Aryloxyalkanoic-8-azabicyclo(3,2,1)octane, the way they are received and heteroaryl-8-azabicyclo(3,2,1)octane

 

(57) Abstract:

Usage: in medicine as anti-depressants. Products: aryloxyalkanoic-8-azabicyclo /3.2.1/ octane f-ly 1, where x denotes-O-, -S - or - NH -, Y is hydrogen or halogen, p is 1 or 2, n is 2, 3 or 4, R is lower alkoxy or the group-C(O)R-1where R1- alkyl, m is an integer of 1 or 2 or their salts. Reagent 1: compound f-crystals 2, where y, p, x, n, R and m have the above meanings, Z is chlorine or bromine. Reagent 2: compound f-crystals 3. Reaction conditions: inert organic solvent under heating. 3 S. and 1 C. p. F.-ly, 3 tables.

The present invention relates to compounds of the formula:

where X is-O-, -S - or-NH-;

Y is hydrogen, halogen and lower alkoxy;

p is 1 or 2;

h 2, 3 or 4;

R is hydrogen, lower alkyl, hydroxy, halogen, amino, lower alkylamino, nitro, lower alkylthio, triptoreline, cyano, trifluromethyl, alkyl, or aryl, where aryl represents ;

R1is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, carboxyla, lower alkylamino, nitro, lower alkyl, cyano and trifloromethyl;

m is 1 or 2;

and their pharmaceutically acceptable acid additive Sol is notizie of the present invention can be used as antipsychotic drugs as inhibitors of consumption of serotonin.

A subclass of compounds of formula I are the compounds of formula II:

< / BR>
where R2is hydrogen or lower alkyl, and X, Y and p are defined above.

The present invention also relates to compounds of formula (III:

< / BR>
where Y, R2and p are defined above, which can be used as intermediates for producing compounds of formula II.

In addition, the present invention relates to compounds of the formula IV:

< / BR>
where R2, Y and p are defined above, which can be used to obtain the compounds of formulas II and III.

Preferred compounds of formula I are the compounds of formula I where X is O or S, n is 3 and R is OCH3and alkyl, where m 2.

The most preferred compounds are the compounds of formula I, where X is 0, n is 3 and R is OCH3and where m 2.

In the description and the claims the above chemical formulas and names include all optical and geometric isomers and mixtures thereof, if such exist, as well as their pharmaceutically acceptable acid additive salt and a solvate such as a hydrate.

In the above definitions, the term "lower" OSN is orodo straight or branched chain, which does not contain ninasimone, for example methyl, ethyl, isopropyl, 2-butyl, neopentyl, n-hexyl, etc.

The term "alkoxy" refers to a monovalent Deputy containing alkyl group linked through an ether oxygen and having this etheric oxygen its trivalent communication, for example methoxy, ethoxy, propoxy, butoxy, intoxi etc.

The term "aryl" means , where R1is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, lower alkylamino, nitro, cyano or trifluoromethyl.

The term "lower alkylthio" refers to a monovalent Deputy, having the formula lower alkyl-S-.

The term "halogen" includes the members of the group consisting of chlorine, fluorine, bromine and iodine.

Compounds of the present invention can be obtained in the following way /the substituents are the same as defined above, if it is not specifically mentioned/:

The aldehyde of the formula:

< / BR>
subjected to reaction with orthoformate in the presence of catalytic amount of p-toluensulfonyl acid, resulting in a receive connection /V/ formula:

< / BR>
where R3is lower alkyl. Typically, the reaction is carried out in Nissel">

Then the connection V is subjected to reaction with fosforiliruyusciye agent such as triethylphosphite, and triftoratsetata boron in an appropriate solvent, such as dichloromethane, resulting in a receive connection formula VI:

< / BR>
Typically, this reaction proceeds at temperatures from -25oC to room temperature for 10 to 30 hours.

The resulting compound VI is subjected to reaction with n-butyllithium or other suitable agent, such as diisopropylamide lithium and tropine formula:

< / BR>
resulting in a receive connection VII formula:

< / BR>
Typically, this reaction proceeds in an appropriate solvent such as tetrahydrofuran at temperatures between -78oto room temperature for 10 to 30 hours.

The obtained compound VII is subjected to reaction with aqueous HCl in acetone by heating in a vessel under reflux for 2 to 8 hours, resulting in a receive connection VIII of the present invention of the formula:

< / BR>
Compound VIII is an intermediate compound, which is used to produce the target compounds of the present invention.

Obtaining compounds where X is-O-

The compounds of formula:

< / BR>
used for synthesis

Compound VIII is subjected to reaction with hydroxylaminopurine and ammonium acetate, resulting in a receive connection IX of the present invention of the formula:

< / BR>
This reaction usually proceeds at reflux for 3 to 25 hours in the presence of a solvent such as aqueous ethanol, methanol, etc.

Compound IX is subjected to cyclization using a base such as sodium hydroxide or ethoxide sodium, heating under reflux, resulting in a receive connection X of the present invention of the formula:

< / BR>
This reaction is carried out in an appropriate solvent, such as ethanol, methanol, etc., for 2 to 10 hours.

Compound X may be subjected to removal of methyl groups using reaction with vinylchloride or other suitable demetrious agent, after which the connection is heated under reflux in the presence of strong acids and receive connection XI of the present invention of the formula:

< / BR>
Reaction with vinylchloride carried out in a halogenated hydrocarbon solvent, such as 1,2-dichloroethane or chloroform, for 2 to 10 hours. Reaction with a strong acid, such as HCl, also carry out n the Addendum XI is subjected to reaction with sodium carbonate and a compound XII General formula:

< / BR>
where Z is chlorine or bromine, and h=2, 3, or 4, resulting in a gain target benzisoxazole of the present invention of the formula:

< / BR>
This reaction usually proceeds in an appropriate solvent, such as acetonitrile, dimethylformamide, etc., and optionally in the presence of catalytic amounts of potassium iodide, when the distillation temperature for 10 to 30 hours.

Obtaining compounds, where X is

The compounds of formula:

< / BR>
used for synthesis indazol-substituted compounds of the present invention, can be obtained as follows.

Compound VIII is subjected to reaction with hydrazinehydrate in standard mode and in an appropriate solvent, such as ethanol or methanol, and the obtained compound formula XIII:

< / BR>
This reaction is usually carried out at a temperature of distillation for 4 to 20 hours.

Compound XIII is subjected to cyclization by reaction with hydrazone and potassium carbonate in an appropriate solvent, such as dimethylformamide, and receives the connection XIV of the present invention of the formula:

< / BR>
Typically, this reaction occurs at a temperature of from 90oC to temperature distillation of Holocene intermediate compounds of formula XV:

This reaction is carried out in a dipolar aprotic solvent such as dimethylformamide or dimethylsulfoxide at ambient temperature for 2 to 20 hours.

Then compound XV was restored using a metal hydride such as lithium aluminum hydride, and received the compound XVI of the present invention of the formula:

< / BR>
Typically this reaction is carried out in an ethereal solvent such as tetrahydrofuran or diethyl ether at reflux distilled for 1 to 5 hours.

Compound XVI, which is an intermediate precursor of the target indazols, is subjected to reaction with compound XII and get the target indazols of the present invention of the formula:

< / BR>
This reaction is carried out mainly under conditions similar to the conditions of synthesis benzisoxazol-substituted target compounds of the present invention.

Obtaining compounds where X is-S-

The compounds of formula:

< / BR>
used in the synthesis benzisothiazolinone compounds of the present invention, can be obtained as follows.

Compound VIII is subjected to reaction with sulfur in the solution of ammonia in a solvent such as 2-methoxyethanol, and get a connection XVII This is of 2 to 5 hours.

Then compound XVII is subjected to reaction with vinylchloride and potassium carbonate when heated with reverse refrigerators in an appropriate solvent, such as dichloroethane, for 2 to 10 hours, and the resulting product is then subjected to reaction with HCl in ethanol at reflux, under standard reaction off, resulting in a receive connection XVIII of the present invention of the formula:

< / BR>
Compound XVIII, which is an intermediate precursor of the target benzisothiazole, is subjected to alkylation in a manner analogous to the method of alkylation of other target compounds of the present invention.

Compounds of the present invention are intended for use in the treatment of psychosis due to their ability to cause antipsychotic response in animals. Antipsychotic activity was determined using the test rearing mice in cages carried out by the method described P. Protais, etc. Psychopharmacol. 50:1 /1976/ and B. Costall, Eur.Pharmacol. 50:39 /1978/.

Mice-male-SC-1 /23-27 grams/ were kept in standard laboratory conditions. Then each mouse was placed in wire cages /4"X10" or 101,CH mm and left for 1 hour to adapt the it in all animals the behavior of climbing for 30 minutes. Connection, the subjects on antipsychotic activity, was administered intraperitoneally or orally at various intervals, such as 30 min, 60 min, etc., prior to the introduction of provocative tests of apomorphine, when srinilaya dose of 10-60 mg/kg

To assess the behavior of climbing spent 3 measurements after 10, 20 and 30 minutes after injection of apomorphine in accordance with the following criteria:

The conduct of climbing mice Dial

4 paws on the bottom of the cell

/absence of climbing/ 0

2 paws on the wall of the cell

/excitement/ 1

4 paws on the wall of the cell

/rearing/ 2

The mouse that constantly showed signs of climbing before the introduction of apomorphine were excluded from the test.

When fully developed apiformis-called carabini animals hung on the walls of the cells almost motionless for a long period of time. In contrast, rearing, simply due to motor stimulation, lasts only a few minutes.

Criteria of climbing summarized /maximum score: 6 mouse 3 read and complete reference for the control group /filler was injected intraperitoneally and apomorphine subcutaneously/ up to 100% ED<'s what I characteristic of the compounds of the present compounds and also the values for the standard antipsychotic drugs are presented in table 1.

Antipsychotic response occurs when compounds of the present invention administered to an animal in need this introduction, effective oral, parenteral or intravenous dose of from 0.01 to 50 mg/kg of body weight per day. However, it should be noted that for each of the individual regimen medicines must be installed in accordance with individual need and clinical indications by the doctor for administering the above-mentioned compounds. It should be also noted that the above doses are examples only, and they anybody case, do not limit the scope of the present invention.

The compound of the present invention can also be used to treat depression and/or obsessive-compulsive disorders because of their ability to inhibition of the absorption of serotonin.

Some researchers believe that subjects with serotonergic hypofunction be the subgroup of patients with biochemically caused by depression. Other scholars that changes in serotonergic function to determine the changes, asosu analysis, allowing to measure the absorption of3H-serotonin in whole rat brain and hypothalamic-uptake. The following analysis was used as a biochemical test for the potential of antidepressants that block the absorption of serotonin /5-hydroxytryptamine [NT]/.

3N-NT transport was determined in tissues of the Central nervous system, resulting in a set its uptake, sodium and toaddiction, inhibition by wabana, metabolic inhibitors, tryptamine analogues and tricyclic antidepressants.

Procedure

A. Animals

Male rats CR Wistar

C. Reagents

1. Bicarbonate buffer Krebs-Henseleit, pH 7,4 /CNW/.

Received 1 l of sample, containing the following salts (see table. 2).

The sample was subjected to aeration with 95% O2/5% CO2within 60 minutes, the pH was maintained at 7,4 0,1.

2. Added of 0.32 M sucrose: of 21.9 g of sucrose, Hon. No. 200 ml.

3. 0.1 mm stock solution of serotonin creationinterface was dissolved in 0.01 n HCl. This solution was used to obtain the titer of the specific activity of radioactively labeled NT.

4. Used a specific activity of 5-[1,2-3H(N)]-hydroc the analysis was 50 nm. The dilution factor was 0.8. KNW brought to the content of [3N]-NT in the amount of 62.5 nm.

To 100 ml of KHBB added:

A/ 56,1 ál of 0.1 mm 5HT 56,1 nm

B/ of 0.64 nm3H-5HT 6,4

All of 62.5 nm.

For most analyses 1 mm stock solution of the test compounds prepared in an appropriate solvent and serially diluted so that the final concentration in the analysis ranged from 2 to 10-8up to 2 10-5M. For each analysis used seven concentrations. C.

Obtaining tissues.

Male Wistar rats were decapitated and quickly removed the brain. Either the whole brain was removed, the cerebellum, or the hypothalamus weighed and homogeneously in 9 volumes of ice sucrose /0,32 M/ with the help of homogenizer Potter /Potter-Eivejhem/. The homogenate was centrifuged at 1000 g for 10 min at 0 4oC. the Supernatant /S1/ decantation and used to determine the absorption.

1. Analysis

800 ál of KHBB + [3H]-5HT.

20 μl of the filler or the appropriate medicines.

200 μl of tissue suspension.

The tubes were incubated at 37oC for 5 min in an atmosphere of 95% O2/5%CO2. For each of Irka was immediately centrifuged for 10 minutes at 4000 g/. The supernatant was aspirated and the precipitate was dissolved by adding 1 ml of solubilizer /Triton X-100 and 50% ethanol, 1:4.about. /. The contents of the test tubes thoroughly stirred, poured into scintillation vials and measured in 10 ml of liquid scintillation mixture. Active uptake was expressed as the difference between the number of reference at 37oC and 0oC. the Percentage of inhibition for each concentration orignaly in three dimensions. IC50-values were obtained by log-proitalia.

The results of this analysis for typical compounds of the present invention, and the known compounds shown in table 3.

The antidepressant response was observed when introduced into the body in need of this introduction, an effective oral, parenteral or intravenous dose of the compounds of the present invention comprising from 1 to 100 mg of body weight per day. However, it should be noted that for each of the individual regimen medicines must be installed in accordance with individual need and purpose of the attending physician according to clinical indications. It should be also noted that the above doses are illustrated the VA compounds of the present invention can be introduced by any standard method, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions and suspensions, and in some cases intravenously in the form of sterile solutions.

Compounds of the present invention, which is effective themselves, may be introduced in the form of their pharmaceutically acceptable acid additive salts in order to ensure their stability, ability to crystallization, increased solubility and other properties.

Examples of preferred pharmaceutically acceptable acid additive salts are salts of inorganic acids such as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric, Perlina acid; and salts of organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.

Active compounds of the present invention can be administered orally, for example in combination with an inert diluent or edible carrier. These compounds may be incorporated in gelatin capsules or compressed tablets. For oral conducting connection can be used in combination with fillers in the form of tablets, lozenges, capsules, elixirs, suspensions, SGAs connection however, this content may vary depending on the specific shape and is usually about 4 to 75% of the mass. Compounds of the present invention can be manufactured in a standard single form containing a metered quantity of these compounds. Preferred compositions and preparations of the present invention are such single dosage form for oral administration which contain 1.0 to 300 mg of active compound.

Tablets, coated tablets, capsules, lozenges, etc. can also contain the following ingredients: a binder, such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose; disintegrity agent, such as alginic acid, PrimogelTM, corn starch, etc., a lubricant such as magnesium stearate or Sterotex; agent for improving sliding, such as colloidal silicon dioxide; and a sweetening substance, such as sucrose or saccharin or a flavoring substance, such as peppermint, methyl salicylate, or orange flavoring. If a single form is used capsule, in addition to the above ingredients it may contain riccia physical appearance of a single form, for example, coating. So, for example, tablets and pills may be coated with sugar, shellac or other intersolubility coatings. Syrup, in addition to the active compounds, may contain a sweetening agent such as sucrose, and certain preservatives, dyes and fragrances. Materials for the manufacture of compositions of the present invention should be pharmaceutically pure and used in non-toxic amounts.

For parenteral administration the active compounds of the present invention can be used in solutions or suspensions. These preparations should contain at least 0.1% of active ingredient, but its content can vary from 0.5 and up to about 30 mass. The number of active compounds in such compositions should correspond to the required dose. Preferred compositions and preparations of the present invention are such single dosage forms for parenteral administration which contain 05 100 mg of the active ingredient.

The solutions or suspensions may also contain the following components: a sterile diluent such as water for injection, saline solution, fatty oil, polyethylene glycol, glycerin, Pro or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and toning agents, such as sodium chloride or dextrose. The parenteral preparation can be made in the form of ampoules, disposable syringes or bottles, reusable, made of glass or plastic.

Examples of typical compounds of the present invention obtained by the methods described above are the following connections:

[4-[2-[3-[6-fluoro-1,2-benzisothiazol-3 - yl]-8-azabicyclo[3.2.1]-Octan-8-yl]propoxy]3-methoxyphenyl]ethanol;

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]propoxy]2-were]Etalon;

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]propoxy]-2-methoxyphenyl]Etalon;

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]propoxy]3-methylaminophenol]Etalon;

N-[4-[2-[3- [6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8 - yl]propoxy]3-methoxyphenyl]ndimethylacetamide;

[4-[2-[3-[6-chloro-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]propoxy]3-methoxyphenyl]Etalon;

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -8-sabicic the n-8-yl]propoxy, 3-bromophenyl]Etalon;

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1]-Octan-8-yl] propoxy, 3-methylmercaptopurine]Etalon;

[4-[2-[3-[6-the fluorescent-1,2-benzisothiazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]butoxy]3-methoxyphenyl]Etalon;

[4-[2-[3-[6-the fluorescent-1,2-benzisothiazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]ethoxy 3-methoxyphenyl]Etalon; and

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] -Octan-8-yl]propoxy]phenyl]alanon.

The following examples are only illustrative implementation of the present invention and in no way should be construed as limiting its scope. All temperatures are given inoC if it is not specifically mentioned.

Example 1.

A. Diethyl-1-(2-forefeel)-1-methoxymethane phosphonate

Triphoridae boron /71/ g drop was added to a solution of 2-foreversoldierette /81/ g and triethylphosphite /g/ 950 ml of dichloromethane at -25oC. the resulting solution was brought to room temperature and stirred for 20 hours. Then added water and the resulting mixture was vigorously stirred for 10 minutes. The organic layer was separated, washed with saline solution, dried by magnesium sulfate, filtered and concentrated, resulting in a received liquid residue. After purification by HPLC trienyl)-1-methoxymethamphetamine in liquid form.

b. (2-Forefeel)(8-methyl-8-azabicyclo [3.2.1]Octan-3-yl)methanon

Diethyl-1-(2-forefeel)-1-methoxymetopon /96g/ was dissolved in tetrahydrofuran /THF/ /1600 ml/. The solution was cooled to -78oC and n-utility /n-Buli/ /172 ml of 2.5 M solution in hexane/ added drop by drop with such a rate that the temperature did not exceed -65oC. the resulting solution was stirred for 1 hour. Tropine /g/ was dissolved in THF /100 ml, and then slowly dropwise added to the reaction mixture. Upon completion of the addition the mixture was slowly added to room temperature and stirred over night. To the reaction mixture was added water, salt was separated and the organic layer was dried with magnesium sulfate, filtered and concentrated, resulting in the obtained oily residue. This residue was dissolved in acetone /2 l/. Then add water /350 ml and concentrated hydrochloric acid /18 ml and the resulting mixture was heated under reflux for 3 hours. The acetone was removed in vacuo, the aqueous phase was extracted with ethyl acetate, podslushivaet K2CO3and the product was extracted in dichloromethane. The combined organic layers were washed with saline, dried with magnesium sulfate, filtered, concentrated and the floor is l-8-azabicyclo[3.2.1] Octan-3-yl) Methoxymethane

A mixture of (2-forefeel)(8-methyl-8-azabicyclo[3.2.Octan-3-yl) methanone /29,5 g/, hydroxylaminopurine /16.5 g/ and ammonium acetate /27.5 g/ heated in 80 ml of irrigating a mixture of ethanol and water /3:1/ for 19 hours. The mixture was cooled and the precipitated product collected /25,2 g/.

d. 3-(1,2-Benzisoxazol-3-yl)-8-methyl-8-azabicyclo[3.2.1] -octane-hydrochloride-monohydrate

A solution of (2-forefeel)(8-methyl-8-azabicyclo[3.2.1] Octan-3-yl) methanosarcina /14 g/ 56 ml of 10% aqueous solution of hydroxy sodium and 140 ml of ethanol was heated under reflux for 4 hours. The resulting solution was cooled, diluted with water and the product was extracted in dichloromethane. The combined organic layers were washed with saline, dried with magnesium sulfate, filtered, concentrated and received in the result of 13.1 g of oily substance. The crude product was dissolved in methanol and acidified. The solvent was removed, was added ethyl acetate and the product was led out of the solution. The product was collected by filtration and obtained 5.5 g of 3-(1,2-Benzino-casasol-3-yl)-8-methyl-8-azabicyclo [3.2.1]octahedrally-monohydrate in the form of crystals, so pl. 232 233oC.

Analysis: for C15H21ClN2O2/%/:

Calculated: 60,70 C; 7,1 H; 9,44 N

oC. the resulting suspension was heated under reflux for 3 hours, then the solution was cooled and the solvent was removed in vacuum. The residue is suspended in 125 ml of ethanol and acidified HC1 in isopropanol to a pH of about 1/ and the mixture was heated under reflux for 2 hours. The mixture was cooled and received a 3.9 g of crystalline 3-/1,2-benzisoxazol-3-yl/-8-azabicyclo [3.2.1]octahedrally, so pl. 264 268oC.

Analysis: for C14H17ClN2O /%/:

Calculated: C 63,51; H 6,47; N OF 10.58

Found: C 63,67; H 6,51; N 10,42

f. [4-[4-[3-[1,2-Benzisoxazol-3-yl] -8-azabicyclo[3.2.1] Octan-8-yl] butoxy]-3-methoxyphenyl]alanon, hydrochloride

A mixture of 3-(1,2-benzisoxazol-3-yl)-8-azabicyclo[3.2.1] octane /3.7 g/, 4-(4-bromobutoxy)-3-methoxyphenylalanine /5.3g/ and potassium carbonate (4.5 g) was heated under reflux at 65 mm acetonitrile for 22 hours. The resulting mixture was cooled to room temperature, and then filtered. The filtrate was diluted with dichloromethane and then washed with water and brine, dried off with K2CO3was filtered , concentrated and received a 7.1 g of the crude product. After purification by HPLC on silica gel /elwira with ethyl acetate/ received 4,6 of the product. the ATEM to the solution was added isopropyl ether and the hydrochloride was led. After filtering received 4,48 g[4- [4-[3-[1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1] Octan-8 - yl]butoxy]-3-methoxyphenyl]economicrelated, so pl. 216, 5 218oC.

Analysis for C27H33ClN2O4/%/:

Calculated: 66,86 C; 6,86 H, N 5,78

Found: up 66,78 C; 7,11 H; N OF 5.53

Example 2.

A. Diethyl-1-(2,4-differenl)-1-methoxymetopon

Triphoridae boron /86g/ added drop by drop to a solution of 2,4-differentialgeometrie /114 g/ and triethylphosphite /101 g/ 1.2 l of dichloromethane at -25oC. the resulting solution was heated to room temperature and stirred for 20 hours. Then added water and the mixture is vigorously stirred for 10 minutes the Organic layer was separated, washed with brine, dried with magnesium sulfate, filtered and concentrated, resulting in a received liquid residue. After HPLC purification on silica gel /elwira dichloromethane and then 5% mixture of ethyl acetate and dichloromethane/ received 136 g of diethyl-1- (2,4-defloriani)-1-methoxymethamphetamine in liquid form.

b. (2,4-Defloriani)(8-methyl-8 - azabicyclo[3.2.1]Octan-3-yl)-methanomicrobiales

Diethyl-1-(2,4-defloriani) -tility /103,4 ml of 2.5 M solution in hexane/ so, to ensure that the temperature did not rise above -65oC. the resulting solution was stirred for 1 hour. Then to the reaction mixture slowly drop by drop added tropine /32,7 g/ dissolved in THF /100 ml. After complete addition, the mixture is slowly brought to room temperature and stirred over night. To the reaction mixture were added a saturated solution of NaCl /1.5 l/. The layers were separated and the organic layer was collected and dried with magnesium sulfate. The solvent was removed by rotary evaporator and obtained oily substance /73 g/. This oily substance /38 g/ was dissolved in acetone /2 l/. Then slowly added the water /350 ml and concentrated HCl /182/ ml and the resulting mixture was heated under reflux for 3 hours. The acetone was removed with a rotary evaporator. The aqueous residue was extracted with ethyl acetate, podslushivaet K2CO3, were extracted with dichloromethane /DHM/ and was dried by magnesium sulfate. After evaporation of solvent received 31,3 g of an oily material, which was then utverjdali. Part of the obtained solids /3 g/ were dissolved in the standard /75 ml/. Then was added HCl in standard up until the solution is acidic, then added ethyl ether /75 ml and receive salt R>
Calculated: C 59,70; H 6,01; N WITH 4.64

Found: C 59,52; H by 5.87; N 4,55

C. Z-(2,4-Defloriani)(8-methyl-8-azabicyclo[3.2.1] Octan-3-yl) methanosarcinaceae

A mixture of (2,4-defloriani)(8-methyl-8-azabicyclo[3.2.1] Octan-3-yl)methanone /20 g/, hydroxylaminopurine /10.6 g/ and ammonium acetate /18,7 g/ was heated for 19 hours of 67.5 ml of a mixture of ethanol and water /3:2/ under reflux. The mixture was concentrated to obtain approximately half of its original volume, besieged and received of 21.3 g of solid substance.

d. 3-[6-Fluorescent-1,2-benzisoxazol-3-yl] -8-methyl-8-azabicyclo [3.2.1]octahedrally

A mixture of (E)-(2,4-defloriani)(8-methyl-8-azabicyclo(3.2.1]-Octan-3-yl) methanosarcina /18 g/, 10% NaOH /36,4 ml/ ethanol /150 ml/ was heated under reflux for 4 hours. The reaction mixture was cooled and concentrated on a rotary evaporator. The mixture was diluted with water to 500 ml and was extracted with ethyl ether /2 x 1 l/. The ether extract was dried with magnesium sulfate and concentrated, resulting in the obtained oily residue /13,6 g/, which is then left for a few hours for curing. Part of this solid /3.0 g/ were dissolved in the standard and was added ethanol HCl drop by drop until, until the solution becomes acidic. The result is effected from a solution.

Analysis for C15H17FN2OHCl /%/:

Calculated: C 60,71; H 6,11; N 9,44

Found: C 60,83; H 6,17; N WAS 9.33

e. 3-(6-fluorescent-1,2-benzisoxazol-3-yl)-3-azabicyclo[3.2.1]octahedrally

Vinylchloride /2.9 g/ drop) was added to a solution of 3 - (6-fluorescent-1,2-benzisoxazol-3-yl)-8-methyl-8-azabicyclo[3.2.1] octane /5.6 g/ and potassium carbonate /3.6 g/ in 124 ml of 1,2-dichloroethane at 0oC. the resulting suspension was heated under reflux for 3 hours, the solution was cooled and the solvent was removed in vacuum. The residue is suspended in 125 ml of ethanol and acidified by HCl in ethanol to a pH of about 1/, and the mixture was heated under reflux for 2 hours. The mixture was cooled and was obtained 3.6 g of 3-(6-fluorescent-1,2-benzisoxazol-3-yl)-8 - azabicyclo[3.2.1]octahedrally /so pl. 248 250oC/, crystallized from the solution.

Analysis for C14H16ClFN2O /%/:

Calculated: C 59,46; H 5,71; N TO 9.91

Found: C 59,59; H 5,73; N 9,83

f. [4-[3-[3-[6-the Fluorescent-1,2-benzisoxazol-3-yl]-8 - azabicyclo-[3.1.1]Octan-8-yl]propoxy]-3-methoxyphenylalanine, hydrochloride

A mixture of 3-[6-fluorescent-1,2-benzisoxazol-3-yl]-8-azabicyclo[3.2.1]octane /3,3 g/, K2CO3/of 2.21 g/, 4-(3-chloropropoxy)-3 - methoxyphenylalanine /3,9 g/ and acetonitrile /150 ml/ stirred and nagni. The residue was purified using preparative chromatography /Prep 500/ /5% methanol/ 1% triethylamine /94% DHM/ and obtained 3.4 g of oily substance. This substance was dissolved in ethanol /40 ml and was added HCl in ethanol until then, until the solution becomes acidic. Then added ethyl ether /approximately 100 ml and was obtained 2.4 g[4-[3-[3- [6-the fluorescent-1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1]Octan-8-yl]propoxy]-3 - methoxyphenyl of economicrelated deposited from solution in the form of a solid substance, so pl. 219 220oC.

Analysis for C26H30ClN2O4/%/:

Calculated: C 63,86; H 6,18; N 5,73

Found: C 63,69; H 6,09; N the ceiling of 5.60

Example 3.

[4-[3-[3-[1,2-Benzisoxazol-3-yl] -3 - azabicyclo[3.2.1]-Octan-8-yl]propoxy]-3-methoxyphenyl]aanonpolar

A mixture of 3-(1,2-benzisoxazol-3-yl)-8-azabicyclo[3.2.1] octane /3.2 g of 4-(3-chloropropoxy)-3-methoxyphenylacetone /4.0 g/, potassium carbonate /3,9 g/ and catalytic amounts of potassium iodide were heated under reflux in 60 ml of acetonitrile for 19 hours. The resulting mixture was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic layer was washed with water, dried with magnesium sulfate, filtered and concentrated, resulting in a received 7,1 g mA the solid substance was collected by filtration, suspended in water and podslushivaet 10% NaOH solution. The product was extracted in dichloromethane, and then washed with water and brine, dried off with K2CO3was filtered , concentrated and obtained 4.0 g of the crude product. After purification by HPLC on silica gel with elution by ethyl acetate/ received 2.7 g of oily product. This oily product /2.5 g/ was dissolved in hot ethanol and treated with an equivalent amount of fumaric acid. Then to the solution was added isopropyl ether and fumarate were led. After filtering received 2.85 g[4-[3- [3-[1,2-benzisoxazol-3-yl] -8-azabicyclo[3.2.1]Octan-8 - yl]propoxy]-3-methoxyphenyl]canoperate, so pl. 176 178oC.

Analysis for C30H34N2O8/%/:

Calculated: C 65,44; H 6,22; N 5,09

Found: C 65,11; H 6,25; N 5,06

Example 4.

[4-[2-[3-[6-the fluorescent-1,2-benzisoxazol-3-yl] -3 - azabicyclo[3.2.1]Octan-8-yl]ethoxy]-3-methoxyphenyl]aanonpolar

A mixture of 3-[6-fluorescent-1,2-benzisoxazol-3-yl)-3-azabicyclo[3.2.1]octane /3.0 g/, 4-(2-Chloroethoxy)-3-methoxyphenylalanine /3.6 g/, and potassium carbonate /2.2 g/ heated under irrigation in 200 ml of acetonitrile for 22 hours. The resulting mixture was cooled to room temperature and panola and ethyl acetate, as a result, were received and added fumaric acid /0,76 g/. The product was led from the solution by adding ethyl ether and was obtained 2.0 g[4-[2-[3-[6-the Fluorescent-1,2-benzisoxazol-3 - yl] -8-azabicyclo[3.2.1] Octan-8-yl] ethoxy] -3-methoxyphenyl] canoperate in powder form, so pl. 171 172oC.

Analysis for C29H31FN2O8/%/:

Calculated: C 62,81; H 5,63; N OF 5.05

Found: C 62,69; H 5,61; N 5,02

Example 5.

[4-[2-[3-[1,2-Benzisoxazol-3-yl]-8 - azabicyclo[3.2.1]Octan-8-yl]ethoxy] -3-methoxyphenyl]aanonpolar

A mixture of 3-(1,2-benzisoxazol-3-yl)-8-azabicyclo[3.2.1]octane /8,4 g/, 4-(2-chloroethoxy)-3-methoxyphenylalanine /4.1 g/, potassium carbonate /4.1 g/ and catalytic amounts of potassium iodide was heated under irrigation in 60 ml of acetonitrile for 19 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was dissolved in diethyl ether and acidified with HCl in isopropanol. The solid is collected by filtration, suspended in water and podslushivaet 10% NaOH solution. The product was extracted in dichloromethane, and then washed with water and brine, dried off with K2CO3, was filtered and was concentrated in the acetate/ received 2.8 g of oily product. This product /2,55 g/ was dissolved in hot ethanol and the solution was treated with an equivalent amount of fumaric acid. Then to the solution was added isopropyl ether and fumarate were led. After filtering received 2,95 g[4-[2-[3-[1,2-benzisoxazol-3-yl] -8 - azabicyclo[3.2.1] Octan-8-yl] ethoxy] -3-methoxyphenyl] canoperate, so pl. 182 - 183oC.

Analysis for C29H32N2O3/%/:

Calculated: C 64,91; H 6,01; N 5,22

Found: C 64,92; H of 6.02; N 5,20

Example 6.

[4-[4-[3-[6-the Fluorescent-1,2-benzisoxazol-3-yl] -8 - azabicyclo[3.2.1]Octan-8-yl]butoxy]-3-methoxyphenyl]aanonpolar

A mixture of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-8-azabicyclo [3.2.1] octane /3.5 g/, 4-(4-bromobutoxy)-3-methoxyphenylalanine /5,1 g/ and potassium carbonate /2.4 g/, was heated under irrigation in 200 ml of acetonitrile for 22 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate, which was received with 5.3 g of oily product. This product was dissolved with methanol and was added fumaric acid /1,4 g/. The product has led adding ethyl ester and was obtained as the result of 4.2 g[4-[4-[3-[6-the fluorescent-1,2-besisik

Analysis for C31H35FN2O8/%/:

Calculated: C 63,90; H 6,07; N 4,81

Found: C 63,68; H 5,95; N 4,69

Example 7.

A. 3-(1H-Indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane

A mixture of (2-forefeel)(8-methyl-8-azabicyclo-[3.2.1] -Octan-3-yl)methanone /24,6 g/, hydrazine hydrate is added /14.4 oz/ ethanol /250 ml/ was heated to a temperature of distillation for 4 hours. Then the reaction mixture was cooled to room temperature and concentrated, resulting in the obtained oily residue. This residue was dissolved in dimethylformamide /DMF/ /250 ml/, after which the reaction mixture was added potassium carbonate /28G/, and the resulting mixture was heated under reflux for 2 days. The mixture is then cooled and filtered, and the DMF was removed in vacuum. The residue was dissolved in ethanol and the solution was besieged with 5.2 g of 3-(1H-indazol-3-)-8 - methyl-8-azabicyclo[3.2.1]-octane in the form of a powder, so pl. 191 192oC.

Analysis for C15H19N3/%/:

Calculated: C 74,64; H of 7.95; N 17,41

Found: C 74,53; H 83,02; N 17,21

b. 3-(1H-Indazol-3-yl)-8-azabicyclo[3.2.1]octane

Bromide CYANOGEN /18.2/ added /one piece/ suspension /1H-indazol-3-yl/-8-methyl-8-azabicyclo[3.2.1] octane /20.7 g/ and sodium carbonate /23.7 g/ 340 ml of DMF at room temperature. Smeo washed with water and brine, was dried by magnesium sulfate, filtered and concentrated, resulting in received of 22.2 g of oily substance. After trituration with a mixture of ethyl acetate and hexane was obtained 11.9 g of a solid substance.

Part of the obtained above cyanamide /6.8 g/ in 130 ml of THF drop by drop at 0oC was treated with lithium aluminum hydride /1 M in 57 ml of THF/. The resulting mixture was heated under reflux for 1 hour and then was cooled to 0oC and was filled with water, after which the mixture was diluted with 7 ml of 20% NaOH-solution and 7 ml of water. Then add the sodium sulfate, the mixture was filtered and the filtrate was concentrated, which was obtained 6.2 g of foamy substance that alkilirovanie without further purification.

C.[4-[3-[3-[1H-Indazol-3-yl] -8 - azabicyclo[3.2.1]Octan-8-yl]propoxy] -3-methoxyphenyl]alanon

A mixture of 3-(1H-indazol-3-yl)-8-azabicyclo[3.2.1] octane /5,46 g/, 4-(3-chloropropoxy)-3-methoxyphenylalanine /6.4g/, potassium carbonate /6.6 g/ and catalytic amounts of potassium iodide was heated under irrigation in 100 ml of acetonitrile for 17 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was dissolved in 6 n HCl solution and was extracted with ethyl acetate. The aqueous layer podslushivayuschim, drained K2CO3was filtered and concentrated, resulting in a received 7.0 g foamy substance. After purification by HPLC on silica gel /elwira first ethyl acetate and then a mixture of 10% methanol and 90% ethyl acetate/ received 4,2 g foamy product. This product has led adding ethyl acetate, after which the solid product was recrystallized from a mixture of ethyl acetate and hexane and was obtained 2.8 g[4-[3-[3-[1H-indazol-3-yl]-8 - azabicyclo[3.2.1]Octan-8-yl] propoxy]-3-methoxyphenyl]ethanone in powder form, so pl. 173-175oC.

Analysis for C26H31N3O3/%/:

Calculated: C 72,03; H 7,21; N RS 9.69

Found: C 71,69; H 7,14; N FOR 9.64

Example 8. [4-[2-[3-[1H-Indazol-3-yl]-8-azabicyclo[3.2.1]Octan-8-yl] ethoxy]-3-methoxyphenyl]alanon

A mixture of 3-(1H-indazol-3-yl)-8-azabicyclo[3.2.1] octane /4.1 g of 4-(2-chloroethoxy)-3-methoxyphenylalanine /5,9 g/ and potassium carbonate /2.7 g/ was heated in a 125 ml deleverage acetonitrile for 22 hours. The resulting mixture was cooled to room temperature, and then filtered. The filtrate was concentrated and purified by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate/ result was obtained 2.3 g of oily product. This product is] ethoxy]-3-methoxyphenyl of ethanone in powder form, so pl. 154 - 155oC.

Analysis for C25H29N3O3/%/:

Calculated: C71,56; H 6,98; N 10,02

Found: C71,42; H 6,95; N 9,98

Example 9.

[4-[4-[3-[1H-Indazol-3-yl] -8 - azabicyclo[3.2.1]Octan-8-yl]butoxy]-3-methoxyphenyl]aanonpolar, hemihydrate

A mixture of 3-(1H-indazol-3-yl)-8-azabicyclo[3.2.1] octane /3.1 g of 4-(4-bromobutoxy)-3-methoxyphenylalanine /4.52 g/ potassium carbonate /3.7 g/ heated under irrigation in 56 ml of acetonitrile for 22 hours. The resulting mixture was cooled to room temperature, and then filtered. The filtrate was diluted with dichloromethane, and then washed with water and brine, dried off with K2CO3was filtered and concentrated, the result of which was obtained 6.0 g of crude product. This product was purified by HPLC on silica gel /elwira mixture of triethylamine/ and obtained 3.4 g of product as an oily substance. This substance was dissolved in ethanol and the solution was treated with an equivalent amount of fumaric acid. The solvent was removed in vacuo, and the resulting foamy substance was led out of the water and resulted 3.3 grams[4-[4-[3-[1H-indazol-3-yl]-8-azabicyclo[3.2.1]Octan-8-yl]butoxy]-3-methoxyphenyl]canoperate hemihydrate as a powder, so pl. N 7,34

Found: C65,08; H 6,74; N 7,22

Example 10.

A. 3-(Floro-1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane

A mixture of (2,4-defloriani)(8-azabicyclo[3.2.1] Octan-3-yl)methanone /31,2 g/, hydrazine hydrate is added /14,2 ml/ ethanol /300 ml/ was heated under reflux for 5 hours. Then the mixture was cooled to room temperature, concentrated, diluted with water and was extracted in a mixture of isopropanol and chloroform /1:4/. After concentration was obtained 27 g of oily residue. Part of this balance /17,7 g/ was dissolved in DFM /180 ml/. Then to the mixture was added potassium carbonate /16,8 g/ and was heated under reflux for 20 hours. Then the reaction mixture was cooled and filtered, and the DMF was removed in vacuum. The residue was diluted with water and the product was extracted in isopropanol/ chloroform /1: 4/. The combined organic layers were dried with magnesium sulfate, filtered and concentrated, resulting in received 18 g of crude product. After purification by HPLC /with elution with a mixture of ethyl acetate, methanol and triethylamine/ received to 7.3 g of product.

b. 3-(6-fluorescent-1H-indazol-3-yl)-8-azabicyclo[3.2.1]octane

Bromide CYANOGEN /11.4 g/ one portion was added to a suspension of (6-fluorescent-1H-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane /23,4 g/ cancontribute. To the residue was added water and the product was extracted in isopropanol/chloroform /1:4/. The combined organic layers were dried sulfate, filtered and concentrated. The residue was purified using WAIK /elwira a mixture of ethyl acetate, methanol and triethylamine/ and received 4.5 g of intermediate compounds of cyanamide.

The cyanamide /14.3 g/ 125 ml THF at 0oC drop was treated with lithium aluminum hydride /1M in THF, 105 ml/. The resulting mixture was heated under reflux for 1 hour and then was cooled to 0oC and poured water. The mixture was diluted with 12 ml of 20% NaOH solution and 12 ml of water, after which the mixture was filtered on celite and concentrated. Then added water and the product was extracted in isopropanol/diethyl ether /1:4/. The combined organic layers were dried with magnesium sulfate, filtered and concentrated, resulting in a received 10.6 g of product, which was subjected to alkylation without further purification.

C.[4-[2-[3-[6-the fluorescent-1H-indazol-3-yl] -8 - azabicyclo[3.2.1]Octan-8-yl] ethoxy]-3-methoxyphenyl]alanon

A mixture of 3-(6-fluorescent-1H-indazol-3-yl] -8-azabicyclo[3.2.1] -octane /3.8 g/, 4-(2-chloroethoxy)-3-methoxyphenylalanine /4.8 g/ and potassium carbonate /4.8 g/ heated in 125 ml of acetonitrile at reflux distilled in was decesari by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate, which was obtained 3.8 g of product as an oily substance. This product was dissolved in isopropyl alcohol /isopropyl alcohol/ and after crystallization was obtained 2.1 g[4-[2-[3-[6-the fluorescent-1H-indazol-3-yl] -8 - azabicyclo[3.2.1]Octan-8-yl]ethoxy]-3-methoxyphenyl]ethanone in powder form, so pl. 151 152oC.

Analysis for C25H28FN3O3/%/:

Calculated: C68,63; H6,45; N9,60

Found: C68,48; H6,45; N9,51

Example 11.

[4-[4-3-[6-fluorescent-1H-indazol-3-yl] -8 - azabicyclo[3.2.1] Octan-8-yl] butoxy]-methoxyphenyl]alanon

A mixture of 3-(6-fluorescent-1H-indazol-3-yl)-8-azabicyclo[3.2.1] -octane /6.0 g/, 4-(4-bromobutoxy)-3-methoxyphenylalanine /7.6 g/ and potassium carbonate /6.7 g/ was heated at reflux distilled in 150 ml of acetonitrile for 22 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate, which was obtained 4.6 g of oily product. This product was dissolved in isopropyl alcohol and after crystallization was obtained 2.2 g[4-[4-[3-[6-the fluorescent-1H-indazol-3-yl]-8 - azabicyclo[3.2.1]Octan-8-yl]butoxy]-3-methoxyphenyl]ethanone in powder form, so pl. 148 149oC.

Analysis for C27

[4-[3-[3-[6-the fluorescent-1H-indazol-3-yl]-8 - azabicyclo[3.2.1]Octan-8-yl]propoxy]-3-methoxyphenyl]alanon

A mixture of 3-(6-fluorescent-1H-indazol-3-yl)-8-azabicyclo[3.2.1] octane /4.3 g/, 4-(3-chloropropoxy)-3-methoxyphenylalanine /4.7g/ and potassium carbonate /2.8 g/ heated under irrigation in 150 ml of acetonitrile for 18 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was dissolved in water and was extracted with a mixture of CHCl3/ IPS. The combined organic layers were dried with magnesium sulfate, filtered and concentrated. After purification by HPLC on silica gel /elwira first ethyl acetate and then 10% methanol-89% ethyl acetate-1% tea/ received 3.1 g foamy product. This product was dissolved in methanol /50 ml/ and after crystallization was obtained 2.8 g[4-[3-[3-[6-the fluorescent-1H-indazol-3-yl]-8 - azabicyclo[3.2.1]Octan-8-yl]propoxy]-3-methoxyphenyl]ethanone in the form of a solid substance, so pl. 157 158oC.

Analysis for C26H30FN3O3/%/:

Calculated: C69,14; H6,71; N9,31

Found: C68,97; H6,99; H9,31

Example 13.

A. 3-[1,2-Benzisothiazol-3-yl]-8-methyl-8-azabicyclo[3.2.1]octane hydrochloride

A mixture of (2-forfinal)(8-methyl-8-azabicyclo[3.2.1] Octan-3-yl of metanoia /20 g/ sulfur /3.2 g/ saturated which was ladli. The reaction mixture was poured into water /250 ml, was extracted DHM and the organic phase was concentrated, resulting in the obtained oily residue. This residue was purified by HPLC on silica gel /elwira a mixture of ethyl acetate, methanol and triethylamine/ and obtained oily substance /6.3 g/, which is then left to cure. The obtained solid substance /2.0 g/ was dissolved in methanol. Then was added HCl in ether until then, until the solution becomes acidic. The obtained Sol product /1.7 g/ besieged from solution was added ethyl ether. The residue twice recrystallized from methanol, and was obtained 0.5 g of 3-[1,2-Benzisothiazol-3-yl]-8-methyl-8-azabicyclo-[3.2.1]octane hydrochloride, T. pl. 271 273oC.

Analysis for C15H19ClN2/%/:

Calculated: C 61,09; H 6,51; N 9,50

Found: C, in comparison with 60.87; H of 6.49; N 9,38

b. 3-(1,2-Benzisothiazol-3-yl)-8-azabicyclo[3.2.1]octane

Vinylchloride /4.4 g/ drop) was added to a solution of 3-(1,2 - benzisothiazol-3-yl)-8-methyl-8-azabicyclo[3.2.1] octane /8,9 g/ and potassium carbonate /4,76 g/ 250 ml of 1,2-dichloroethane. The resulting suspension was heated under reflux for 3 hours, after which the solution was cooled and the solvent was removed in vacuum. The residue is suspended in saprolegnia for 1 hour. The mixture was cooled, was podslushivaet and were extracted in dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered and concentrated, the result of which was obtained 8.5 g of 3-(1,2-benzisothiazol-3-yl)-8-azabicyclo[3.2.1]octane, which is used in the next stage without purification.

c. [4-[2-[3-[1,2-Benzisothiazol-3-yl] -8 - azabicyclo[3.2.1] Octan-8-yl] ethoxy]-3-methoxyphenyl]alanon, fumarate

A mixture of 3-(1,2-benzisothiazol-3-yl)-8-azabicyclo[3.2.1]octane /4.8 g/, 4-(2-chloroethoxy)-3-methoxyphenylalanine /5.8 g/, and potassium carbonate /3.5 g/ was heated at reflux distilled in 250 ml of acetonitrile for 22 hours. The resulting mixture was cooled to room temperature, and then filtered. The filtrate was concentrated and purified by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate, which was obtained 2.8 g of oily product. This product was dissolved in ethanol and fumaric acid /0,82 g, dissolved in ethanol/ and added to the free base in solution. The obtained product was besieged from solution by addition of ethyl ether. The mother liquor was otparyvali in order to remove solvent, podslushivaet NaOH and was extracted with DHM. Then, this crude free base was purified painim described above, recrystallized from methanol and collected 0.8 g of salt. Food samples were combined and received 1.9 grams[4-[2-[3-[1,2-benzisothiazol-3-yl]-8 - azabicyclo[3.2.1] Octan-8-yl] ethoxy] -3-methoxyphenyl of canoperate in the form of a solid substance, so pl. 157 158oC.

Analysis for C29N32N2O7S /%/:

Calculated: C 63,03; H of 5.84; N 5,07

Found: C 62,95; H 5,78; N 5,00

Example 14.

[4-[3-[3-[1,2-Benzisothiazol-3-yl]-8 - azabicyclo[3.2.1]Octan-8-yl]propoxy]-3-methoxyphenyl]aanonpolar

A mixture of 3-(1,2-Benzino-3-yl)-8-azabicyclo[3.2.1]octane /2.8 g/, 4-(3-chloropropoxy)-3-methoxyphenylalanine /3.1 g/ and potassium carbonate /1.8 g/ heated in 150 ml of acetonitrile at reflux distilled for 22 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate, which was obtained 3.8 g of oily product. This product was dissolved in methanol and fumaric acid /1.1 g, dissolved in methanol/ and added to the free base in solution. Product /4.0 g/ besieged from solution by addition of ethyl ether. The product is then recrystallized from methanol, and was obtained 2.8 g[4-[3-[3-[1,2-Ben">

Analysis for C30H34N2O7S /%/:

Calculated: C 63,59; H equal to 6.05; N 4,94

Found: C 63,83; H 6,00; N 5,00

Example 15.

[4-[4-[3-[1,2-Benzisothiazol-3-yl] -3 - azabicyclo[3.2.1] Octan-8-yl] butoxy]-3-methoxyphenyl]alanon, hydrochloride

A mixture of 3-(1,2-Benzisothiazol-3-yl)-8-azabicyclo[3.2.1] octane /3.6 g of 4-(4-bromobutoxy)-3-methoxyphenylalanine /5.3g/ and potassium carbonate /2.5 g/ heated in 150 ml of acetonitrile at reflux distilled for 22 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC on silica gel /elwira mixture of triethylamine, methanol and ethyl acetate/, resulting in received of 5.4 g of oily product. This product was dissolved in methanol and one drop was added HCl in ether until then, until the solution becomes acidic. The product was led from the solution by adding ethyl ether and was obtained 3.2 g of powder. After recrystallization of this product from methanol was obtained 2.1 g[4-[4-[3- [1,2-benzisothiazol-3-yl] -8-azabicyclo[3.2.1]Octan-8 - yl]butoxy] -3-methoxyphenyl]alanon-hydrochloride, T. pl. 205 206oC.

Analysis for C27H33ClN2O3S /%/:

Calculated: C 64,70; H of 6.65; N 5,59

Found: C 64,45; H 6,63; N 5,49.

Gorod or halogen;

p is an integer 1 or 2;

n is an integer 2, 3 or 4;

R lower alkoxyl or group-C(O)R1where R1alkyl;

m is an integer 1 or 2,

or their pharmaceutically acceptable acid additive salt.

2. The compound of General formula I on p. 1, showing antipsychotic and/or antidepressant activity.

3. The method of obtaining compounds of General formula I on p. 1, characterized in that heteroaryl-8-azabicyclo(3,2,1)octane General formula

< / BR>
subjected to interaction with aryloxyalkanoic General formula

< / BR>
where Y, p, X, n, R and m have the above meanings; Z is chlorine or bromine.

4. Heteroaryl-8-azabicyclo (3,2,1)octane General formula

< / BR>
where Y, p, X have the above meanings;

R2hydrogen or lower alkyl.

 

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< / BR>
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< / BR>
where X is hydrogen or halogen, or lower alkyl, which find wide application in the synthesis of derivatives of 7-hydroxy-5,6-califonication [1] used in the aniline-dye industry for dyeing different types of fibers

The invention relates to new biologically active compounds derived from 4-oxo-1,4-dihydropyrimidin having antiallergic activity, which can find application in pharmaceutical industry and medicine

The invention relates to a method of obtaining new ethers of 1-benzyl-3-hydroxymethylimidazole and their salts with pharmaceutically acceptable bases

The invention relates to the derivatives of benzene, substituted heterocyclic ring represented by the General formula

XZ (1) where R cycloalkyl group having 3-8 carbon atoms;

X halogen atom;

The Z group of the formula

-Nor-Nin which cycloalkyl group may be substituted by an alkyl group having 1-6 carbon atoms, to a process for their preparation and herbicides containing them as active ingredient

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: indazol receptors of formula I demonstrate antagonistic activity with respect to CRF receptor, which can be used in medicine. , in which R represents phenyl or pyridinyl, optionally substituted with alkyl, alkoxygroup or halogen; R1 represents -NRaRb, -CRcRdRe, CO2Ra or -C(O)NRaRb; Ra and Rb are selected from hydrogen, alkyl-, cycloalkyl-, aryl- or heterocyclyl-containing groups or together with nitrogen atom form heterocycle; Rc represents hydrogen, hydroxyl-group, alkoxy-group or -NRa Rb; Rd and Re are selected from hydrogen, alkyl-, aryl- or heterocyclyl-containing groups or together with carbon atom form cycloalkyl or heterocycle; Rc and Rd together form group =CRR`, where R represents heteroalkyl, halogenalkyl, alkyl, or hydrogen, and R` represents alkyl-, cycloalkyl-, aryl- or heterocyclyl-containing groups; Ra′′′ and Rb′′′ are selected from hydrogen, alkyl-, cycloalkyl-, aryl- or heteroaryl-containing groups or together with nitrogen atom form heterocycle.

EFFECT: obtaining novel biologically active compounds.

2 cl, 12 ex, 2 tbl

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