2-teenfemalemonologue and method for producing 3-(1 - piperazinil)-1,2 - benzisothiazole


C07C313/16 - having sulfur atoms of sulfenic groups bound to carbon atoms of six-membered aromatic rings

 

(57) Abstract:

Describes the new 2-teenfemalemonologue General formula IIA, where R1means (C) or (a), showing neuroleptic activity. Also described is a method of obtaining an intermediate product. 2 c. and 16 C.p. f-crystals.

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Background of the invention

The present invention relates to methods for the preparation of 3-(1-piperazinil)-1,2-benzisothiazole or its pharmaceutically acceptable salts and to new intermediate compounds used in the implementation of these methods. 3-(1-Piperazinil)-1,2-benzisothiazol is the primary intermediate compound used in the preparation 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro - 1,3-dihydro-2H-indol-2-it (ziprasidone). This connection manifests neuroleptic activity.

In U.S. patent N 4831031, issued may 16, 1989, which is fully incorporated into this patent application by reference, describes hydrochloride 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6 - chloro-1,3-dihydro-2H-indol-2-it formula:

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where Ar denotes benzisothiazol-3-yl, which is obtained in the form of a hemihydrate (hereinafter referred to as "hemihydrate").

U.S. patent N 5312925, issued may 17, rodnoi salt ziprasidone, the methods of its production, pharmaceutical compositions and methods of treatment of psychotic disorders.

U.S. patent N 5359068, issued October 25, 1994, which is fully incorporated into this patent application by reference, relates to a method of obtaining ziprasidone and intermediate connections of its receipt.

U.S. patent N 5206366, issued April 27, 1993, which is fully incorporated into this patent application by reference, relates to a method of obtaining ziprasidone water-based.

U.S. patent N 4590196, issued may 20, 1986, relates to 1-(1,2-benzisothiazol-3-yl)piperazine, which is the penultimate intermediate compound obtained in accordance with the methods of the present invention.

The Japan patent N 6220030, published on August 9, 1994, relates to the production of derivatives of 3-amino-1,2-benzisothiazole by the interaction of derivatives of bis-(2-tianfeng)disulfide with inorganic salts of metals and subsequent processing by the developer.

Summary of the invention

The present invention relates to a compound of the formula:

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where R1does

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or

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The present invention relates also to method of obtaining the means

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or

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subjected to interaction with piperazine at a temperature of from about 80oC to about 170oC, R1preferably is a group of formula "c". The amount of piperazine is preferably from about 2 molar equivalents to about 15 molar equivalents based on the amount of the compounds of formula II. The amount of piperazine most preferably is about 10 molar equivalents based on the amount of the compounds of formula II.

The preferred implementation of the present invention relates to a method for conversion of compounds of formula II to the compound of formula I in the presence of the clarifier piperazine. Acceptable clarifiers piperazine are isopropanol, pyridine or tert-butanol, preferably isopropanol. Dodge preferably used in amounts of about 1.2 volume (calculated (ml/g) to the weight of the compounds of formula (II) piperazine.

The preferred implementation of the present invention relates to a method for conversion of compounds of formula II in which R1does

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or

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in the compound of formula I, which then lies in the fact that exercise maintains the business oxidants are dimethyl sulfoxide, the air, the salt of copper (II), bisulfite, metabisulfite or hydrogen peroxide, preferably dimethyl sulfoxide. The number specified thiol oxidant, in particular dimethyl sulfoxide, preferably 2-4 molar equivalents based on the amount of the compounds of formula (II).

The most preferable implementation of the present invention relates to a method for conversion of compounds of formula II in which R1refers to a group "c", in the compound of formula I, which lies in the fact that the compound of formula II is subjected to interaction with piperazine, Dodge piperazine (most preferably, isopropanol) and thiol oxidant (most preferably dimethylsulfoxide).

The term "Dodge piperazine" used here, the value applies to the solvent, which when heated under reflux capable of dissolving piperazine, hardened in the head and the steam space of the reactor. Professionals in this field know that piperazine is solidified at a temperature of about 108oC, so it will harden in any zone of the reactor with the same or lower temperature. Professionals in this field also invest reactor.

The area located above the solution level inside the reactor, is included in the reaction region and is called the head space of the reactor. Steam space is the space inside and around the various feed lines going to the reactor and from him.

The term "salt of copper (II)" used here, the value applies to copper chloride (CuCl2), copper bromide (CuBr2) or copper sulfate (CuSO4).

The term "bisulfite" used here, the value applies to sodium bisulfite (NaHSO3) or potassium bisulfite (KHSO3).

The term "metabisulfite" used here, the value applies to sodium metabisulfite (Na2S2O5) or potassium metabisulfite (K2S2O5).

Detailed description of the invention

The compounds of formula I and ziprasidon can be obtained as shown in the following schemes of reactions outlined in the description of the invention. Except where otherwise indicated, the compounds of formula I, II and IIa and R1specified in the diagrams reactions and in the description of the invention have the above values.

Circuit 1

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Scheme 2

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Scheme 1 shows the receiving promezhutochnya, shown in scheme 2.

Shown in scheme 1, the compound of formula II in which R1does

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can be purchased commercially or obtained in accordance with the method described in Japan patent N 6220030, published on August 9, 1994

The compound of formula II in which R1does

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you can get as a result of interaction of the compounds of formula:

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from about 1-10 equivalents of piperazine, preferably with 2-5 equivalents of piperazine. The temperature of the above reaction is in the range from about 25oC to about 105oC, preferably it is approximately 65oC. the reaction Time is from about 1 hour to about 20 hours, preferably from about 2 to about 6 hours.

The compound of formula V is obtained from the amide of the formula:

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as a result of interaction from about 1 to 3 equivalents glorieuses agent such as phosphorus oxychloride (POCl3) trichloride phosphorus (PCl3or pentachloride phosphorus (PCl5) in an inert solvent. As glorieuses agent preferably using 1.2 equivalents of phosphorus oxychloride. Acceptable solvents are dimethylformamide, dimethylacetamide or but about 3.5 hours. The reaction is carried out at a temperature from about 30oC to about 100oC, preferably about 70oC.

The compound of formula VI is commercially available.

The compounds of formula II in which R1does

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you can get as a result of interaction of bis(2-tianfeng)disulfide with the compound of the formula:

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in an inert solvent. Acceptable inert solvents are isopropanol, ethanol or tetrahydrofuran, preferably isopropanol. The above reaction is carried out at a temperature of about 50oC to about 120oC. the reaction Time is from about 1 hour to about 3 hours, preferably about 2 hours.

The compound of formula II in which R1does

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or

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can be converted into a compound of formula I in the result of the interaction of from about 2 to 20 equivalents of piperazine (preferably anhydrous). Piperazine is preferably used in such a quantity that minimizes bis-substitution of the free amine in piperazino group of compounds of formula I. R1preferably means

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When R1denotes the above group of formula "c", predpochtitel. The temperature of the above reaction is in the range from about 76oC to 200oC, preferably it is equal to approximately 120oC. the reaction Time varies depending on the temperature at which reaction takes place. With increasing reaction temperature, the reaction time is reduced. If the reaction is carried out at a temperature of approximately 80oC, after 2 days you can get only a small amount of product. If the reaction is carried out at a temperature of approximately 200oC, in the reactor it is necessary to create a high pressure in order to prevent the loss of piperazine and clarifier, and the reaction time will be about 1 hour. When the reaction is carried out at high temperatures, the pressure inside the reactor should be about 3.5 - 4.2 ATM., and thus it corresponds to the standard characteristics of the pressure industrial reactors. When the reaction is carried out at the ideal temperature of approximately 120oC, the reaction time is about 24 hours.

As a result of interaction of the compounds of formula II in which R1does

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or

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with piperazine formed thiol, which is a by-product of the formula:

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The preferred assistenza formula II, in which R1does

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The process of oxidation in situ can be facilitated by adding to the reactor from about 1 to about 10 equivalents, preferably 4 equivalents of oxidant. Acceptable oxidants are dimethylsulfoxide, air, salt copper (II), bisulfite, metabisulfite or hydrogen peroxide, preferably dimethyl sulfoxide. The sulfoxide as a developer is preferably used in an amount of from about 2 to 5 equivalents.

In accordance with another preferred embodiment of this reaction in the reactor add clarifier piperazine in an amount of from about 0.5 to about 5 volumes to prevent curing of piperazine in the head space and the steam reactor. Acceptable clarifiers piperazine have a boiling point in the range of from about 70oC to about 130oC and represent isopropanol or tert-butanol, pyridine, toluene or diglyme, preferably isopropanol. Dodge piperazine is preferably used in an amount of about 1.2 volume (calculated (ml/g) to the weight of the compounds of formula (II).

The compound of the formula I can be converted into a more stable pharmaceutically acceptable salts of the compounds of formula Ia, in the treatment of the free base of formula I, pharmaceutically acceptable acid of the formula RH in the polar solvent. Acceptable acids of the formula RH are acids which form non-toxic salts accession acids, for example salts containing pharmaceutically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)]. The acid is preferably hydrochloric acid. Acceptable solvents are lower alcohols, such as methanol, ethanol, isopropanol or tert-butanol, toluene, ethers, such as diethyl ether or tetrahydrofuran, or mixtures of the above solvents. The solvent is preferably a mixture of isopropanol and toluene.

The compound of formula I or Ia in turn ziprasidone in accordance with the methods described in U.S. patent N 4831031, 5206366 or 5359068, issued respectively on may 16, 1989, April 27, 1993, and October 25, 1994

Figure 2 shows the receiving ziprasidone of the compounds of the formula I or Ia according to the methods described in U.S. patent N 4831031, issued may 16, 1989, the Compound of formula I or Ia, casinoaction combination typically is carried out in a polar solvent, such as a lower alcohol, for example ethanol, dimethylformamide or methyl isobutyl ketone, and in the presence of a weak base such as a tertiary amine base, such as triethylamine or diisopropylethylamine. This reaction is preferably carried out in the presence of catalytic amounts of sodium iodide and a neutralizing agent for hydrochloride, such as sodium carbonate. This reaction preferably is carried out at the boiling point under reflux solvent used.

Alternatively, scheme 2 also applies to the conversion of compounds of formula I or Ia in ziprasidon in accordance with the methods described in U.S. patent N 5206366, issued April 27, 1993, the Compound of formula I or Ia, in particular, is subjected to the interaction with the compound of the formula III, in which Hal represents fluorine, chlorine, bromine or iodine. The reaction mix is carried out in water at the boiling point under reflux with the use of such a Converter, as galoidvodorodnykh acid.

The compounds of formula I can alternatively be turned into ziprasidone in accordance with the methods described in U.S. patent N 5359068, issued October 25, 1994

The compounds of formula I, in particular, can be the slots with obtaining the compounds of formula:

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The compound of formula IX can then be treated with a reducing agent to obtain compounds of the formula:

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The compound of formula X can then be treated with a compound of the formula R2-CH2-CO2R3where R2denotes CO2R3or CN, and R3means (C1-C6)alkyl,

obtaining the compounds of formula:

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where R2denotes CN or CO2R3and R3means (C1-C6)alkyl.

The compound of formula XI can then be treated with acid at elevated temperature to obtain compounds of formula XI in which R2and R3both represent hydrogen.

The compound of formula XI can then be processed (C1-C6)alkanol in the presence of acid catalyst esterification with obtaining the compounds of formula XI in which R2denotes hydrogen, and R3means (C1-C6)alkyl.

The compound of formula XI in which R2denotes hydrogen, CN or CO2R3and R3denotes hydrogen or (C1-C6)alkyl, can then be processed by the recovery provided that when R2denotes CN or CO2R3and R3means (C1-C6)Ala is a description of the stages of the transformation of compounds of formula I in ziprasidon described in U.S. patent N 5359068, issued October 25, 1994

Ziprasidone (hemihydrate or monohydrate) can be used as an adjunct tool in accordance with the description given in the above U.S. patents N 4831031 or 5312925 (related respectively to the hemihydrate and monohydrate). This substance you can enter needy subject separately or, preferably, in combination with pharmaceutically acceptable carriers or diluents in the form of pharmaceutical compositions obtained in accordance with conventional pharmaceutical practice. Ziprasidone (hemihydrate or monohydrate) can be administered orally or parenterally, including intravenously or intramuscularly. Acceptable pharmaceutical carriers are solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions used in the form of various dosage forms such as tablets, powders, cakes, syrups and solutions for injection. These pharmaceutical compositions optionally can contain additional ingredients such as flavorings, binders and fillers. Thus, for oral administration can be used tablets containing time and, such as starch, alginic acid and certain complex silicates, and also binders, such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. In addition, for the manufacture of tablets often use lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type can be filled with soft and hard gelatin capsules. For their manufacture it is preferable to use materials such as lactose or milk sugar and high molecular weight glycols. In the manufacture of aqueous suspensions or elixirs for oral administration the active ingredient can be combined with various sweetening or flavoring agents, dyes or pigments and, if desired, emulsifying or suspendresume substances, with such diluents as water, ethanol, propylene glycol, glycerin and mixtures thereof.

For parenteral administration, you can use the solution or suspension ziprasidone (hemihydrate or monohydrate) in sesame or peanut oil, aqueous solution of propylene glycol, or in sterile aqueous solution. Such aqueous solutions, if necessary, should be supplemented sootvetstvovala solution or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Sterile water environment can be easily obtained in accordance with standard methods known to experts in this field.

Effective dose ziprasidone (hemihydrate or monohydrate), as is known, depends on the method of administration and other factors, such as age and weight need of the subject.

The examples given below illustrate intermediate compounds and methods for their preparation the present invention. Commercial reagents used without further purification. The melting temperature is not adjusted. Data of NMR spectroscopy indicated in Micros () and correlated with the timing of deuterium in the solvent of the sample. Except where otherwise indicated, all mass spectra obtained under electron impact (EI, 70 eV). Except where otherwise indicated, the analyses performed by chromatography on columns of silica gel with a particle size of 32 - 63 μm under pressure in a nitrogen atmosphere (flash chromatography). For liquid chromatography high pressure equipment used LDC Analytical constaMetric3200 HPLC (Thermo Separation Products Co the creators of acidic potassium phosphate (KH2PO4) with a pH of 6.0, adjustable potassium hydroxide (KOH), 15% methanol; the volumetric rate of 1.0 ml/min; detector: UV 229 nm; dispenser: 10 ál; samples received in the mobile phase (0.05 mg/ml)) is performed on a column of BondC8 , 3.9 x 150 mm (Mac-Mod Analytical, Inc. , Chadds Ford, PA 19317). Room temperature is 20 - 25oC.

Legend

NMR spectrum NMR; (s) - singlet, (d) - doublet, (t) triplet, (q) Quartet, (m) - multiplet; HRMS - mass spectrometry high fracture; FAB-MS - mass spectrometry with the bombardment of accelerated atoms; because the boiling point.

Example 1

Hydrochloride 3-(1-piperazinil)-1,2-benzisothiazole

How A

In a 500 ml round bottom flask, equipped with a mechanical stirrer, thermometer, reflux condenser, in the upper part of which has inlet for nitrogen and a connecting tube leading to the bleaching scrubber, download bis(2-tianfeng)disulfide (20,0 g, to 74.5 mmol), anhydrous piperazine (64,2 g, 745 mmol), dimethyl sulfoxide (12.8 g, 164 mmol) and isopropanol (24 ml). The flask is rinsed with nitrogen, the reactants melt (at a temperature of approximately 80oC) and heated to boiling point under reflux (110 - 126oC). After heating raffia (producing elution with a mixture of methylene chloride : isopropanol : triethylamine with a ratio of 15 : 5 : 1), the results of which indicate the completion of the reaction. The solution is cooled to 85 - 90oC and at this temperature, add water (130 ml). The resulting suspension is cooled down to 30 - 35oC. the Reaction mixture was concentrated under reduced pressure (because = 50 - 60oC at a pressure of 110 mm), which gives approximately 30 ml of distillate. The distillate is treated with bleaching agent to destroy the dimethyl sulfide (DMS). Using Drager tubes Drgerweck Ag Lbeck , Germany) designed for the determination of dimethyl sulfide in parts per million, establish that couples in the head space of the reaction flask contain less than 1 part per million residual LCA. A sample of the crude reaction mixture was analyzed by thin-layer chromatography high pressure. The crude reaction mixture contains 3-(1-piperazinil)-1,2-benzisothiazol(80%), 3,3'-(1,4-piperazinil)-bis-1,2-benzisothiazol (4,6%) and 2-(1-piperazinil)-piperazine (4%). Then add isopropanol (28 ml) and water (71 ml), the suspension is cooled to 30oC, granularit for 0.5 hours and filtered through diatomaceous earth such as celite (Celite), with 3,3'-(1,4-piperazinil)-bis-1,2-benzisothiazole. The filter residue is washed with 56 ml of a mixture of isopropanol : water (1:1). To caledonienne layers of toluene, washed with water (100 ml), and then treated with decolorizing charcoal, for example DARKO KB-B(2 g). Layer celite washed with toluene (60 ml), wash water is combined with the filtrate and concentrate under reduced pressure to 90 ml of the concentrate added isopropanol (220 ml) and the yellow solution is cooled to 20oC. the pH of the solution slowly adjusted to 3.5 - 4.0, adding to 9.8 ml of concentrated hydrochloric acid. The resulting suspension is cooled to 0 to 5oC, granularit for 1 hour and then filtered. The precipitated product is washed with cold isopropanol (80 ml) and dried in vacuum at 40 ° oC for 24 hours. Specified in the header connection (43,2 g) was isolated as a pale yellow solid with a yield of 77.6 per cent (purity 98.5% of the defined liquid chromatography high pressure). Spectroscopic and physical properties of solids identical to an authentic sample (note: the connection is a strong irritant).1H NMR (D2O): 7,80 (m, 2H), 7,49 (m, 1H), 7,35 (m, 1H), to 3.58 (m, 4H) and of 3.42 (m, 4H).

13C NMR (dimethylsulfoxide): 162,72, 152,10, 128,15, 127,09, 124,63, 124,12, 121,21, 48,48 and 42,49.

Example 2

Hydrochloride 3-(1-piperazinil)-1,2-benzisothiazole

Bis(2-tianfeng)disulfide (5,00 g, the temperature of the boiling point under reflux (115oC). The yellow solution is heated under reflux (110-115oC) for 23 hours and then cooled to 95oC. Then add water (30 ml), the resulting suspension is cooled to 25oC and filtered. The filter residue is washed with 12 ml of a mixture water : isopropanol (261). Wash water is mixed with the filtrate and add toluene (50 ml). The toluene layer is separated and the aqueous layer was extracted with additional toluene (25 ml). The combined layers of toluene, washed with water (20 ml), treated with activated carbon (DARKO KB-B(0.5 g), filtered and concentrated under reduced pressure (42oC at a pressure of 700 mm RT. Art. ) to 12 ml of the concentrate added isopropanol (30 ml), after which the pH was adjusted to 4.4 by adding concentrated hydrochloric acid. The resulting suspension is cooled to 0-5oC, granularit for 1 hour and filtered. The precipitated product is washed with cold isopropanol (10 ml), dried in vacuum at a temperature of 42oC obtaining 3,22 g (total yield 34%) of 3-(1-piperazinil)-1,2-benzisothiazole. The analysis performed by thin-layer chromatography shows the presence of product in one spot.

The pH of the aqueous layer was adjusted to 4.0 by adding con will contentresult under reduced pressure to obtain oil, which is dissolved in methanol (19 ml). The solution is cooled in an ice bath and while stirring, add 10% solution of hydrogen peroxide (7 ml). The solution is stirred for 10 minutes and analyzed by thin-layer chromatography, the results of which indicate the completion of the reaction. Then add water (12 ml) and granularit suspension for 1.5 hours. The product is filtered and dried in vacuum at 40 ° oC to obtain 1.64 g (yield 33%) of bis(2-tianfeng)disulfide, intended for recycling.

Example 3

Hydrochloride 3-(1-piperazinil)-1,2-benzisothiazole

In a dry 300 ml round-bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, in the upper part of which has inlet for nitrogen, and addition funnel for pressure equalization, download anhydrous piperazine (of 49.4 g of 0.57 mol) and tert-butanol (10 ml). The flask is rinsed with nitrogen and heated to 100oC in the oil bath. In an addition funnel impose a solution of 3-chloro-1,2-benzisothiazole (19,45 g, 0.11 mol) in tert-butanol (10 ml), and within 20 minutes, slowly add it to the reaction flask, resulting in an exothermic reaction (112 - 118oC). After the addition, the yellow solution heating the om within 24 hours. The results of thin-layer chromatography shows that the reaction is complete. The reaction mixture is cooled to 85oC and add 120 ml of water. The turbid solution is filtered and the filter residue is washed with 60 ml of a mixture of tert-butanol : water (1:1). The pH of the mixture of filtrate and wash water was adjusted to 12.2 by adding 50% aqueous solution of caustic soda. The aqueous solution is extracted with toluene (200 ml), the layers separated and the aqueous layer was extracted with fresh toluene (100 ml). The combined layers of toluene, washed with water (75 ml), after which the toluene solution concentrate to 90 ml under vacuum at a temperature of 48oC. To the concentrate is added isopropanol (210 ml) and the pH slowly adjusted to 3.8 by adding a 7.6 ml of concentrated hydrochloric acid. The resulting suspension is cooled to 0oC, granularit for 45 minutes and filtered. The filter residue is washed with cold isopropanol (50 ml) and dried in vacuum at 40 ° oC obtaining 23,59 g (yield 80%) of the hydrochloride of 3-(1-piperazinil)-1,2-benzisothiazole in a solid white color with a grayish tint.

Example 4

3-(1-Piperazinil)-1,2-benzisothiazol

In 6 ml round bottom flask, equipped with magnetic stirrer, reflux condenser, the top is asola (0.25 g, of 0.93 mmol), anhydrous piperazine (0,80 g to 9.32 mmol) and isopropanol (0.25 ml). The flask is rinsed with nitrogen and immersed in an oil bath with a temperature of 120oC, which gives a yellow solution, which was heated under reflux. The reddish solution was heated for 25 hours at a temperature of 116 - 120oC, cooled to 25oC and add 5 ml of methanol. The results of thin-layer chromatography (mixture of methylene chloride : isopropanol : triethylamine with a ratio of 15:5:1) show that the reaction is substantially completed. The crude reaction solution was analyzed by liquid chromatography high pressure to obtain 3-(1-piperazinil)-1,2-benzisothiazole with the release of 70%.

Example 5

3-(1-Piperazinil)-1,2-benzisothiazol

In a round bottom flask, equipped with a mechanical stirrer, thermometer, reflux condenser, in the upper part of which has inlet for nitrogen, and addition funnel, download anhydrous piperazine (17,2 g, 0.20 mol) and isopropanol (3.0 ml). The flask is rinsed with nitrogen and incubated in the atmosphere, after which the mixture is heated to a temperature of 90oC with obtaining a solution. A solution of 1-(2-cianfanelli)piperazine (of 4.38 g, 20.0 mmol) in isopropanol (2.0 ml) for 1 hour and slowly add to rinicom (118oC) within 24 hours. The reddish solution is cooled to room temperature and analyzed with liquid chromatography high pressure. The analysis results show that the obtained 3-(1-piperazinil)-1,2-benzisothiazol with the release of 55%.

Example 6

3-(2-Cianfanelli)-1,2-benzisothiazol

How A

In a 50 ml round bottom flask, equipped with magnetic stirrer, thermometer and reflux condenser, the top of which has inlet for nitrogen, download bis(2-tianfeng)disulfide (1,25 g of 4.66 mmol), anhydrous piperazine (4,01 g and 46.6 mmol) and dimethylsulfoxide (0,80 g of 10.3 mmol) in 15 ml of tetrahydrofuran. The flask is rinsed with nitrogen and heat the mixture under reflux (75oC) for 25 hours. The reaction mixture is cooled to 25oC and remove the tetrahydrofuran under reduced pressure. The obtained solid substance was dissolved in 40 ml of a mixture of methylene chloride : water (1:1), the layers separated and the organic layer washed with water (20 ml). Solution in methylene chloride evaporated to obtain crude solid (0.85 grams), which crystallized from isopropanol (17 ml) to give pale-yellow crystals. The product is filtered and dried in vacuum at 40 ° oC to obtain 0.39 g (the), a 7.92 (m, 1H), to 7.77 (m, 1H), of 7.70 (m, 1H), EUR 7.57 (m, 2H) and of 7.48 (m, 2H).13C NMR (CDCl3): 154,99, 152,30, 134,83, 134,56, 134,06, 133,24, 129,07, 128,51, 125,33, 123,29, 120,13, 117,13 and 116,95. Calculated for C14H8N2S2: C, 62,66; H, 3,00; N, 10,44; S 23,90. Found: C, 62,43; H, 3,01; N Is 10.68; S, 24,05.

In addition, to confirm the structure of the product obtained x-ray crystal structure.

Example 7

3-(2-Cianfanelli)-1,2-benzisothiazol

Method B

Bis(2-tianfeng)disulfide (0.40 g, 1.48 mmol) and 2-mercaptobenzoic (0.20 g, 1.48 mmol) is mixed in 2 ml of isopropanol and heated under reflux (90oC) for 25 hours in an atmosphere of nitrogen (N2). The results of the analysis performed by thin-layer chromatography, high pressure, show that the obtained 3-(2-cianfanelli)-1,2-benzisothiazol with the release of 69%.

Example 8

1-(2-Cianfanelli)piperazine

Anhydrous piperazine (22,5 g, 261 mmol) and tetrahydrofuran (100 ml) are mixed in a nitrogen atmosphere and heated to a temperature of 60 - 65oC. 3-Chloro-1,2-benzisothiazol (10.0 g, or 59.0 mmol) for one hour and slowly added to the warm solution of piperazine and the resulting reddish solution is heated at a temperature of 65oC for 17 hours. The results of thin-layer chromatography to room temperature and filtered. To the solution was added toluene (100 ml). After which he concentrated under reduced pressure (40oC) to half volume. Solution in toluene, washed with water (100 ml) and the aqueous layer was extracted with fresh toluene (25 ml). The combined layers of toluene concentrate under reduced pressure to about 30 ml Cooled the solution to 0 to 5oC, to him slowly add hexane (50 ml). The obtained crystals granularit for 1 hour at a temperature of 0 to 5oC, filtered and washed sediment filter fresh hexane (15 ml); the solid is dried for 18 hours at a temperature of 23oC obtaining 11,51 g (yield 89%) of crystalline solid yellow (so pl. = 67 - 71oC). The results of NMR spectroscopy show that the obtained crude sulfenamid containing about 5% of 1,4-bis(2-cianfanelli)piperazine. Sulfenamid stored at a temperature of from 0 to -10oC to avoid his slow transformation into 1,4-bis(2-cianfanelli)piperazine occurring when heated during storage at room temperature. 1H NMR (CDCl3): 7,63 (m, 1H), 7,56 (m, 3H), 7,21 (m, 1H), 2,96 (m, 4H) are 2.87 (m, 4H).13C NMR (CDCl3): 142,69, 133,55, 132,67, 128,14, 126,69, 116,80, 110,24, 57,34 and 47,06. HRMS found: 220,0878; C11H13N3S. Calculated (FABP+1): 220,0908. < / BR>
2. The method of obtaining 3-(1-piperazinil)-1,2-benzisothiazole formula I

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characterized in that the compound of formula II

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where R1does

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or

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subjected to interaction with piperazine at a temperature of from about 80oWith up to about 170oC.

3. The method according to p. 2, wherein R1is

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4. The method according to p. 3, wherein the piperazine is present in an amount of from about 2 molar equivalents to about 15 molar equivalents based on the amount of the compounds of formula II.

5. The method according to p. 4, wherein the piperazine is present in an amount of 10 molar equivalents based on the amount of the compounds of formula II.

6. The method according to p. 5, characterized in that the interaction of the compounds of formula II with piperazine carried out in the presence of the clarifier piperazine.

7. The method according to p. 6, characterized in that the clarifier piperazine represents isopropanol, pyridine or tert-butanol.

8. The method according to p. 7, characterized in that the clarifier piperazine represents isopropanol.

9. The method according to p. 8, characterized in that the number of clarifier piperazine isopropanol soedinenie formula II, where R1is

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or

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subjected to interaction with piperazine in the presence of thiol oxidant.

11. The method according to p. 10, characterized in that the compound of formula II is subjected to interaction with piperazine and thiol oxidant in the presence of the clarifier piperazine.

12. The method according to p. 11, wherein R1in the compound of formula II is a group of the formula

< / BR>
13. The method according to p. 12, characterized in that as a thiol oxidant use sulfoxide, air, salt, copper (II), bisulfite, metabisulfite or hydrogen peroxide.

14. The method according to p. 13, characterized in that as a clarifier piperazine using isopropanol, pyridine or tert-butanol.

15. The method according to p. 14, characterized in that as a clarifier piperazine using isopropanol.

16. The method according to p. 15, characterized in that as a thiol oxidant use sulfoxide.

17. The method according to p. 16, wherein the specified number of thiol oxidant, dimethyl sulfoxide, is 2 to 4 molar equivalents based on the amount of the compounds of formula II.

18. The method according to p. 17, characterized in that cenia formula II.

 

Same patents:

The invention relates to new derivatives of erythromycin, method of production thereof, to pharmaceutical compositions based on them and to intermediate compounds

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new substituted benzopyranones that have antiatherosclerotic and antithrombotic action

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-etoxycarbonyl)metaxia - Mona, of the formula I

< / BR>
which has analepticheskih, hypoglycemic and hypolipidemic effect

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to a method for producing 6-fluoro-1,2-benzisothiazole formula

(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

(III)where R and R3have the specified values, which are subjected to interaction with a halogenation agent to obtain the corresponding sulfanilamide formula

(IV)Subjected to interaction obtained sulfanilamide with ammonia in the compounds of the formula

(I)

Polucheniya pharmaceutically active compounds, which can be used, for example, as antipsychotic agents and as inhibitors of reuptake of serotonin

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess qualities to estrogen modulators, of general formula (1) or its pharmaceutically acceptable salt, where R1 represents hydrogen atom or (C1-C6)alkyl, -SO2NR7R8, phenyl (C1-C3)alkyl or (C1-C3)alkyl, substituted with 5-8-member heterocyclic radical, containing nitrogen atom; R2 and R3 each independently represents hydrogen atom or hydroxyl, halogen atom or (C1-C6)alkoxy; X represents O, S, SO, SO2 or NR4; R4 represents hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted with 5-8-member saturated heterocyclic radical, containing one nitrogen atom, or group -COR7, -CO2R7 or -SO2NR7R8, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom or phenyl(C1-C3)alkoxy; Y represents direct bond, -(CR10R11)n- or -R10C=CR11-; R7 and R8 each independently represents hydrogen atom or (C1-C6)alkyl group; R10 and R11 each independently represent hydrogen atom or cyano, or group CONR7R8; n equals 1 or 2; A represents (C3-C12)cycloalkyl or phenyl, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy; when X represents NR4, Y and R2 together with containing them indazole cycle can also form 1H-pyrano[4,3,2-cd)indazole; on condition that: 1) when X represents O, S or NR4, R1 represents hydrogen atom or (C1-C6)alkyl, and Y stands for direct bond, then A is not optionally substituted phenyl; 2) when X represents O, R1O represents 6-OH or 6-OCH3, Y represents direct bond and A represents cyclopeptyl, then (R2, R3) or (R3, R2) are different from (H, CI) in position 4, 5; 3) when X stands for O, R1O represents 6-OH, R2 and R3 represent H, and Y represents CH=CH, then A is not phenyl or methoxyphenyl; 4) when X represents SO2, A represents phenyl and R1O represents 5-or 6-OCH3, then (R2, R3) or (R3, R2) are different from (H, OCH3) in position 6- or 5-, compound not being one of the following: 3-phenyl-5-(phenylmethoxy)-1H-indazole; n-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5]isoxazole; 3-(4-chlorphenylmethyl)-6-hydroxy-7-(n-propyl)-benz[4,5]isoxazole; 6-hydroxy-3-(2-phenylethyl)-7(n-propyl)-benz[4,5]isoxazole; 3-cyclopropyl-6-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5|isoxazole; 3-cyclohexylmethyl-6-hydroxy-3-phenylmethyl-7-propyl-benz[4,5]isoxazole. Invention also relates to pharmaceutical composition, application and method of prevention and treatment of disease, where modulation of estrogen receptors is required.

EFFECT: obtaining novel compounds, which possess qualities of estrogen receptors modulators.

18 cl, 7 dwg, 8 tbl, 97 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to fungus control, specifically to 5-iodotetrazole derivatives , in which R1 denotes butylene, straight unsubstituted alkyl with 8-16 carbon atoms, straight or branched unsubstituted or mono- or multi-, identically or differently substituted alkyl with 1-8 carbon atoms, where the substitutes are or mono- or multi-, identically or differently substituted alkyl residues selected from a group comprising unsubstituted alkoxy or 1-6 carbon atoms and alkoxy with 1-6 carbon atoms, substituted with dioxalonyl, phenyl which is up to five times identically or differently substituted with halogen, alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon aotms, alkoxy with 1-3 carbon atoms, alkylthio with 1-4 carbon atoms, morpholinyl, except the following compounds: 1-tert-butyl-5-iodotetrazole, 1-ethyl-5-iodotetrazole, 1-methyl-5-iodotetrazole. Said 5-iodotetrazole derivatives are obtained by treating tetrazoles of general formula , in which R1 assumes values given above, with iodine in an organic solvent in the presence of a base and, if needed, in the presence of a diluent. The invention also relates to a fungicidal agent, containing 5-iodotetrazole derivatives of general formula , in which R1 denotes hydrogen, alkylene with 1-4 carbon atoms, straight unsubstituted alkyl with 8-16 carbon atoms, straight or branched unsubstituted or mono- or multi-, identically or differently substituted alkyl with 1-8 carbon atoms, where the substitutes are mono- or multi-, identically or differently substituted alkyl residues selected from a group comprising unsubstituted alkoxy with 1-6 carbon atoms and alkoxy with 1-6 carbon atoms, substituted dioxalonyl, unsubstituted phenyl, phenyl which is up to five times identically or differently substituted with halogen, alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, alkylthio with 1-4 carbon atoms, morpholinyl and at least one solvent or diluent, as well as auxiliary additives if necessary. The invention also relates to paint material containing compounds of formula (Ia).

EFFECT: said fungicidal agent can be used in a method of protecting plants and paint materials from attack and/or decomposition by fungi by exposing the fungi or habitat thereof to the said agent.

11 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a method for preparing an immobilised 1,2-benzisothiazolin-3-one complex, an antimicrobial composition containing it and to using the above composition as an antimicrobial agent. The immobilised 1,2-benzisothiazolin-3-one is prepared by heating 1,2-benzisothiazolin-3-one and zinc chloride brought to the boiling point with partial condensation in C1-C4 alcohol to prepare a solution to be cooled and added with the immobilising effective amount of zinc oxide. The prepared mixture is brought to the boiling point with partial condensation, cooled to room temperature and filtered to prepare the immobilised 1,2 - benzisothiazolin-3-one/zinc oxide complex.

EFFECT: declared inventions provide producing the antimicrobial immobilised 1,2 - benzisothiazolin-3-one/zinc oxide complexes applicable as preserving agents due to their wash-out resistance.

12 cl, 4 dwg, 2 tbl, 22 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to bicyclic heterocycles of formula I and formula II , in which radicals and symbols have values specified in the formula of the invention. These compounds have inhibiting activity in relation to MEK kinase. The invention also refers to a pharmaceutical composition for treatment of hyperproliferation disease or inflammatory disease, to a method for inhibition of abnormal growth of cells or treatment of hyperproliferation disorders and to a treatment method of inflammatory diseases of a mammal. Besides, the invention refers to use of a pharmaceutical composition for preparation of a medicinal agent for treatment of the above diseases of a mammal.

EFFECT: improving compound application efficiency.

19 cl, 29 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to 1,2-benzizothiazolin-3-one or its salt, immobilised on zinc oxide (BIT/ZnO), method of obtaining complex of immobilised on zinc oxide 1,2-benzothiazolin-3-one and to application of 1,2-benzizothiazolin-3-one or its salt, immobilised on zinc oxide. Method of obtaining complex of immobilised on zinc oxide 1,2-benzothiazolin-3-one includes: obtaining mixture, which includes immobilising effective quantity of zinc oxide: liquid phase, which includes water, C1-C4 branched or non-branched alcohol or their mixture; and antimicrobial agent, dissolved in liquid phase and selected from the group, which consists of 1,2-benzizothiazolin-3-one, salts of 1,2-benzizothiazolin-3-one and their mixtures; and depositing antimicrobial agent with obtaining complex of 1,2-benzizothiazolin-3-one, immobilised on zinc oxide.

EFFECT: claimed inventions ensure obtaining antimicrobial complexes of immobilised 1,2-benzizothiazolin-3-one/zinc oxide, which are useful as preservatives because of their stability to washing out.

15 cl, 4 dwg, 12 tbl, 22 ex

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