Pharmaceutical mixtures and method of their active substance production

(57) 2-Methyl 1-10- (4-methyl-1-piperazinyl (-411-thieno [2,3-))] [1,5] benzodiazepine, or its addition salts with acids have pharmaceutical properties and are particularly useful in the treatment of disorders of the nervous system.

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BACKGROUND OF THE INVENTION

Many drugs are commonly used to treat central nervous system disorders. Among these drugs, one category is known as antipsychotics for the treatment of serious mental conditions such as schizophrenia-like diseases and schizophrenia-like diseases. Drugs used for such conditions often exhibit side effects and therefore better products are needed to control or alleviate symptoms in a safer or more effective manner.

In addition, many patients show no response at all, at least partially responding to treatment with existing drugs, and estimates of such patients who respond only partially or do not respond are between 40 and 80% of the treated.

Since the introduction of antipsychotics, it has been observed that patients are susceptible to suffering from severe pyramids and drug-induced symptoms. These include drugs induced by arkinsonism, acute dysstonic reactions, akathisia, persistent dyskinesia, and persistent dystonia. Simpson Angus Rock, Barnes Akathisia Scale, and Abnormal Unwanted Movement Scale (AIMS) are well known scales for detecting (minor pyramidal symptoms). The overwhelming majority of drugs used to treat schizophrenia are prone to cause these side effects when used at doses that have a beneficial effect on the symptoms of the disease. The number of adverse cases and / or lack of efficacy in a significant number of patients often results in non-compliance or even discontinuation of appropriate treatment.

Many of these drugs have sedative effects and may also have an adverse effect on the effective symptoms of the disease causing depression. In some cases, prolonged drug administration results in unchangeable conditions such as protracted dyskinesia and protracted dystonia as noted above.

The widely used antipsychotic haloperidol is one such drug which has been reported to cause a high incidence / more pyramidal symptoms and may also cause protracted dyskinesia. Recently, clozapine, which is one of a wide group of tricyclic antipsychotides, has been introduced. A tic which is emphasized that it has no side effects. However, it has been found that these compounds of agranulocytosis patients, a condition resulting from decreased white blood cell counts which may be life-threatening; therefore, this medicine can only be used now under strict medical supervision and control.

Another group of antipsychotic compounds is that described in British Patent Specification 1,533,235. This group includes thienobenzodiazepines having the following structural core:

<img file="CS9101168A2_D0002.tif" />

<img file="CS9101168A2_D0003.tif" />

H

The major compound, from this group, flumezapine (7-fluoro-2-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b7] -1,7-benzodiazepine), has been developed to form administered clinically to psychiatric patients suffering from schizophrenia. A total of 17 patients were treated with flumezapine before the clique test was terminated after consultation with the US Food and Drug Administration, because unacceptably high levels of raised enzyme levels occurred in the treated patients. Creatinine phosphokinase (CPK) and liver enzymes serum glutamate oxalacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT), determined from blood samples,

Π^{/ ηί} that were taken from patients were basically higher than normal, suggesting the possibility of toxicity. Due to its tendency to increase liver enzyme levels, flumezapine resembles chlorpromazine, an antipsychotic that has been used for a long time, but its safety has been taken into account.

In clinical trials with flumezapine, two patients showed particularly severe side effects, as measured by _E using the AIMS scale as described above.

The present inventors have now discovered a compound having surprising and unexpected properties as compared to fluezapine and other related compounds.

The compound of the invention has the formula I

<img file="CS9101168A2_D0004.tif" />

optionally one of its acid addition salts. The free base of Formula I is 2-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] -1,17-benzodiazepine.

The compound of the invention provides surprising and excellent results, which are described in more detail below. These results were obtained in experiments related to central nervous system activity testing and clinical trials. Their results demonstrate the utility of the compound with respect to the relatively safe and effective treatment of a wide range of central nervous system disorders.

The pharmacological test results show that the compound of the invention is a dopamine antagonist at D-1 receptors

Λ-. ' and D-2 and additionally has antimuscarinic anticholinergic properties and antagonist activity at 5HT-2 receptor sites. It also has antagonist activity on noradrenergic [beta] -receptors, which shows that the compound is a potent neuroleptic with relaxing, anxiolytic or anti-emetic (anti-drug) properties and is therefore useful in the treatment of psychiatric conditions such as schizophrenia, schizophrenia-like diseases and acute mania. . At low doses, the compound is indicated for use in the treatment of mild anxiety states.

As mentioned above, the compound of the invention exhibits a high level of activity in clinical evaluations of psychiatric patients suffering from schizophrenia. This compound exhibits high activity at surprisingly low dose levels. Dose levels are lower than expected from the observations made with this compound in the initial animal model tests. The expression profile of this compound in patients is similar to that of known antipsychotic agents when used with success. There is a clear pattern between compound conversion and known antipsychotic agents in terms of its characteristics on most scales such as the Psychiatric Rating Scale, the Brief Psychiatry Rating Scale (BPRS), the Schizophrenia Sub-scale, and the Clinical General Impression, Clinical Global Impression (CGI). ,_TO

In the first completed public study of a compound of the invention in schizophrenic patients, six of the eight patients treated for at least 2 weeks showed an improvement in the range of 66-87% at 4 weeks, determined on a BPRS scale, at daily doses of 5-7 30 mg. Preliminary results obtained from the other three initiated clinical trials now show that this high level of efficacy is confirmed and at lower doses than or at the lower end of the dose level used in the first study, for example at 2.5 and 5 mg daily.

In addition, in patients treated with therapeutic doses ⁷ (only a mild and transient increase in liver enzymes and plasma levels of creatinine phosphokinase (CPK) are lower than flumezapine, indicating a lesser adverse effect on muscle tissue. Furthermore, the compound of the invention causes a lower increase in prolactin levels than commonly used neuroleptic drugs menstrual cycle, and less gynecologically (mast) and galactorrhea. No change in white blood cell counts was observed in clinical trials.

In toxicity studies conducted in dogs with a very similar compound, 2-ethyl-10- (4-methyl-1-piperazinyl) -4H-thieno [1,3-b7 / 1,7] benzodiazepine, at a dose of 8 mg / kg, It was noted that in four of the eight dogs, cholesterol levels increased significantly, while no increase in cholesterol levels occurred in the compound of the invention.

Overall, therefore, in a clinical situation, the compound of the invention exhibits a superior superiority and a better side-effect profile than the hitherto known antipsyehotic agents: The compound also has a highly advantageous level of activity.

The compound of the present invention can be used both in its free base forms and in its acid addition salt forms. The acid addition salts are preferably pharmaceutically acceptable, non-toxic acid addition salts such as inorganic acids, for example hydrochloric, hydrobromic, nitric, phosphoric or sulfuric acids. Of the organic acids, organic carboxylic acids, such as glycolic, maleic, hydromaleic, fumaric, malic, tartaric, tartaric, citric or lactic acids, or organic sulfonic acids, such as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, toluene, p-sulfonic acid or naphthalene-2-sulfonic acid. In addition, other pharmaceutically acceptable acid addition salts of the invention, such as picric or tartaric acid salts, are also included in the pharmaceutically acceptable addition salts since they may serve as intermediates in the purification or preparation of other, e.g. pharmaceutically acceptable acid addition salts, or are suitable salts. to identify, characterize and purify the free base.

According to a further aspect of the invention, there is provided a process for the preparation of a compound of formula I or an acid addition salt thereof, comprising reacting (a) N-methylpiperazine with a compound of formula II

N =

NH

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(II) wherein Q is a leaving group, or (b) for a compound of formula III

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Αόη.

(III) closes the circle.

Suitable reaction conditions as well as the satisfactory meanings of the substituent Q can be readily selected for these processes.

In reaction (a), the group may be, for example, an amino group or a mono- or dialkyl-substituted amino group (each alkyl substituent preferably having 1 to 4 carbon atoms), hydroxyl, thiol or alkoxy, alkylthio or alkylsulfonyl containing suitably 1 to 4 carbon atoms, e.g. methoxy or methylthio, or halogen, especially chlorine. Preferably Q is amino (-NHg), hydroxyl or thiol, with amino being most preferred.

The reaction is preferably carried out at a temperature in the range of 50 to 200 ° C.

When Q is an amino group, the intermediate compound of formula II may also exist in the imine form:

NH 4 NH-C_x !

and when Q is hydroxyl or thiol, the intermediates of formula II may be in their amide or thioamide form:

WITH

^ - NH - C or ^ NH - C \

The amidine of formula II (Q is -NF 3) may be in the form of a salt, for example a mineral acid salt such as a hydrochloride.

It may be reacted with N-methylpiperazine in an organic solvent such as anisole, toluene, dimethylformamide or dimethylsulfoxide, preferably at a temperature in the range of from 100 to 150 ° C.

Amidine is prepared by condensation of a thiophene compound of formula

NC

<img file="CS9101168A2_D0007.tif" />

OH with ortho-halonitrobenzene in the presence of a base, for example sodium hydride, in a solvent such as tetrahydrofuran or n-butyllithium in tetrahydrofuran, or potassium or hydroxide carbonate in dimethylsulfoxide, or tetraalkylammonium salt in a biphasic system to give nitronitrile of formula:

<img file="CS9101168A2_D0008.tif" />

which can be simultaneously reduced and ring-closed to the amidine of formula II using, for example, stannous chloride and hydrogen chloride in aqueous ethanol, or the like, reduction with hydrogen and palladium on carbon or ammonium polysulfide followed by acid-catalyzed ring closure.

When Q is hydroxyl, the reaction (a) is preferably carried out in the presence of titanium tetrachloride which has the ability to react with N-methylpiperazine to form a metal amine compound. Other metal chlorides such as zirconium chloride, hafnium chloride may also be used. or vanadium chloride The reaction may be carried out in the presence of an acid binding agent such as a tertiary amine, triethylamine.

Similarly, the reaction can be carried out using an excess of N-methylpiperazine as an acid binding agent. A suitable organic solvent such as toluene or chlorobenzene may be used as the reaction medium, although the use of anisole, at least as a co-solvent, is particularly desirable due to its ability to form a soluble complex with TiCl 2.

If desired, elevated temperatures, for example up to 200 ° C, can be used to accelerate the reaction. A preferred temperature range for carrying out the reaction is 80 to 120 ° C.

The intermediate amide of formula II (Q is -OH) can be prepared from the corresponding amidine (Q is -NS 4) by alkaline hydrolysis, or can be derived from compounds of formula IV

<img file="CS9101168A2_D0009.tif" />

wherein R is an ester group, preferably C₃alkyl, by ring closure using, for example, methylsulfinylmethanide in a suitable solvent such as dimethylsulfoxide. Similarly, the amide can be prepared by ring closure of an amino acid using, for example, dicyclohexylcarbodiimide (DCC) in a suitable solvent such as tetrahydrofuran. The amino acid can be obtained, for example, with the above esters by basic hydrolysis using, for example, sodium hydroxide in ethanol.

The thioamides of formula II (Q is -SH), iminothioethers, iminoethers or iminohalides, or other derivatives containing active Q groups as specified above tend to be more reactive to N-methylpiperazine and can usually be reacted without the need for presence of TiCl 2, but otherwise using the same temperature conditions and solvent.

The thioamide of formula II (Q is -SH) can be prepared by treating a solution of the corresponding amide in an anhydrous basic solvent such as pyridine with phosphorus sulfide. Similarly, the amide can be converted to an iminoether, iminothioether or iminohalide, or to other derivatives containing active Q groups, by treatment with the usual reactants, such as, for example, iminochloride and phosphorus pentachloride.

Intermediate compounds of formula II in which Q is a cleavable group, especially those in which Q is -NHg, -OH or -SH and when Q is their -NH 2 salts, are new compounds and are another feature of this invention.

Due to the above reaction (b), the compound of formula II can be ring-closed using, for example, titanium tetrachloride as a catalyst and anisole as a solvent. The reaction is preferably carried out at a temperature of 100 to 250 ° C, for example 150 to 200 ° C.

The intermediate compound of formula III is preferably prepared in situ without isolation by reaction of a compound of formula IV

<img file="CS9101168A2_D0010.tif" />

wherein R is an ester group, preferably C 1-6 alkyl, with N-methylpiperazine, by heating to a temperature comprised between 30 and 120 ° C, for example 100 ° C, in a suitable solvent such as anisole, and using titanium tetrachloride as a catalyst.

The compound of formula IV can be prepared from the corresponding nitro compound of formula V

<img file="CS9101168A2_D0011.tif" />

Such compounds of formula V in which the phi is an ester group, such as C 1 -C 4 alkyl, are novel and form a further feature of the invention.

If appropriate, this nitro compound can be converted to the amine of formula IV without isolation, prior to reaction with N-methylpiperazine. Intermediate compounds of formula V can be obtained by condensation of thiophene of formula VI

<img file="CS9101168A2_D0012.tif" />

CH (VI) with ortho-halonitrobenzene, preferably ortho fluoro- or chloro-nitrobenzene, in the presence of a base, for example (a) sodium hydride in a solvent such as tetrahydrofuran and at a temperature of -20 to 30 ° C, or (b) v the presence of anhydrous potassium carbonate or lithium hydroxide in a solvent such as dimethyl sulfoxide at a temperature of from 90 to 120 ° C. The compound of formula V is converted to the compound of formula IV by reduction, for example, catalytically, using hydrogen and palladium on carbon, or chemically using stannous chloride and hydrogen chloride in aqueous ethanol, or ammonium polysulfide, or zinc in aqueous ammonium chloride solution.

It will be appreciated that the compound of formula (I) may be isolated by itself or converted into an acid addition salt using conventional methods.

As mentioned above, my compound of the invention has useful central nervous system activity. This activity has been demonstrated in models using well established procedures. For example, the compound has been evaluated in many of the atandartal behaviors derived from antipsychotic activity. The compound counteracts apomorphine-induced behavioral escalation and hypothermia in mice (Moore, NA et al. Psychopharmacology 94 (2), 263-266 (1988) and 96. 539 (1988)) at doses less than 10 mg / kg. The compound also inhibits conditioned avoidance responses in rats (ED? Q 4.7 mg / kg), but unlike standard compounds, it induces catalepsy only at very high doses (ED? Q 39.4 mg / kg). This distribution between the doses required to block the conditioned escalated response and to induce catalepsy shows that this compound is less able to induce particularly severe side effects in clinical trials.

The compound of the invention is also active at less than 10 mg / kg in an apomorphine-induced behavioral test as described above. It measures the ability of the compound to prevent a disruption in the behavioral response response caused by 24-hour pretreatment with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a dopamine receptor inactivating agent (Meller et al. 1988). This assay shows that the compound exhibits activity at both the D1 and D-2 receptors.

In addition, the compound of the invention has been found to have an excellent activity profile in many in vitro experiments measuring the degree of binding to neural receptors.

Consistent with the observations made in the behavioral tests, the compound is active at both D1 and D-2 dopamine receptors, as reported less than 1 µM in 1 H-SCH2339O (Billard, V et al. Life Sciences 35 1885 (1984)). and 1 H-spiperone (Seeman, P. P. et al. Nature 261 717 (1976)) individually

<img file="CS9101168A2_D0013.tif" />

Nat. Acad. Sci. USA 71 1725 (1974), which shows that it has antimuscarinic-anticholinergic activity. In addition, the compound demonstrates the greatest potency at the 5-HT-2 receptor by displacing H-spiperone from binding sites in the anterior cerebral cortex (Peroutka, SJ and Snyder, SH Mol. Pharmacol. 16, 687 (1979)) at low levels. nonomolar concentrations. The compound is also active at the 5-HT-IC receptor #

This activity profile in in vitro receptor binding assays as well as observed in behavioral tests would indicate that the compound is effective in the treatment of psychotic conditions, but is less prone to produce strong side effects.

The compound of the invention is effective over a wide dosage range, the actual dose being administered being dependent on the conditions of treatment. For example, dosages from 0.05 to 30 mg, preferably 0.1 to 20 mg, per day may be used to treat adult humans. A single daily dose is usually sufficient, although divided doses may also be given. For the treatment of psychotic disorders, a dose in the range of from 2 to 15 mg, preferably 2.5 to 10 mg, per day is suitable, while a lower dosage range, such as 0.1 to 5 mg, preferably 0.5 to 1 mg. When choosing a suitable regimen for patients suffering from psychotic disease, it may often be necessary to start with a dose of 2 to 15 mg per day and reduce the dose to 0.5 to 1 mg per day once the disease is controlled. Studies using the compound (labeled radiolabelled according to the invention) have found residues in the saliva, so that the compound can optionally be monitored to determine the completion of treatment.

The compound of the invention is normally administered orally or by injection, and is usually used in the form of a pharmaceutical composition for this purpose.

Accordingly, the invention includes a pharmaceutical composition comprising as an active ingredient a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier. In preparing the compositions of the invention, conventional techniques for preparing pharmaceutical compositions can be used. For example, the active ingredient is usually admixed with a carrier, or diluted with a carrier, or enclosed within a carrier, which may be in the form of capsules, cachets, or paper.

<img file="CS9101168A2_D0014.tif" />

- 13 and other packaging. If the carrier acts as a diluent, it may^tTo be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active substance. The active ingredient may be absorbed onto a granular solid shell, for example in the form of some suitable carriers. Lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methylcellulose, methyl and methyl- propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.

The compositions of the invention may, if desired, be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

Depending on the route of administration, the compositions may be formulated as tablets, capsules, injectable solutions for parenteral use, suspensions or elixirs for oral use, or as suppositories.

Preferably, the compositions are formulated in a unit dosage form, each containing 0.1 to 20 mg, more usually 0.5 to 10 mg, of the active ingredient.

A preferred dosage form of the invention is a capsule or tablet containing 0.1 to 20 mg or 0.5 to 10 mg of active ingredient together with a pharmaceutically acceptable carrier. Another preferred embodiment is an injection which, in unit dosage form, contains 0.1 to 20 mg or 0.5 to 10 mg of the active compound together with a pharmaceutically acceptable diluent thereof. The type of injection that is particularly required is a sustained release formulation for intramuscular injection.

The invention is further illustrated in the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

1. 2-Amino-5-methylthiophene-3-carbonitrile

A mixture of sulfur (217.8 g, 6.79 moles), propionaldehyde (472.5 g, 587 ml, 8.13 moles) and dimethylformamide (1350 ml) was charged to a 51 liter flange-necked flask equipped with a stirrer, air cooler, wide range thermometer β and dropping funnel. To the cooled stirred reaction mixture was added triethylamine (576 mL,

4.13 mol) dropwise while maintaining the temperature of the reaction mixture between 5 and 10 ° C using an ice bath. Once the addition was complete, the flask was heated to 18 ° C for 50 minutes while keeping the mixture under constant stirring. A solution of malononitrile (450 g, 6.8 moles) in dimethylformamide (900 mL) was then added dropwise over 70 minutes while maintaining the temperature of the flask at approximately 20 ° C during the addition. When the addition was complete, the mixture was stirred at 15-20 ° C for an additional 45 minutes, then a thin layer chromatography (TLC) sample was taken. The mixture was then poured on ice (4 L) / water (8 L) with stirring to precipitate the desired product. After 10 minutes the stirrer was disconnected and the solid was allowed to settle. The aqueous slurry was removed by decantation and the solid collected by filtration. The isolated solid was washed thoroughly with water (deionized, 4 L) then dried overnight in vacuo at 70-75 ° C to give the title compound (585 g), mp 100 ° C.

2. 2- (2-Nitroanilino) -5-methylthiophene-3-carbonitrile

To a stirred slurry of sodium hydride (14.4 g, 50% dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 ml) under nitrogen was added dropwise a solution of 2-fluoronitrobenzene (28.2 g, 0.2 mol) and 2-amino-5-methylthiophene-3-carbonitrile (27.6 g,

0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25 ° C for 24 hours, poured onto crushed ice and extracted with dichloromethane (3 x 500 mL). The combined extracts were washed with 2N hydrochloric acid (2 x 200 mL), water (2 x 200 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from ethanol to give the title compound (35.2 g), mp 99-102 ° C.

15 -3,4-Amino-2-methyl-1H-thieno [2,3-b] 1,57benzodiazepine. hydrochloride

To a stirred slurry of 2- (2-nitroanilino) -5-methylthiophene-3-carbonitrile (3 g&gt; 0.011 mol) in ethanol (35 mL) at 50 ° C was added an anhydrous stannous chloride solution (6.95 g, 0.037 mol) at 50 ° C. ) in hydrochloric acid (26 ml,

M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallize at 5 ° C overnight. The salt was filtered off, washed with a small amount of water, dried (4.3 g), mp &amp; gt; 250 ° C and used in the next step without further purification.

4. 2-Methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] 75,17,7-benzodiazepine

The crude 4-amino-2-methyl-10H-thieno [2,3-b] -2,5,7-benzodiazepine hydrochloride (4.3 g) was heated to reflux in a mixture of N-methylpiperazine (15 mL), dimethylsulfoxide (20 mL). ml) and toluene (20 ml) under nitrogen for 20 hours. The mixture is cooled to about 50 ° C, water (20 ml) is added and the product is left to crystallize at 5 ° C overnight. The product was filtered off and recrystallized from acetonitrile (30 mL) to give the title compound (1.65 g), mp 195 ° C.

The structure of the compound was confirmed spectroscopically:

3

NCH.

<img file="CS9101168A2_D0015.tif" />

16 [beta] 2-CH2-, 2.45 (4H, m, 3 * -CH₂) 3.49 (4H, m, 2'-CH₂), 5.00 (H, broad s, 10-NH), 6.23 (H, broad s, 3-CH), 6-35-7-10 (4H, m,

6,7,8,9-H).

³C NMR (CDCl 3)?₃): 1228.5 (s, C-2), 127.8 (d, G-3),

119.1 (s, C-3a), 157.4 (s, C-4), 140.8 (s, C-5a), 123.4, 122.6,

124.1 (d, C-6,7.8), 118.8 (d, C-9), 142.5 (s, C-9a), 151.8 (s, 1 ').

C-10a), 46.5 (t, 2'-C), 54.8 (t, 3 * -C) 45.9 (q, -4 * -C), 15.2 (q, 2-Me) ).

Mass spectrum gives M⁺ 312 and large fragment ions of m / z 255, 242, 229 and 213.

Example 2

1. Methyl 2-amino-5-methylthiophene-3-carboxylate

To a stirred mixture of methyl cyanoacetate (3.9 g, 0.04 mol), sulfur (1.26 g, 0.04 mol) and triethylamine (3.2 mL, 0.02 mol) in dry methylformamide (12 mL) under an atmosphere A solution of freshly distilled propionaldehyde (2.5 g, 0.043 mol) in dry dimethylformamide (2 mL) was added dropwise at 45 ° C while maintaining the temperature at 45-47 ° C. The mixture was stirred at 45 ° C for 1.5 hours and then partitioned between water and ethyl acetate. The organic extract was washed with water, dried and evaporated. The title compound was purified by chromatography on neutral alumina (alumina) eluting with chloroform-hexane (4.8 g).

2. Methyl 2- (2-nitroanilino) -5-methylthiophene-3-carboxylate

To a stirred suspension of sodium hydride (2 g) in dry tetrahydrofuran (25 ml) under a nitrogen atmosphere was added a solution of methyl 2-amino-5-methylthiophene-3-carboxylate (4.8 g, *).

0.028 mol) and 2-fluoronitrobenzene (4.0 g, 0.025 mol) in dry tetrahydrofuran (30 ml). The mixture was stirred at 25 ° C for 20 hours, poured onto ice and partitioned between 2N hydrochloric acid and ethyl acetate. The organic extract is dried over magnesium sulphate, the solvent is evaporated under reduced pressure and the title compound is purified by chromatography on

17 silica gel, eluting with toluene. Crystallize from ethanol (4.1 g).

3 · 2-Methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] yl] -5,7-benzodiazepine

Methyl 2- (2-nitroanilino) -5-methylthiophene-3-carboxylate (3.7 g, 0.0013 mol) was hydrogenated in a Parr apparatus at a pressure of 4.218 kg / cm 2 (60% ethanol / ethyl acetate). 2: 1, 150 ml) with palladium on charcoal (10%, 200 mg) as a catalyst After removal of the catalyst and solvent, the crude diaminoester was dissolved in a mixture of N-methylpiperazine (21 ml) and anisole (55 ml). a solution of titanium tetrachloride (3.45 ml) in anisole (15 ml) was added under stirring under nitrogen. The mixture was stirred at 100 ° C for 1 hour, then under reflux for 48 hours to achieve ring closure of 1- [2- (2-aminoanilino) -5-methylthiophen-3-yl] carbonyl-4-methylpiperazine.

After allowing to cool to 80 ° C, a mixture of 30% ammonia solution (10 mL) and isopropanol (10 mL) was added continuously, followed by the addition of ethyl acetate (25 mL). The inorganic precipitate was removed by filtration, and the filtrate was washed with water (3 x 25 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure. The product was purified by Florisil chromatography, eluted with ethyl acetate and finally crystallized from acetonitrile (40 mL) to give the title compound (2.32 g), which was identical to the above described compound.

Example 3

A powder blend of the active ingredient and silicone starch is prepared and filled into gelatin capsules.

For 300 mg capsules

Compound of the Invention 5.0 mg

Silicone 2.9 mg

Starch liquid 292.1 mg

<td> 5,0</td><td>mg</td>

<td> 0,9</td><td>mg</td>

<td> 75,0</td><td>mg</td>

<td> 15,0</td><td>mg</td>

<td> 204,1</td><td>mg</td>

Example 4

Tablets are prepared by granulating the active compound with a suitable diluent, lubricant, disintegrant and binder material. They contain:

A compound of the invention

Magnesium stearate

Microcrystalline cellulose

Povidone

Starch, directly compressible Example 5. Injection of the active ingredient in water is prepared in the form of a dried stopper for reconstitution in a suitable sterile diluent before use (to a total volume of 10 ml).

Compound of the Invention 20.0 mg

Mannitol 20.0 mg

1N hydrochloric acid and / or 1N sodium hydroxide to adjust the pH to 5 to 5.5

Example 6 _of / / “Ív

-Uncontrollable? .....

The injection for intramuscular injection is made from a sterile suspension of the active ingredient, micronized, in an oily vehicle

Compound of the Invention 65.0 mg

Aluminum stearate 0.04 mg

Seed oil 2 ml

Example 7

A blend of the active compound with silicone starch and normal starch is prepared by blending it into solids. _ofgelatin capsules.

For 290 mg capsules

Compound of the Invention 2.5 mg

Starch liquid with 0.96% silicone 220 217.5 mg

Liquid starch 70.0 mg