N-substituted azaheterocyclic carboxylic acids or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition and method of inhibiting neurogenic inflammation

 

(57) Abstract:

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the group or in which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines. The compounds of formula (I) inhibit neurogenic inflammation and can find application in medicine. EPassporte. 6 C. and 3 h.p. f-crystals, 2 PL.

The invention relates to new N-substituted azaheterocyclic carboxylic acids and their esters (1), in which a substituted alkyl chain forms part of a substituent at the nitrogen atom, or their salts, to processes for their preparation, to compositions containing these compounds and to their use for the clinical treatment of pain, hyperalgesia and/or inflammatory conditions in which C-fibers play a pathophysiological role, causing neurogenic pain or inflammation.

The nervous system has a significant effect on the inflammatory response. Antiaromatase stimulation of sensory nerves leads to localized vasodilation and increased vascular permeability (Anexo and others, VG. J. Pharmacol. 1967, 31, S. 138-151), and a similar reaction was observed after injection of peptides, which are known to be present in sensory nerves. Based on these and other data, it was postulated that released from sensory nerve endings peptides are carriers of many inflammatory reactions in tissues such as skin, ligaments, eyes, brain, skin, urinary tract, gastro-intestinal and respiratory tracts. So podslastite, dermatitis, rhinitis, asthma, cystitis, inflammation of the gums, thrombophlebitis, glaucoma, gastrointestinal disease or migraine.

In U.S. patent N 4383999 and N 4514414, as well as in the European patents EP 236342 and EP 231996 patented some derivatives of N-(4,4-disubstituted-3-butenyl) azaheterocyclic carboxylic acids as inhibitors of GABA uptake. In Europatent NN 342635 and 374801 as inhibitors of GABA uptake patented N-substituted azaheterocyclic carboxylic acids, in which respectively oximetery group and vinyl ether group form part of the substituent at the nitrogen atom. In addition, in applications WO 9107389 and WO 9220658 as inhibitors of GABA uptake declared N-substituted usacycling carboxylic acid. In EP 221572 patented, 1-aryloxyalkyl-3-carboxylic acid are inhibitors of GABA uptake.

In addition to the above-cited documents in U.S. patent NN 3074953 disclosed ethyl ester 1-(3-(10,11-dihydro-5H-dibenzo [a.d] cyclohepten-5-ilidene)-1-propyl) -4-phenyl-4-piperidinecarboxylic acid as a psychotropic medication. Ether derivatives of 1-substituted 4 - phenyl-4-piperidinecarboxylic acids, similar to the above-cited connection, described as YAponii NN 49032544 and 48040357, France NN 2121423, UK N 1294550 US and Germany 2101066 disclosed 1-substituted 4-dialkylamino-4 - piperazinecarboxamide as psychotropic agents for the treatment of schizophrenia and as inhibitors of inflammation. In addition, U.S. patent N 3177211 described 10- ((aminocarbonyl-1 - piperidyl) alkyl) phenothiazines used as hypotonic, antiemetic, antipyretic and sedative agents. In example 7 specifically disclosed compounds: 10-(3-(3-carbomethoxy-1-piperidyl) propyl)phenothiazines and 10-(3-(3-carborexics-1-piperidyl)propyl) phenothiazines.

The present invention relates to new N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I),

< / BR>
in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6- alkoxy; Y is a group >N-CH2-, >CH-CH2or >C=CH-, in which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8-, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH= CH-, -CH2CH2CH2- -CH=CH-, -NR9-(C=O)-, -O-CH2-, -(C=O)- or -(S= O)-, where R7, R8and R8independently represent a hydrogen atom or a C1-Cwho is hydrogen or when m =2, can both be bond; and R6is hydroxyl or C1-C8-alkoxygroup; or their pharmaceutically acceptable salts.

The compounds of formula I can exist as geometric and optical isomers, and this formula includes all isomers and mixtures thereof. The isomers can be separated using standard techniques, such as chromato-graphic techniques or fractional crystallization of suitable salts.

Preferably, the substances of the formula I exist as an individual geometric or optical isomers.

The compounds of this invention may not necessarily exist in the form of a pharmaceutically acceptable acid additive salts, or when the carboxylic acid group is not etherification, in the form of a pharmaceutically acceptable metal salts or ammonium salts, optionally alkyl.

Examples of such salts include additive salts of inorganic and organic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable additive salts of inorganic or organic acids, and include pharmaceutically the application.

Used herein, the term "patient" refers to any mammal that when treatment can get relief of neurogenic inflammation. This term especially refers to people, but is not limited to only such patients. It is shown that the new compounds of formula (I) inhibit neurogenic inflammation, which enables selection of neuropeptides from peripheral and Central endings of sensory C-fibers. This can be demonstrated experimentally in animal models with pain induced by formalin, or edema in the paw (Weiler and Cowan, Agents Action, I. 34, S. 264-269). In these models, the new compounds of formula (I) exhibit a strong inhibitory effect. The compounds of formula (I) can be used in the treatment of all pain, hyperalgesia and/or inflammatory conditions in which C-fibers play a pathophysiological role, causing neurogenic pain or inflammation, that is:

the state of acute pain such as migraine, postoperative pain, burns, pain after Stripping (Zoster) and pain, which is usually associated with acute inflammation, chronic, painful and/or inflammatory condition, examples of which are the various types of neuropathy (diabetic, posttraumatic, toxic, pain in cancer, chronic headache, cough, asthma, chronic pancreatitis, inflammatory skin diseases, including psoriasis and autoimmune dermatosis, osteoporotic pain.

The compounds of formula (I) can be prepared in the following way:

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The compound of formula II in which R1, R2X, Y, and g - such as above, and W is a suitable removable group, such as halogen, pair-toluensulfonate or mutilata group can interact with azaheterocyclic compound of formula III in which R4, R5, R6, m and n, such as described above. This alkylation reaction may be carried out in a solvent such as acetone, disutility ether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran or toluene, in the presence of a base, for example potassium carbonate, and a catalyst, such as alkali metal iodide, at a temperature up to the boiling point of the used solvent under reflux, during, for example, from 1 to 120 hours Upon receipt of esters in which R6is alkoxygroup, substances of the formula (I) in which R6is hydroxyl, can be obtained by hydrolysis of the ester grta, such as methanol or ethanol, for example, for 0.5 to 6 hours

Compounds of formulas II and III can be readily prepared using methods known to experts in the field of chemistry.

In certain circumstances it may be necessary to protect the intermediates used in the above methods, for example the substances of the formula III, a suitable protecting group. For example, the carboxylic acid can be etherification. The introduction and removal of such groups are described in the book "Protective groups in organic chemistry" (edited by J. F. W. Mc Ornie, New York, 1973).

Pharmacological methods

The magnitude of inhibition of pain induced by formalin, or tumor substances of the present invention was evaluated in live mice (in. vivo) almost by the method of Weiler-Aceto and Cowan (Agents Action. 34, S. 265-269).

The female NMR1 mice weighing about 20 g were doing the injection of 20 μl of 1% formalin in the left hind paw. Then the animals were placed on a heated table (31oC) and assessed the pain reaction. After 1 h, animals were killed and released the blood. Remove the left and right hind paws, and the difference between the weight of these paws were used as indications of the edematous response in the leg after formalin injection.

For the above indications the dosage may vary depending on the compounds of formula I, its mode of administration and the desired therapeutic effect. However, in General satisfactory results are obtained with a dosage of about 0.5 to 1000 mg, preferably about 1 to 500 mg of the substances of the formula I, which is convenient to take from 1 to 5 times a day, not necessarily in the form of the drug slow release. Usually convenient for oral destination dosage form includes from about 0.5 to 1000 mg, preferably about 1 to 500 mg of the substances of the formula I in a mixture with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in the form of a pharmaceutically acceptable acid salt additive or, if possible, in the form of a metal salt or lower alkylamine. Such salt forms exhibit the activity of the same order as the activity of the free base forms.

This invention also relates to pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt, and usually such compositions also contain a pharmaceutical carrier or diluent. Compositions containing Sedih forms, for example capsules, tablets, solutions or suspensions.

Applied pharmaceutical carrier may be conventional solid or liquid carrier. Examples of solid carriers are lactose, white earth, sucrose, talc, gelatin, agar, pectin, gum acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

Similarly, the carrier or diluent may include any known in the prior art material, slowing down the selection, such as glycerol monostearate or distearate glycerin, either in pure form or mixed with wax.

In the case of using a solid carrier for oral administration, the drug can be tablet, placed in a hard gelatin capsule in powder or beads, or it can be in the form of tablets or pills. The amount of solid carrier may vary widely, but typically it is from about 25 mg to 1 g In the case of using a liquid medium, the drug may be in the form of syrup, emulsion, soft gelatin capsule or sterile water for injection, such as a suspension in an aqueous or non-aqueous fluid or solution.

In accordance with this invention, when the appointment of patients, such as humans, the dosage of the substances as medicines is 1-500 mg / day, for example about 100 mg per dose.

A typical tablet which may be prepared by conventional tabletting techniques, contains:

Core

Active compound (as free compound or its salt) 100 mg

Colloidal silicon dioxide (AerosilR) 1.5 mg

Microcrystalline cellulose (AvicelR) - 70 mg

Modified cellulose resin (AC-Di-SolR) - 7.5 mg

Magnesium stearate

Floor

The hypromellose about 9 mg

havasetR9-40 T approximately - 0.9 mg

R is a registered trademark

x - as a plasticizer for film coating used the acylated monoglyceride.

For the introduction of medication you can use any technique in which the active substance is efficiently transported to the appropriate or desired site of action, such as oral or parenteral, for example, rectal, dermal, subcutaneous, through the nose, intramuscular, intravenous, through the urethra; eye solution or Masi formula I and containing products is additionally illustrated by the following examples that however should not be construed as limiting the invention.

Abbreviations used below: TLC is thin layer chromatography, THF is tetrahydrofuran, CDCl3- deuterochloroform (d-HLF) and d6-DMSO - perdeuteromethoxy. Structures of the compounds are confirmed by either elemental analysis or PMR spectrum, which in the appropriate place presents peaks attributed to the characteristic protons in the analyzed compound. Chemical shifts of protons in the PMR spectrum (b) are given in ppm (M. D.). Reduction in NMR: s-singlet, d-doublet, t - triplet, m = multiplet, sh - wide, So pl. is the melting temperature, which is given inoC, without correction. Chromatographic separation was performed on a column, using the methodology described B. C. Steele and others in the journal J. Org. Chem. 1978, 43 so, S. 2923 - 2925, on silica gel 60 by Merck (product 9385). Analysis by liquid chromatography high resolution (IHVR) was carried out using a column of 5 μm C18 h mm, which was suirable when the gradient from 20 to 80% of a mixture of 0.1% triperoxonane acid /acetone and 0.1% triperoxonane acid/water over 30 minutes at 35 C. as the source of materials used or known substance or substances, the 1-dihydro-5H-dibenzo [a,d] Cycloheptane-5-ilidene)- 1-propyl)-3-piperidinecarboxylic acid

The solution cyclopropylmethyl bromide in dry tetrahydrofuran was prepared from 12.1 g (0.1 mol) of cyclopropylamine, of 2.45 g (0.1 mol) of magnesium shavings and 65 ml of dry THF. In this solution in an atmosphere of nitrogen is added dropwise a solution of 10.4 g (0.05 mole) of 10,11-dihydro-5H-dibenzo-[a,d] cyclohepten-5-it in 25 ml of dry THF and after complete addition the mixture is refluxed for 30 minutes, the Reaction mixture was cooled in an ice bath and carefully add 50 ml of saturated solution of ammonium chloride. The mixture is neutralized 2 N. hydrochloric acid and extracted 2 times with diethyl ether (200 ml). The combined organic extracts are dried with sodium sulfate and the solvent is evaporated in vacuum, obtaining of 13.1 g of crude 5-cyclopropyl-10,11-dihydro-5H - dibenzo-[a,d]cyclohepten-5-ol.

The above crude alcohol (13.1 g) was dissolved in 150 ml of dichloromethane and added dropwise a solution of 9.2 g (60 mmol) of methyl trimethylsilyl in 50 ml of dichloromethane. Upon completion of the addition the mixture is stirred for 15 min at room temperature and add 50 ml of water. Share phase, and the organic phase is washed with saturated sodium bicarbonate solution (2 times 50 ml). The organic phase is dried with sodium sulfate and the solvent Wierda condition.

A mixture of the above crude bromide (6.3 g, 20 mmol), 4,7 g (30 mmol) of ethyl ester of (R)-3-piperidine - carboxylic acid, 5.5 g (40 mmol) of potassium carbonate and 50 ml of acetone is stirred 124 h at room temperature. The mixture is filtered, and the solvent is evaporated in vacuum. The oily residue is purified on 200 g of silica gel (eluent is a mixture of ethyl acetate/n-heptane-1/1) to give 4.4 g of ethyl ester of (R)-1-(3-(10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5-ilidene) -1-propyl)- 3-piperidinecarboxylic acid in the form of oil. Rf =0,38 (silica gel; a mixture of ethyl acetate/n-heptane=1/1).

The above ester (4.4 g, 11 mol) is dissolved in 40 ml of ethanol and add to 8.3 ml of 4 n sodium hydroxide solution. The mixture is vigorously stirred for 7 h at room temperature. Add 700 ml of dichloromethane and then a 2.5 N. hydrochloric acid to pH 1. Share phase, the organic phase is dried with magnesium sulfate, and the solvent is evaporated in vacuum. The residue re-evaporated (2 times) from acetone and then triturated with a mixture of acetone and diethyl ether.

Solid allocate filtration and air-dried, obtaining 2.2 g specified in the header of the substance in the solid state.

So pl. 206-208oC. Calculated for C24H27NO2HCI,%: is the odik, similar to that described in Example 1a:

EXAMPLE 1b. Hydrochloride (S)-1-(3-(10,11-dihydro-5H-dibenzo-[a,d] cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylic acid

So pl. 216-218oC. PMR Spectrum (200 MHz, d6 - DMSO)n1,43 (SHS, 1H), 1,78 (CL, 2H), 1,96 (SHS, 1H) 2,5 (sm, 1H, CH-COOH) 2,84 (BL, 2H) 3,16 (CL, 2H) 3,26 (CL, 4H) to 3.34 (s, 4H) 5,78 (t, 1H) 7,07 (DD, 1H, C=CH=CH2) 7,12-7,29 (m,7H).

EXAMPLE 1c. Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenzo-[a,d] cyclohepten-5-ilidene)-1-propyl) -1,2,5,6-tetrahydro-3 - pyridineboronic acid

So pl. 140-145oC. Calculated for C24H25NO2HClC3H6, %:

C AND 71.4; H - 7,1; N - 3,1

Found: C Is 71.5; H - 6,9; N - 3,1.

EXAMPLE 1d Hydrochloride (R)-1-(3-fluoren-9-ilidene)-1-propyl)- 3-piperidinecarboxylic acid

So pl. 217-219oC. Calculated for C22H23NO2HCl1/4H2O, %:

C - 70,6; H, 6.5; the N - 3,7; Cl - 9,5

Found: And 70.8; H - 6,6; N - 3,5; Cl - 9,4.

EXAMPLE 1e Hydrochloride (R) -1-(3-(3-methyl-10,11-dihydro-5H - dibenzo [a,d] cyclohepten-5-ilidene)-1-propyl) -3-piperidinecarboxylic acid

So pl. 218 to 221oC Calculated for C24H23NO2HCl, %:

C - TO 72.87; H - 7,35; N - 3,40

Found: C - 72,60; H - 7,58; N - 3,24.

EXAMPLE 2. Sodium salt of 1-(3-(5H-dibenzo [a,d] cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylic of ciprofibrate, 1.3 g (53 mmol) of magnesium shavings and 35 ml of dry THF. In this solution in an atmosphere of nitrogen is added dropwise a solution of 6.0 g (28 mmol) of 5H - dibenzo- [a,d] cyclohepten-5-it in 15 ml of dry THF, and after complete addition the mixture is refluxed for 30 minutes, the Reaction mixture was cooled in an ice bath and carefully add 35 ml of saturated solution of ammonium chloride. The mixture is diluted with 50 ml of water and extracted 2 times with diethyl ether (50 ml). The combined organic extracts are "washed with water, dried with sodium sulfate and the solvent is evaporated in vacuum, obtaining 8.6 g of crude 5-cyclopropyl-5H-dibenzo [Ah.d] cyclohepten-5-ol.

To the above crude alcohol (8.6 g) add 60 ml of glacial acetic acid. The mixture is cooled in an ice bath and add a mixture of 30 ml of glacial acetic acid and 15 ml of 47% Hydrobromic acid. The mixture is stirred for 30 minutes, poured into 300 ml of water and extracted 2 times with diethyl ether (100 ml). The combined organic extracts washed with water, dried with sodium sulfate and the solvent is evaporated in vacuum, obtaining 6.8 g of 5-(3-bromo-1 - propylidene)-5H-dibenzo [a,d] cycloheptene in the solid state. So pl. 88-89oC.

A mixture of the above bromide acetone is boiled for 15 hours under reflux. The mixture is filtered, and the solvent is evaporated in vacuum. The oily residue is dissolved in 60 ml of ethyl acetate and washed with 2 N. hydrochloric acid (2 x 30 ml). The organic phase is dried, and the solvent is evaporated in vacuum. The residue is dissolved in 25 ml of acetone, treated with gaseous hydrogen chloride, and the mixture is diluted with 120 ml of diethyl ether. The solvent is decanted, and the oily residue is dried in vacuum, obtaining 5.6 g of the hydrochloride of the ethyl ester of 1-(3-(5H-dibenzo [a,d] cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylic acid in amorphous solids.

The above ester (4.5 g, 11 mmol) is dissolved in 80 ml of ethanol and add 180 ml of 32% sodium hydroxide solution. The mixture is boiled for 1 hour under reflux. Add to the cooled reaction mixture of dichloromethane and ethyl acetate. Share phase, and the aqueous phase is treated with activated bone charcoal and filtered through militarily filter (0.22 μm). The solvent is evaporated from the filtrate under vacuum. The residue is dissolved in a mixture of water and dichloromethane (1:3). Share phase, the organic phase is dried with magnesium sulfate, and the solvent is evaporated in vacuum. The residue is dissolved in water and dried by freezing, getting 3.0 g specified in the header westhroid 1-(3-(thioxanthen-9-ilidene)-1-propyl) - 3-piperidinecarboxylic acid

The solution cyclopropylmethyl bromide in dry tetrahydrofuran was prepared from 18.2 g (150 mmol) of cyclopropylamine, 2.9 g (150 mmol) of magnesium shavings and 80 ml of dry THF. In this solution in an atmosphere of nitrogen is added dropwise a solution of 12.7 g (60 mmol) thioxanthen-9-it is in 70 ml of dry THF, and after complete addition the mixture is refluxed for 20 minutes, the Reaction mixture was cooled in an ice bath and carefully add 70 ml of saturated solution of ammonium chloride. The mixture is diluted with 100 ml of water and extracted 2 times with diethyl ether (100 ml). The combined organic extracts washed with water, dried with sodium sulfate and the solvent is evaporated in vacuum, obtaining of 25.2 g of crude 9-cyclopropyl-9H-thioxanthen-9-ol.

To the above crude alcohol (25,2 g) add 120 ml of glacial acetic acid. The mixture is cooled in an ice bath and add a mixture of 60 ml of glacial acetic acid and 30 ml of 47% Hydrobromic acid. The mixture is stirred for 30 minutes, poured into 600 ml of water and extracted 3 times with diethyl ether (200 ml). The combined organic extracts washed with water, dried with sodium sulfate and the solvent is evaporated in vacuum, obtaining 19.5 g n what about the above bromide (2.0 g, 6.3 mmol), 1.2 g (6.3 mmol) of ethyl ester of 3-piperidinecarboxylic acid, 2.9 g (21 mmol) of potassium carbonate and 60 ml of acetone is stirred for 3 h and then boiled for 16 hours under reflux. The mixture is filtered, and the solvent is evaporated in vacuum. The oily residue is purified on silica gel (dichloromethane/methanol 98:2) to give 1.3 g of ethyl ester of 1-(3-(thioxanthen-9-ilidene)-1-propyl)-3-piperidinecarboxylic acid in the form of oil. Rf = 0.21 in (silica gel, dichloromethane/methanol = 98:2).

The above ester (0.74 g, 1.8 mmol) dissolved in 25 ml of ethanol and add 6 ml of 40% sodium hydroxide solution. The mixture is boiled for 1 hour under reflux. Add 25 ml of 10% hydrochloric acid and then 150 ml of dichloromethane. Share phase and the organic phase is washed with water, dried with magnesium sulfate, and the solvent is evaporated in vacuum, obtaining 0.6 g specified in the header of the substance in the solid state. So pl. 150-160oC. the Sample is dissolved in acetone and precipitated in diethyl ether. The formed solid substance produce by filtration and dried in vacuum.

Calculated for C22H23NO2SHCl,5H2OH, %:

C IS 64.3; H - 6,1; N -3,4

Found: C - 64,0; H - 6,2; N - 3,5.

Range of TMR (d - HLF)n: 5,74 (t, lH).

EXAMPLE 4. Hikaru 10,11-dihydro-5H-dibenzo [b,f] azepine (8,1 g, 40 mmol) in 60 ml dibutylamino ether, stored in a nitrogen atmosphere, carefully add 1.6 g (40 mmol) of a 60% dispersion of sodium hydride in oil. The reaction mixture was refluxed for 4 h and then allow it to cool to 80oC. was Added 10.7 g (48 mmol) of 3-bromo-1-propyl tetrahydro-2-pernerova ether and the mixture refluxed for 16 hours To the cooled reaction mixture is added 20 ml of water and separated phases. The solvent is evaporated from the organic phase and the residue dissolved in a mixture of 150 ml of methanol and 50 ml of 4 N. hydrochloric acid. The mixture is refluxed for 15 min and then stirred for 1 h at room temperature. Add 250 ml water and the mixture extracted 2 times with ethyl acetate (200 ml). The combined organic extracts are dried with sodium sulfate, filtered and the solvent is evaporated in vacuum. You get a residue, which is optionally purified chromatographically on silica gel (200 g), blueroom a mixture of n-heptane and ethyl acetate (3: 2). Obtain 5.5 g of 3-(10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1-propanol in the form of oil. Rf = 0,30 (silica gel, n-heptane/ethyl acetate = 1:1).

The above alcohol (3.0 g, 12 mmol) is dissolved in 100 ml of toluene and added to 4.0 ml treaties stirred for 2 hours Add water and separate the phases. The organic phase is dried with magnesium sulfate, and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in 50 ml of acetone. To this solution was added to 5.4 g (18 mmol) of the ethyl ester tartrate (R)-3 - piperidinecarboxylic acid and 4.1 g (30 mmol) of potassium carbonate, and the mixture is refluxed for 3 days. The mixture is allowed to cool, then filtered and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in diethyl ether. The resulting mixture is extracted with 2 times 5% solution of tartaric acid (100 ml). The combined aqueous extracts washed with diethyl ether and the pH adjusted to 7-8 by addition of potassium carbonate solution. The neutralized aqueous mixture was extracted 2 times with ethyl acetate (200 ml). United an ethyl acetate extracts washed with water, brine and dried with magnesium sulfate. The solvent is evaporated in vacuum, obtaining a residue which is dissolved in diethyl ether (50 ml). Obtain 2.8 g of ethyl ester of (R)-1-(3-(10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1 - propyl)-3-piperidinecarboxylic acid in the form of butter.

The above ester (2.8 g, 7.1 mmol) dissolved in 10 ml ethanol and added with 5.3 ml of 4 n sodium hydroxide solution. Cccii (pH 1). The resulting mixture is extracted with 300 ml of dichloromethane and the organic extract is dried with magnesium sulfate. The solvent is evaporated in a vacuum, getting a foamy residue, which was re-evaporated with acetone. The result is 2.3 g specified in the header of the substance in the amorphous solid state.

Calculated for C23H28N2O2HClH2O, %:

C IS 65.9; H - 7,5; N - 6,7

Found: C - 66,1; H - 7,6; N - 6,2.

EXAMPLE 5. Hydrochloride (R)-1-(4-(10, 11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1-butyl)-3-piperidinecarboxylic acid

To a solution of 10,11-dihydro-5H-dibenzo [b,f] azepine (16.2 g, 83 mmol) in 120 ml dibutylamino ether, stored in a nitrogen atmosphere, carefully add 3.2 g (80 mmol) of a 60% dispersion of sodium hydride in oil. The reaction mixture was refluxed for 4 h and then allow it to cool to 80oC. Type of 18.5 g (96 mmol) of 4-chloro-1-butyl tetrahydro-2-pernerova ether and the mixture refluxed for 16 hours It was cooled to room temperature, the reaction mixture is added 40 ml of water and separated phases. The organic phase is evaporated to dryness, and the residue dissolved in a mixture of 300 ml of methanol and 100 ml of 4 N. hydrochloric acid. The mixture is refluxed in TK with ethyl acetate (200 ml). The combined organic extracts are dried with sodium sulfate, filtered and the solvent is evaporated. You get a residue, which is purified chromatographically on silica gel (400 g), blueroom a mixture of n-heptane and ethyl acetate (3:2). Get to 13.1 g (59%) of 4-(10,11-dihydro-5H-dibenzo [b,f], azepin-5-yl)-1-butanol in the form of oil, which solidified upon standing in the refrigerator overnight. Rf = 0.34 in (silica gel, n-heptane/ethyl acetate = 1:1).

The above alcohol (5.4 g, 20 mmol) is dissolved in 160 ml of toluene and added to 7.0 ml of triethylamine. Added dropwise 2.5 ml (32 mmol) chloride methanesulfonyl and upon completion of addition the reaction mixture is stirred for 2 hours, water is Added and the separated phase. The organic phase is dried with magnesium sulfate, and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in 85 ml of acetone. To this solution was added 9.0 g (30 mmol) of the ethyl ester tartrate (R)-3-piperidinecarboxylic acid and 7.0 g (51 mmol) of potassium carbonate and the mixture is refluxed for 16 hours After cooling to room temperature the mixture is filtered through celite and the solvent is removed by evaporation. The residue is dissolved in 100 ml diethyl ether and extracted 3 times with 5% solution of tartaric acid (125 mlekiem potassium carbonate solution. The neutralized aqueous mixture is extracted 4 times with ethyl acetate (200 ml). United an ethyl acetate extracts washed with water, brine and dried with magnesium sulfate. The solvent is evaporated in vacuum, obtaining a residue which is dissolved in diethyl ether (50 ml). Obtain 2.6 g (32%) of ethyl ester 1-(4-(10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1-butyl)-3-piperidinecarboxylic acid in the form of oil. This residue is optionally purified chromatographically on silica gel (65 g), blueroom a mixture of dichloromethane and methanol (to 99.2:0.8). Rf = 0,20 (silica gel, n - heptane/ethyl acetate = 1:1).

The above ester (1.5 g, 3.7 mmol) dissolved in 10 ml of ethanol and add a solution of 0.52 g of sodium hydroxide in 2 ml of water. The mixture is stirred for 2 h at room temperature and add concentrated hydrochloric acid until a pH value less than 1 (2 ml). Add 75 ml of dichloromethane and then with 50 ml water and the phases are separated. The organic phase is dried with magnesium sulfate, and the solvent is evaporated in vacuum. To the residue is added 15 ml of acetone, which is again evaporated. Dry white product add 30 ml of acetone and, after filtration and drying obtain 1.3 g (84%) specified in the header of the substance in the form of a white solid. So pl. 222-224oC.

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EXAMPLE 6. Hydrochloride (R)-1-(2-(10,11-dihydro-5H - dibenzo [b,f] azepin-5-yl) ethyl)-3-piperidinecarboxylic acid

In a round bottom flask with a capacity of 500 ml, equipped with magnetic stirrer, thermometer, dropping funnel and scrubber, dissolve 19.5 g (100 mmol) of 10,11-dihydro-5H-dibenzo [b, f] azepine in 100 ml dry toluene. Slowly add to 13.6 g (120 mmol) of chloroacetanilide. The reaction mixture is heated at 95oC for 30 min and then allow it to cool to room temperature. With stirring 50 ml of 0.2 n sodium hydroxide solution. Add 100 ml of toluene and separated phases. The organic phase is washed with 3 times 50 ml of 0.2 n sodium hydroxide solution, until the pH value does not exceed 10, and then 3 times with water 50 ml and 50 ml brine. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining an oily residue, which crystallized during curing over night. The product is obtained with a quantitative yield and used in subsequent reactions without purification.

The above crude amide (20 g, 74 mmol) under nitrogen atmosphere was dissolved in 150 ml dry THF and cooled to 5oC. Add sodium borohydride (2.3 g, 60 mmol) and then dropwise introduced to 9.4 ml (76 moldoveichisinau amount of sodium borohydride (2.0 g, 53 mmol) and epirate boron TRIFLUORIDE (6 ml, 49 mmol) and continue stirring overnight. Added dropwise 20 ml of methanol and stirring is continued for 1 hour Add 20 ml of water to dissolve the precipitate, and then 100 ml of ethyl acetate. Share phase and the aqueous phase is extracted 2 times with ethyl acetate (100 ml). The combined organic extracts washed with water (4 times 100 ml) and 100 ml of brine. The solvent is evaporated in vacuum and the residue twice otparivat with toluene. The obtained crude product is purified chromatographically on a column of silica gel (400 g), eluruumi dichloromethane. Obtain 15.0 g (79%) of 5-(2-chloroethyl)- 10.11-dihydro-5H-dibenzo [b, f] azepine. Rf = 0.70 and (silica gel, dichlorotin).

The above chloride (10.0 g, 39 mmol) is dissolved in 175 ml of toluene and added to 3.3 g of potassium iodide. To this solution was added 18.0 g (60 mmol) of the ethyl ester tartrate (R)-3 - piperidinecarboxylic acid and 14.0 g (120 mmol) of potassium carbonate and the mixture is refluxed for 72 hours After cooling to room temperature the mixture is filtered through celite and the solvent is removed by evaporation. The residue is purified chromatographically on a column of silica gel (300 g), eluruumi a mixture of n-heptane and ethyl acetate (1:1). Obtain 1.6 g (11%) atelierul, n-heptane/ethyl acetate = 1:1).

The above ester (1.28 g, 3.4 mmol) dissolved in 10 ml of ethanol and add a solution of 0.52 g of sodium hydroxide in 2 ml of water. The mixture is stirred for 2 h at room temperature and add concentrated hydrochloric acid until a pH value less than 1 (2 ml). Add 75 ml of dichloromethane and then with 50 ml water and the phases are separated. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum. To the residue is added 15 ml of acetone, which is again evaporated. Dry white product add 30 ml of acetone and, after filtration and drying obtain 1.1 g (80%) specified in the header of the substance in the form of a white solid. So pl. 246 - 248oC.

Calculated for C22H26N2O2HCl1/4H2O, %:

WITH - 67,44; H - 7,02; N - 7,15

Found: C - 67,72; H - 7.23 Percent; N - 7,01.

EXAMPLE 7. Hydrochloride (R)-1-(3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl) -1-propyl) -3 - piperidinecarboxylic acid.

In a round bottom flask with a capacity of 100 ml equipped with a magnetic stirrer, thermometer, dropping funnel and the input of nitrogen, dissolved 1.3 g (5.6 mmol) of 3-chloro-10,11-dihydro - 5H-dibenzo [b, f] azepine in 30 ml of dry toluene. Slowly add in a stream of nitrogen 1.01 g (6.7 mmol) of ethylmaleimide. Reaccionar stirring, 2.5 ml of 0.2 N. the sodium hydroxide solution. Add 100 ml of toluene, and the share phase. The organic phase is washed with 3 times 50 ml of water and 50 ml brine. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining an oily residue. The product is obtained with a quantitative yield and used in subsequent reactions without purification.

In a round bottom flask with a capacity of 250 ml, equipped with a magnetic stirrer, thermometer and addition funnel, is placed 920 mg (24 mmol) socialwise hydride. Add 40 ml of dry toluene in a stream of nitrogen and then slowly add 4 ml of tetrahydrofuran. Using a bath of ice water, adjusted the temperature of the mixture up to 15-25oC. the above amide (2.1 g, 6.1 mmol) was dissolved in 12 ml of dry THF and added slowly to a suspension socialwise hydride and keep the temperature at 20 - 25oC. the Reaction mixture was stirred over night at room temperature. Added dropwise 1 ml of water, then 1 ml of 4 n sodium hydroxide and finally 3 ml of water. The formed precipitate is sucked off celite, and the toluene solution is dried with magnesium sulfate. The crude product is purified chromatographically on a column of silica gel (75 g), eluruumi heptane and ethyl acetate = (1:1). Poluchaetsya = 1: 1).

The above alcohol (870 mg, 3 mmol) dissolved in 25 ml of toluene and add 1.0 ml of triethylamine. Added dropwise 0.5 ml (6 mmol) chloride methanesulfonyl, and the reaction mixture is stirred for 2 hours, Add 100 ml of water, then the additional amount (100 ml) of toluene and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in 50 ml of methyl ethyl ketone. To this solution was added 1.4 g (4.7 mmol) of the ethyl ester tartrate (R)-3-piperidinecarboxylic acid and 1.0 g (7.2 mmol) of potassium carbonate, and the mixture is refluxed for 24 h and stirred at room temperature for 24 hours After filtration through celite the solvent is removed by evaporation. The residue is purified chromatographically on a column of silica gel (100 g), eluruumi with a mixture of heptane and ethyl acetate (1:1). Obtain 1.0 g (79%) of ethyl ester of (R)-1-(3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid in the form of oil. Rf = 0.34 in (silica gel, n-heptane/ethyl acetate = 1:1).

The above ester (500 mg, 1.2 mmol) dissolved in 4 ml of ethanol and add a solution of 0.2 g sodium hydroxide in 1 ml of water. The mixture is stirred for 2 h at room temperature and add conc elaut. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum. Adding ethyl acetate to the residue crystallizes, giving, after filtration and drying 0.4 g (68%) specified in the header of the substance in the form of a white solid. So pl. 135-138oC.

Calculated for C23H27N2O2HCl3/4 H2OH, %:

C - 61,48; H - TO 6.57; N - 6,23

Found: C - 61,35; H Is 6.67; N - 5,70.

EXAMPLE 8a.

Hydrochloride (R)-1-(3-(10H-phenothiazines-10-yl) -1 - propyl)-3-piperidinecarboxylic acid

To a solution of fenotiazina (4.0 g, 20 mmol) in 100 ml of dry dimethylformamide, under nitrogen atmosphere, carefully add 1.0 g (25 mmol) of a 60% dispersion of sodium hydride in oil. The reaction mixture was allowed to mix for 15 minutes Add 8.0 g (50 mmol) 1-bromo-3-chloropropane and the mixture is left to mix overnight. Add 2.0 g (40 mmol) of ammonium chloride, then continue to stir for 30 min and the mixture is then poured into 300 ml of water. The mixture is extracted 2 times with dichloromethane (200 ml). The combined organic extracts are dried with magnesium sulfate, filtered and the solvent is evaporated. You get a residue, which is purified chromatographically on a column of silica gel (250 g), eluruumi a mixture of n-heptylate = 1:1).

Dissolve in 100 ml of methyl ethyl ketone, 10 g (60 mmol) of potassium iodide and refluxed for 1 hour Add the above chloride (2.64 g, 90 mmol) in a solution of 10 ml of methyl ethyl ketone and the mixture is refluxed for 3 hours After cooling to approximately 60oC add 2.64 g (9 mmol) of the ethyl ester tartrate (R-3-piperidinecarboxylic acid and 2.0 g (14 mmol) of potassium carbonate. The mixture is refluxed for 24 hours and allowed to mix at room temperature for 24 h After filtering the mixture through celite, the solvent is removed by evaporation. The residue is purified chromatographically on a column of silica gel (150 g) eluruumi with a mixture of heptane and ethyl acetate (6:4). Obtain 2.5 g (87%) of ethyl ester of (R)-1-(3-(10H-phenothiazines-10-yl)-1-propyl) -3-piperidinecarboxylic acid in the form of oil. Rf = 0,20 (silica gel, n-hepten/ethyl acetate = 1: 1).

The above ester (1.7 g, 4.3 mmol) dissolved in 15 ml of ethanol and add to 0.63 g of sodium hydroxide in 2.5 ml of water. The mixture is stirred for 2 h at room temperature and add concentrated hydrochloric acid until a pH value less than 1 (2.5 ml). Add 100 ml of dichloromethane, and then 50 ml of water and separated phases. The organic phase is dried with magnesium sulfate and RA what about the number of dichloromethane. The result after filtering and drying, 0.3 g (18%) specified in the header of a substance in the form of a white solid. Subsequent re-evaporation of the filtrate get 1,08 g (62%) of product. So pl. 123-128oC.

Calculated for C21H25N2O2HCl5/4H2OH, %:

C - 58,95; H - TO 6.43; N - 6,55

Found: C - 59,19; H - 6,52; N - 6,17.

According to the method similar to that described in Example 8a were prepared the following compounds.

EXAMPLE 8b Hydrochloride (10-1- (3-(2-trifluoromethyl-10H-phenothiazines-10-yl) -1-propyl)-3-piperidinecarboxylic acid

So pl. 198-200oC. PMR Spectrum (200 MHz, d6-DMSOn: 1,45 (SHS, 1H), 1,79 - 2,13 (BL, 4H), was 2.76 - 3,44 (BL, 8H) 4,06 (t, 2H) 7,02 (i.e 1H) 7.12-7.42 (m, 6H).

EXAMPLE 8 S. Hydrochloride (R)-1-(3-(5-oxo-10H-phenothiazines - 10-yl)-1-propyl)-3-piperidinecarboxylic acid

In 40 ml of glacial acetic acid was dissolved 2.0 g (7 mmol) of 10-(3-chlorpropyl)-10H - fenotiazina add to 2.25 ml (22 mmol) of 30% hydrogen peroxide and the mixture is stirred for 48 hours under nitrogen atmosphere. The reaction mixture was allowed to mix overnight. Precipitated precipitated crystals are filtered and washed 2 times with water (20 ml), 2 times with diethyl ether (50 ml) and dried in vacuum. Output 10- (3-chlorpropyl)-10H-phenothiazines-5-oxide (m, 2H), 3,63 (t,2H), 4,43 (t, 2H), 7.25 (t, 2H) 7,40 (d,2H) to 7.61 (dt, 2H) 8, 09 (DD, 2H).

Specified in the header of the receive substance according to the method similar to that described in Example 8a using, instead of 10-(3-chloro-propyl)-10H - fenotiazina, 10-(3-chlorpropyl)-10H-phenothiazines-5-oxide. So pl. above 280oC.

Range PMR (400 MHz, d6-DMSO)n: 1,46 (sm, 1H), 1,84 (CL, 2H), 2,01 (sm, 1H), 2,28 (CL, 2H) 3,39 (BL, 2H) 3,54(sm, 1H) 4,39 (t,2H, N-CH2CH2-) 7,41 (m, 2H) 7,79 (d,4H) 8,03 (d,2H) 10,95 (SHS, 1H) 12,85 (SHS, 1H).

EXAMPLE 9. Hydrochloride (R)-1-(3-(10H-phenoxazin-10-yl)-1 - propyl) -3-piperidinecarboxylic acid

To a solution of phenoxazine (3.7 g, 20 mmol) in 100 ml of dry dimethylformamide under nitrogen atmosphere carefully add 1.2 g (30 mmol) of a 60% dispersion of sodium hydride in oil. The reaction mixture was allowed to mix for 15 minutes Add 8.0 g (50 mmol) 1 - bromo-3-chloropropane, and the mixture is left to mix overnight. Add 2.0 g (40 mmol) of ammonium chloride, then continue to stir for 30 min and the mixture is then poured into 300 ml of water. The mixture is extracted 2 times with dichloromethane (200 ml). The combined organic extracts are dried with magnesium sulfate, filtered and the solvent is evaporated in vacuum. You get with a quantitative yield of 10-(3-chlorpropyl) -10H-phenoxazin as m is varaut in 100 ml of methyl ethyl ketone, 10 g (60 mmol) of potassium iodide and refluxed for 1 h Add the above chloride (5.2 g, 20 mmol) in solution in 10 ml of methyl ethyl ketone, and the mixture is refluxed for 3 hours After cooling to approximately 60oC type of 5.3 g (1.8 mmol) of the ethyl ester tartrate (R) -3-piperidinecarboxylic acid and 4.0 g (28 mmol) of potassium carbonate. The mixture is refluxed for 24 hours and allowed to mix at room temperature for 24 h After filtering the mixture through celite, the solvent is removed by evaporation in a vacuum. The residue is purified chromatographically on a column of silica gel (250 g), eluruumi with a mixture of heptane and ethyl acetate (1:1). Get 5,2 g (67%) of ethyl ester of (R)-1-(3-(10H-phenoxazin-10-yl)-1-propyl) - 3-piperidinecarboxylic acid in the form of oil. Rf= 0.25 in (silica gel, n-heptane/ethyl acetate = 1:1).

The above ester (2,34 g, 6 mmol) dissolved in 25 ml of ethanol and add a solution of 0.9 g of sodium hydroxide in 3.5 ml of water. The mixture is stirred for 2 h at room temperature and add concentrated hydrochloric acid until a pH value less than 1 (3.5 ml). Add 100 ml of dichloromethane, and then 70 ml of water and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum, obtaining 1.8 g (77%) of product. For additional purification of the product is VA. So pl. 217 to 220oC.

Calculated for C21H24N2O3HCl,%:

C - 64,86; H - 6,48; N - 7,20

Found: C - 64,56; H - 6,70; N - 6,89.

EXAMPLE 10. Hydrochloride (S)-1-(3-(10,11-dihydro-5H-dibenzo- [b,f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid

To a solution of 10,11-dihydro-5H-dibenzo [b,f] azepine (8.1 g, 40 mmol) in 60 ml dibutylamino ether, stored in a nitrogen atmosphere, carefully add 1.6 g (40 mmol) of a 60% dispersion of sodium hydride in oil. The reaction mixture was refluxed for 4 h and then allow it to cool to 80oC. Add 10.7 g (48 mmol) of 3-bromo-1-propyl tetrahydro-2-pernerova ether and the mixture refluxed for 16 hours, After cooling the reaction mixture to room temperature, add 20 ml of water and separated phases. The solvent is evaporated to dryness of the organic phase and the residue dissolved in a mixture of 150 ml of methanol and 50 ml of 4 N. hydrochloric acid. The mixture is refluxed for 15 min and then stirred for 1 h at room temperature. Add 250 ml water and the mixture extracted 2 times with ethyl acetate (200 ml). The combined organic extracts are dried with sodium sulfate, filtered and the solvent is evaporated in vacuum. You get cetate (3:2). Obtain 5.5 g (54%) of 3-(10,11-dihydro-5H - dibenzo [b, f] azepin-5-yl)-1-propanol in the form of oil, which solidified upon cooling in the refrigerator over night. Rf = 0,30 (silica gel, n-heptane/ethyl acetate = 1:1).

The above alcohol (2.5 g, 9.9 mmol) was dissolved in 20 ml of dry THF in a nitrogen atmosphere add 2.0 ml of triethylamine. Added dropwise of 0.77 ml (9.9 mmol) chloride methanesulfonyl and upon completion of addition the reaction mixture is stirred for 45 min and then filtered. Add to the filtrate 3.4 ml of triethylamine and then add 4,55 g (15 mmol) of the ethyl ester tartrate (S)-3 - piperidinecarboxylic acid. The mixture is refluxed for 48 h and incubated for 7 days at room temperature. After filtration through celite the solvent is evaporated in vacuum, obtaining a residue, which is optionally purified chromatographically on a column of silica gel (200 g), eluruumi a mixture of dichloromethane and methanol (9:1). Obtain 0.4 g (9%) of ethyl ester of (S)-1-3-(10,11-dihydro-5H-dibenzo [b,f] azepin - 5-yl)-1-propyl) -3-piperidinecarboxylic acid in the form of oil. Rf = 0,30 (silica gel, dichloromethane/methanol= 9:1).

The above ester (0.35 g, 0.89 mmol) was dissolved in 3 ml of ethanol and add 0,26 ml of 12 n sodium hydroxide solution. Sesaot 50 ml of dichloromethane and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum. The residue re-evaporated 2 times with acetone. The result after drying of 0.2 g (62%) specified in the header of a substance in the form of a white amorphous product.

Retention time when GHUR is 21,36 minutes

Calculated for C23H28N2O2HCl 3/4 H2OH, %:

WITH - 66,65; H - 7,42; N - 6,76

Found: C - 66,99; H - Of 7.48; N - 6,36.

EXAMPLE 11. Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenzo [b,f] - azepin-5-yl)-1-propyl)-3-pyrrolidinyloxy acid

3-(10,11-Dihydro-5H-dibenzo [b, f] azepin-5-yl)-1-propanol (2.0 g, 7.9 mmol), prepared as described in Example 10, dissolved in 25 ml of dry THF in a nitrogen atmosphere add to 2.75 ml of triethylamine. Added dropwise and 0.61 ml (7.9 mmol) chloride methanesulfonyl and upon completion of addition the reaction mixture is stirred for 45 min and then filtered. Add to the filtrate 2.4 g (12 mmol) of methyl ester of 3-pyrrolidinyloxy acid. The mixture is refluxed for 4 h and stirred her 48 h at room temperature. Add 2.2 ml of triethylamine and the mixture is refluxed for 24 hours After cooling to room temperature, the solvent vapour is Tana and methanol (9: 1). Obtain 0.9 g (27%) of methyl ester 1-3-(10,11-dihydro - 5H-dibenzo [b,f] azepin-5-yl)-1-propyl)-3 - pyrrolidinyloxy acid in the form of oil. Rf =0.15 in (silica gel, dichloromethane/methanol/acetic acid = 20:2:1).

The above ester (0,85 g, 2.2 mmol) dissolved in 6 ml ethanol and added 0.5 n sodium hydroxide solution. With continuous addition of 0.25 n sodium hydroxide maintain pH of a mixture of about 12 for 3 days. Add diluted (about 1 N.) hydrochloric acid until pH = 7 and the solvent is evaporated in vacuum. The residue is purified chromatographically on a column of silica gel (50 g), eluruumi a mixture of dichloromethane, methanol and acetic acid (20:2:1). Fraction of the product is evaporated with dichloromethane. The result is 0.04 g (3,8%) 1-3-(10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1 - propyl)-3-pyrrolidinyloxy acid in the form of an amorphous product.

Retention time when GHUR is 21,66 minutes

Range PMR (400 MHz, d-HLF)n: 1,68 (m, 1H), 2,01 (m, 2H), 1 to 2.15 (m, 2H) of 2.38 (m, 2H) 2.63 in (m, 1H) 2,81 (m, 1H) 2,95 (m, 2H), 3,13 (m, 6H) of 3.80 (t, 2H) 6,92 (t, 2H) 7,01 (m, 2H) 7,06-to 7.18 (m, 4H)

EXAMPLE 12. Hydrochloride (R)-1-(3-(11H-10-oxa-5-Aza-5H-dibenzo [a,d] cyclohepten-5-yl) - 1-propyl)-3-piperidinecarboxylic acid

In a round bottom flask with a capacity of 500 ml, equipped with a magnetic is Aptana (cooked, as described in the journal J. Med Chem. so 7, S. 609, 1964) in 50 ml of dry Toluca. Slowly add 4,2 g (24 mmol) of 3-bromopropionitrile. The reaction mixture is heated at 95oC for 30 min and then allow it to cool to room temperature. With stirring, add 10 ml of 0.2 n sodium hydroxide solution. Add another 50 ml of toluene and separated phases. The organic phase is washed 3 times with 20 ml of 0.2 n sodium hydroxide solution, as long as the pH does not exceed 10, and then 3 times with water (20 ml) and 20 ml of brine. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining an oily residue. The product is obtained with a quantitative yield and used in subsequent reactions without purification.

The above crude amide (3.5 g, 10 mmol) under nitrogen atmosphere was dissolved in 20 ml of dry THF and cooled to 5oC. Add sodium borohydride (0.31 g, 8 mmol) and then slowly, dropwise injected 2.0 ml (16 mmol) of epirate boron TRIFLUORIDE. The reaction mixture was stirred over night, add an additional amount of sodium borohydride (1.2 g, 32 mmol) and epirate boron TRIFLUORIDE (5 ml, 40 mmol) and continue stirring overnight. Water is added to dissolve the precipitate and then 100 ml E extracts washed with water (4 times 100 ml) and 100 ml of brine. After drying with magnesium sulfate the solvent is evaporated in vacuum. The obtained crude product is purified chromatographically on a column of silica gel (200 g), eluruumi dichloromethane. Obtain 0.8 g (13%) 3-bromo-1-(11H-10-oxa-5-Aza-5H-dibenzo [a, d] cyclohepten-5-yl)-1-propane, Rf=0,62 (silica gel, dichloromethane).

Dissolved in 50 ml of methyl ethyl ketone 3 g (18 mmol) of potassium iodide and refluxed for 30 minutes Add the above bromide (0.8 g, 2.5 mmol) in a solution of 20 ml of methyl ethyl ketone, and the mixture is refluxed for 90 minutes After cooling to approximately 60oC add 0.8 g (2.7 mmol) of the ethyl ester tartrate (R)-3-piperidinecarboxylic acid and 0.62 g (5.3 mmol) of potassium carbonate. The mixture is refluxed for 24 hours and allowed to mix at room temperature for 24 h After filtering the mixture through celite, the solvent is removed by evaporation. The residue is purified chromatographically on a column of silica gel (100 g), eluruumi with a mixture of heptane and ethyl acetate (1:1). Obtain 0.4 g (37%) of ethyl ester of (R)-1-(3-(11H-10-oxa-5-Aza-5H-dibenzo [a,d] cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acid in the form of oil. Rf = 0,17 (silica gel, n-heptane/ethyl acetate = 1:1).

Pointed to by mesilat 2 h at room temperature and add concentrated hydrochloric acid until a pH value less than 1 (0.5 ml). Add 50 ml of dichloromethane, and then 10 ml of water and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum. The residue re-evaporated 2 times with acetone and 1 time evaporated with ethyl acetate. After drying obtain 0.3 g (77%) specified in the header of the substance in the form of an amorphous substance.

Retention time when GHUR is 22,57 minutes

Calculated for C22H26N2O3HCl1/ 2C4H8O2, %:

C - 64,49; H - 6,99; N - 6,27

Found: C - 64,32; H - 7,05; N - 5,99.

EXAMPLE 13. Hydrochloride (R)-1-(3-(10, 11-dihydro-5H-dibenzo [b,f] azepin-5-yl)-1-propyl)-1,2,5,6-tetrahydro-3 - pyridineboronic acid

Prepared as described in Example 4,3- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl)-1-propanol (1,75 g, 6,9 mmol) was dissolved in 20 ml of THF and store in a nitrogen atmosphere. Add the 1.44 ml of triethylamine and then dropwise added 0.54 ml (6,9 mmol) chloride methanesulfonyl. Upon completion of addition the reaction mixture is stirred for 45 minutes the Reaction mixture is filtered and added to 1.99 g (10 mmol) of the hydrochloride of the ethyl ester of 1,2,5,6-tetrahydro-3-piperidine-carboxylic acid and 2.4 ml of triethylamine. The mixture is stirred at room temperature for 9 days. Add tetrahedra column of silica gel (100 g), eluruumi with a mixture of heptane and ethyl acetate (1:1). Obtain 2.1 g (78%) of ethyl ester of 1-(3-(10,11-dihydro-5H-dibenzo [b,f] azepin-5-yl)- 1-propyl)-1,2,5,6-tetrahydro-3-pyridineboronic acid in the form of oil. Rf = 0.25 in (silica gel, n-heptane/ethyl acetate = 1:1).

The above ester (1.7 g, 4.4 mmol) dissolved in 10 ml ethanol and added to 2.7 ml of 4 n sodium hydroxide solution. The mixture is stirred for 3 h at room temperature and add 4 N. hydrochloric acid (3.8 ml), then add 100 ml of dichloromethane and separated phases. The organic phase is dried with magnesium sulfate. The solvent is evaporated in vacuum, obtaining 1.3 g (76%) specified in the header of a substance in the form of a white amorphous product.

Retention time when GHUR is 21,16 minutes

Calculated for C23H26N2O2HCl2xH2O, %:

WITH - 66,26; H - 7,01; N - 6,72.

Found: C - 66,57; H - 7,21; N - 6,33.

EXAMPLE 14. Hydrochloride (R)-1-(3-(6,7-dihydro-5H-dibenzo [b,g] -Asotin-12-yl)-1-propyl)-3-piperidinecarboxylic acid

In a round bottom flask with a capacity of 100 ml equipped with a magnetic stirrer, thermometer and addition funnel, dissolved 2.1 g (10 mmol) 5,6,7,12-tetrahydrobenzo [b, g] azocine (prepared as described in journal of Chem. Pharm. Bull. so 26, S. 942, 1978) in 60 ml of dry toluene is for 2 h and then allow it to cool to room temperature. With stirring, add 5 ml of 0.2 n sodium hydroxide solution and 60 ml of water. Add 100 ml of toluene and separated phases. The organic phase is washed with 3 times 75 ml of water and 75 ml of brine. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining 3.1 g (95%) ethyl ester of 3-(6,7-dihydro-5H-dibenzo [b,g] Asotin - 12-yl)-3-oxopropanoic acid in the form of butter.

In a three-neck round bottom flask with a capacity of 250 ml, equipped with a magnetic stirrer, thermometer and addition funnel, is placed 1.4 g (37 mmol) socialwise hydride. Add 60 ml of dry toluene in a stream of nitrogen and then slowly add 6 ml of tetrahydrofuran. Using a bath of ice water, adjusted the temperature of the mixture up to 15-25oC. After stirring for 30 min the above amide (3.0 g, 9.3 mmol) was dissolved in 18 ml of dry toluene and added slowly to a suspension socialwise hydride at 20-25oC. the Reaction mixture was stirred over night at room temperature. Added dropwise 1.5 ml of water, then 1.5 ml of 4 n sodium hydroxide solution and finally with 4.5 ml of water. The formed precipitate is sucked off celite and the toluene solution is dried with magnesium sulfate and evaporated in vacuum. The crude residue purified, Hirohito-5H-dibenzo [b,g] Asotin-12-yl)-1-propanol in the form of butter.

Rf = 0,37 (silica gel, n-heptane/ethyl acetate = 1:1).

The above alcohol (1.2 mg, 4.5 mmol) dissolved in 25 ml of toluene and added 1.5 ml of triethylamine. Added dropwise 0.75 ml (9 mmol) chloride methanesulfonyl and the reaction mixture is stirred for 2 hours, Add 100 ml of water, then the additional amount (100 ml) of toluene and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in 75 ml of methyl ethyl ketone. To this solution was added 2.1 g (7 mmol) of the ethyl ester tartrate (R)-3-piperidine-carboxylic acid and 1.5 g (11 mmol) of potassium carbonate and the mixture is refluxed for 24 h and stirred at room temperature for 8 days. After filtration through celite the solvent is removed by evaporation. The residue is purified chromatographically on a column of silica gel (75 g), eluruumi with a mixture of heptane and ethyl acetate (1:1). Obtain 1.1 g (61%) of ethyl ester of (R)-1-(3-(6,7- dihydro-5H-dibenzo [b,g] Asotin-12-yl)-1-propyl)-3 - piperidinecarboxylic acid in the form of oil. Rf =0,29 (silica gel, n-heptane/ethyl acetate= 1:1).

The above ester (500 mg, 1.2 mmol) dissolved in 7 ml of ethanol and add a solution of 0.2 g of sodium hydroxide in 1.5 ml of water. The mixture is stirred for 2 who make 100 ml of dichloromethane, then 50 ml of water, and the phases are separated. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum. The residue re-evaporated with acetone, add ethyl acetate and the product is filtered and washed with diethyl ether. After drying obtain 0.4 g (71%) specified in the header of the substance in the form of an amorphous substance.

Retention time when GHUR is 22,70 minutes

Calculated for C24H30N2O2HCl1/4C4H8O2, %:

WITH - 68,72; H - 7,56; N - 6,41

Found: C - 69,12; H - 7,94; N - 6,12.

EXAMPLE 15. Hydrochloride (R)-1-(3-(10, 11-dihydro-5H-dibenzo- [a,d] cyclohepten-5-ilidene)-1-propyl) -3-piperidinecarboxylic acid

In a round bottom flask with a capacity of 50 ml, equipped with a magnetic stirrer, thermometer and addition funnel, suspended in dry toluene under nitrogen atmosphere 0.8 g (20 mmol) of a 60% dispersion of sodium hydride in oil. Add a solution of 3.0 g (14 mmol) of 10,11-dihydro-5H-dibenzo [a,d] cycloheptene-5-carbonitrile (prepared as described in the journal J. Med, Chem), 6, S. 251, 1963) in 15 ml dry toluene. The reaction mixture is heated for 30 min to boil and then refluxed for 150 minutes After cooling to about 50oC added dropwise a solution of 4.5 g (20 mmol) 3-bromo-ilnicka for 5 h and then stirred overnight at room temperature. After filtration of precipitated precipitated salt solution was washed with 100 ml of 1 N. hydrochloric acid, diluted by adding 100 ml of toluene and finally washed with water. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining 7.2 g(99%), 5-(3-(tetrahydropyran-2-yloxy) -1-propyl) -10, 11-dihydro-5H - dibenzo- [a, d] cyclohepten-5-carbonitrile.

In a round-bottom three-neck flask with a capacity of 100 ml add in nitrogen atmosphere 3.5 g (45 mmol) of a 50% dispersion of sodium amide in toluene. Add a solution of 4.0 g (11 mmol) of the above nitrile in 50 ml of dry toluene. The reaction mixture is refluxed for 16 hours After cooling to room temperature, carefully add 100 ml of water. Add toluene, and the organic phase is washed with diluted hydrochloric acid. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining 3.0 g (81%) of crude 2-(3 - 10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-yl)-1 - propyloxy)tetrahydropyran in the form of butter.

The above tetrahydropyran (3.0 g, 9 mmol) dissolved in 30 ml of methanol and add 10 ml of 4 N. hydrochloric acid. The reaction mixture is refluxed for 15 minutes and stirred for 1 h at room Temka extracts are dried with magnesium sulfate, filtered and evaporated in vacuum. Get the remnant that purify chromatography on a column of silica gel (100 g) eluruumi with a mixture of heptane and ethyl acetate = (2:1). Obtain 0.6 g(24%) 3-(10, 11-dihydro-5H-dibenzo [a, d] -cyclohepten-5-yl)-1-propanol in the form of oil, Rf = 0,37 (silica gel, n-heptane/ethyl acetate = 1:1).

The above alcohol (0.55 g, 2 mmol) dissolved in 25 ml of toluene and add 1.0 ml of triethylamine. Added dropwise 0.5 ml (6 mmol) chloride methanesulfonyl and the reaction mixture is stirred for 2 hours Add 75 ml of water, then 100 ml of toluene and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in 50 ml of methyl ethyl ketone. To this solution was added 1.0 g (3.3 mmol) of the ethyl ester tartrate (R)-3-piperidine-carboxylic acid and 0.75 g (5.5 mmol) of potassium carbonate and the mixture is refluxed for 24 h and then stirred at room temperature for 3 days. After filtration through a medium of hyflo the solvent is evaporated in vacuum, obtaining a residue, which is purified chromatographically on a column of silica gel (50 g) eluruumi with a mixture of heptane and ethyl acetate = (1:1). Obtain 0.25 g (29%) ethyl ester (R)-1-(3-(10,11- dihydro-5H-dibenzo [a,d] is 1:1).

The above ester (240 mg, 0.61 mmol) dissolved in 4 ml of ethanol and add a solution of 100 mg of sodium hydroxide in 1 ml of water. The mixture is stirred for 2 h at room temperature and add concentrated hydrochloric acid to pH values below 1 (0.4 ml). Add 100 ml of dichloromethane, and then 50 ml of water and separated phases. The organic phase is dried with magnesium sulfate. The solvent is evaporated in vacuum and the residue re-evaporated with acetone, add ethyl acetate and the product is filtered and washed with diethyl ether. The result after drying of 0.2 g (73 %) specified in the header of the substance in the form of an amorphous product.

Mass spectrum (El) 363,2 (M+- HCl, 15%)

Calculated for C24H28NO2HCl3/2H2O, %:

WITH - 67,52; H - 7,74; N - 3,28

Found: C - 67,70; H - To 7.77; N - 3,44.

EXAMPLE 16. Hydrochloride (R)-1-(3-(3-methoxy-10,11-dihydro - 5H-divineo [b, f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid

In a round bottom flask with a capacity of 100 ml equipped with a magnetic stirrer, thermometer, dropping funnel and the input of nitrogen, dissolved 1.2 g (5.3 mmol) of 3-methoxy-10,11-dihydro-5H - dibenzo [b, f] azepine in 30 ml of dry toluene. Slowly add in a stream of nitrogen 1.01 g (6.7 mmol) of ethylmaleimide. The reaction mixture is boiled snii add 2.5 ml of 0.2 N. the sodium hydroxide solution. Add 100 ml of toluene and separated phases. The organic phase is washed with 3 times 50 ml of water and 50 ml brine. After drying with magnesium sulfate the organic phase is evaporated in vacuum, obtaining an oily residue. The product is obtained with a quantitative yield and used in subsequent reactions without purification.

In a round-bottom three-neck flask with a capacity of 250 ml, equipped with a magnetic stirrer, thermometer and addition funnel, is placed 800 mg (21 mmol) socialwise hydride.

Add 40 ml of dry toluene in a stream of nitrogen and then slowly add 4 ml of tetrahydrofuran. Using a bath of ice water, adjusted the temperature of the mixture up to 15-25oC. the above amide (1,96 g, 5.3 mmol) dissolved in 10 ml of dry toluene and added slowly to a suspension socialwise hydride, maintaining the temperature at 20-25oC. the Reaction mixture was stirred over night at room temperature. Added dropwise 1 ml of water, then 1 ml of 4 n sodium hydroxide and finally 3 ml of water. The formed precipitate is sucked off celite, and the toluene solution is dried with magnesium sulfate. The solvent is removed by evaporation in a vacuum. The crude product is purified chromatographically on the ro-5H-dibenzo [b, f] azepin-5-yl)-1-propanol in the form of oil, Rf= 0.25 in (silica gel, n-heptane/ethyl acetate = 1:1).

The above alcohol (900 mg, 3.2 mmol) dissolved in 25 ml of toluene and added to 1.1 ml of triethylamine. Added dropwise 1.0 ml (13 mmol) chloride methanesulfonyl and the reaction mixture is stirred for 2 hours, Add 100 ml of water, then the additional amount (100 ml) of toluene and separated phases. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum, obtaining a residue which is dissolved in 50 ml of methyl ethyl ketone. To this solution was added 1.44 g (4.8 millimoles) of ethyl ester tartrate (R)-3-piperidinecarboxylic acid and 1.1 g (8.0 mmol) of potassium carbonate, and the mixture is refluxed for 24 h and stirred at room temperature for 72 hours After filtration through a filter hiflo the solvent is removed by evaporation in a vacuum. The residue is purified chromatographically on a column of silica gel (50 g), eluruumi with a mixture of heptane and ethyl acetate (1:1).

Obtain 0.2 g (14%) of the ethyl ester of 1-(3-(3-methoxy-10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid in the form of oil. Rf=0.15 in (silica gel, n-heptane/ethyl acetate = 1:1).

The above ester (190 mg, 0.45 mmol) dissolved in 4 ml of ethanol and Aut concentrated hydrochloric acid to pH values less than 1(0.4 ml). Add 100 ml of dichloromethane, then with 50 ml water and the phases are separated. The organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuum. The residue re-evaporated with acetone, add ethyl acetate; the product is filtered and washed with diethyl ether. Get after drying of 0.13 g (67%) specified in the header of the substance in the form of an amorphous product.

Retention time when GHUR is 22,25 min Calculated for C24H30N2O3HCl 2H2OH, %:

C-61,74; H-7,50; N-6,00

Found: C - 61,83; H - 7,51; N Is 5.98.

EXAMPLE 17. Hydrochloride (In,) -1-(3-(10-methyl-11-oxo-10, 11 - dihydro-5H-dibenzo [b,e] diazepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid.

Added to a solution of 10.0 g (48 mmol) of H-oxo-10,11 - dihydro-5H-dibenzo [b, e] diazepine (prepared as described in journal of the Synthesis, S. 550, 1985) in 100 ml of dry dimethylformamide, under nitrogen atmosphere 2.1 g (52 mmol) of a 60% dispersion of sodium hydride in oil. The reaction mixture is stirred for 1.5 h and added slowly with 3.27 ml (52 mmol) of iodomethane, keeping the temperature below 30oC, and the mixture is stirred over night. The reaction is interrupted by adding 20 ml of saturated solution of ammonium chloride and poured into 300 ml of ice water. The solid is filtered off, washed with ysbyty subjected to recrystallization from 200 ml of methanol. Obtain 6.7 g (63%) of 10-methyl-11-oxo-10,11 - dihydro-5H-dibenzo [b,e] [1,4] diazepine. So pl. 210-211oC. PMR Spectrum (200 MHz, d6-DMSO)n: 3,37 (s, 3H, N-CH3), of 6.90 (t, 1H) 6,97 - 7,14 (m, 4H) 7,24 and 7.36 (m, 2H), 7,66 (DD, 1H), to $ 7.91 (CL, IH, NH)

10-Methyl-11-oxo-10,11-dihydro-5H-dibenzo [b,e] [1,4] diazepin (5 g, 22 mmol) is dissolved in 50 ml of dry THF under nitrogen atmosphere. While cooling with ice bath, slowly add 23% solution in hexane (9.1 ml, 25 mmol) n-utility and stirred for 30 minutes At room temperature, slowly add a solution 6,28 g (27 mmol) of 2-(3-bromo-1-propoxy)tetrahydro-2H-Piran in 10 ml of dry THF. The reaction mixture is heated to 60oC for 1 h and then stirred overnight at room temperature. The reaction is interrupted by adding 20 ml of saturated solution of ammonium chloride and poured into 200 ml of ice water. The mixture is extracted 3 times with dichloromethane (150 ml). The combined organic extracts are washed 2 times with water (80 ml), dried with magnesium sulfate, filtered and the solvent is evaporated in vacuum. Gain of 9.8 g of residue, which is purified chromatographically on a column of silica gel (900 ml), eluruumi a mixture of dichloromethane and ethyl acetate (6:1). Obtain 5.7 g (69%) of 10-methyl-5-(3-(tetrahydro-2H-Piran - 2-yloxy) -1-propyl)-5,10-dihydro-5H-dibenzo [b,e] [1,kusnoy acid, 20 ml THF and 10 ml water dissolve 5.6 g (15 mmol) of 10 - methyl-5-(3-(tetrahydro-2H-Piran-2-yloxy)-1-propyl)-5,10 - dihydro-5H-dibenzo [b,e] [1,4] diazepin-11-she, and the mixture is heated at 45 C for b hours. Add 200 ml of water, and the mixture is extracted 4 times with ethyl acetate (100 ml). The combined organic extracts are washed 4 times with water (100 ml), dried with magnesium sulfate, filtered and the solvent is evaporated in vacuum. Gain of 5.3 g of residue, which is purified chromatographically on a column of silica gel (500 ml), eluruumi a mixture of n-heptane and ethyl acetate (1:3). Obtain 2.3 g (53%) of 10-methyl-5-(3-hydroxy-1 - propyl)-5,10-dihydro-5H-dibenzo [b,e] [1,4] diazepin-11-it is in the form of white crystals. Rf = 0.34 in (silica gel, n-heptane/ethyl acetate = 1:3). So pl. 177-178oC.

10-Methyl-5- (3-hydroxy-1-propyl) -5,10-dihydro-5H - dibenzo [b,e] [1,4] diazepin-11-he (2 g, 7 mmol) dissolved in a mixture of 50 ml of dried THF and 3.0 ml of triethylamine in a nitrogen atmosphere. Added dropwise to 0.69 ml (9 mmol) chloride methanesulfonyl in 10 ml THF and the reaction mixture stirred for 1 h the Solvent is removed by evaporation in vacuo and the residue is dissolved in 200 ml of dichloromethane. The organic solution is washed 3 times with water (50 ml), dried with magnesium sulfate, filtered and the solvent is evaporated in vacuum. Recip"ptx2">

A mixture of 2.5 g (7 mmol) of the above methanesulfonate, of 2.56 g (8.3 mmol) of the ethyl ester tartrate (R) -3-piperidinecarboxylic acid and of 5.81 g (42 mmol) of dry potassium carbonate in 50 ml of methyl ethyl ketone is refluxed for 60 h in nitrogen atmosphere. The reaction mixture was filtered, and the filter residue is washed with excess ethyl acetate. The combined organic extracts washed 1 time with 100 ml of saturated solution of ammonium chloride, 2 times with water (100 ml), 1 time with brine (50 ml), dried with magnesium sulfate, filtered and the solvent is evaporated in vacuum. Obtain 3.13 g (29%) of crude ethyl ester (R)-1-(3- (10-methyl-11-oxo-10,11-dihydro-5H-dibenzo [b, e] diazepin-5 - yl)-1-propyl)-3-piperidinecarboxylic acid, which is used without further purification.

The above ester (2.5 g, 6 mmol) dissolved in a mixture of 20 ml ethanol and 10 ml of water. Add 300 mg (7 mmol) of sodium hydroxide and the reaction mixture was stirred over night at room temperature. Add 300 ml of water and the mixture is washed 2 times with diethyl ether (100 ml) and 1 time with 100 ml of ethyl acetate. The aqueous phase is acidified with 2.2 ml of concentrated hydrochloric acid and washed 3 times with dichloromethane (100 ml). The water is evaporated, getting foam, Kotorosl of acetone and 30 ml of 2-propanol. Add 100 ml of diethyl ether and the mixture is stirred over night. The precipitate is filtered and washed with diethyl ether and dried in vacuum. The result of 1.14 g (45%) specified in the header of the substance in the form of white crystals. So pl. 204-206oC.

Calculated: C23H27N3O3HCl 7/4H2O, %:

WITH - 59,86; H - 6,88; N -9,11

Found: C - 59,93; H - 6,97; N - 8,97

EXAMPLE 18. Hydrochloride (R)-1-(3-(9H-oxo-10H-acridine - 10-yl)-1-propyl)-3-piperidinecarboxylic acid

Added to a solution of 15.0 g (77 mmol) of acridone in 200 ml of dry dimethylformamide, under nitrogen atmosphere 3.7 g (92 mmol) of a 60% dispersion of sodium hydride in oil, four portions. The reaction mixture is stirred until the gas evolution stops. Added dropwise a solution of 21.7 g (92 mmol) of 2-(3-bromo-1 - propyloxy)tetrahydro-2H-Piran in 100 ml of dry THF. The reaction mixture is heated to 80oC for 4 h and then stirred overnight at room temperature. The reaction mixture is poured into 800 ml of ice water and extracted 4 times with ethyl acetate (200 ml). The combined organic extracts are washed 3 times with water (300 ml), dried with magnesium sulfate, filtered, the solvent is evaporated in vacuum. The residue is dissolved in 150 ml diethyl ether to provide recrystallization from 150 ml of 96% ethanol, filtered and washed with 30 ml of 96% ethanol and 50 ml of diethyl ether. This procedure is repeated 2 times, obtaining 8.5 g (33%) 10-(3-tetrahydro - 2H-Piran-2-yloxy)-1-propyl)acridine-9-it is in the form of yellowish crystals. So pl. to 140.5-141,5oC.

Range PMR (200 MHz, d-HLF)n: 1,50-2,00 (m, 6H), 2,22 (m,2H) 3,61 (m, 2H) of 3.97 (m, 2H), 4.53-in (dt, 2H), 4,63 (t, 1H), 7.24 to to 7.32 (DD, 2H), to 7.61-7,76 (m, 4H), 8,58 (DD, 2H).

10-(3 - Tetrahydro-2H-Piran-2-yloxy)-1-propyl) acridine-9-he makes the connection specified in the header, using the same technique as described in Example 17. So pl. >280oC.

Range PMR (400 MHz, d6 - DMSO)n: 1,48 (SHS, 1H), 1,89 (BL, 2H), 2,02 (sm, 1H) 2,30 (CL, 2H) 2,98 (sm, 2H), 3.42 points (BL, 4H), 3,62 (SHS, 1H), 4,57 (t, 2H, N - CH2-CH2-), 7,37 (t, 2H), 7,86 (dt, 2H), of 7.97 (d, 2H), scored 8.38 (DD,2H), 11,00 (SHS,1H), 12,85 (SHS, 1H).

The applicant proposes additional pharmacological data presented in table 2, confirming the inhibition of the claimed compounds the pain. The tests by which the received biological data described above.

The proposed connection, as shown by tests on their toxicity, are of low toxicity.

With regard to pharmacological methods described in this description, the test experimentally demonstrates the displaced azaheterocyclic carboxylic acids of the formula I

< / BR>
in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy;

Y is a group or in which only the underlined atom participates in the cyclic system;

X is a group-O-, -S-; CR7R8-, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C=O)-, -O-CH2-, -(C=O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl;

r = 1, 2, or 3;

m = 1 or 2;

n = 1 when m =1 and n = 0 when m = 2;

R4and R5each represents a hydrogen atom or, when m = 2, can both work together to make the connection;

R6is hydroxyl or C1-C8-alkoxygroup,

or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-carbomethoxy-1-piperidyl)propyl)phenothiazines and 10-(3-(3-carborexics-1-piperidyl)propyl)phenothiazines or their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that it is chosen from the following:

(R)-1-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylate acid:

(S)-1-(3-(10,11-the site, located between[a, d] cyclohepten-5-ilidene)-1-propyl)-1,2,5,6-tetrahydro-3-piridinkarbonovaya acid;

1-(3-(5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylate acid;

1-(3-thioxanthen-9-ilidene)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(4-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-butyl)-3-piperidinecarboxylate acid;

(R)-1-(2-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-ethyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(3-chloro-10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(10H-phenothiazines-10-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(10H-phenothiazines-10-yl)-1-propyl)-3-piperidinecarboxylate acid;

(S)-1-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylate acid;

1-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-3-pyrrolidinyloxy acid;

(R)-1-(3-(3-methyl-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(2-trifluoromethyl-10H-phenothiazines-10-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(5-oxo-10H-phenothiazines-10-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(11H-10-oxa-5-Aza-5H-dibenzo[a, d]cyclohe is trihydro-3-piridinkarbonovaya acid;

(R)-1-(3-(6,7-dihydro-5H-dibenzo[b, g] Asotin-12-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-methoxy-10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b, e][1,4]diazepin-5-yl)-1-propyl)-3-piperidinecarboxylate acid;

(R)-1-(3-(9H-oxo-10H-acridine-10-yl)-1-propyl)-3-piperidinecarboxylate acid;

or its pharmaceutically acceptable salt.

3. A method of obtaining a connection on p. 1, characterized in that a) a compound of the formula (II)

subjected to interaction with the compound of the formula (III)

and radicals of the compounds (II) and (III) R1, R2, R4, R5, R6X, Y, r, m, n have the meanings specified in paragraph 1, and W is a suitable removable group, such as halogen, paraganaralaruleta or mutilata group, or (b) hydrolyzing the compound of formula (I) in which R6is C1-C8-alkoxygroup, with the formation of the compounds of formula I in which R6is hydroxyl.

4. (R)-1-(3-(fluoren-9-ilidene)-1-propyl)-3-piperidinylcarbonyl acid or its salt.

5. Pharmaceutical composition, inesca carboxylic acid, selected from compounds under item 1 or 4, along with a pharmaceutically acceptable carrier or diluent.

6. The pharmaceutical composition according to p. 5, characterized in that it contains a unit dose of from 0.5 to 1000 mg of the active component.

7. N-substituted azaheterocyclic carboxylic acids selected from the compounds under item 1 or 4, inhibiting neurogenic inflammation.

8. The method of inhibition of neurogenic inflammation in a subject, characterized in that it includes the introduction of this subject compounds on p. 1.

9. The method of inhibition of neurogenic inflammation in a subject, characterized in that it includes the introduction of this subject the pharmaceutical composition under item 5.

Priority points:

04.01.94 - PP.1 - 9;

09.11.94 - p. 2 (clarification of signs);

03.01.95 - p. 2 (clarification of signs).

 

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