Monohydrate 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil) ethyl)-6-chloro-1,3-dihydro-2h-indol-2-he hydrochloride and method thereof

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds possessing neuroleptic activity. The inventive product - monohydrate 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6 - chloro-1,3-dihydro-2H-indol-2-he hydrochloride. Specified monohydrate has a high stability upon receipt of the compositions possessing neuroleptic activity. Monohydrate is produced by interaction of anhydrous 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl) -6-chloro-1,3-dihydro-2H-indol-2-one with hydrochloric acid, preferably 0.3 to 3.0 M concentration, better 0,7 M. 2 S. and 2 C.p. f-crystals, 6 ill.

The invention relates to a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate.

In U.S. patent N 4831031 included in this description as the reference material described 5-(2-(4-(1,2- benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3-dihydro-2H-indol-2 - he hydrochloride General formula:

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in which Ar-benzisothiazol-3-yl, obtained in the form of a hemihydrate (further oboznachaetto 5-(2-(4- (1,2-benzisothiazol-2-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - direto-2H-indol-2-he hydrochloride (hereinafter referred to as "monohydrate"), with important and non-obvious properties. As monohydrate practically stable in relation to the absorption of moisture, it is possible to avoid the problems associated with the preparation of compositions with active components, changing the weight in the preparation of tablets or capsules.

In Fig. 1 shows the x-ray spectrum monohydrate powder with a water content of 3.97 wt. in Fig. 2 x-ray spectrum of the hemihydrate powder with a water content of 2.55 wt. in Fig. 3 x-ray spectrum of the anhydrous powder 5- (2-(4-(1,2-benzisothiazol-2-yl)-1-piperazinyl)ethyl)-6 - chloro-1,3-dihydro-2H-indol-2-he hydrochloride (hereinafter referred to as "anhydrous derivative"), with a water content of 0, 13 wt. in Fig. 4 - IR spectrum monohydrate with water content of 3.97 weight. in Fig. 5 IR range hemihydrate with water content of 2.55 wt. in Fig. 6 IR spectrum of anhydrous derivative with a water content of 0.13 wt.

theoretical value of water content in the monohydrate is of 3.85 wt. In the context of this invention the water content of the monohydrate is in the range from about 3.8 to about 4.5 wt.

The monohydrate can be characterized by the content of water in the x-ray spectrum of the powder shown in Fig. 1, and the IR spectrum, preveden the holding in which the water is about 0.13 wt. the x-ray spectrum of the powder is shown in Fig. 3, and the IR spectrum in Fig. 6. The anhydrous compound can be obtained by drying hemihydrate or monohydrate. These three characteristics monohydrate differ from the corresponding characteristics of the hemihydrate, the water content of which is approximately 2.55 wt. the x-ray spectrum of the powder shown in Fig. 2, and the infrared spectrum of Fig. 5. Hemihydrate can be obtained according to the method described in example 16, column 13, lines 13 to 17 of U.S. patent N 4831-31.

The monohydrate can be obtained by the reaction of anhydrous 5-(2-(4- (1,2-benzisothiazol-2-yl)-1-piperazinil)ethyl-6-chloro-1,3-dihydro-2H-indol-2-one with aqueous solution of hydrochloric acid. In General, the reaction proceeds at temperatures ranging from room temperature up to about 100oC, usually in the range from about 60 to about 65oC. depending on the reaction temperature and other conditions, the reaction time is usually from 2 to 48 hours; the most convenient times within 3-24 hours

The concentration of hydrochloric acid in the reaction mixture ranges from about 0.3 to about 3.0 M, the preferred value is about 0.7 m

Hot slurry formed in the reaction, moneytraveltravel processing. The filter residue is dried under the strict conditions to ensure that water content in the range of 3.8 to 4.5 wt. which corresponds to the stable monohydrate.

Monohydrate according to the present invention can be used as a neuroleptic drugs, as described in the aforementioned U.S. patent N 4831031. Man monohydrate can be entered either by itself, or more preferably in combination with suitable pharmaceutical point of view the media or spreaders in accordance with conventional pharmaceutical practice. The monohydrate can be administered orally or parenteral, including intravenous and intramuscular routes of administration. In a number of suitable pharmaceutical carriers include solid diluents or fillers, as well as sterile aqueous solutions and various organic solvents. The obtained pharmaceutical composition can be administered in various dosages and forms, for example in the form of tablets, powders, capsules, syrups and solutions for injection. These pharmaceutical compositions optionally can contain additional components, such as flavorings, binders, excipients. So for oral administration used A different disintegrator, such as starch, alginic acid and certain complex silicates, together with binders, such as polyvinylpyrrolidone, sucrose, gelatin and juice of acacia. Often advanced at reception of tablets used lubricants, for example magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used as a filler for soft and hard filled gelatin capsules. The preferred products for this purpose are lactose or milk sugar and high molecular weight glycols. Upon receipt of an aqueous suspension or Alexiou for oral administration, the main active ingredient can be mixed with various classicisme or flavors, dyes, and, if desired, emulsifiers or suspendresume means, as well as diluents, for example water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, you can use a solution or suspension of the new compounds of General formula 1 in peanut or sesame oil, aqueous solution of propylene glycol, or in sterile aqueous solutions. These aqueous solutions can be appropriately buffered, the first solution or glucose. Such aqueous solutions are particularly preferred for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All used for this purpose sterile aqueous medium can be easily obtained in accordance with customary methods known to experts in this field.

The effective dosage of the compounds of General formula 1, as it usually occurs depends on the method of administration and other factors, such as age and weight of the patient.

The stability of the compositions examined by keeping the samples in the conditions corresponding to 31, 51, 71, and 81% relative humidity at room temperature for 4 h and 8 days. For each of the samples to determine the water content and shoot the x-ray and IR spectra. Sustainable designs in the described conditions does not give any significant change characteristics after aging in these conditions.

Example 1. Clean three-neck round-bottom flask of 2 l equipped with a thermometer, mechanical stirrer, reflux condenser and external heating, twice washed with deionized and subjected to ultrafiltration with water. Then in the flask is charged with 750 ml of deionized and subjected to ultrafiltration wodelet 50 g anhydrous 5-(2-(4-(1,2-benzisothiazol-2-yl) -1-piperazinil)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-it. The reaction mixture is heated at 60-65oC for 24 h, the Residue is filtered in hot condition (approximately 55oC) filter paper and the residue is washed twice with portions of 200 ml of deionized and subjected to ultrafiltration water. After air drying at 40-50oC for 7 h, the water content is 3.9% of the x-ray powder is shown in Fig. 1.

After further drying in a period of 21.5 hours at 50oC the water content of the product falls to 0.19% of the corresponding radiograph shown in Fig. 3. Thus, after the described processing receive anhydrous derived.

Example 2. In clean three-neck round bottom flask with 150 ml equipped with a thermometer, magnetic stirrer, reflux condenser with input of nitrogen and bath for heating load of 5.00 g of anhydrous free base 5-(2 - (4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-Midol-2-it, 75 ml of deionized water and 5.0 ml of concentrated (37,3%) hydrochloric acid, resulting in the 0,76 M aqueous solution of hydrochloric acid. The resulting reaction mixture is heated at 60-65oC for 3 hours Bath for heating is then removed and cooled the mixture to room temperature. The product is filtered Nari 50oC. After drying, the water content is 4.2% of the radiograph shown in Fig. 1. The output of the monohydrate is 96% (5,43 g).

After further drying in a period of 21.5 hours at 50oC the water content of the product falls to 0.19% of the corresponding radiograph shown in Fig. 3. Thus, after the described processing receive anhydrous derived.

Example 3. In a clean, dry reactor at 20 gpm (75,7 l) load 17.4 gallon (66 l) deionized water and of 4.44 l of concentrated hydrochloric acid, getting 0,77 M solution. To the solution add of 4.44 kg anhydrous free base 5-(2-(4-(1,2- benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3-dihydro-2H-indol-2 - it. The mixture is heated to 65oC and incubated for 18 h, then cooled to room temperature and taken samples which research suggests has been full of salt formation. The product is filtered and washed with two portions of 5 gallons (18.9 l) deionized water, then dried in air at 50oC for 30 hours the Dried product contains 4.4% water, his x-rays are shown in Fig. 1, it is confirmed that the obtained target monohydrate.

Anhydrous free base used in predshestvuyuschih is-chloro-1,3-dihydro-2H-indol-2-it.

In a clean, dry glass tank 20 gpm (75,7 l) load 19 gallons (72 liters) of deionized water and of 4.44 kg of sodium carbonate; after dissolution of carbonate injected 4,29 kg (17.5 per mole) 5-(2 - chloroethyl)-6-chlorobenzol and 3,62 kg (16.5 moles) of 1-(1,2-benzisothiazol-3 - yl)piperazine. Water the mixture is heated at boiling under reflux and maintained at this temperature for 14 hours after completion of the reaction the solution is cooled to 20oC and filtered. The wet product is again transferred to the suspension in 23 liters of isopropyl alcohol at room temperature for 2 hours the Product is separated by filtration on two large craters off, washed with each of them 3.4 l fresh isopropyl alcohol. The product is dried in vacuum at 30-40oC as long, until the remains of isopropyl alcohol, obtained in the result of 5.89 kg (output 86,4%) of the desired product as free base, consistent with the standard characteristics according to high performance liquid chromatography (HPLC).

1. Monohydrate 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-he hydrochloride.

2. A method of obtaining a connection on p. 1, wherein interact anhydrous 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperaz the use of hydrochloric acid in the reaction mixture in a concentration of about 0.3 to 3.0 M

4. The method according to p. 2, characterized in that the concentration of hydrochloric acid in the reaction mixture is approximately 0.7 M

 

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(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

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R4is hydrogen or C1-C6alkyl

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Z1or Z2each independently NH or a direct link X-O

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SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

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EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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