno [1,4-b] [1,7] benzodiazepin-10-one in 30 ml of absolute dioxane is added dropwise simultaneously within 30 minutes 2.2 g of chloroacetyl chloride and 2 ml of triethylamine and continue stirring for three hours. Allow to cool, filter, evaporate the filtrate to dryness and chromatograph on a column of silica gel using a mixture of petroleum ether / ethyl acetate (1: 1), recrystallize from toluene to give 2.0 g of the title product as an oil which slowly crystallizes. Sp. 220 ° C.

Example 4 3-Chloro-4-chloroacetyl-9,10-dihydro-4H-thieno [4,4-b] N, N-benzodiazepin-10-one A solution of 5 ml of sulfuryl chloride in 100 ml of methylene chloride is added dropwise to the solution. with 12 g of 4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] 1,5-benzo-20-diazepin-10-one in 300 ml of methylene chloride at 20 ° C.

The mixture is allowed to stand for 12 hours at room temperature, then extracted with sodium hydrogen carbonate solution and washed with water. The phase is dried and concentrated. The residue is crystallized from a small amount of methanol. 7 g of the title product are obtained, m.p. 214-216 ° C (crystallized from acetonitrile).

Example 5 9,10-Dihydro-4- [7- (4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-d] 7H, 5'-benzodiazepin-10-one 3.5 g of 4-chloroacetylx-9,10-dihydro-4H-thieno [3,4-b] 30 / 1,57benzodiazepin-10-one, 8.1 g of N-methylpiperazine and 50 ml of toluene are stirred for two hours at 80 ° C: Add 60 ml of dilute sodium hydroxide solution, separate the layers, shake the aqueous phase several more times with toluene and evaporate to dryness in vacuo.

35 The residue is crystallized from a small amount of acetone. 4.2 g of the title product are obtained, m.p. 177-178 ° C (crystallized from acetone).

17 65002

Correspondingly, 9,10-dihydro-3-methyl-4 - [(4-methyl-piperazin-1-yl) -acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one is obtained, m.p. 263-264 ° C (crystallized from ethanol), its hemifumarate, 5 m.p. 254-258 ° C and its dihydrochloride, m.p. 229-234 ° C (dec.); 9.10-Dihydro-1-methyl-4- (7β-methylpiperazin-1-yl) -acetyl-4H-thieno [3,4-b] 2,7-benzodiazepin-10-one, m.p.

19 2-194 ° C; 3-chloro-9,10-dihydro-4 - [(4-methylpiperazin-1-yl) -10-acetyl] -4H-thieno [3,4-b] Z3 · [5,7] benzodiazepin-10-one, m.p.

239 ° C; or

9.10-dihydro-1,3-dimethyl-4- (14-methyl-piperazin-1-yl) -acetyl] -4H-thieno [3,4-b] [3,5] benzodiazepin-10-one, m.p. 204-205 ° C

15 by administration of 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [3,5] benzodiazepin-10-one, 4-chloroacetyl-9,10-dihydro-1-methyl- 4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, 3-chloro-4-chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] β, 57-benzodiazepine 10-one, or 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] -N, 5,5-benzodiazepin-10-one to react with N-methylpiperazine.

Example 6 9,10-Dihydro-4- (7,4-diethylpiperazin-1-yl) acetyl] -4H-thieno [1,4] benzodiazepin-10-one 14.9 g 4 -chloroacetyl-9,10-dihydro-4H-thieno [3,4-b] β, 5,5-benzodiazepin-10-one, 21 g of N-methylpiperazine 30 and 70 ml of dioxane are stirred for one hour at 80 ° C, and the solution is evaporated to dryness in vacuo. To the residue are added 150 ml of isopropanol and 40 ml of water, 25 ml of concentrated hydrochloric acid are added dropwise, cooled in an ice bath to give 9,10-dihydro-4- [7- (4-methyl-piperazin-1-yl) -acetyl] -4H-35-thieno , 4-b7 / 1,5 / Benzodiazepin-10-one dihydrochloride and N-methylpiperazine hydrochloride. The hydrochlorides are dissolved in water and chloroform, the pH is adjusted to 8.2 with 2N sodium hydroxide solution, the aqueous phase is shaken thoroughly with chloroform, the organic solution is dried and evaporated to dryness in vacuo. 16 g of the title product are obtained, m.p. 177-179 ° C (crystallized from acetone).

Correspondingly, 9,10-dihydro-4- (morpholinoacetyl) -4H-thieno [3,4-b]? 1-57-benzodiazepin-10-one is obtained, m.p. 151-156 ° C; 4- [4- (4-benzylpiperazin-1-yl) acetyl] -9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, mp · 129-133 ° C; and 4- [7- (4-ethylpiperazin-1-yl) acetyl] -9,10-dihydro-4H-thieno [3,4-b] 2,7,5-benzodiazepin-10-one, m.p. 184-186 ° C; reacting 4-chloroacetyl-9,10-dihydro-4H-thieno [3,5,5] benzodiazepin-10-one with morpholine, N-benzylpiperazine and N-ethylpiperazine, and 9,10-dihydro-3-methyl-4- ( morpholinoacetyl) -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 24 2-244 ° C; 9,10-Dihydro-3-methyl-4- (piperidinoacetyl) -4H-thieno [3,4-b] ~ 1,57benzodiazepin-10-one, m.p. 237 ° C; 9.10-Dihydro-3-methyl-4 - [(4-ethylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [b] benzodiazepin-10-one, m.p. 195-198 ° C; and 9,10-dihydro-3-methyl-4 - [(4-benzylpiperazin-1-yl) -25-acetyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one,

mp. 212-214 ° C

is obtained analogously by reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] [1,1] -benzodiazepin-10-one with morpholine, piperidine, N-ethylpiperazine and N-benzyl -lipiperazine.

Example 7 9,10-Dihydro-4- (pyrrolidinoacetyl) -4H-thieno [3,4-b] -3,5,5,7,7-benzodiazepin-10-one 1.9 g of 4-chloroacetyl-9,10-dihydro-4H- Thieno £ 3,4-b7-, 1,5-benzodiazepin-10-one, 0.55 g of pyrrolidine, 0.85 g of 19 6-300 2 ground sodium carbonate and 15 ml of absolute ethanol are heated at reflux for 2 hours, the hot solution is filtered and concentrated in vacuo. Dissolve in dichloromethane, wash the organic solution with water at pH 7.5, concentrate to give 1.4 g of the title product, m.p. 186-188 ° C. Example 8 9,10-Dihydro-4- (piperidin-1-yl-acetyl) -4H-thieno [3,4-b] [3,5] benzodiazepin-10-one 1.9 g of 4-chloroacetyl-9,10-dihydro -4H-Thieno / 3,4-157-10 (T, 5) benzodiazepin-10-one, 3.7 g of piperidine and 15 ml of dioxane are stirred for one hour at 80 [deg.] C., concentrated in vacuo and the residue is recrystallized from isopropanol. phenol / water. 2.0 g of the title product are obtained, m.p. 199-202 ° C. Correspondingly, 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). decomposing) 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-ylacetyl) -4K-thieno [3,4-b] [3,5] benzodiazepin-10-one (m.p. 188-190 ° C) by giving 25 React 4-chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno, 3,4,4,5-benzodiazepin-10-one with morpholine; 9.10-Dihydro-1,3-dimethyl-4- (piperidin-1-yl-acetyl) -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one (m.p. 162-164 ° C) by giving 4-Chloroacetyl-9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one to react with piperidine.

Correspondingly, 9,10-dihydro-4- [3- (4-methylpiperazin-1-yl) -propionyl] -4H-thieno [3,4-b] [3,5] benzodiazepin-10-one, m.p. 185-187 ° C or 9,10-dihydro-3-methyl-4- [3- (4-methylpiperazin-1-yl) -2,6002 propionyl] -4H-thieno [3,4-b] [1,5] benzodiazepin-10-one ,

mp. 114-119 ° C

giving 4- (3-chloropropionyl) -9,10-dihydro-4H-thieno [3,4-f] 27, 2,5-benzodiazepin-10-one or 4- (3-chloropropionyl) -9,10-dihydro-3-methyl -4-tienoZ3,4 ~ B7

Zl, E, 7-benzodiazepin-10-one to react with N-methylpiperazine.

Example 9 4- (Dimethylaminoacetyl) -9,10-dihydro-4H-thieno [1,4] b7-β., 5-benzodiazepin-10-one 2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno 3,4-b7-T, 57-Benzodiazepin-10-one, 6 ml of a 40% aqueous solution of dimethylamine and 10 ml of dichloromethane are stirred for 2 hours at 35 [deg.] C., 0.35 g of sodium carbonate are added and the mixture is evaporated to dryness in vacuo. A small amount of water is added, the solution is shaken repeatedly with chloroform, the organic solution is dried over sodium sulfate and evaporated to dryness. 1.9 g of the title product are obtained, m.p. 173-176 ° C.

Correspondingly, 4- (diethylaminoacetyl) -9,10-dihydro-3-methyl-4H-thieno [3,4-f] benzodiazepin-10-one is obtained, m.p. 196-197 ° (crystallized from toluene), 4- (diethylaminoacetyl) -9,10-dihydro-1,3-dimethyl-4H-thieno [3,4-b] [3,5] benzodiazepin-10-one, m.p. 186-187 ° C (crystallized from toluene) or 30 (diethylaminoacetyl) -9,10-dihydro-4H-thieno [1,2- b] o, β-benzodiazepin-10-one, m.p. 98-108 ° C by giving 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] β, 5j-benzodiazepin-10-one, 35 4-chloroacetyl-9,10-dihydro- 1,3-dimethyl-4H-thieno [3,4-b] zZ,5,5-benzodiazepin-10-one or 4-chloroacetyl-9,10-dihydro-4H-thieno [1,4-b] [T, 57] benzo [21 -: 0 0 2 diazepin-10-one to react with diethylamine.

Example 10 9,10-Dihydro-3-methyl-4- (pyrrolidinoacetyl) -4H-5-thieno [3,4-b] 2H-benzodiazepin-10-one

Correspondingly, as in Example 4, the title product is obtained, m.p. 235.5-237 ° C, by reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-e] / T, 57-10 benzodiazepin-10-one with pyrrolidine.

Example 11 4- (Dimethylaminoacetyl) -9,10-dihydro-3-methyl-4H-thieno [3,4-b] 2H-benzodiazepin-10-one Correspondingly, as in Example 5, the title product is obtained, m.p. 212-214 ° C, by reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno [3,4-b] 1,5,5-benzodiazepin-10-one with dimethylamine.

Example 12 9.10-Dihydro-4-Zr (methyl-piperazin-1-yl) acetyl] -4H-thieno [5,4-b] [1,5] benzodazazin-10-one

A mixture of 1.00 g of (4-methylpiperazin-1-yl) -25 acetic acid and 0.20 g of 75% sodium hydride (in paraffin oil) in 16 ml of dimethylformamide is heated at 50-80 ° C until hydrogen evolution has ceased. finished (2-3 hours). To the sodium salt of the acid formed is added 1.35 g of 9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-.10-one and at -10 ° C is added dropwise 0.99 g of 98%: of phosphorus oxychloride 10

O

within minutes. Stir for 4 hours at -10 ° C, 4 hours at 0 ° C and 20 hours at room temperature. The mixture is poured onto ice, adjusted to pH 3.5 with sodium hydroxide solution, shaken with methylene chloride, adjusted to pH 9 with aqueous phase and washed with water and concentrated in vacuo. 0.6 g of 9,10-dihydro-4 - [(4-methyl-piperazin-1-yl) acetyl] -4H-thieno [3,4-b] [1,5] benzodiazine is obtained. -onia, sp. 177-178 ° C (crystallized from acetone). Correspondingly, 9,10-dihydro-3-methyl-4-ZT (4-methylpiperazin-1-yl) acetyl] -4H-thieno [3,4-b] [C] benzodiazepin-10-one is obtained, m.p. . 263-264 ° C 5 or

9.10-Dihydro-1,3-dimethyl-4-ZT (4-methyl-piperazin-1-yl) -acetyl--4H-thieno [5,4-b] [1,5] benzodiazepin-10-one, m.p. 204-205 ° C

by reacting 10 (4-methylpiperazin-1-yl) acetic acid with sodium hydride, 9,10-dihydro-3-methyl-4H-thieno [3,4-b] [3,5] benzodiazepin-10-one, or With 9.10-dihydro-1,3-dimethyl-4H-thieno [1,4-b] [1,1,5] benzodiazepin-10-one and phosphorus oxychloride.

Example 13 9,10-Dihydro-4 - [[4-methyl-piperazin-1-yl] acetyl] -4H-thieno [1,4-b] [1,5] benzodiazepin-10-one To a suspension of 1 58 g of (4-methylpiperazin-1-yl) acetic acid in 20 ml of tetrahydrofuran are added dropwise at 0 ° C to 1.1 g of chloroformic acid ethyl ester. 2.18 g of 9.10-dihydro-4H-thieno [C3,4-b] T are added. The benzodiazepin-10-one formed in the resulting suspension is stirred for a further hour at 0 ° C and finally for four hours at room temperature. Pour into 160 ml of 2N sodium hydroxide solution, extract with toluene and evaporate the organic phase to dryness. After purification by column chromatography (silica gel; dioxane / methanol 1: 1) the title product is obtained, m.p. 177-179 ° C. Correspondingly, 9,10-dihydro-3-methyl-4 - [(4-methylpiperazin-1-yl) acet-30-yl] -4H-thieno [1,4-b] Z, 7,7-benzodiazepin-10-one (m.p. 263-26 4 ° C) by reacting 9,10-dihydro-3-methyl-4H-thieno [3,4-c] [3,5] benzodiazepin-10-one 35 (4-methylpiperazin-1-yl) with acetic acid and chloroformic acid ethyl ester.

23 6 'j 0 0 2

Example 14 9,10-Dihydro-3-methyl-4-Z- (4-methylpiperazin-1-yl) acetyl] -4H-thieno [7,7] -4,7,7,5,5-benzodiazepin-10-one 2.0 g 9, 10-dihydro-3-methyl-4- (piperazin-1-yl-5-acetyl) -4H-thieno [3,4-1,17] 7,57 -benzodiazepin-10-one, 1.3 g of 98% formic acid and 0, 3 g of a 35% aqueous formaldehyde solution are heated for two hours at 10 DEG-105 DEG C., whereupon the mixture liquefies as a gas evolves. Concentrate in vacuo, dilute with water, adjust the pH to 3.5 with dilute hydrochloric acid and shake with dichloromethane. The pH of the aqueous phase is adjusted to 9 and extracted with dichloromethane. The organic phase is washed, dried and concentrated. Recrystallization of the residue from methanol gives 9,10-dihydro-3-methyl-4-T '(4-methylpiperazin-15-yl-1-yl) acetyl] -4H-thieno [7,4-b] 1,5,7,7-benzodiazepine. 10-one, m.p. 263-264 ° C.

*

Claims (5)

A process for the preparation of novel therapeutically useful substituted 9,10-dihydro-4H-thieno [3,4-b7] I, 57-5 benzodiazepin-10-ones of the general formula I H O R1 I / (I) 10. N R2 CO-AN (R4) R5 wherein R3 is a hydrogen atom or an alkyl radical of 1-4 carbon atoms, 2R is a halogen atom, a hydrogen atom or an alkyl radical of 1-4 carbon atoms, 4 R is an alkyl radical of 1 -4 carbon atoms, R 5 is an alkyl radical of 1-4 carbon atoms, or 45 R and R together with the nitrogen atom to which they are attached, represent a morpholine group, a pyrrolidino group, a piperidino group or an optionally at the 4-position by a methyl, ethyl or benzyl group substituted piperazin-1-yl group and A is a straight-chain or branched alkylene group having 1-5 carbon atoms, and their acid addition salts, characterized in that a) a haloacylthienobenzodiazepinone of the general formula XI CX. uCi 35. X 2 CO-A-R3 26 6 5 0 0 2 12 3 van R and R denote the same as above and R is a halogen atom, aminated with a secondary amine of the general form V H and (R) denote the same as above, b) a reaction product obtained by amination with piperazine and having the general formula X 11 ) 2 Wherein R, R and A are the same as above, methylated or ethylated, or c) a thienobenzodiazepinone of the general formula II H, P R1 (r '<H VR2 R 2 and R 2 are the same as above, acylated with a compound of general formula IX Z-CO-N (R 1) R 2 (IX) wherein A, R and R are the same as above and Z is a removal group and, optionally, the obtained bases are transferred into the acid addition salts or the obtained acid addition salts are transferred into the