Benzisothiazol or benzisoxazol-3-carboxamide or their pharmaceutically acceptable salts, processes for their preparation and pharmaceutical composition having antipsychotic activity

 

(57) Abstract:

Usage: in medicine, as substances that have antipsychotic activity. The inventive product benzisothiazol or benzisoxazol-3-carboxamide f-ly I, where R1Is h or lower alkyl; R2lower alkyl or a group of f-crystals, II, III, IV, V, VI, VII, VIII, IX, And where the lowest alkylen, group f-ly-CH2CH=CH-CH2-CH2CCH2-; X is O or S; W is N or a group CH; Z is H, lower alkoxygroup or halogen, and the solid line indicates the place of attachment of the group to the designated member of f-crystals or their pharmaceutically acceptable salts and farbkomposition with the appropriate media containing 1 360 mg of compound I in a single dose. Compound I is produced by interaction of the compounds X, where R2Is Cl, Br, I or group OSO2R6where R6-alkyl, phenyl or drowned, connection f-ly XI or interaction of the compound f-crystals XII, where Hal Is Cl or Br, with a compound of f-crystals XIII. Structure f-l I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII: 3 S. and 2 C.p. f-crystals, 2 tab.

The invention concerns benzisothiazol and benzisoxazol-3-carboxamido formula I

(where R1hydrogen or lower alkyl; R2lower alkyl or the group one of the following formulas

(Z), (Z) N (Z)

(Z) (Z) N (Z)

(Z) where R3 is od; X is oxygen or sulfur; W is nitrogen or CH; Z is hydrogen, lower alkyl, lower alkoxygroup or halogen, where the continuous trait (---) indicates the place of attachment of the group to the designated member of formulas; and it concerns the geometric and optical isomers of the above compounds or their pharmaceutically acceptable salts for the treatment of mental disorders, both independently and in combination with inert adjuvants.

Benzisothiazol and benzisoxazol-3-carboxamide that meets the invention, also generate a number of derivatives of these compounds, where and. R2group one of the following formulas:

(Z) (Z) (Z) b. R2group one of the following formulas:

N (Z) N or (Z) s R2a group of the formula:

(Z) d. R2a group of the formula

< / BR>
Throughout the text of the description and in the attached the claims, the term "alkyl" means a hydrocarbon radical straight or branched chain, containing no unsaturated structural elements and containing 1-7 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl, etc., the term "alkoxygroup" means a monovalent Deputy containing alkyl group attached through an oxygen, prosthetics-, propoxy, butoxy-, 1,1-dimethylmethoxy, intoxi-, 3-methyl-pentoxil-, 2-ethylpentane group, etc., the term "halogen" refers to the collection, which includes chlorine, fluorine, bromine and iodine. The term "lower" refers to any of the mentioned groups and corresponds to the group containing up to 6 carbon atoms, inclusive.

Connections matching the invention, in its molecular structure is asymmetrical and exist in the form of optical antipodes or their racemic forms. Optical antipode can be obtained from the corresponding racemic forms by standard optical technique of separation, including, for example, separation diastereomeric salts of these compounds, characterized by the presence of the basic amino group and an optically active acid, or by synthesis from optically active substances predecessors.

The invention includes all optical isomers and racemic forms. The formulas of these compounds are given in order that the specialist could focus in all kinds of optical isomers of these compounds defined by the specified image.

Symbol "E" and "L" indicate a particular location substituents associated with the grouping C=1 piperazinil-2-butenes tion with respect to each other. In butenes "Z" hydrogen atoms are located on one side of the double bond, i.e., in CIS-position relative to each other.

Benzisothiazol and benzisoxazol-3-carboxamide that meets the invention, preferably obtained by alkylation of haloalkylthio formula I

where R1And X have the above meanings; l chlorine, bromine or iodine, with a secondary amine of the formula II

HNW-R2where R and W have the specified values.

In N-organic, dipolar aprotic solvent, at elevated temperatures in the range of 50-200aboutWith, preferably in the temperature range 120-190aboutC. in Addition to the N-methylpyrrolidone you can use other dipolar aprotic solvents, such as, for example, dimethylacetamide, dimethylformamide, hexamethylphosphoramide and dimethylsulfoxide at a temperature of condensation of providing a satisfactory reaction rate in the temperature range when they are compatible with the solvent.

You can also use the base as it is a carbonate or bicarbonate of an alkaline or alkaline-earth metal, for example, a carbonate or bicarbonate of lithium, sodium or potassium, both independently and in combination with the promoter alkylation: iodide shch what romotion of condensation are, respectively, the potassium carbonate and sodium iodide.

If the alkylation proceeds under the action of the base and alkylation promoter, a solvent may be acetonitrile, and the alkylation is carried out in the temperature interval from 50aboutTo return temperature distillation of the reaction medium, preferably in the temperature range from 75aboutTo return temperature distillation.

Alternatively benzisothiazol and benzisoxazol-3-carboxamide that meets the present invention, is produced by or acid halide of formula III

where X has the values l represents chlorine or bromine, with a heterocyclic amine of the formula II

HA-NW-R2where R1, R2And W have the values given.

In the presence of an acid acceptor: tertiary amines, such as trialkylamine, namely, trimethylamine, triethylamine or Tripropylamine, or heterocyclic amine, such as pyridine, picoline, lutidine or collidine, in a suitable solvent. Suitable solvents include, for example, dichloromethane, trichloromethane. 1,1 - and 1,2-dichloroethane, preferably dichloromethane; and aromatic solvents such as benzene, toluene and xylene, preferably toluene. Preretirement.

Benzisothiazol and benzisoxazol-3-carboxamide that meets the invention is also obtained by aminating a complex ether benzisothiazol or benzisoxazol-3-carboxylic acid, having the formula IY

where R5alkyl; X has the value, aminoalkenes formula Y

HOH where a and R1have the following values, with the formation of hydroxyethylnitrosamine formula YI

translated in complying with the invention benzisothiazol and benzisoxazol-carboxamide. Preferably amination in an aromatic solvent, e.g. benzene, toluene, xylene or matlole or alcohol, for example ethyl, 2-propyl or 1-butyl, at temperatures of 100-140aboutC. the Preferred solvent is toluene. If the amination reaction is carried out at room temperature, then it is better to use a reactor operating under pressure.

Hydroxyethylaminomethyl YI is transformed into the final product, namely benzisothiazol or benzisoxazol by processing hydroxyethylnitrosamine YI-sulphonylchloride formula YII

R6SO2Hal where R6alkyl, phenyl or toluene; l chlorine or bromine, in the presence of acid accepi the reaction temperature in the range of 0-25aboutWith the formation of the sulfonate of the formula YIII hydroxyethylnitrosamine YI:

where A, R1, R6X is defined above,

processed (preferably without isolation in pure form) piperidine or piperazine II, taken as it is or in the form of a solution in an ether solvent such as 1,2-dimethoxyethane, 2-methoxyethylamine ether, tetrahydrofuran or dioxane, at the reaction temperature of 25aboutTo return temperature distillation of the reaction medium. Preferred ether solvent is tetrahydrofuran, and the preferred temperature of the reaction temperature reverse distillation.

Under sulfating you can use an additional solvent, such as tetrahydrofuran.

Preferred sulfonium reagents 7 are alkylsulfonate, of which the best methanesulfonanilide.

As intermediate products for the preparation of the desired benzisothiazol and benzisoxazol-3-carboxamido, were obtained following the sulfonates of N-(hydroxyalkyl)-benzisoxazol and benzisothiazol-3-carboxamide:

A. Methanesulfonate N-methyl-N-(2-hydroxyethyl)-1,2-benzisothiazol-3-carboxamide;

b. who yl)-N-(2-hydroxyethyl)-1,2-benzisoxazol-3-carboxamide;

d. Methanesulfonate N-(1-methylethyl)-N-(3-hydroxypropyl)-1,2-benzisoxazol-3-carboxamide.

Raw materials and auxiliary substances for the synthesis of benzisothiazol and benzisoxazol-3-carboxamide according to the invention are either available commercially, or they can be obtained by methods well known to specialists in this field. For example, 3-halogenbenzonitriles III and 3-haloaluminate-benzisothiazole I get the way that was described by Amoretti al. see Amoretti L. et al. IL FARACO (Ed. Sc.), 1972, V. 27, p. 855. Appropriate benzisoxazole, for example, the starting materials of formulas I and III, where X is oxygen, obtained by adapting techniques that have described Amoretti al. see ibid., p. 859-861, or disclosed Sato and Herein, see U.S. patent N 4758503, 1988.

In particular, 3-haloalkaliphilic benzisothiazol or benzisoxazol II, where R1methyl, And alkyl with 2 to 4 carbon atoms, and X, Y, Hal and n are defined above, is obtained by alkylation of benzisothiazol or benzisoxazol-3-carboxamide IX, where R1methyl, and X, Y and n are defined above, dihaloalkanes X formula lAHal, where A and radicals l - what is described above, in the presence of alkali metal hydride, e.g. sodium hydride or an oil emulsion, is intervale 0-25aboutC.

< / BR>
The necessary reagents are available and listed in the directory or they can be prepared by conventional methods. So, for example, 4-(4-forestsoil)piperidine reagent to obtain the corresponding invention benzisothiazol and benzisoxazol-3-carboxamido, where R2has the formula

where W represents CH, described in U.S. patent N 3576810, 1971;

4-(6-Chloro-1,2-benzisoxazol-3-yl)piperidine, serves as a substrate in obtaining the final desired compounds according to the invention, i.e. compounds in which R2has the formula

N (Z) and W represents CH, discussed in U.S. patent N 4327103, 1982;

4-(Benzothiazol-3-yl)piperazines, namely pieperazinove substrates for the synthesis of carboxamides containing the radical R2formula

N (Z) and the radical W represents hydrogen, is described in U.S. patent N 4452799, 1984.

The reagents required for building molecular structures benzisothiazol and benzisoxazol-3-carboxamido with radical And formula-CH2SN= SNSN2- or-CH2WITH CLO2- namely, amines of the formula

HH2CH=CHCH2NW-R2< / BR>
HH2CCCH2NW-R2where R1, R2W and m are defined above referred to in Cass is surrounding to the invention, useful for the treatment of mental disorders due to its ability to block the anxiety caused by apomorphine, in mammals.

Antidiureticescoy activity determined during the so-called "tests on climbing mice" (limbing mice assay) according to the method similar to that described by Prote al. see P. Protais et al. Psychopharmacol. 1976, V. 50, p. 1, and Costall, see Costal B. Eur. J. Pharmacol. 1978, V. 50, p. 39.

The test objects were the males of mice SC-1 body weight 23-27 g, divided in groups according to the standard method of laboratory tests. Mice were placed in wire cages with dimensions 4 x 4 x 10 inches and was sustained for 1 s for adapting and adjusting to a new environment. Then the mice were injected by the injection of subcutaneous apomorphine at the dosage of 1.5 mg per 1 kg of body weight, so that all experimental animals, this dose was forced for 30 min to climb (climb) the walls of the cells. Compounds to be tested on antidiureticescoy activity, was administered by injection into the abdominal cavity for 30 minutes before the quantification of apomorphine at the dosage of 10 mg/kg

To quantify "Serebriany on the wall of the cage" would take on 3 values (10, 20 and 30 min after the appointment of apomorphine) capacitylimited experiment did not take into account.

An advanced form of Serebriany on the wall under the effect of apomorphine was expressed in the long-term animals hanging on the walls of the cells for the most part stationary. In contrast climbing, caused locomotor stimulation, usually lasts only a few seconds. The behavior of mice Points vkarabkivatsya on the wall of the cage rests all 4 paws on the floor 0 ( Serebriany on the wall of the cells is not observed); clings 2 front paws over the wall of the cage 1 ( standing on hind legs); clinging to the wall of the cage all 4 paws 2 (" climbing the wall") and hangs

Points assessment Serebriany were summarized separately (maximum total points: 6 per mouse for three readings). 100% took the sum of the scores for the control group, animals in which the abdominal cavity is injected with a diluent, and subcutaneous apomorphine. The values of the ED50was calculated by the method of linear regression analysis with 95% confidence. In table. 1 presents antidiuretichesky activity, expressed in terms of the index ED50for the specified table. 1 benzisothiazol and benzisoxazol-3-carboxamido, and two standard antineuritic.

Antidiuretichesky activity has reached the, those in need of such treatment, an effective dosage is from 0.01 to 50 mg per 1 kg body weight per day via the oral cavity, as well as by intravenous injection into the tissue from the outside. In particular, an effective dosage of 25 mg per 1 kg body weight per day. It should be borne in mind that each experimental animal requires regulation of individual dosage (taking into account the specific characteristics of the organism) by a qualified technician, which introduces animals specified connection or watching the correctness of the latter. It should also be borne in mind that these doses are given solely for illustrative purposes and in no way limit the scope and practical application of the invention.

Antidiureticeski nature considered benzisothiazol and benzisoxazol-3-carboxamido is a paradoxical consequence of their weak ability to cause undesirable extrapyramidal (tra pyramidal side effects. The degree of undesirable activity, due to the extrapyramidal side effect, set the suppression of stereotyped behavior induced by apomorphine, using the technique described by Andenes al. see Anden, N. E. et al. J. Pharma. Pharmacol. 1967, V. 19, p. 627, and Ersoy body 125-200 g, which broke into groups with access to food and water ad libitum. Drugs were prepared in distilled water, in which case insolubility components were added surface-active agent (surfactant). The appointment can be varied. Volumetric dosage was 10 ml per 1 kg of body weight. During the initial evaluation the number of animals in the group was equal to six. The drug was administered one hour before the readout points. Animals were placed one by one in a plastic "tanks" size 24 x 14 x 13 see Animals of the control group was injected only solvent without drugs. Preparing a solution of apomorphine hydrochloride with a concentration of 15 mg of the compounds in 10 ml of 0.03% ascorbic acid solution containing 30 g of ascorbic acid in 100 ml of a 1% physiological saline solution, which increased the stability of apomorphine hydrochloride in solution. The solution of apomorphine hydrochloride was administered subcutaneously at a dose of 1.5 mg per 1 kg of live weight (volumetric dosage was 1 ml per 1 kg of live weight). After 50 min after drug administration were noted stereotype animal behavior, stereotypic activity classified as sniffing, licking and chewing movements, repeating netnote eroticheskoe disorders.

For the performance indicator drugs (in) took the relative number of such "protected" animals observed in each group. In the case when in the course of this test, antineuritic showed little effect, believed that this testifies to their weak ability to cause undesirable extrapyramidal side effects and/or about the presence of these animals dyskinesia, slow motion, see Moore and Gershon (Moore N. C. S. who Clinical neuropharmacology, 1989, V. 12, p. 167).

Reaction dosage was determined as an initial assessment, except that the group consisted of 10 animals, and these animals drug dose was administered nesistematizirovanna. The animals of one group were injected only solvent. The index ED50stereotyped behavior was calculated by the method of probit analysis (robit analysis).

In table. 2 shows the values of (%) suppression of stereotypic behavior, manifested by the action of apomorphine, for the considered benzisothiazol and benzisoxazol-3-carboxamido that meets the invention, along with two standard drugs.

Connections matching the invention include:

A. N-[2-((1-methyl)-4-piperazinil)ethyl]-6-methyl-1,2-benzoic C. 5-hydroxy-N-[2-((1-methyl)-4-piperazinil)ethyl]-1,2-benzisothiazol-3 - carboxamide;

d. 7-chloro-N-[2-((1-methyl)-4-piperazinil)ethyl]-1,2-benzisothiazol-3 - carboxamide;

that is, N-2-[(1-methyl)-4-piperazinil)ethyl)] -6-trifloromethyl - 1,2-benzisothiazol-3-carboxamide;

f. 6,7-sodium dichloro-N-[2-((1-methyl)-4-piperazinil)ethyl]-6-methyl-1,2 - benzisothiazol-3-carboxamide;

g. N-[2-[1-(3-methylbenzyl)] -4-piperazinylmethyl] -1,2-benzisothiazol-3 - carboxamide;

h. N-[2-[1-(3,4-dichlorobenzyl)] -4-piperazinylmethyl]-1,2-benzisothiazol - 3-carboxamide;

i. N-[2-[1-(2-hydroxybenzyl)]-4-piperazinylmethyl]-1,2-benzisothiazol-3 - carboxamide;

j. N-[2-[1-(4-trifluromethyl)benzyl]-4-piperazinylmethyl]-1,2-benzisothiazol - 3-carboxamide;

k. N-[4-(1-(2-methoxyphenyl)-4-piperazinil)-2-butenyl]-1,2-benzisothiazol - 3-carboxamide;

l. N-[3-(1-(1,2-benzisothiazol-3-yl)-4-piperazinil)propyl]-1,2-benzisothiazol - 3-carboxamide;

m. N-methyl-N-[2-(benzo[b]thiophene-3-yl)-4-piperazinil)ethyl]-1,2-benzisoxazol - 3-carboxamide.

Effective amounts of compounds conforming to the invention, can be assigned in various ways, for example, through the gastro-intestinal tract in the form of capsules or tablets, injections into the tissue of sterile solutions or suspensions, and in some cases intravenously, flame on its own, but you can also enter in recipes and to appoint in the form of their pharmaceutically acceptable additive salts to improve stability, convenience of crystallization, increased solubility, etc.

Preferred pharmaceutically acceptable additive salts include salts of mineral acids such as hydrochloric, nitric, sulfuric, etc., salts of monobasic carboxylic acids, such as, for example, acetic, propionic, etc., as well as dibasic carboxylic acids, such as, for example, maleic, fumaric, oxalic acid, etc. and besides, trekhosnovnykh carboxylic acids, such as, for example, carboxyesterase, lemon, etc.

For admission through the oral cavity active compounds conforming to the invention, it is possible to assign, for example, in combination with an inert diluent or edible carrier. These substances can be enclosed in gelatin capsules or compressed into tablets. When therapeutic purpose through the mouth these substances can be combined with excipients and used in the form of tablets, wafers, capsules, elixirs, suspensions, syrups, wafers, chewing gum, etc., Such formulations should contain at least 0.5% of active compound, but this content can warrantiesthe offer active compounds in such composition is it provides a suitable dosage. Preferred compositions and formulations that meet present invention, is prepared in such a way that the dose unit forms of drugs through the oral cavity is 1.0 to 300 mg of active compound.

Tablets, pills, capsules, wafers, etc. can also contain the following ingredients: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; razmelchitel, such as alginic acid, Primogel" (Primogel), corn starch, etc., a lubricating substance, such as magnesium stearate or Sterates" (Sterotes; glidant (a substance that facilitates sliding), such as colloidal silica; sweetening additive such as sucrose or saccharin or a flavoring, such as peppermint, methyl salicylate, orange flavoring. If the dosage unit form is a capsule, in addition to the substances mentioned above types, it also contains a liquid carrier such as fatty acid. Other dosage unit forms of medication may contain various other substances, modifying the physical nature of a dosage unit form, for example, may have a coating. Thus tablets or Belyaninov may contain sucrose, which is the sweetening agent and certain preservatives, pigments, dyes and fragrances. Substances used out in the preparation of these compositions should be pharmaceutically pure and in the doses in which they are applied, non-toxic.

When therapeutic purpose injections into tissues outside the active compounds responsible invention can be included in the composition of the solution or suspension. Such formulations must contain not less than 0.1% mentioned active compounds, but this content can vary in the range of 0.5-50% by weight of the solution or suspension. The content of active substance in these compositions is such that it provides a suitable dosage. Preferred compositions and formulations that meet present invention are prepared so that a dosage of one piece form medicines intended for introduction into the tissue of the organism from the outside, is 0.5-100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, physiological saline solution, fixed oils, polyethylene glycol, glycerine, propylene glycol or other synthetic e as ascorbic acid or sodium bisulfite; gelatinous agents, such as ethylenediaminetetraacetic acid; buffers reagents, such as acetates, citrates or phosphates; and regulators toychest (tonicity such as sodium chloride or dextrose.

Prescription formulations for direct injection into the tissue from the outside, can be enclosed in ampoules, rassasyvanie seams or flask made of glass or plastic, containing several doses.

P R I m e R 1. The hydrochloride of N-methyl-N-[4-(1-(4-forestsoil)-4-piperidinyl)-butyl]-1,2-benzisothiazol-3 - carb

For 17 h in a gas atmosphere of nitrogen was heated at 70aboutWith a mixture containing 5,12 g of N-methyl-N-(4-bromobutyl)-1,2-benzisothiazol-3-carboxamide, 3.75 g of 4-heroesonline, 6,77 g of potassium carbonate, 0,350 g of sodium iodide and 75 ml of dimethylformamide. The reaction mixture was diluted by the introduction of 300 ml of water and 20 ml of 5% sodium hydroxide solution, after which it was carried out by extraction with ether. Combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered, followed by evaporation of the filtrate under reduced pressure. The residue was purified by chromatography on silica gel using as vinyaya liquid solution of methyl alcohol in dichlorome the alcohol got the hydrochloric salt of the desired compound. Recrystallization from dichloromethane and ethyl acetate was obtained (45.9% of the yield of 3.15 g of product with a melting point 148-150aboutDec.

Calculated C 61,28; H 5,96; N 8,57.

C25H29ClFN3O2S

Found, C 61,22; H 5,98; N 8,54.

P R I m m e R 2. N-[2-(1-(6-Chloro-1,2-benzisoxazol-3-yl)-4-piperidinyl)ethyl]-1,2 - benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing 2.9 g of N-(2-chloroethyl)-1,2-benzisothiazol-3-carboxamide and of 3.48 g of 1-(6-chloro-1,2-antisocial-3-yl)piperidine in 125 ml of dehydrated N-methylpyrrolidinone. After 5 h the mixture was allowed to cool to room temperature, the mixture was diluted with water and a saturated aqueous solution of sodium carbonate was reported by the basicity of the mixture, after which it was carried out by extraction with ethyl acetate. The organic phase is washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated in vacuum. The resulting residue was subjected to chromatographic purification on silica gel using ether as vinyaya fluid. The appropriate fractions were collected together and evaporated. The resulting residue was ground in the presence of dichloromethane and uh, 59,93; H 4,80; N 12,71.

C22H21Cl4O2S

Found, C 59,98; H 4,91; N 12,65.

P R I m e R 3. N-[3-(1-(6-Chloro-1,2-benzisoxazol-3-yl)-4-piperidinyl)propyl] 1,2-benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing 5.0 g of N-(3-chloropropyl)-1,2-benzisothiazol-3-carboxamide, of 5.40 g of the hydrochloride of 1-(6-chloro-1,2-benzisoxazol-3-yl)piperidine, of 5.40 g of potassium carbonate and 100 mg of sodium iodide in 100 ml of dehydrated N-methylpyrrolidinone. After 36 h the reaction mixture was allowed to cool at room temperature and perform the separation of the phases in an ethyl acetate and water. The organic phase is washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The resulting residue was subjected to chromatographic purification on silica gel using ethyl acetate as a diluent. The appropriate fractions were collected together and concentrated. The filtrate was treated with a solution of hydrogen chloride in ether. The mixture was subjected to recrystallization from methanol, dichloromethane and ether, resulting in (at 29.4% yield) 2,87 g of product with a melting point 221-223aboutC.

P R I m e R 4. The hydrochloride of N-methyl-N-[4-(1-(6-the fluorescent-1,2-benzisoxazol-3-yl)-4-piperidinyl)butyl]-1,2-b antisocial-3-carboxamide.

For 21 h in a gas atmosphere of nitrogen was heated at 75aboutWith a mixture containing 4,84 g of N-methyl-N-(4-bromobutyl)-1,2-benzisothiazol-3-carboxamide and 3.15 g of 1-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine, 4,50 g of potassium carbonate, 0,560 g of sodium iodide and 200 ml of acetonitrile. The reaction mixture was filtered, the filtered cake of residue was washed with dichloromethane, after which the filtrate was concentrated under reduced pressure. The obtained residue was transferred into dichloromethane, washed with 5% aqueous solution of sodium hydroxide and water, obezvozhivani over anhydrous sodium sulfate and filtered, followed by evaporation of the filtrate under reduced pressure. The resulting residue was subjected to chromatographic purification on silica gel using 5-10% solution of methanol in dichloromethane as vinyaya fluid. The appropriate fractions were collected together and concentrated. The residue was treated with a solution of hydrogen chloride in ethanol. Recrystallization from dichloromethane and ethyl acetate was obtained (39,7% yield) 2,60 g of the product with so pl. 204-205aboutDec.

P R I m e R 5. N-[2-(1-(4-(2-Oxo-1-benzimidazolinyl)piperidine)ethyl] -1,2 - benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing 5.0 g of 1,2-benzisothiazol-3-[N-(2-chloroethyl)-carboxamide and by 5.87 g of 4-(2-oxo-1-benzimidazolinyl)of piperidine in 150 ml of 1-methyl-2-pyrrolidinone. After 18 h the reaction mixture was allowed to cool to room temperature, then poured this mixture into the water. The aqueous phase was extracted with ethyl acetate. Combined organic extracts were washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The resulting residue was subjected to recrystallization from ethyl acetate, the resulting (46,0% output) is 4.03 g of the product with so pl. 174-177aboutC.

Calculated C 62,69; H 5,50; N 16,61.

C17H24N4O2S

Found, C 62,54; H 5,43; N 16,39.

P R I m e R 6. The dihydrochloride of N-[2-(1-methyl)-4-piperazinil)ethyl]-1,2-benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing of 3.9 g of N-(2-chloroethyl)-1,2-benzisothiazol-3-carboxamide and 3.6 ml of 1-methylpiperazine in 150 ml of dehydrated N-meu mixture with water followed by extraction with ethyl acetate. The organic phase is washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, then the filtrate was collected together and concentrated in vacuum. The residue was subjected to chromatographic purification on silica gel using a mixture of methyl alcohol and ethyl acetate, taken in the ratio 1:1, as a flushing fluid. The appropriate fractions were collected together and concentrated. The residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. Recrystallization and precipitation from methanol, dichloromethane and ethyl acetate was obtained (37,9% yield) of 2.33 g of salt with so pl. 227-230aboutC.

Calculated C 47,75; H 5,88; N 14,85.

C15H22Cl2N4OS

Found, C 47,86; H 5,95; N 14,80.

P R I m e R 7. Hemihydrate of the dihydrochloride of N-[2-(1-benzyl)-4-piperazinil)ethyl]-1,2-benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing 3.0 g of N-(2-chloroethyl)-1,2-benzisothiazol-3-carboxamide and 2.6 ml of 1-benzylpiperazine in 100 ml of dehydrated N-methylpyrrolidinone. After 5 h the reaction mixture was allowed to cool at room temperature, was diluted with water and saturated aqueous sodium carbonate soo who was obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The residue was subjected to chromatographic purification on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and evaporated. The resulting residue was dissolved in ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from methanol, dichloromethane and ether, resulting in (40.9% of output) of 2.36 g of the product with so pl. 207-210aboutC.

Calculated C 54,53; N 5,88; N 12,11.

C21H27Cl2N4O1,5S

Found, C 54,86; H 5,69; N 12,36.

P R I m e R 8. The dihydrochloride of N-[2-(1-2-methoxyphenyl)-4-piperazinil)ethyl] -benzisothiazol-3 - carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 120aboutWith a mixture containing 2.24 g of 1,2-benzisothiazol-3-[N-(2-chloroethyl) carboxamide and 1.8 g of 1-(2-methoxyphenyl)piperazine in 100 g ml anhydrous 1-methyl-2-pyrrolidinone. After 24 h the reaction mixture was cooled to room temperature and poured into saturated aqueous solution of sodium carbonate, followed by extraction with ether. The organic extracts were combined together, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in ve vinyaya fluid. Appropriate fractions were combined together and concentrated. The resulting residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from ether and dichloromethane, the resulting (30,6% yield) of 1.34 g of product with a melting point 205-208aboutC.

Calculated C 53,73; H 5,58; N 11,93.

C21H24N4O2S.2HCl

Found, C 53,52; H 5,35; N 11,73.

P R I m e R 9. N-[2-(1-(3-Course)-4-piperazinil)ethyl]-1.2-benzisothiazol-3 - carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing to 4.23 g of 1,2-benzisothiazol-3-[N-(2-chloroethyl)] carboxamide and 4.15 g of 1-(3-course)piperazine in 125 ml of anhydrous 1-methyl-pyrrolidinone. After 18 h the reaction mixture was cooled to room temperature and poured into saturated aqueous solution of sodium carbonate. The aqueous phase was extracted with ether, then the combined organic extracts were washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The resulting residue was subjected to chromatographicaliy on silica gel using ether as is or in a solid substance. Recrystallization from ether and dichloromethane were obtained (37,2% yield) 2,62 g of the product with so pl. 115-117aboutC.

Calculated C 59,92; H 5,28; N 13,97.

C20H21ClN4OS

Found, C 59,84; H 5,15; N 13,93.

P R I m e R 10. The dihydrochloride N-[3-(1-(2-methoxyphenyl)-4-piperazinil)propyl]-1,2-benzisothiazol-3 - carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing of 4.2 g of N-(3-chloropropyl)-1,2-benzisothiazol-3-carboxamide, and 3.3 g of 1-(2-methoxyphenyl)piperazine, 4,55 g of potassium carbonate and 100 mg of sodium iodide in 150 ml of dehydrated N-methylpyrrolidinone. After 24 h the reaction mixture was allowed to cool to room temperature and was carried out by separation of the phases in ether and water. The organic phase was obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The resulting residue was subjected to chromatographicaliy on silica gel using ether as vinyaya fluid. The appropriate fractions were collected together and evaporated. The residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. Recrystallization of the precipitate from methanol, dichloromethane and ether was obtained (26,6% output) N4O2S

Found, C 54,60; H Of 5.75; N 11,51.

P R I m e R 11. The dihydrochloride of N-methyl-N-[3-(1-(2-methoxyphenyl)-4-piperazinil)-propyl]-1,2 - benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 80aboutWith a mixture containing 3.4 g of N-methyl-N-(3-bromopropyl)-1,2-benzisothiazol-3-carboxamide, of 2.09 g of 1-(2-methoxyphenyl)piperazine, 3.0 g of potassium carbonate and 100 mg of sodium iodide in 125 ml of anhydrous acetonitrile. After 24 h the mixture was allowed to cool to room temperature, after which this mixture is evaporated in vacuum. Then spent the separation of residue in an ethyl acetate and water. The organic phase was obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The obtained residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and concentrated. The resulting residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from dichloromethane and ethyl acetate, the resulting (30,0% yield) of 1.62 g of product with a melting point 166-169aboutC.

Calculated C>P R I m e R 12. The dihydrochloride N-[4-(1-(2-methoxyphenyl)-4-piperazinil)butyl]-1,2-benzisothiazol-3 - carboxamide.

From evening to morning with stirring, they were heated to 80aboutWith a mixture containing 2,44 g chloride 1,2-benzisothiazol-3-carboxylic acid, 3,26 g of 1-(2-methoxyphenyl)-4-(4-aminobutyl)piperazine and 6 ml of triethylamine in 100 ml of dehydrated "screening" (sieve-dried toluene. After 24 h the reaction mixture was cooled to room temperature, then poured into water. Next, the separated organic phase and the aqueous phase was extracted with ether. The ether extracts and the toluene phase was combined together, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The obtained residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and concentrated. The resulting residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from ethanol and ethyl acetate, followed by dehydration at a temperature reverse distillation of the toluene under vacuum, comprising 0.1 mm RT. Art. in the resulting (at 34.6% of the output is SUB>OS.HCl

Found, C 55,49; H 5,80; N 11,19.

P R I m e p 13. Hemihydrate of the dihydrochloride of N-methyl-N-[4-1-(2-methoxyphenyl)-4-piperazinil)butyl]-1,2-benzisothiazol - 3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 80aboutWith a mixture of 3.42 g of N-methyl-N-(4-bromobutyl)-1,2-benzisothiazol-3-carboxamide, a 2.01 g of 1-(2-methoxyphenyl)piperazine, 2.9 g of potassium carbonate and 20 mg of sodium iodide in 100 ml of dehydrated acetonitrile. After 18 h the reaction mixture was allowed to cool to room temperature, after which this mixture is evaporated in vacuum. Then spent the separation of balance acetate and water. The organic phase was obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The obtained residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from dichloromethane and ether, the resulting (34,3% yield) of 1.87 g of the product with so pl. 169-171aboutC.

Calculated C 55,37; H 6,38; N 10,76.

C24H30N4.O2S.2HCl.0.5 H2O

Found, C Of 55.64; H, 6.42 Per; N 10,75.

P R I m e R 14. N-[2-(1-(1,2-benzisothiazol-3-yl)-4-piperazinil)ethyl]-1,2-b is camping, containing 1.2 g of 1,2-benzisothiazol-3-[N-(2-chloroethyl) carboxamide and 1.3 g of 1,2-benzisothiazol-3-yl-piperazine in 25 ml of 1-methyl-2-pyrrolidinone. After 2 h the reaction mixture was cooled to room temperature, then poured into saturated aqueous solution of sodium carbonate. The aqueous phase was extracted with ether, then the organic extracts were combined together, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The obtained residue was subjected to chromatographicaliy on silica gel using ether as vinyaya fluid. The appropriate fractions were collected together and concentrated. The remaining solid was subjected to recrystallization from ether, the resulting (62,8% yield) of 1.33 g of the product with so pl. 160-163aboutC.

Calculated C 59,55; H 5,00; N 16,53.

C21H21N5OS2< / BR>
Found, C 59,20; H 4,99; N To 16.31.

P R I m e R 15. Hydrochloride N-[4-(1-(1,2-benzisothiazol-3-yl)4-piperazinil)-butyl]-1,2-benzisothiazol - 3-carboxamide.

From evening to morning with stirring, they were heated to 80aboutWith a mixture containing 2.6 g of chloride 1,2-benzisothiazol-3-carboxylic acid, of 3.45 g of 1-(1,2-benzisothiazol-3-yl)-4-(4-aminobut the mixture was cooled to room temperature, then poured into water. Next, the separated organic phase and the aqueous phase was extracted with ethyl acetate. An ethyl acetate extracts and the toluene phase was combined together and obezvozhivani over anhydrous magnesium sulfate. The organic phase was filtered, followed by concentration of the filtrate in vacuo. The obtained residue was subjected to chromatographicaliy on silica gel using ethyl acetate. The appropriate fractions were collected together and concentrated in vacuum. The resulting residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. The precipitate was plunged recrystallization from dichloromethane and ether, and obezvozhivani when the return temperature distillation of isopropyl alcohol in a vacuum of 0.1 mm RT.article in the resulting (27,1% yield) of 1.60 g of product with a melting point 203-205aboutC.

Calculated C 55,57; H Vs. 5.47; N 14,09.

C23H23N5OS2.HCl.0.5 H2O.

Found, C 55,32; H 5,20; N 13,86.

P R I m e R 16. The hydrochloride of N-methyl-N-[4-(1-(6-ferebant[b]thiophene-3-yl)-4-piperazinil)butyl] 1,2-benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen at a temperature reverse distillation of the solvent was heated Smena, 5.0 g of potassium carbonate, 350 mg of sodium iodide and 200 ml of acetonitrile. After 16 h the reaction mixture was filtered, the filtered sludge cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The obtained residue was transferred into dichloromethane, washed with 5% sodium hydroxide solution and water, and then obezvozhivani over anhydrous sodium sulfate and filtered, followed by concentration of the filtrate. The resulting residue was subjected to chromatographicaliy on silica gel from flowing through him a 7.5% solution of methanol in dichloromethane. The appropriate fractions were collected together and concentrated. To the residue was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from dichloromethane and ethyl acetate, resulting in (44.2% of output) 2,80 g of the product with so pl. 183-185aboutC.

Calculated C 57,85; H 5,44; N 10,79.

C25H28ClFN4OS2< / BR>
Found, C 57,66; H To 5.21; N 10,61.

P R I m e R 17. The hydrochloride of N-methyl-N-[4-(1-(1,2-benzisothiazol-3-yl)-4-piperazinyl)butyl]-1,2 - benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 80aboutWith a mixture containing 4.0 g of N-methyl-N-(4-bromobutyl)-1,2-benzoic the sodium in 100 ml of dehydrated acetonitrile. After 18 h the reaction mixture was allowed to cool to room temperature, and then held her concentration in vacuum. Then spent the separation of residue in an ethyl acetate and water. The organic phase was obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The obtained residue was subjected to chromatographicaliy on silica gel using a mixture containing 10% methanol and 90% ethyl acetate, as vinyaya fluid. The appropriate fractions were collected together and evaporated. The resulting residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. Recrystallization from dichloromethane and ether was obtained (55,7% output) to 3.36 g of the product with so pl. 210-211aboutC.

Calculated C 57,41; H 5,62; N 13,95.

C24H28ClN5OS2< / BR>
Found, C 57,22; H 5,49; N 13,83.

P R I m e R 18. The dihydrochloride N-[4-(1-(2-methoxyphenyl)-4-piperazinil)-2-butynyl]-1,2-benzisothiazol - 3-carboxamide.

A mixture containing 2.0 g of chloride 1,2-benzisothiazol-3-carboxylic acid and 2,63 g of 1-(2-methoxyphenyl)-4-(4-amino-2-butenyl)piperazine in 100 ml of dichloromethane, with stirring, was introduced dropwise and 2.83 ml of triethylamine. Perepechatano. The organic phase was obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and concentrated. OST - the current carried in a mixture of ether with dichloromethane. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from methanol, dichloromethane and ether, the resulting (45,7% yield) of 2.27 g of the product with so pl. 162-164aboutC.

Calculated C 55,98; H 5,31; N 11,35.

C23H26Cl2N4O2S

Found, C 55,84; H Is 5.06; N 11,25.

P R I m e R 19. The dihydrochloride Z-N-[4-(1-(2-methoxyphenyl)-4-piperazinil)-2-butenyl]-1,2-benzisothiazol - 3-carboxamide.

In a mixture containing 1.77 g of the chloride 1,2-benzisothiazol-3-carboxylic acid and of 2.34 g Z-1-(2-methoxyphenyl)-4-(4-amino-2-butenyl)piperazine in 100 ml of dichloromethane, with stirring, was introduced dropwise of 2.51 ml of triethylamine. Stirring is continued from evening to morning. After 24 h the reaction mixture was diluted by adding water and a saturated aqueous solution of sodium carbonate, and then spend the magnesium and filtered, followed by concentration of the filtrate in vacuo. The obtained residue was transferred into a mixture of dichloromethane and ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from methanol, dichloromethane and ether, the resulting (51,7% yield) 2,31 g of the product with so pl. 184-187aboutC.

Calculated C 55,76; H 5,70; N 11,31.

C23H28Cl2N4O2S

Found, C 55,52; H 5,65; N 11,21.

P R I m e R 20. N-[4-(1-(2-Pyrimidyl)-4-piperidinyl)-2-butynyl]-1,2-benzisothiazol-3-carboxamide.

In a mixture containing 2.55 g of the chloride 1,2-benzisothiazol-carboxylic acid and 3.0 g of 1-(2-pyrimidyl)-4-(4-amino-2-butenyl)piperazine in 100 ml of dichloromethane, with stirring, was introduced dropwise 3,62 ml of triethylamine. Stirring is continued from evening to morning. 24 the reaction mixture was diluted with water, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The resulting residue was subjected to recrystallization from dichloromethane, ether and hexane, the resulting (72.3% of output) to 3.67 g of the product with so pl. 102-104aboutC.

Calculated C 61,21; H 5,14; N 21,41.

C20H20N6OS

Found, C 61,10; H To 4.92; N Each Holding 21.25.

P R is A.

For 17 h in a gas atmosphere of nitrogen was heated at 75aboutWith a mixture containing 4,22 g of N-methyl-N-(4-bromobutyl)-1,2-benzisoxazol-3-carboxamide, to 3.89 g of 1-(6-ferebant[b] thiophene-3-yl)piperazine of 5.00 g of potassium carbonate, 0,80 g of sodium iodide and 200 ml of acetonitrile. Then the reaction mixture was filtered, the cake of filtered residue was washed with dichloromethane, and the filtrate evaporated. The resulting residue was transferred into dichloromethane, washed with 5% sodium hydroxide solution and water, obezvozhivani over anhydrous sodium sulfate and filtered, followed by evaporation of the filtrate under reduced pressure. The resulting residue was subjected to chromatographic purification on silica gel using a 7.5% aqueous solution of methyl alcohol in ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and evaporated. There was added a solution of hydrogen chloride in ethanol. Recrystallization of the precipitate from ethanol and ethyl acetate was obtained (30,8% yield) 2,11 g of the product with so pl. 145-147aboutC.

Calculated C 59,69; H 5,61; N 11,14.

C25H28ClFN4O2S

Found, C 59,72; H 5,72; N Of 11.15.

P R I m e R 22. N-[2-(1-(2-methoxyphenyl)-4-piperazinil)ethyl]-1,2-benzisothiazol-3-societal-3-carboxamide, 4.15 g of N-(2-methoxyphenyl)piperazine and 100 ml of N-methylpyrrolidinone. The reaction mixture was allowed to cool, then diluted with 400 ml of 5% sodium hydroxide solution. The resulting aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, then obezvozhivani over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The resulting residue was subjected to chromatographicaliy on silica gel using 5% aqueous solution of methyl alcohol in dichloromethane. The appropriate fractions were collected together and concentrated. Recrystallization of the resulting residue from ether and hexanol was obtained (at 32.8% of output) 2,22 g of product with a melting point 107-110aboutC.

Calculated C To 66.30; H 6,36; N 14,73.

C21H24N4O3< / BR>
Found, C 66,38; H 6,22; N 14,72.

P R I m e R 23. Hydrochloride N-[2-(1-(6-ferebant[b]thiophene-3-yl)-4-piperazinil)ethyl]-1,2 - benzisothiazol-3-carboxamide.

During 3,0 h was heated at 160aboutWith a mixture containing 4,40 g of N-(2-chloroethyl)-1,2-benzisoxazol-3-carboxamide, 5,90 g 6-fluorescent-3-(1-piperazinil)benzo[b] thiophene and 100 ml of N-methylpyrrolidinone. The reaction mixture was allowed to cool, then diluted its 350 is reagirovanie ether. The combined extracts were washed with water and brine, obezvozhivani over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The resulting residue was subjected to chromatographicaliy on silica gel using 75% ethyl acetate solution in hexano as vinyaya fluid. The appropriate fractions were collected together and concentrated. To the resulting residue was added a solution of hydrogen chloride in ethanol. Recrystallization of the precipitate from methyl and ethyl alcohols was obtained (23,6% yield) of 2.13 g of the product with so pl. 225-228aboutC.

Calculated C 57,32; H To 4.81; N 12,15.

C22H22ClFN4O2S

Found, C 57,24; H Of 4.45; N 12,07.

P R I m e R 24. The hydrochloride hemihydrate N-[2-(1-(4-forestsoil)-4-piperidinyl)ethyl]-1,2-benzisothiazol-3 - carboxamide.

In the gas atmosphere of nitrogen with stirring, they were heated to 180aboutWith a mixture containing 3.5 g of N-(2-chloroethyl)-1,2-benzisothiazol-3-carboxamide and 3,63 g of 1-(4-forestsoil)of piperidine in 125 ml of anhydrous 1-methyl-2-pyrrolidinone. After 3 h the reaction mixture was cooled to room temperature, then poured this mixture into a saturated aqueous solution of sodium carbonate. Water the phrase ekstragirovaniya and filtered, followed by concentration of the filtrate in vacuo. The resulting residue is triturated with ether, the filtrate was concentrated. The resulting residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. Appropriate fractions were combined together and concentrated. The residue was transferred into the ether. There was added a solution of hydrogen chloride in ether. The residue was subjected to recrystallization from methanol, dichloromethane and ether, the resulting (18,1% yield) of 1.21 g of product with a melting point 188-190aboutC.

Calculated C 57,82; H Of 5.29; N 9,19.

C22H24ClFN3Othe 2.5S

Found, C 57,73; H Is 5.06; N Is 9.09.

P R I m e R 25. N-Methyl-N-(4-bromobutyl)-1,2-benzisoxazol-3-carboxamide.

It cooled in an ice bath) suspension containing 1,09 g hydroxyl sodium in the form of a 60% dispersion in oil and 10 ml of dimethylformamide was added a solution of 4.38 g of N-methyl-1,2-benzisothiazol-3-carboxamide and 10 ml of dimethylformamide under conditions of mixing intensity, providing weak hydrogen gas. When the specified adding the reaction mixture was stirred at the temperature of the ice bath for 10 minutes and Then the ice bath was removed and the resulting speciali at room temperature from night till morning, then added to it in 250 ml of water. Then the mixture was extracted with ether. The combined extracts were washed with water and saturated sodium chloride solution, obezvozhivani over anhydrous sodium sulfate and filtered. Next, the filtrate was concentrated and the resulting residue was subjected to chromatographicaliy on 500 g of silica gel. In column thus missed a 5% solution of ethyl acetate in dichloromethane. The appropriate fractions were collected together and evaporated, resulting in (at 55% yield) 4,28 oily product.

P R I m e R 26. Maleate 6-fluorescent-3-(1-piperazinil)benzo[b]thiophene.

Within 2 h in the gas atmosphere of nitrogen was heated at 176aboutWith a mixture containing 40.1 per g of 6-fluorescent-3-aminobenzo[b]thiophene-2-carboxylate, of 13.1 g of 1-methylpiperazine and 100 ml of 1-methyl-2-pyrrolidinone. Then the solution was diluted with water in an amount of 400 ml and was extracted with ether. The combined extracts were washed with water and brine, obezvozhivani over anhydrous sodium sulfate and filtered, followed by concentration of the filtrate under reduced pressure, resulting to 9.32 g of 3-amino-6-ferebant[b]thiophene.

During the next 14 h in the gas atmosphere of nitrogen was heated at 192aboutWith a mixture containing to 9.32 g 3 am is whether water in an amount of 500 ml and was extracted with ether. The combined extracts were washed with water and brine, obezvozhivani over anhydrous potassium carbonate and filtered, followed by concentration of the filtrate under reduced pressure. The resulting residue was subjected to chromatographicaliy on silica gel with leaching 30% solution of methanol in dichloromethane, the resulting 3.03 g of oily substances in the form of free base. To a solution containing 3.03 g of the specified free base and 20 ml of 2-propyl alcohol was added to the solution containing 1,49 g of maleic acid in 20 ml of 2-propyl alcohol. The mixture was concentrated under reduced pressure, and the residue was subjected to recrystallization from methyl alcohol and ethyl acetate, the resulting (8,80% yield) of 2.72 g of the product with so pl. 173-175aboutC.

Calculated C 54,54; H A 4.86; N 7,95.

C16H17FN

Found, C 54,53; H 4,69; N 8,01.

P R I m e R 27. N-(1-Methylethyl)-N-(2-hydroxyethyl)-1,2-benzisoxazol-3-carboxamide.

Within 4 h in a sealed container was heated to 140aboutWith a mixture containing 10: 0 g ethyl-1,2-benzisoxazol-3-carboxylate, 16,1 g 2-(1-methylethylamine)of ethanol and 80 ml of toluene. The solution was diluted with ether in a quantity of 50 ml, washed with 5%-is ovali under reduced pressure. The resulting residue was subjected to chromatographicaliy on silica gel using as vinyaya liquid 60% solution of ethyl acetate in hexano, resulting in (81,4% yield) of 10.6 g of product. Recrystallization from dichloromethane and hexanol was obtained samples of the substance with a melting point 92-94aboutC.

Calculated C 62,89; H 6,50; N 11,28.

C13H16N2O3< / BR>
Found, C 63,00; H 6,51; N 11,24.

P R I m e R 28. Hemihydrate hydrochloride of N-methyl-N-[2-1-(6-fluorescent-1,2-benzisoxazol-3-yl)-4-piperazinil)ethyl] -1,2-benzisothiazol-3-carboxamide.

In the gas atmosphere of nitrogen at 0aboutIn terms stirring to a mixture containing of 4.00 g of N-methyl-N-(2-hydroxyethyl)-1,2-benzisoxazol-3-carboxamide and 2.48 ml of triethylamine in 100 ml of toluene, dehydrated "screening" (sieve dried), dropwise introduced to 1.34 ml methanesulfonanilide. After adding the reagent, and the mixture was stirred and slowly warmed to room temperature. After 45 min was added and 3.72 g of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine. The resulting mixture with stirring, was heated for 18 hours at a temperature reverse distillation. Next, the mixture was allowed to cool to room rate is th the solution was extracted with ethyl acetate. The combined extracts were washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. The resulting residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and evaporated. The resulting residue was dissolved in dichloromethane, and this solution was added a solution of hydrogen chloride in ethanol and then ether. The resulting Sol was subjected to recrystallization from dichloromethane and ether, resulting in the (14,0% yield) was obtained 1.45 g of product with so pl. 211-214aboutC.

Calculated C 57,07; H To 5.21; N 11,58.

C23H23N4O2S.HCl 0.5 H2O

Found, C 57,04; H 5,08; N To 11.52.

P R I m e R 29. Hemihydrate hydrochloride of N-methyl-N[(2-(1-(4-forestsoil)-4-piperidinyl)ethyl]-1,2-benzisothiazol - 3-carboxamide.

In the gas atmosphere of nitrogen at 0aboutTo a mixture containing of 3.43 g of N-methyl-N-(2-hydroxyethyl)-1,2-benzisothiazol-3-carboxamide and 2.13 ml of triethylamine in 100 ml of toluene, dehydrated "screening" (sieve dried) was added dropwise to 1.15 ml of methanesulfonanilide. After that, the mixture was allowed to warm to room is its mixture for 18 h with stirring, they were heated at a temperature reverse distillation. Then the mixture was allowed to cool to room temperature and added it to 5% of the resultant aqueous solution of sodium bicarbonate. After that, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Combined organic fractions were washed with water, obezvozhivani over magnesium sulfate and filtered. The filtrate was concentrated in vacuum. The resulting residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and concentrated. The resulting residue was dissolved in dichloromethane, and this solution was added a solution of hydrogen chloride in ethanol and then ether. Sol was subjected to recrystallization from dichloromethane and ethyl acetate, resulting in (22,6% yield) was obtained 1.54 g of product with so pl. 214-217aboutC.

Calculated C 58,65; H 5,56; N 8,92.

C23H24FN3O2S.HCl 0.5 H2O

Found, C 58,28; H Of 5.68; N 8,78.

P R I m e R 30. The hydrochloride of N-methyl-N-[(2-((1-(4-forestsoil)-4-piperidinyl)-ethyl]-1,2 - benzisoxazol-3-carboxamide.

The solution to 4.98 g of N-methyl-N-(2-hydroxyethyl)-1,2-benzisoxazol-3-carboxamide and a 2.36 g of triethylamine in 55 ml of toluene at 0aboutTo the mixture was added 6,48 g of the hydrochloride of 4-(4-forestsoil)of piperidine and 6,46 g of triethylamine. The resulting reaction mixture was heated for 13 hours at a temperature reverse distillation. This mixture was filtered, followed by concentration of the filtrate under reduced pressure. The resulting residue was dissolved in 225 ml of dichloromethane, washed with 10% sodium hydroxide solution and water, obezvozhivani over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to chromatographicaliy on silica gel using 0-10% ethanol in ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and concentrated, resulting in 3,74 g of the product as free base. The latter was transferred into the hydrochloride with a solution of hydrogen chloride in ethanol. Recrystallization from methyl alcohol and ethyl acetate was obtained (22,2% yield) of 2.24 g of the product with so pl. 218 to 221aboutC.

Calculated C Of 61.95; H 5,65; N 9,42.

C23H25ClFN3O3< / BR>
Found, C 61,82; H To 5.57; N 9,37.

P R I m e R 31. N-[1-Methylethyl)-N-[(2-(1-(6-the fluorescent-1,2-benzisoxazol-3-yl)-4 - piperidinyl)ethyl]-1,2-benzisoxazol-3-carboxamide.

In the gas atmosphere of nitrogen at 0aboutRapidly in the 3-carboxamide, of 3.27 g of triethylamine in 150 ml of tetrahydrofuran. The resulting mixture was stirred at 0aboutC for 30 minutes To this mixture was quickly added to the suspension containing 7,80 g of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine and 6,53 g of triethylamine in 60 ml of tetrahydrofuran. The resulting mixture was heated for 12 hours at a temperature reverse distillation. Then added water, and the solution was concentrated at low temperature. The residue was dissolved in 150 ml of dichloromethane, washed with 10% sodium hydroxide solution and water, obezvozhivani over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to chromatographicaliy on silica gel using 80% ethyl acetate solution in hexano. The appropriate fractions were collected together and evaporated, and the residue was subjected to recrystallization from ether, resulting in a (16,0% yield) was obtained 2,33 g of the product with so pl. 118-120aboutC.

Calculated C 66,65; H 6,04; N To 12.44.

C25H27FN4O3.

Found, C 66,63; H 6,04; N 12,41.

P R I m e R 32. N-Methyl-N-[(2-(1-(6-the fluorescent-1,2-benzisoxazol-3-yl)-4-piperidinyl) ethyl]-1,2-benzisoxazol-3-carboxamide.

In the gas atmosphere of nitrogen at 0 isoxazol-3-carboxamide of 3.27 g of triethylamine in 100 ml of tetrahydrofuran. The mixture was stirred at 0aboutC for 60 minutes To this mixture was quickly added to the suspension containing 8,10 g of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine and 7,26 g of triethylamine in 80 ml of tetrahydrofuran. The mixture was heated for 16 hours at a temperature reverse distillation. Then added water, and the solution was concentrated at low temperature. The resulting residue was diluted with 10% sodium hydroxide solution and was extracted with 50% solution of ether in toluene. Combined extracts were washed with water and brine, obezvozhivani over anhydrous potassium carbonate and filtered, followed by concentration of the filtrate under reduced pressure. The resulting residue was subjected to chromatographicaliy on silica gel using ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and evaporated. The residue was subjected to recrystallization from ether, the resulting (22,1% yield) 3,01 g of the product with so pl. 94-97aboutC.

Calculated C 65,39; H 5,49; N 13,26.

C23H23FN4O3< / BR>
Found, C 65,30; H 5,51; N Of 13.18.

P R I m e R 33. Hemihydrate hydrochloride N-(1-methylethyl)-N-[(3-(1-(4-forestsoil)-4-piperidinyl)propyl]-1,2-benzisoxazol-3-cavora, containing 7,80 g of N-(1-methylethyl)-N-(3-hydroxypropyl)-1,2-benzisoxazol-3-carboxamide and 3.05 g of triethylamine in 200 ml of toluene. The resulting mixture was stirred at 0aboutC. After 45 min the solution was injected to 7.95 g of the hydrochloride of 4-(4-forestsoil)of piperidine and 8,71 g of triethylamine. The resulting mixture was heated for 16 hours at a temperature reverse distillation. Next, the reaction mixture was washed with 10% sodium hydroxide solution, water and brine, obezvozhivani over anhydrous sodium sulfate and filtered, followed by concentration of the filtrate. The resulting residue was subjected to chromatographicaliy on silica gel using 5-10% solution of methanol in ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and evaporated. Then, the solution of this residue in methyl alcohol was acidified with a solution of hydrogen chloride in ethanol and diluted with ether. The mixture froze and got a solid substance. Recrystallization of this solid from ethanol and ethyl acetate was obtained (10,2% yield) of 1.50 g of the product with so pl. 177-179aboutC.

Calculated C 62,83; H Of 6.49; N 8,45.

C26H31ClFN3O3.0.5 H2O

Found, C 62,86; H 6,28; N 8,30.

In the gas atmosphere of nitrogen with stirring, they were heated to 120aboutWith a mixture containing 7,13 g of N-methyl-N-(3-chloropropyl)-1,2-benzisothiazol-3-carboxamide, 6,44 g of 1-(4-forestsoil)piperidine, 7,33 g of potassium carbonate and 300 mg of sodium iodide in 150 ml of anhydrous 1-methyl-2-pyrrolidinone. After 24 h the mixture was allowed to cool to room temperature and perform the separation of balance acetate and water. The organic phase is washed with water, obezvozhivani over anhydrous magnesium sulfate and filtered, followed by concentration of the filtrate in vacuo. Crude residue was twice subjected to chromatographicaliy on silica using a mixture containing 10% methanol and 90% ethyl acetate as vinyaya fluid. The appropriate fractions were collected together and evaporated. The resulting residue was dissolved in ether. There was added a solution of hydrogen chloride in ethanol. Recrystallization of the precipitate from dichloromethane and ether was obtained (5,09% yield) 0,642 g of the product with so pl. 189-191aboutC.

Calculated C 60,56; H 5,72; N 8,83.

C24H27ClFN3O2S

Found, C 60,32; H Of 5.75; N 8,70.

P R I m e R 35. N-methyl-N-3-(1-(4-forestsoil)-4-piperidinyl)propyl)-1,2 - benzisoxazol-3-carboxamide.

aboutC.

Calculated C 68,07; H Is 6.19; N 9,92.

C24H26FN3O3< / BR>
Found, C 68,02; H 6,14; N 9,89.

Below is data on toxicity for the claimed compounds identified in the analysis of POE (explicit Primary effect) and expressed in the form of acute lethal dose 50.

Below is the method providedare male Wistar rats (125-300 g). Before the test, animals were placed for 24 hours at least in a room with controlled climate, providing plenty of food and water. On the day of testing, animals were removed from their normal cells and placed 4/cage in white translucent plastic boxes (HH cm) with lids of metal rods, and moved into the room for testing.

Connections are made using distilled water, and if they are insoluble, add surfactant and constantly stir the resulting suspension.

Before the introduction of drugs of all animals were examined for the presence of any anomalistic, which could subsequently be confusing effects of the medicine. These include the position of the eyes, clear eyes, the blood around the eyes or nose, unusual gait, abnormal behavior during handling and anomalous behavior in plastic boxes. Then determine body temperature (rectal or IPR).

Then animals injected the medicine, the control group receives the media. Usually the amount of dose is 10 cm3/kg, the usual way of introduction is intraperitoneally.

Animals see in plastic boxes neprerusovane, details of which are given in the Appendix, is given for each animal after 1, 2, 4 and 6 h after drug administration (pain response is also measured through 1/2 h) and the results recorded. During the test, the room should be quiet. The obvious effects that are visible between these periods of time are recorded. Animals provide food and water after 6 h and incubated up to 24 h, while watching their common explicit state. All parameters are given as the maximum normalized percentage, except for the temperature of the body, which is given as the difference with the control media. The results are given in table. 3.

Normalized to 100%

Using values normalized percentages for different parameters, perform the following calculations:

Normalized percentage mortality x 0.8. Parameters measured: Mortality.

Note the time of death for each animal and note the time when there was the first and last death. Evaluation:

Death +1

There is no death 0

Pharmaceutical Tablet:

The ingredients In each

the tablet mg

N-Methyl-N[4-(1-(6-fluoro-

1,2-benzisoxazol-3-yl)-

4-piperidinyl)-butyl]

1,2-benzisothiazol-3-CT-

boxlid 300 Polivinilacetat N-methyl-N-[4-(1-(6-fluoro-1,2-benzisoxazol-3-yl)-4-piperidinyl)butyl] 1,2-benzisothiazol-3-carboxamide, polyvinylpyrrolidone and lactose together, pass through a sieve of 40 mesh. Add slowly the alcohol and mix thoroughly. Miss wet mass through a sieve 4 mesh. Dry the granules at 50aboutWith until the morning. Pass the dry granules through a sieve of 20 mesh. Sift stearic acid, talc and corn starch through a sieve of 60 mesh. before mixing in the drum with the granulate. Tabletirujut using standard 7/16-inch punch, 10 tablets have a weight of 4.5 g Myltse:

The ingredients In each

the candle mg

N-Methyl-N-[4-(1-(6-the fluorine-

1,2-benzisoxazol-3-yl)-

4-piperidinyl)butyl] -1,2-benzisothiazol-3 - carboxamid 300 Glycerin 3000 Purified water 200

Glycerin is heated in a suitable vessel to approximately 120aboutC. the Drug is dissolved with gentle mixing the heated glycerin after which purified water is added, mixed, and the hot mixture is immediately poured into the form.

The emulsion. Number

The ingredients.

Gelatin type a (received

tion of cyclotouriste-

those predecessors; it is used when the pH 3,2) 4 grams

N-Methyl-N-[4-(1-(6-the fluorine-

1,2-benzisoxazol-3-yl)-4-

piperidinyl) butyl]-1,2-

benzisothiazol-3-carboxy - MFA 360 mg

Aromar CLASS="ptx2">

To about 300 ml of purified water is added to the gelatin and medicine, brewed for a few minutes, heated to dissolve the gelatin, then the temperature rises to about 98aboutC and maintained at that temperature for about 20 minutes, Cooled to 50aboutWith and add flavouring substance, alcohol and enough purified water to 500 ml. Add oil, mix thoroughly with the mixture and pass it through a homogenizer or colloid mill to obtain a complete and uniform dispersion of the oil.

1. Benzisothiazol or benzisoxazol-3-carboxamide General formula I

< / BR>
where R1hydrogen or lower alkyl;

R2lower alkyl or the group one of the General formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
And lower alkylene, a group of the formula CH2CH=CHCH2or-CH2C CCH2-;

X is oxygen or sulfur;

W is nitrogen or a group CH-;

Z is hydrogen, lower alkoxygroup or halogen;

the solid line (_____ indicates the place of attachment of the group to the designated member of formulas;

or their pharmaceutically acceptable salts.

2. Connection on p. 1 with antipsychotic activity.

3. Pharmaceutical composition, obladayushhie formula I in a quantity 1-360 mg per single dose and a suitable carrier.

4. The method of obtaining benzisothiazol or benzisoxazol-3-carboxamido General formula

< / BR>
where R1hydrogen or lower alkyl;

R2lower alkyl or the group one of the General formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
A lower alkylene, a group of the formula-CH2-CH=CH-CH2- or-CH2C C-CH2-;

X is oxygen or sulfur;

W is nitrogen or a group-CH-;

Z is hydrogen, lower alkoxygroup or halogen;

the solid line indicates the place of attachment of the group to the designated member of formulas

characterized in that compounds of General formula

< / BR>
where R1,A,X have the above meanings;

R' is chlorine, bromine, iodine or group OSO2R6where R6alkyl, phenyl or tolyl,

subjected to interaction with the compound of General formula

< / BR>
where R2and W have the specified values.

5. The method of obtaining benzisothiazol or benzisoxazol-3-carboxamido General formula

< / BR>
where R1hydrogen or lower alkyl;

R2lower alkyl or the group one of the General formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
A lower alkylene, a group of the formula-CH2-CH=CH-CH2or

-CH2CCH2-;

X is oxygen or takes the place of attachment of the group to the designated member of formulas

characterized in that the compound of General formula

< / BR>
where X has the above meanings;

Hal is chlorine or bromine,

subjected to interaction with the compound of General formula

< / BR>
where A, R1, R2and W have the specified values.

 

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