SA95160196B1 - Pharmaceutical compounds - Google Patents

Abstract

Abstract: The present invention relates to compounds of -2- 1 - methyl - 10 - (4 - methyl [1,5] -[piperazinyl) -4H- thieno[2,3-b benzodiazepine, or an acidic salt of that source having pharmacological properties and a particular use for the treatment of Central nervous system disorders.

Description

Y — _ pharmaceutical compounds Full Description BACKGROUND The present invention relates to new organic compounds and their uses as pharmaceutical OLS from that source. There are currently many drugs for the treatment of diseases of the central nervous system. Among these drugs is a group known as antipsychotics (185) that are used in the treatment of serious mental illnesses such as schizophrenia and schizophrenia, as the drugs available to treat such diseases are often accompanied by undesirable side effects, and therefore the need A list of better products that control or eliminate these symptoms in the safest and most effective way. Seiad reports that ¢ many patients do not respond to 0 drugs or only a partial percentage respond to current drugs » This partial percentage or percentage of non-responders varies from $e to Ar ./ of which 3 treat them. Since these types of antipsychotics have been presented, it has been noted that patients are prone to suffering from the abuse of these drugs, as symptoms appear that occur outside the brain, extra pyramidal, and do not include Parkinsoism and reactions of deficiency of the elements of acute potentiation, a cute dystonic reactions Simpson Angus Scale and Barnes Akathisia Estimation Scale are well-known measures for evaluating extra-brain symptoms. pyramidal and that the vast majority of drugs available for the treatment of mental schizophrenia are likely to have side effects outside the brain, extra, pyramidal v, when used in doses to give a beneficial effect for the treatment of these diseases. Given

The severity of adverse events and/or lack of efficacy in a large number of consecutive patients resulted in poor response and delayed treatment. Many of these drugs are associated with an analgesic effect that may also have no undesirable effect on the symptoms affecting the disease causing depression. and in am cases; The long-term use of the drug leads to irreversible conditions, such as delayed movement and delay in the strengthening elements referred to above. Among the commonly used antipsychotics is the haloperidol, which is one of these drugs, which has been reported as causing a high level of extra pyramidal symptoms, and thus can cause delayed movement. More specifically, Glos, clozapine, is considered one of 0 of this large group of LW tricylic antipsychotics, which was approved by ALIS on the grounds that it is free of extra pyramidal effects. On the other hand, SA has been found to cause agranulocytosis & in some patients; As a result of this AU, there is a decrease in the number of white blood cells, which threatens the patient's life; OY can only be used under strict medical supervision and observation. Another group of antipsychotic compounds was described in British Patent No. 775 077. This group includes thieno- benzodiazepines that have the following structural core: N= ¢/ H. 3 The basic compound has been developed from this ie pas!

m_(7-fluoro -2- methyl - 10 - (4 - methyl - 1 - piperazinyl) -4H- thieno[2,3-b]- [1,5] - benzodiazepine) to the stage of clinical use for psychiatric patients who suffer from mental schizophrenia. As a total of VY patients received treatment. b Flumezapine clinically, before the clinical treatment ends, by consulting des Drugs and US Food Ins (FDA) 0 for an unexpected rise 3 The enzyme level was significantly increased 3 Untreated patients. Erythromycin creatinine phosphokinase (CPK), liver enzymes, serum glutamate oxalacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) ¢ taken from patients' blood samples, which were significantly increased (3) were normal drugs, indicating the possibility of toxicity. With regard to ALC, to raise liver enzyme levels ¢, flumezapine is 0 similar to chlorpromazine, which is considered a psychiatric antidepressant 5 which has long-term use, although its safety is questionable. Flumezapine Two patients reported dramatic side effects of the extra pyramidal as measured by the above-mentioned AIMS General description of the invention \o They have now discovered a compound with unexpected and surprising properties compared to oS A 4 flumezapine and other related compounds.The compound of this invention is of the formula: We 0 0 B or the salt of the addition of acid from that source and the free base of the formula (I) is: methyl - 10 - (4 - methyl - 1 - piperazinyl)-4H-thieno[2,3-b]-[1,5] benzodiazepine Y. -2 .

A©m According to an alternative naming system; Where the sulfur atom is named with a number (1) and the numbering is in a counterclockwise direction as in the structural formula shown above, where the invention compound is named methyl - 4 - (4 - methyl - 1 - piperazinyl) -10H- -2 thieno[2,3-b]-[1,5] benzodiazepine 0. The compound of the invention gave remarkable and surprising results »which will be described in more detail below in experimental screens for testing central nervous system activity and in clinical trials which demonstrate its benefit3 as an effective and relatively safe treatment. For a large percentage of diseases of the nervous system ss A. Detailed description 1 The results of pharmaceutical tests show that the compound of the invention is an anti-dopamine at 0-1 and D-2 receptors, and in addition to that it has antimuscarinic properties. Antimuscarinic, anticholinergic, anticholinergic, point antagonist at 2 = SHT receptors, and also an active noradrehergic o - receptors. These properties indicate that the compound is a neuroleptic with the ability to relieve tension, sedative, or antiemetic, and is useful in treating conditions Psychiatric conditions such as schizophrenia, schizophrenia, and severe acute schizophrenia; the lowest doses of the compound demonstrate its effectiveness in the treatment of cases of mild distress. As mentioned above, the compound OB of the invention has shown a high level in the clinical evaluation of psychiatric patients with schizophrenia Jal has shown a surprisingly high efficacy using triple doses. It was found that the given dose levels are less responsive in patients following known antipsychotic agents when used in a manner. A clear similarity appeared between the compound's delivery and antipsychotic agents

Brief Psychiatric Rating Scale (BPRS)

Clinical Global Impression (CCI). In the invention's first completed open study on schizophrenia; Six of the eight patients who completed at least two weeks of treatment ¢ showed improvement wn 6 7215 and 7/87 within 4 weeks » and as set by the BPRS in daily doses from © to 0 mg . The first results from the other three clinical trials appeared to confirm a high level of efficacy using lower doses or at lower LU ied) 3

Study 1 eg from Y,0 to 0 mg. Moreover, only a slight, transient elevation of liver enzymes occurs in patients receiving dose-treated patients with a plasma creatinine phosphokinase (CPK) 3 level lower than flumezapine, indicating a low adverse effect on muscle tissue. Moreover; The compound of the invention causes a slight increase in prolactin levels compared to other drugs currently used, which leads to less disturbances to the menstrual cycle and a decrease in the proportion of male breast enlargement and milk flow.In clinical studies, no change was observed in the number of white blood cells. Studies of the poisoning of dogs with a highly recognizable rheumatic compound ethyl - 10 - (4 - methyl - 1 - piperazinyl) -4H - thieno[2,3-b}-[1,5]benzodiazepine -2) showed significant increases in levels of Cholesterol » While the entrainment compound x did not show any increase in cholesterol levels. oY".

The compound of the invention can be used either in the form of its free base or in the form of an acid addition salt. Preferably, the additive salts of a pharmaceutically acceptable acid and non-toxic additive salts are suitable such as inorganic acids, for example “hydrochloric”, hydrobromic ¢, nitric ¢, sulfuric ¢ or phosphoric acids or ° organic acids For example organic carboxylic maleic 3 « glycollic J acid ¢ , hydroxymaleic ™ button malic 3 ¢ fumaric < and tartaric ¢ lactic acid sf ¢ or organic sulfonic acids organic sulphonic acids such as Jul methane sulphonic ¢ and hydroxyethane sulphonic 3 ¢ ethane sulphonic — 2 and -toluene p- sulphonic or naphthalene —2- sulphonic acid. In addition to the pharmacologically acceptable 0 BLY acid salts from that source, other acid addition salts are considered to be included in the invention, for example, those that are with oxalic acid or picric acid, as they have the ability to form intermediates in purification or in the preparation of other materials by way of paralysis; Pharmaceutically acceptable, such as acidic addition salts, are useful for determination, specification, or purification of the free base. Ve according to another aspect of the invention whereby a process is provided for the production of a compound of formula No. (0) or an addition salt comprising: 0 reaction N - methyl piperazine / N=C TI. an 8 2 H where © is a root capable of Bd) or – A

pu A —_ (b) m closed component ald of the form: ANT) Oy / NS : NH, C ry 7 on (111) a / 0 MN 3 — 8 Appropriate reaction conditions and appropriate amounts of Odd Q operations can be selected. In reaction 00 the root 0 is for example a mono or dialkyl - substituted amino group (each alkyl substituent maskingly comprises 1 to 4 atoms 5 Os— ( and hydroxyl and thiol or alkylthio » alkoxy or alkylsulphonyl group containing suitably 1 to ; carbon atoms » on the methylthio group Jl) Jou or a methoxy group or a halogen atom, especially a chlorine atom, and it is preferred that © is an amino -( hydroxyl (NH) 0 or a thiol, and amino is the most preferred It is preferable to carry out the reaction at a temperature from OQ” to 71 degrees gta 4. When © is an amino OB » imino intermediate of the formula (IT) it can also remain in the form of imino sis !. : 80 1 SS 811 > SS Vo When Q is a hydroxyl or a thiol the intermediates of the formula (ID) can still be in the forms of thioamide J and amide . 0 It 1 Cy 3 NHC L oy".

Z and it is possible OF to be an amidine of formula Q (I) to be (NH; in the form of a salt eg salt of a metal acid such as hydrochloride. which can react with N- methylpiperazine in An organic solvent such as anisole dimethylformamid 3 toluene or dimethyl-sulphoxide, preferably at an average temperature of 100 to 151 degrees C. Amidine is prepared by condensing the thiophene compound of the formula : 71 H MN g CH, with ortho-halonitrobenzene, in the presence of a base, for example, sodium hydride in a methylated solvent tetrahydrofuran or tetrahydrofuran (3 n- butyl lithim) or potassium carbonate 0 Or lithium hydroxide in dimethylsulphoxide or with tatraalkyl - ammonium 3 a two - phase system (olor) to form nitronitrile formula: NC 9 / 1 and water NT H which can To be allocated automatically and cyclically sealed with amidine of formula (if) on he eg using aqueous ethanol (3 hydrogen chloride 3 stannous chloride) or alternatively vo by dl pd with hydrogen and palladium [palladium krepon ammonium sl polysulphide or by means of an acid - catalysed ring closure. 'And when © is hydorxyl » it is preferable to conduct a reaction (7) 3 in the presence of titanium tetrachloride, which is characterized by its ability to interact with N- methylpiperazine to form complex A

1. Others, such as metal chlorides, can be used as metal chlorides, La gaseous, or metal amine. The reaction can be carried out in the presence of vanadium or hafnium zirconium bonding agents. triethylamine « ¢ acid binding

In an alternative way, N- methylpiperazine, the reaction can be carried out by using an excess of toluene Js as an acidic agent. and can | The use of an organic solvent, Jon °, is desirable in the form of anisole as a reaction medium » although the use of chlorobenzene due to its abilities to form a special co - solvent compound » at least as an auxiliary solvent. For solubility with Ba 110 om Jl, if desired, the temperature used can be raised, for example, (3 C degrees) to speed up the reaction, and the preferred temperature for conducting the reaction ranges from 80 C 0 200 C 171 to 2 9 KM amidine From the (OH) carbon © ( (I) intermediate of the formula amid can be prepared or can be derived from alkaline hydrolysis SU by analyzing (NH, be : compounds of the formula Ra ROS Vo ~= 0 s 3 8 b using alkyl and preferably ester ji is an R group since sodium methylsulphinyl methanide is weightless as ¢ ring closure It was prepared by Samide OB “in an alternative way, dimethylsulphoxide Js, in a binder solvent dicyclo - (DCC) Jl used as amino acid ze by the cyclic closure of amino acid, and it was possible to obtain tetrahydrofuran Jee as a binder solvent hexylcarbodiimide ~~ 0 basic preceding by basic hydrolysis asters eg from esters eg ethanol in sodium hydroxide using 5 al

The thicamides of formula (I) ( 0 be - SH ) include iminoethers: iminorhio - esters, iminohalides, or other derivatives containing an active © radical as cel ony and intended to be more potent. In N- methylpiperazine oll and can react without the need for TIC, but on the other hand, the same conditions of temperature 0 and the same solvent must be used. And thicamide sad of formula (II) ( 0 can be 511- ) and that 24a lyl amide bonded in an anhydrous basic solvent such as pyridine with phosphorous pentasulphide. Similar ¢ the amide can be converted to iminothioether and iminoether or iminohalide or other derivatives comprising active © derivatives by conventional eel ic adh Ll 0 for example as in the case of phosphorous pentachloride s iminochloride . Intermediate compounds of formula (I) where © is a cleavage radical, specifically when © is OH, - NH, or 811 and when © is an ANH salt; of the type of new compounds and constitute an additional aspect of the present invention. Regarding reaction (b) above; It is possible for the compound of formula (I) to be encapsulated and cyclic, for example, by using titanium tetrachloride as a catalyst and anisole as a solvent, and it is preferable to conduct the reaction at a temperature of A ¢ — Yo. From VO ¢ _ Yoo m and the intermediate compound of the formula (I) is prepared in a preferred way in situ Jad separation by means of the compound of the formula: ji, 20,0 b 7 ff \ ov 3 Mulla Al J 3 8 7 except

17

N-ben with alkyl ester: 8818 and it is preferable to use the term R as Asses

Jo m and at 071 mu v 0 by heating to a temperature between methylpiperazine

TiCly and using anisole Jt as a suitable solvent on 35 cp 000 paths about JU as a catalyst. i" aN ; AT

H

New and constitutes another aspect of the invention » as 8 is (V) and is considered to be compounds of formula . Ben alkyl, for example, preferred ester 48 gost without (IV) the formula amine can be converted into a nitro amine compound OB and this was appropriate (V) and intermediate compounds of the formula can be made ‎ . N- methylpiperazine was separated and before reaction with 01: formula thiphene by condensation of Tariq (© 041) 3 HOON and 60 p in chloro - nitrobenzene or ortho fluoro and in the form of ortho - halonitrobenzene with Jul in a solvent eg sodium hydride 0 Jl) having a base » eg anhydrous potassium (<=) m - 2 0 m or Yo and at a temperature of tetrahydrofuran Ve i> > This is when dimethylsulphoxide Jee is dissolved in lithium hydroxide or carbonate (IV) at a temperature of 80 °C to 10 °C » and the compound of formula (0) is converted to the compound of the formula palladium by reduction, for example, in a catalytic way using hydrogen and palladium and stannous chloride or by a chemical method using anhydrous chloride carbon /

CA

Z - 3 hydrogen chloride in aqueous ethanol or ammonium polysuiphide or zinc Sl in aqueous ammonium chloride . It must be assessed » that the compound of the invention can be isolated by itself or ah to a salt by adding acid, using traditional methods. As mentioned above, the compound of the invention has a beneficial effect on the central nervous system. This efficacy has been demonstrated in models using well-defined procedures. For example, the compound is evaluated by a number of standard tests. It detects antipsychotic activity. Where it contrasts with apomorphine - induced JU upward climbing behavior and hypothermia in the mouse

Psychopharmacology 94 (2), 263 - 266 (1988), and 96, 539) Moore, N.A. etal 01 mg/kg. The compound also showed 01 inhibition in doses less than (19888) EDs conditioned avoidance response.

Cad) kg) but, unlike standard compounds, they act on cataplexy and chapter 0 (with 7 mg / kg ¢ EDs) shows ile only at catalepsy doses 1 between doses required ad response Conditioned avoidance and muscle stiffness; This indicates that CSA is less susceptible to clasic extrapyramidal side effects in the clinic. And the compound of the invention, La, was active when using doses less than 10 mg / kg in lm) based on apomorphine — induced 0 of the climbing test referred to above »which Measures the ability of the compound to prevent the degradation of the Fo response) which is provided § 1 hour before treatment with N- (EEDQ) cethoxycarbonyl -2- ethoxy 1,2 - dihydroquinoline and an inactivating agent of the receptor (Meller). et al., Central D1 dopamine receptors, Plenum Press, 1988) « dopamine. This test shows that the compound has activity with both 0-1 and 0-2 receptors. oY"

In addition, it was found that the compound of the invention includes a positive aspect of efficacy in a number of CHE binding assays in the laboratory, which were designed to measure the degree of binding of nerve receptors. While maintaining the observation of the behavioral tests, the compound is active and effective at 0 complex of 1-1 D2 receptors, and as demonstrated by BY ICs from 1.24 in: (Billard, W. et al.

Life Sciences 35 1885 (1984) and H-spiperone 50123390 - 3 (Seeman, et al. Nature 261 717 (1976)) respectively. The compound with BY ICs of 1uM in 0708 includes - 38 The connecting bayonet described by: ‎Yamamura , HI and Snyder , SH in Proc.

Nat.Acad.

Sci.

USA 71 1725 (1974) 01, which demonstrates antimuscarinic - anticholinergic activity. In addition, “the compound demonstrates great activity at the 111-5-2 receptor displacing spiperone-11 from binding sites in the rat frontal cortex” 1979 (687 16) (Peroutka, SJ and Snyder, SH mol.

Pharmacol At low concentrations in gram particles equivalent to a nanomolar part, the compound is also active at the receptor ©1- 117- 5. The effectiveness of the receptor binding experiment in the laboratory »as observed in behavioral tests » shows that the compound is effective in treating psychological conditions and is Less inducing of extracerebral side effects. The actual extrapyramidal given is effective and independent of the treatment condition. For example in the treatment of adults; So the daily used ae is from © 100 to 0 ? Milligram » It is preferred from 0.1 to Yo milligram. A single dose per day is normally sufficient, although divided Sle A can be used to treat psychotic mental illness » A dose ranging from ? to Vo milligram » and hundred ov

— and 1 - preferably from 01 JY, mg Log is appropriate as in cases of mild distress; A dose with a low rate, for example, how much cpl mda 0 Aen, and it is preferable, + to 1 milligram, “can be more appropriate, and in the case of choosing an appropriate diet for patients suffering from mental illness,” it is necessary and frequently that Is at a dose of 0 ? to Vo milligrams per day » and when the disease is controlled; The dose is reduced in a manner ranging from 0.9 to / milligram per day. 3 Studies using a radio-labelled compound of the invention (“CaaS”) on residues in saliva. Thus the compound can be monitored in patients to assess response. And the compound of this invention is taken normally orally or by injection. This purpose is 0 and it is usually used in the form of a pharmaceutical compound. JUL, the invention comprises a pharmaceutical compound consisting of a compound with active pols as in formula (I) or a pharmaceutically acceptable acid addition salt from that source; And linked to a pharmaceutically acceptable carrier. and in the preparation of the compounds of the invention; Traditional technology can be used to prepare pharmaceutical compounds. For example » an active ingredient is usually mixed with a carrier or ve is diluted with a carrier. Or it is enclosed in a carrier, which can be in the form of a capsule, a paper sachet or any other container. and when the carrier acts as a solvent; It can be a solid, semi-solid, or a liquid substance that acts as a transport medium, or an inactive additive, J, or an intermediate for the active ingredient. The active ingredient can be absorbed on a solid container A> or ¢ in the form of a sachet for example » and from some 1 for examples of suitable carriers ¢ lactose ¢ calcium phosphate ¢ gum acacia ¢ starches ¢ mannitol ¢ sorbitol ¢ sucrose ¢ dextrose 00 propyl ¢ methyl ¢ methyl cellulose «syrup» gelatin ¢ tragacanth ¢ alginates «¢ magnesium stearate ¢ talc » benzoate » hydroxy or mineral oil. If desired, 7 compounds of the invention can be combined to provide sustained or delayed rapid release of the active ingredient after patient administration. Mr. Dr

According to the method of administration » the compounds can be formed in the form of pills » capsules; and parenteral solutions for non-intestinal use. Suspensions or 65 for oral use or suppositories. It is preferable “of the compounds to be formed in unit form CAs or and each dose includes from 0.1 to 70 mg and the most usual of #,.” to 10 milligrams oo of the active ingredient. Preferably of the invention the composition is a capsule or tablet comprising an average of 1.1 to yo mg or 1.6 to 10 mg of a pharmaceutically acceptable active ingredient and carrier. Or take the form of a capsule or tablet comprising a rate of about 7.5 to 0 1 be an injection which shall be in the form of a dose comprising a rate of J from \ to Y. mg or from 0.9 to yo. milligrams of the element ERI) with Js i.e. Laas sid la nia. The formation of the desired syringe is particularly in the form of the formation of a stable release of an intramuscular syringe. The invention is illustrated using the following examples: Example 1 amino -5- methylthiophene -3- carbonitrile) 1 \o - 2 Ld of sulfur (T,V3 cpl YAV, A) mol (propionaldehyd) is placed (497.59 g OAV mL » (pV Ve.) dimethylformamide 3 (Joe ANY) in a © liter flannel-necked flask fitted with a pneumatic stirrer ¢, air condenser, long-reach thermometer, and drip funnel. Add triethylamine (7 ml 17 mol) 0 drip for ve min into the cooled reaction mixture which has been stirred while the temperature of the flask is maintained between 0 - 10 C in an ice bath and after the addition is complete The flask is allowed to infuse for 18 m sl min while keeping the mixture well stirred, thus a solution of malononitrile (+ 46 g ¢ 1,A mol) in dimethylformamide is added

(yy - deh) ml) by dripping for a period of 1 minute, while maintaining the temperature of the flask around a boiling point, ve, during the addition process and after the addition process is completed »the mixture is stirred and thus the required product precipitates. After 10 minutes, the stirrer is separated and the solid settles. The aqueous liquid is filtered away and the solid is separated by filtration and the separated material, ML oo, is washed (ionised (FE) and then drained in IA overnight at 0 - 5 °C to give the main compound SAG) gram) at a melting point of 1001 C. Nitroaniliono) -5- methylthiophene -3- carbonitrile ( 1 - 2) - 2 to stir a stirred slurry aqueous mixture of sodium hydride (¢ rh 1 g + fon) dispersed on a plane (J 5 GY coe) and tetrahydrofuran (© ml) under Clas nitrogen | 0 dropwise with a solution of Y + el > YA,Y) 2 - fluoro nitrobenzene, + mol) and YV,7) 2-amino-5-methylthiophene-3-carbonitrile g ¢ Y + mol ) & You) and the mixture is stirred at Yo m for ye hour and then poured into eB and extracted Dael (J— © ++ x 1) dichloromethane — washing the combined extracts with hydrochloric acid to 2 (Je Yor XY) and water (? Yoo x ml); Drying is done through magnesium sulphate and the solvent is removed under reduced pressure. The rest of the ethanol is crystallized to give the main compound (TL) gram) at kB fusion of mp. - amino -2- methyl - 10H - 4 J Stirring a stirred slurry aqueous mixture of - (2-nitroaniliono) -5- methyl - 2 cpl = YT) thiophene -3- carbonitrile Y. (Js) in (Jo Yo) ethanol at a temperature of -C for 0 minutes where stannous chloride is added to Sb (1.40 TV cpl, + mol) in hydrochloric acid ( 171 ml ¢ © 0 (JY) the mixture is stirred under CINE UPS, th » and concentrated under pressure and allowed to crystallize for a night at m" oY

- Hara m. The salt is filtered, washed with a small amount of water and stirred (£1g) at a point of . m and used without additional purification in the next stage. You are greater than mp. Fusion of 2 -methyl-10- (4-methyl -1- piperazinyl) - 4H - thieno[2,3 -b][1,5]- ) ¢ benzodiazepine

Crude 4 - amino -2- methyl -10H- thieno [2,3 -b] [1,5] benzo- diazepine hydrochloride (0 mL) and (V2) N - methylpiperazine in a mixture of LAL > g) are reconstituted £,T)

Yoo dry td under an atmosphere (J 01 (toluene ml (and Y +) dimethylsulphoxide 4 ml) and the product is allowed to crystallize (0) water slp) in a live © m ¢ and Lo Jd hour. It is cooled ml (Y +) acetonitrile. The product was filtered and crystallized from J (0) at a temperature of 8 °C for a night. 1156 °C mp. A to give the main compound (1.10 grams) at a melting point of 0. The object was installed using an optical density meter: spectroscopically 2 t 3 t l \ ge 8 CH 7 m 3

BEEN

; 3 +7 \ i J 3 g x ~ 93 7 “ib

BECH

3 'H NMR (CDCly): 8 2.30 (3H, S, 4 -CH3) , 2.2028 (3H, 5, 2-CH3) , 2.45 (4H, m, 3' -CH,) 3.49 (4H, m,2' -CHy), 5.00 (H, btoad s, 10 -NH), 6.23 (H, broad s, 3-CH), 6- hm 35-7-10 (4H, m, 6,7,8, 9-H). 3C NMR (CDCl3): 8 128.5 (s m C -2),127.8(dm C-3), 119.1 (s, C- 3a) 1574 (s,C-4),140.08(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,C-10a),46.5(t,2'- C),54.8(,3'-C)459(q,-4 - 0.15.2)1 , 2-11© Y.oY"

The mass spectra show +14 in the amount of YAY and ions with a major particle Dl” in the magnitudes of Yoo, 7 751, and YAY. Example? methyl - 2 - amino -5- methylthiophene -3- carboxylate ( ) ° to stir a mixture of methyl cyanoacetate (4,¥ g ued 2 mol sulfur 1771 (g + ; mol) and triethylamine ( 7.7 ml 2.307 mol (in dimethylformamide undivided (VY) ml) under nitrogen atmosphere to which a solution of (0) kis propinoaldehyde (Y,0) g / v0 tY mol (3) methylformamide undivided (? ml) and maintaining the temperature at -40 L. The mixture is stirred at pio 0 for an hour and a half, after which the water is separated from ethyl acetate, and the organic extract is washed with water, diluted and evaporated. Then the Purification of the main compound by chromatographic separation on neutral alumina and filtering it with chloroform - hexane (6A grams). methyl 2- (2- nitroaniliono) -5- methylthiophene -3- carboxylate ) ¥ Vo To stir a suspension of (Y) sodium hydride g) in dry tetrahydrofuran (Yo) ml) under nitrogen atmosphere added solutions of -3- methyl 2- amino -5- methylthiophene ¢,A) carboxylate gm l mol ( 3 fluoronitrobenzene -2 (+,¢ gm 17 mol) 3 tetrahydrofuran dry 1) ml) and the mixture is stirred at a temperature of Yo C for a period of Yo hour and poured into ice, and ethyl 3 277 hydrochloric acid 2N acetate 000 is separated »and the organic extracts have been dried through magnesium sulphate. Silica gel is filtered with toluene and crystallized from ethanol (5.1 grams) with a melting point of 1170 - 1177 mp.

methyl-10 - (4 - methyl - 1 - piperazinyl) -4H- thieno[2,3-b]- [1,5] ) > -2 benzodiazepine Y,V) methyl 2- (2) is hydrogenated - nitroanilino) -5- methylthiophene -3- carboxylate pl 0.007 mol) in a parr device at 260 psi (psi) in 0 [yy) ethanol -ethyl acetate 0 ml) with palladium palladium on a charcoal catalyst Ql 710 (charcoal catalyst 00 mg). After removing the catalyst and the solvent, the -diamino ester mother is dissolved in a mixture of 1 (N- methylpiperazine 7 ml) and anisole (0© ml) and titanium tetrachloride J sls (£0.7 ml) is added ) in Vo (anisole ml) to the above solution under nitrogen atmosphere with stirring. The mixture is stirred at 100 m for an hour and under 0 re-flow for 47 hours to create a ring closure for amino - anilino) -5- methylthiophen -3- yl ] carbonyl } -4- methylpiperazine -2 (-2[{-1.z) and after allowing to cool down to 80 °C, a mixture of 7730 percent of ammonia solution (+ / ml) and (10) isopropanol ml (carefully) is added, followed by Yo) ethyl acetate. ml). The technology of the product is carried out by chromatographic separation on florisil, and it is separated with ethyl acetate, and finally it is crystallized from acetonitrile (50 ml) in order to give the main compound (YL YY) (gram) identical to the compound described above. Example ? 7 The pulvule formula is prepared by mixing the active agent with silicone starch 5 and packing it into hard gelatin capsules.

Per capsule 200 mg Compound of the invention 0 mg Silicone 4 mg A flowable starch YAY, Starch flowable mg Example ¢ A tablet formulation is made by granulating the agent Lill with a diluent Suitable as a lubricant, disintegrant, binder and compressing adhesive. 0 Compound of the invention 8 mg Magnesium stearate 4, ; Microcrystalline cellulose milligrams in milligrams Povidone 0 milligrams Yee, Starch, directly compressible milligrams Example o An aqueous liquid of an active agent is prepared as an ag plug and a freeze-dried plug to recreate it in A sterile and suitable cist before use (total volume 01 ml) The compound of the invention 00 mg Yo Mannitol mg N Hydrochloric acid and / or N sodium hydroxide to adjust pH to 5-5.5. oY" ‏

Example + A controlled release syringe is formed; As an intramuscular injection of a sterile suspension of an active agent ppm 410 in an oleaginous vehicle. The compound of the invention 6 mg aluminum stearate 4; Milligrams of Sesame oil? Example V 0 A medicinal formula is prepared by mixing an active agent with silicon starch and starch and packing it into hard gelatin capsules. Per capsule, 0 > 0 mg, the compound of the invention 8 mg, flowable starch, starch flowable with 33 / 1, Silicone 220 YY 0? Vu Starch flowable milligrams

Claims (1)

Y vr — — protectants methyl - 10 - (4 - methyl - 1 - piperazinyl) -4H- thieno[2,3-b]- [1,5] - \vo -2 benzodiazepine Y ¢ or salt Add acid from that source. methyl - 10 - (4 - methyl - 1 - piperazinyl) -4H- thieno[2,3-b]- [1,5] - Y 2 -2 benzodiazepine Y » or a pharmaceutically acceptable acid additive salt from that source. methyl - 10 - (4 - methyl - 1 - piperazinyl) -4H- thieno[2,3-b]- [1,5] - Y 1 -2 benzodiazepine Y 401 - compound according to claim? or? For use as a pharmacist's knee sleeve. \ 0 -— Using Las compound for protection element No. X or 7 3 Manufacturing a drug to treat the central nervous system led Y defect. 1 + - Use of a compound according to Claim No. ? or? To manufacture a drug for the treatment of mental illness Y schizophrenia. VY \ - use of a compound and mouth of claim number Y or 7 3 Manufacture of a drug for the treatment of disease Y 4.5 Schizophreniform . A \ - The use of the Les compound of claim number Y or 7 to manufacture a drug for the treatment of mites (acute mania >) Y . oy". 1 4 - Use of Compound Gs for claim No. or ? To manufacture a drug to treat mild anxiety states. | A 0 0 1 - A pharmaceutical compound containing compound Gs of claim number Y with Y carrier or acceptable solvent GY Ae from that source. 11 1 - Dosage unit form consisting of Yo - 0.1 mg of a compound according to rin Protection No. Y 1 1 - Dosage unit form consisting of 0 = 1 mg of a compound according to element Y Claim No. N1 - Compound Y is composed of a compound of claim No. 7 with a pharmaceutically acceptable solvent or carrier from that source. 1 4 - A pharmaceutical compound in the form of a capsule or a tablet consisting of 0.1 Y - 70 mg of a compound of element Bl No. . 1 0 - A pharmaceutical compound in the form of a capsule or tablet consisting of 8,. - 100 milligrams of CY compound