N-substituted azaheterocyclic carboxylic acids and their esters, method for their preparing, pharmaceutical composition, method for inhibition of neurogenous pain, inflammation and blood glucose level in patient

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

 

The present invention relates to new N-substituted azaheterocyclic carboxylic acids and their esters, in which a substituted alkyl chain forms part of the N-substituent, or their salts, to processes for their preparation, to their containing compositions and to their use for the clinical treatment of painful, giperalgeticheskie and/or inflammatory conditions in which C-fibers play a pathophysiological role by inducing neurogenic pain or inflammation. The invention also relates to the use of these compounds for the treatment of immunity to insulin in insulin dependent diabetes mellitus (NIDDM) or during aging, since it is known that these compounds inhibit the activity containing the neuropeptides of C-fibers and, therefore, inhibit the secretion and circulation of peptide antagonists of insulin, such as CGRP or Amylin.

Background of the invention.

The nervous system has on inflammatory response in a significant impact. Antidrama stimulation of sensory nerves causes local vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151), and similar to the response observed after injection of the peptides present in the sensitive nerves. From these and other data suggest that the peptides released from sensory nerve endings, aposre the comfort of many inflammatory reactions in organs such as the skin, joints, urinary tract, eye, brain membranes, gastrointestinal tract and respiratory tract. Therefore, inhibition of release and/or activity of the peptides sensitive nerves can be used to treat, for example, arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombophlebitis. Further, the strong influence of CGRP on the activity glikogensintetazy skeletal muscle and glucose metabolism in the muscles along with the idea that this peptide is released from the neuromuscular synapse in the excitation of nerve, suggest that CGRP plays a physiological role in glucose metabolism in skeletal muscle, directing phosphorylated glucose from storage of glycogen in the direction of the glycolytic and oxidative pathways (Rossetti et al. Am. J.Physiol. 264, E1-E10, 1993). This peptide may represent an important physiological modulator of intracellular transport of glucose in physiological conditions, as an exercise, and can also help to reduce the activity of insulin and glikogensintetazy skeletal muscle in these pathophysiological conditions, as NIDDM or associated with aging, obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995), in which the levels of circulating plasma CGRP significantly increased. Therefore, inhibition of release and/or activity of neuropeptide fiberglass can be used for the treatment of immunity to insulin, associated with type 2 diabetes or aging.

In U.S. patent No. 4383999 and No. 4514414 and in EP 236342 as well as in EP 231996, some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids are described as inhibitors of GABA capture. In EP 342635 and EP 374801 N-substituted azaheterocyclic carboxylic acids, in which oximetery group and the vinyl ester group are part of the N-substituent, respectively, are described as inhibitors of GABA capture. Further, in WO 9107389 and WO 9220658 N-substituted usacycling carboxylic acids are described as inhibitors of GABA capture.

In addition to the above links, in U.S. patent No. 3074953 ethyl ester 1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-phenyl-4-piperidinecarboxylic acid described as a psychotropic drug. Similar to the above connection 1-substituted ester derivatives of 4-phenyl-4-piperidinecarboxylic acid described (J. Med. Chem. 1967, 10, 627-635 and J. Org. Chem. 1962, 27, 230-240) as analgesic, antispasmodic (anti?) and psychotropic drugs. In JP 49032544, JP 48040357, FR 2121423, GB 1294550 and DE 2101066 1-substituted 4-dialkylamino-4-piperazinecarboxamide described as psychotropic drugs for the treatment of schizophrenia and as inhibitors of inflammation.

Description of the invention.

The present invention relates to new N-substituted azaheterocyclic carbon is the first acids and their esters of the formula I

where R1and R2independently represent hydrogen, halogen, trifluoromethyl, NR6R7, hydroxy, C1-6-alkyl or C1-6-alkoxy; and

Y represents-CH2-,N-CH2or=CH-, where only the underlined atom is part of a ring system;

and

X represents-O-, -S-, -C(R6R7)-, -CH2CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2-(C=O)-, -(C=O)-CH2-, -CH2CH2CH2-, -CH=CH-, -N(R8)-(C=O)-, -(C=O)-N(R8)-, -O-CH2-, -CH2-O-, -S-CH2-, -CH2-S-, -(C=O)-, -N(R9)- or -(S=O)-, where R6, R7, R8and R9independently represent hydrogen or C1-6-alkyl; and

r is 1, 2 or 3; and

Z is selected from

where n is 1 or 2; and

R3represents -(CH2)mHE or - (CH2)pCOR4where m is 0, 1, 2, 3, 4, 5 or 6, and p is 0 or 1, and where R4represents-OH, -NH2, -NHOH, or1-6-alkoxy; and

R5represents hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and

R10represents hydrogen, C1-6-alkyl, C1-6-alkoxy or phenyl, optional what about substituted with halogen, by trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and

R11represents hydrogen or C1-6-alkyl; and

represents an optional single bond or a double bond;

or their pharmaceutically acceptable salts.

The compounds of formula I can exist as geometric and optical isomers, and this includes all isomers and mixtures thereof. The isomers can be separated by standard techniques, such as chromatographic methods or fractionated crystallization of the corresponding salts.

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

Compounds according to the invention may not necessarily exist in the form of pharmaceutically acceptable salts of addition of acid or when the carboxyl group is not etherification - in the form of a pharmaceutically acceptable metal salts or optionally alkyl - ammonium salts.

Examples of such salts include inorganic or organic salts of addition of acids, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable salt add inorganic or organic if you add acids, and include f is rmaceuticals acceptable salt, listed in Journal of Pharmaceutical Science, 66, 2 (1977), which is incorporated herein by reference.

The term "C1-6-alkyl", as used here, separately or in combination, refers to an unbranched or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1,2,2-gametypes.

The term "C1-6-alkoxy", as used here, separately or in combination, refers to an unbranched or branched monovalent Deputy containing C1-6is an alkyl group attached through an oxygen simple ether-free connection of which is connected with simple oxygen ether, and containing from 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentox.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

Illustrative examples of compounds covered by this invention include:

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinecarboxylic;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarbonitrile acid;

1-(3-(0,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinyl)methanol;

4-(4-Chlorophenyl)-1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinol;

4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinecarboxamide acid;

(23,4R)-1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-hydroxy-2-pyrrolidinecarbonyl acid;

4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-morpholinopropan acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-aziridination acid;

2-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1,2,3,4-tetrahydro-4-izohinolinove acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-methyl-[1,4]-diazepan-6-carboxylic acid;

2-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1,2,3,4-tetrahydro-Z-izohinolinove acid;

Hydroxamic 1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acids;

(4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)piperazine-1-yl)acetic acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinyloxy acid;

1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarbonitrile acid;

(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl-3-piperidinecarboxylic;

(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl-2-pyrrolidinecarbonyl acid;

(S)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-p is braiding.arouse acid;

(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-piperidinecarbonitrile acid;

1-(3-(10H-Phenoxazin-10-yl)-1-propyl)-4-piperidinecarbonitrile acid;

1-(3-(3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinyloxy acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-methyl-3-piperidinylcarbonyl acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-chinuklidinyl-carboxylate;

1-(3-(2,8-Dibromo-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid;

1-(3-(3,7-Dichloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid;

1-(3-(3-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-4-piperidinecarbonitrile acid;

1-(3-(3,7-Dimethyl-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl-4-piperidinecarbonitrile acid;

1-(3-(3-Dimethylamino-10,11-dihydro-5H-dibenz[b,f]azatin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid;

or their pharmaceutically acceptable salt.

As used here, the term "patient" includes any mammal, which may help the treatment of neurogenic pain or inflammation or immunity to insulin in NIDDM. The term is particularly applicable to the patient-the person, but is not limited to them.

It was shown that the new compounds formula inhibit neurogenic inflammation which includes the release of neuropeptides from peripheral and Central endings sensitive C-fibers. It can be experimentally demonstrated in animal models of pain or swelling of the feet, caused by formalin (Wheeler and Cowan, Agents Actions 1991, 34, 264-269), where new compounds of formula I exhibit a strong inhibitory effect. The compounds of formula I can be used to treat all painful, giperalgeticheskie and/or inflammatory conditions in which C-fibers play a pathophysiological role, causing neurogenic pain or inflammation, ie:

State, accompanied by acute pain, such as migraine, postoperative pain, burns, bruises, post herpetic pain (shingles) and pain, in most cases associated with acute inflammation; chronic painful and/or inflammatory condition, such as various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spongilla, gout, inflammatory bowel disease, prostatitis, pain in malignant tumors, chronic headache, cough, bronchial asthma, chronic pancreatitis, inflammatory skin diseases, including psoriasis and autoimmune dermatoses pain in osteoporosis.

Further, it was demonstrated that the compounds of General formula I is elichevu glucose tolerance in mice ob/ob, suffering from diabetes and that this may be the result of a decrease in the release of CGRP from peripheral nerve endings. Therefore, compounds of General formula I can be used for the treatment of NIDDM as well as obesity, is associated with aging. It was experimentally demonstrated using subcutaneous glucose to mice ob/ob with or without prior oral treatment with compound of General formula I.

The compounds of formula I can be obtained in accordance with the following method:

The compound of formula II, where R1, R2X, Y and r are defined above, and W represents a suitable leaving group such as halogen, p-toluensulfonate or mesilate may be subjected to interaction with azaheterocyclic compound of formula III where Z is defined above. This alkylation reaction may be carried out in a solvent such as acetone, disutility ether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene, in the presence of a base, e.g. sodium hydride, and catalyst, for example, alkali metal iodide, at a temperature up to the boiling point of the used solvent for, for example, from 1 to 120 hours If you get esters in which R4represents alkoxy, compounds of formula I where R 4HE is a, can be obtained by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous solution of alkali metal hydroxide and an alcohol, such as methanol or ethanol, for example, for about 0.5 to 6 hours

Compounds of formulas II and III can be easily obtained in accordance with methods known to experts in this field.

Under certain circumstances it may be necessary to protect the intermediate products used in these ways, for example, the compound of formula III suitable protective groups. For example, the carboxyl group can be etherification. The introduction and removal of such groups described in "Protective Groups in Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973).

Pharmacological methods.

Pain or swelling of the feet, caused by formalin.

The degree of inhibition of pain or edema induced by formalin in vivo to compounds according to the present invention was evaluated in mice, mainly, by the method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 264-269).

Female NMRI mice weighing about 20 g were injected 20 μl of 1% formalin in the left hind paw. Animals were then placed on a heated (31° (C) the table and assessed the pain reaction. After 1 h they were killed and blood was let. Left and right hind paws were removed and the difference in weight between the legs used as an indicator of reactions from the ka paw, injected formalin.

Reduced release of CGRP.

Female mice ob/ob at the age of 16 weeks was subcutaneously injected glucose (2 g/kg). Through the time periods specified below, glucose oxydase method in blood from the tail vein was determined by the glucose in the blood. Upon completion of the study, animals were decapitated and trunk blood was collected. The content of immunoreactive CGRP in plasma were determined using radioimmunoassay analysis. Used two groups of animals. Within five days before the study, one group was treated by the media, whereas the other group received the compound of formula I through drinking water (100 mg/l).

The values of inhibition of pain response induced by formalin, for some exemplary compounds are shown in table 1.

Table 1.
Inhibition of pain response induced by formalin, 0.1 mg/kg
# Example% Inhibition of pain
213
447
536
834
929

With regard to the above indicators, the dosage will vary depending on the connection f is rmula I, the method of administration and the desired treatment. However, mainly, satisfactory results are obtained by applying a dosage from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I, which is convenient to enter from 1 to 5 times daily, optionally in the form of delayed release. Usually, dosage forms suitable for oral administration contain from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of the formula I mixed with a pharmaceutical carrier or diluent.

The compounds of formula I can be introduced in the form of a pharmaceutically acceptable salt of the added acid or, where possible, in the form of a metal salt or lower alkylamine. Such salt forms exhibit the same level of activity as free basic forms.

This invention also relates to pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt, and, typically, such compositions also contain a pharmaceutical carrier or diluent. Compositions containing compounds according to this invention, can be obtained in accordance with customary methods and traditional forms, such as capsules, tablets, solutions and suspensions.

romenay pharmaceutical carrier can be a widely used solid or liquid media. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, Arabic gum, 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 material that increases the time of the release, known in this field, such as glycerol monostearate or distearate glycerin, individually or in a mixture with wax.

If for oral delivery using solid media, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet, or it can be in the form of tablets or cakes. The amount of solid carrier will vary widely but will usually be in the range from about 25 mg to about 1 g When using liquid media, the drug may be in the form of a syrup, emulsion, soft gelatin capsule or sterile water for injection such as an aqueous or nonaqueous liquid suspension and solution.

Usually the compounds according to this invention are distributed in a standard dosage forms, containing 50-200 mg of the active ingredient or together with a pharmaceutically acceptable carrier at a standard dosage form.

The dose of the compounds according to this invention is 1-500 mg/day, for example, about 100 mg per dose, being introduced to patients, such as people, as a medicine.

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

Kernel:

Active ingredient (in the form free

the compound or its salt) 100 mg

Colloidal silicon dioxide (Areosil®) 1.5 mg

Cellulose, microcryst. (Avicel®) 70 mg

Modified cellulose resin 7.5 mg

(Ac-Di-Sol®)

Magnesium stearate

Floor:

A receiver array, approx. 9 mg

*Myvacett®9-40 T, approx. 0.9 mg

*The acylated monoglyceride used as plasticizer in the coating film.

The route of administration may be any way to effectively deliver the active compound to the appropriate or desired site of action, such as oral or parenteral, for example, rectal, percutaneous, subcutaneous, intranasal, intramuscular, local, intravenous, intraurethral, eye drops or ointment, and oral route of administration is preferred.

EXAMPLES.

The method of obtaining compounds of formula I and containing products is illustrated further in the following examples, which, however, should not be construed as limiting.

Hereinafter, TLC means thin layer chromatography, CDCl3means on tarirovannyjj chloroform, and DMSO-d6means hexadeuterated dimethyl sulfoxide. Structures of compounds were confirmed by using either elemental analysis or NMR, where the peaks attributed to the characteristic protons in the specified in the headers of the compounds represented in characteristic positions. Shift values1H NMR (δ n) are given in ppm (ppm). So pl. means melting point, and is contained in ° and not an exact value. Column chromatography was performed using the method described W.C. Still et al., J. Org. Chem. (1978), 43, 2923-2925 on silica gel 60 Merck (Art. 9385). The compounds used as starting materials, represented either known compounds or compounds that can be easily synthesized by methods known to experts.

Example 1.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid.

To a suspension of 10,11-dihydro-5H-dibenz[b,f]azepine (15.2 g, 0,078 mol) in toluene (100 ml) was added 3-chloropropionitrile (9.50 ml, 0,099 mol) and the resulting mixture was heated under reflux for 1 h was Added saturated aqueous sodium bicarbonate (100 ml) and the phases were separated. The organic phase is washed with saline (100 ml), dried (gSO4) and concentrated in vacuum. This allowed us to get to 23.6 g of 3-chlor-(10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-1-propanone in the form of solids, which was used in the next stage without additional purification.

So pl. 107-108° C.

Calculated for C17H16ClNO: 71,45%; N 5,64%; N 4,90%. Found: 71,45%; N 5,79%; N 5,01%.

To a solution of 3-chloro-1-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone (14.0 g, 0,044 mol) in tetrahydrofuran (150 ml) at 0° With added sodium borohydride (6,66 g, 0,176 mol) followed by the addition of drops of glacial acetic acid (10.0 ml). The resulting mixture was stirred at room temperature overnight and then heated at boiling point for 2 hours was Added borohydride (6.50 g, 172 mmol) and then athirat of boron TRIFLUORIDE (20,0 ml, 0,163 mol) and heated at the boiling temperature was continued for 20 hours was Carefully added water (350 ml) and the phases were separated. The aqueous phase was extracted with toluene (3× 100 ml). The combined organic phases are washed with brine (3× 100 ml), dried (gSO4) and concentrated in vacuum. The residue was purified flash chromatography on silica gel (100 g)using a gradient of heptane and ethyl acetate (10:0→ 10:2) to obtain the 4,58 g (38%) of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine in the form of oil.

TLC: Rf=0,63 (SiO2: ethyl acetate/heptane = 1:2).

A mixture of ethyl ester of 4-piperidinecarboxylic acid (2.55 g, 16.2 mmol), acetonitrile (13 ml), the above chloride (2.00 g, 0,0074 mol) and potassium iodide (1,14 g, 0,0068 mol) load the Wali at the boiling temperature for 4 h and then stirred at room temperature overnight. Was added water (50 ml) and product was extracted with ethyl acetate (3× 20 ml). The combined organic extracts washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. The residue was purified flash chromatography on silica gel using a gradient of heptane and ethyl acetate (10:1→ 1:1) to give 1.6 g (54%) of ethyl ester of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,26 (SiO2: ethyl acetate/heptane = 1:1).

Calculated for C25H32N2About2: 76,50%; N BY 8.22%; N 7,14%. Found: 76,34%; N 8,51%; N 6,88%.

The above ester (1.01 g, 2.57 mmol) was dissolved in ethanol (10 ml) was added sodium hydroxide solution (0,59 g of 14.8 mmol) in water (1.5 ml). The resulting mixture was stirred at room temperature for 3.5 hours was Added a mixture of water (20 ml) and concentrated hydrochloric acid (3.0 ml) and the aqueous phase was extracted with dichloromethane (3× 15 ml). The combined organic extracts were washed with saline (20 ml) and dried (MgSO4). Evaporation of the solvent gave a foam, which was again dissolved in a mixture of methanol (1.0 ml) and ethyl acetate (5.0 ml). Concentration in vacuo was possible to obtain solid, which was suspended in ethyl acetate, was heated at boiling point for 1 minute and allowed to cool to room temperaturestorage substance was filtered and dried to obtain 0.9 g (88%) indicated in the title compound in the form of a powder.

So pl. 195-197° C.

Calculated for C23H28N2O2Cl: 68,90%; N 7,29%; N 6,99%.

Found: 68,90%; N, 7.55 Per Cent; N 6,72%.

Example 2.

The hydrochloride of 4-(4-chlorophenyl)-1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)piperidine-4-ol.

To a suspension of 10,11-dihydro-5H-dibenz[b,f]azepine (27,6 g, 0,141 mol) in toluene (250 ml) was added ethylmalonate (25,0 g, 0,166 mol) and the resulting mixture was heated under reflux for 1 h was Added saturated aqueous sodium bicarbonate (200 ml) and the phases were separated. The organic phase is washed with saline (2× 150 ml), dried (gSO4) and concentrated in vacuum. It was possible to obtain 56,0 g (100%) of ethyl ester of 3-(10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-3-oxopropanoic acid in the form of oil, which was used in the next stage without additional purification.

In a round bottom flask under nitrogen atmosphere contributed sociallyengaged (20,0 g, 0,527 mol). Was added toluene (800 ml) and then was added tetrahydrofuran (80 ml). The resulting suspension was cooled to 10-20° C. the resulting mixture was stirred at room temperature overnight. After cooling, was carefully added 2 n sodium hydroxide (200 ml). Was added water (1.0 l), the organic phase decantation and the aqueous phase was extracted with toluene (3× 300 ml). The combined organic phases are washed with the left solution (2× 100 ml), dried (MgSO4) and concentrated in vacuum. The residue was purified flash chromatography on silica gel (175 g)using a gradient of heptane and ethyl acetate (10:0→ 2:1) to obtain 21.2 g (59%) of 3-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)-1-propanol in the form of oil.

To a stirred solution of the above alcohol (1.01 g, 0,004 mol) and triethylamine (1,02 g 0,010 mol) in toluene (25 ml) at 0° C for 10 minutes was added dropwise methanesulfonanilide (0.6 ml, 0,0077 mol). The resulting mixture was stirred at 0° for 1.5 hours was Added water (50 ml) and the phases were separated. The aqueous phase was extracted with toluene (50 ml) and the combined organic phases are washed with brine (2× 50 ml), dried (gSO4) and concentrated in vacuum. Raw mesilate was stirred with 4-(4-chlorophenyl)piperidine-4-I (0,81 g be 0.008 mol) in acetonitrile (9 ml) and heated at boiling point for 6 hours, the Reaction mixture was allowed to mix at room temperature for 2 days. Was added water (50 ml) and the mixture was extracted with ethyl acetate (3× 15 ml), washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. Was added water (50 ml) and the mixture was acidified by adding concentrated hydrochloric acid (3 ml). The aqueous solution was extracted with dichloromethane (2× 20 ml), washed with brine (2× 20 ml), dried (MgSO4) and the oxygen which has demonstrated in a vacuum. The oil obtained was dissolved in a mixture of ethyl acetate (15 ml) and methanol (2 ml). Small portions was added heptane until then, until the solution became slightly turbid. After 4 h, the crystals were filtered off, washed with heptane and dried to obtain 1.1 g (61%) indicated in the title compound in the form of a solid substance.

So pl. 189-191° C.

Calculated for C28H30N2Oh, HCl: 69,56%; N 6,67%; N 5,79%. Found: 69,88%; N 6,92%; N 5,62%.

Example 3.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinemethanol.

A mixture of 3-(hydroxymethyl)piperidine (1.01 g, 0,0088 mmol), acetonitrile (9 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0,86 g of 0.003 mol, obtained as described in example 1) and potassium iodide (0.56 g of 0.003 mol) was heated at boiling temperature for 18 hours was Added water (20 ml) and the product was extracted with ethyl acetate (3× 15 ml). The combined organic extracts washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. The residue was again dissolved in a mixture of water (20 ml) and concentrated hydrochloric acid (3.0 ml) and was extracted with dichloromethane (3× 10 ml). The combined organic extracts were washed with saline (20 ml), dried (gSO4) and concentrated in vacuum. The residue was evaporated with a mixture of methanol (0.5 ml) and ethyl is the Etat (5 ml) to give 0.8 g (61%) indicated in the title compound in the form of needles.

So pl. 145-147° C.

Calculated for C23N30N2O: 71,39; N 8,07; N 7,24. Found: 71,15; N 8,29; N 7,01.

Example 4.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperazinecarboxamide.

To a stirred solution of 3-(10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-1-propanol (1.44 g, 0,0057 mol, obtained as described in example 2) and triethylamine (1,46 g, 0.014 mol) in toluene (40 ml) at 0° C for 10 minutes was added dropwise methanesulfonanilide (0,88 ml, to 0.011 mol). The resulting mixture was stirred at 0° for 1.5 hours was Added toluene (50 ml) and water (100 ml) and the phases were separated.

The aqueous phase was extracted with toluene (50 ml) and the combined organic phases are washed with brine (2× 100 ml), dried (MgSO4) and concentrated in vacuum. The residue was dissolved in acetonitrile (20 ml) was added 3-piperidinecarboxylic (1,09 g, 0,0085 mol) and potassium carbonate (1,76 g of 0.013 mol). The mixture was heated at boiling temperature for 4 h and stirred at room temperature for 40 hours was Added water (20 ml) and the product was extracted with ethyl acetate (2× 20 ml). The combined organic extracts washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. Was added water (20 ml) and concentrated hydrochloric acid (3.0 ml) and the mixture was extracted with di is loretana (2× 20 ml), dried (MgSO4) and concentrated in vacuum. The residue was again dissolved in a mixture of warm ethyl acetate (10 ml) and methanol (1.0 ml) and after standing for 5 h at room temperature the precipitate was filtered and dried to obtain 1.56 g (64%) of the connection header.

Retention time according to GHUR = 20,44 minutes (column 4× 250 mm 5 μm To 18, elution gradient 20-80% 0,1% triperoxonane acid/acetonitrile and 0.1% triperoxonane acid/water over 30 minutes at 35°).

Calculated for C23H29N3O, HCl, 1.5 N2O: 64,70%; N 7,78%; N 9,84%. Found: 65,13%; N, 7.85%Per Annum; N 9,85%.

Example 5.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid.

A mixture of the hydrochloride of the ethyl ester of 2-piperidinecarboxylic acid (0,60 g of 0.003 mol), acetonitrile (10 ml), 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz [b,f]azepine (0,60 g, 0.002 mol, obtained as described in example 1), potassium iodide (0.40 g, 0.002 mol), potassium carbonate (1,03 g 0,008 mol) and NN-dimethylformamide (5 ml) was heated at boiling point for 85 hours was Added water (50 ml) and the aqueous solution was extracted with ethyl acetate (3× 20 ml). The combined organic extracts washed with brine (2× 50 ml), dried (gSO4) and concentrated in vacuum. The residue was purified column of chromatogr is via on silica gel (15 g), using a gradient of heptane and ethyl acetate (100:0→ 100:25) with receipt of 0.83 g (97%) of ethyl ester of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,58 (SiO2: ethyl acetate/heptane = 1:1).

The above ester (0,83 g, 0.002 mol) was dissolved in a mixture of ethanol (8 ml), water (2 ml) and sodium hydroxide (0,58 g, 0.015 mol) in water (1.5 ml). The reaction mixture was stirred at room temperature for 50 h and at 50° C for 5 hours was Added water (50 ml) and concentrated hydrochloric acid (3 ml) and the resulting mixture was extracted with dichloromethane (3× 10 ml). The combined organic extracts washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. The residue was again dissolved in methanol (2 ml) and ethyl acetate (5 ml) and concentrated in vacuum. The solid residue washed with a small amount of ethyl acetate and dried to obtain 0.6 g (73%) indicated in the title compound in the form of a powder.

So pl. 122-126° C.

Calculated for C23H28N2O2, HCl, and 0.25 H2O: 68,14%; N 7,33%; N 6,91%. Found: 68,34%;SUMMARY 7,63%; N 6,66%.

Example 6.

4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperidinecarboxylate potassium.

The mixture of the dihydrochloride of 2-piperazinecarboxamide acid (of 5.06 g of 0.025 mol), ethanol (100 ml) and concentrated behold the Noah acid (6.0 ml) was heated at boiling point for 6 days. Was added toluene (10 ml) and the resulting mixture was concentrated in vacuo to 2/3 of its original volume. Added to cold saturated aqueous potassium carbonate (80 ml) and the mixture was extracted with toluene (3× 100 ml). The combined organic extracts washed with brine (2× 50 ml), dried (MgSO4) and concentrated in vacuum to obtain 1.0 g (26%) ethyl ester 2-piperazinecarboxamide acid in the form of oil. The oil crystallized upon standing at room temperature.

To a stirred solution of 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1/17 g, 0,0046 mol, obtained as described in example 2) and triethylamine (1.18 g, 0.012 mol) in toluene (30 ml) at 0° C for 10 minutes was added dropwise methanesulfonanilide (0,70 ml 0,009 mol). The resulting mixture was stirred at 0° C for 1 h was Added toluene (50 ml) and water (100 ml) and the phases were separated. The aqueous phase was extracted with toluene (50 ml) and the combined organic phases are washed with brine (2× 100 ml), dried (MgSO4) and concentrated in vacuum. The residue was dissolved in acetonitrile (10 ml) was added ethyl ether. 2-piperazinecarboxamide acid (1.40 g, 0,0089 mol), potassium carbonate (0,67 g, 0,0049 mol) and toluene (5 ml). The resulting mixture was heated at the boiling temperature for 18 hours was Added water (50 ml) and the mixture was extracted with ethyl acetate (3× 20 ml). About yedinenye organic extracts washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. The residue was purified column chromatography on silica gel (27 g)using a gradient of methanol and ethyl acetate (5:100→ 20:100) to give 0.6 g (33%) of the ethyl ester of 4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinecarboxamide acid in the form of oil.

TLC: Rf=0,60 (SiO2: ethyl acetate/methanol = 1:1).

A mixture of the above ester (0.55 g, 0,0014 mol), ethanol (5 ml), water (1 ml) and sodium hydroxide (0.34 g, 0,0085 mol) was stirred at room temperature for 18 hours was Added water (50 ml) and concentrated hydrochloric acid (3 ml) and the solution was washed with dichloromethane (4× 15 ml). The dichloromethane extracts were discarded. The aqueous phase was podslushivaet by adding potassium carbonate (7,1 g) and the mixture was extracted with dichloromethane (4× 15 ml). The combined organic extracts were washed with saline (20 ml), dried (MgSO4) and concentrated in vacuum. This gave 0.6 g of oil, which is triturated with acetonitrile (2 ml)and then dried in vacuum to obtain 0.5 g (90%) indicated in the title compound in the form of a waxy solid.

So pl. 151-155° C.

Calculated for C22H26N3About3K, 0.5 N2ABOUT: WITH 64,05%; N 6,59%; N 10,18%. Found: 64,34%; N, 7.04 Per Cent; N 10.16 Per Cent.

Example 7.

4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperidineacetate sodium.

img src="https://img.russianpatents.com/810/8100308-s.jpg" height="40" width="69" >

To a solution of 3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1.44 g, 0,0057 mol, obtained as described in example 2) in dichloromethane (30 ml) at 0° C was added triethylamine (1.73 g, is 0.017 mol) followed by the addition of methanesulfonanilide (0.9 ml, 0.012 mol). The resulting mixture was stirred for 30 minutes at 0° C. was Added water (50 ml), the phases were separated and the organic layer washed with brine (20 ml), dried (MgSO4) and concentrated in vacuum. The residue was dissolved in acetonitrile (10 ml), was added N-(ethoxycarbonylmethyl) piperazine (2,44 g, 0.014 mol) and the reaction mixture was heated at 82° for 5.5 hours was Added water (50 ml) and the mixture was extracted with ethyl acetate (3× 20 ml). The combined organic extracts washed with brine (30 ml), dried (MgSO4) and concentrated in vacuum. The residue was purified column chromatography on silica gel (35 g)using ethyl acetate as eluent. This gave 1.5 g (63%) of ethyl ester of 4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazineethanol acid in the form of oil.

TLC: Rf=0,18 (SiO2: ethyl acetate).

A mixture of the above ester (0,94 g, 0,0023 mol), ethanol (5 ml), water (1 ml) and sodium hydroxide (0.31 g, 0,0078 mol) was stirred at room temperature for 4.5 hours was Added water (50 ml) and concentrated hydrochloric acid (3 ml) and the solution p is washed with dichloromethane (3× 10 ml). The organic extracts were discarded. The aqueous phase was podslushivaet by adding 4 n sodium hydroxide (20 ml) and potassium carbonate (4 g). The mixture was extracted with dichloromethane (5× 20 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuum to obtain 0.9 g of a foam. The foam was ground and washed with ethyl acetate (2 ml) and dried in vacuum to obtain 0.5 g (56%) indicated in the title compound in the form of a solid substance.

The retention time according to GHUR = 17,81 minutes (column 4× 250 mm 5 μm C18, elution by a gradient of 20-80% 0,1% triperoxonane acid/acetonitrile and 0.1% triperoxonane acid/water over 30 minutes at 35°).

1H NMR (400 MHz, Dl3) δ and 1.60 (m, 2H), 2,10-2,60 (m, N), 3,12 (user. With 4H), 3,68 (m, 2H), 6,83-7,17 (m, 8H).

Example 8.

The hydrochloride of 4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-morpholinylcarbonyl acid.

A mixture of ethyl ester of 2-morpholinylcarbonyl acid (0.50 g, 0,0031 mol, obtained as described in Tetrahedron Letters, Volume 32, 2281-4, 1991), acetonitrile (6 ml), potassium carbonate (0.50 g, 0,0036 mol), potassium iodide (0.54 g, 0,0033 mol), 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl ether methanesulfonate acid (0.36 g, 0,0011 mol, obtained as described in example 2) and 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.40 g, 0,0015 mol, obtained the AK, as described in example 1) was heated at boiling temperature for 22 hours was Added water (50 ml) and the mixture was extracted with ethyl acetate (3× 15 ml). The combined organic phases are washed with saline (20 ml), dried (gS4) and concentrated in vacuum. The product was purified column chromatography on silica gel (30 g)using a gradient of heptane and ethyl acetate (10:0→ 10:4). This gave 0.4 g (42%) of the ethyl ester of 4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-morpholinylcarbonyl acid in the form of oil.

TLC: Rf=0,33 (SIO, SIS2: ethyl acetate/heptane = 1:1).

A mixture of the above ester (0.40 g, 0,0010 mol) and 4 n sodium hydroxide (2 ml) was stirred at room temperature for 17 hours was Added water (50 ml) and concentrated hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate (3× 20 ml). The combined organic extracts were washed with saline (20 ml) and dried (MqSO4). After filtration of the desiccant from the solution began to precipitate solid. After standing for 4 h at room temperature the precipitate was filtered and the product was dried in vacuum. This gave 0.2 g (49%) indicated in the title compound in the form of a solid substance.

So pl. 196 to 199° C.

Calculated for C22H26N2About3, HCl, 0.25 N2O: 64,86%; N, 6.80 PER CENT; N 6,88%. Found: 65,12%; N To 7.09%; N 6,39%.

Example 9.

hydrochloride 2-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1,2,3,4-tetrahydro-3-ethinlestradiol acid.

To a solution of 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1,05 g, 0,0041 mol, obtained as described in example 2) in dichloromethane (40 ml) at 0° C was added triethylamine (1.28 g, of 0.013 mol) followed by the addition of methanesulfonanilide (0.9 ml, 0.012 mol). After stirring for 30 minutes at 0° With added water (50 ml) and the phases were separated. The organic layer was washed with saline (20 ml), dried (gSO4) and concentrated in vacuum. The residue was dissolved in acetonitrile (12 ml) was added methyl ester of 1,2,3,4-tetrahydro-3-ethinlestradiol acid (1.13 g, 0,050 mol), NN-dimethylformamide (5 ml), potassium carbonate (1,32 g 0,096 mol) and potassium iodide (0,30 g, 0.018 mol). The reaction mixture was heated at 82° C for 12 h was Added NN-dimethylformamide (5 ml) and heating was continued for another 16 hours was Added water (50 ml) and the mixture was extracted with ethyl acetate (3× 20 ml). The combined organic extracts washed with brine (2× 20 ml), dried (MgSO4) and concentrated in vacuum. The product was purified column chromatography on silica gel (80 g)using a gradient of heptane and ethyl acetate (10:0→ 10:3) to obtain 1.4 g (76%) of methyl ester of 2-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1,2,3,4-tetrahydro-3-ethinlestradiol acid in the form of oil.

TLC: Rf=0,61 (SiO2: g is ptan/ethyl acetate = 1:1).

A mixture of the above ester (0,80 g, 0,0019 mol), ethanol (5 ml), tetrahydrofuran (5 ml) and 4 n sodium hydroxide (4 ml) was stirred at room temperature for 22 hours was Added water (50 ml) and concentrated hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate (2× 20 ml). The combined organic extracts were washed with saline (10 ml), dried (MgSO4) and concentrated in vacuum. This gave 0.8 g of solid, which was ground and washed with ethyl acetate (2× 5 ml). Drying in a vacuum was possible to obtain 0.6 g (75%) indicated in the title compound in the form of a solid substance.

So pl. 205-208° C.

Calculated for C27H28N2O2, HCl, 0.25 N2O: 71,51%; N 6,56%; N 6,18%. Found: 71,34%; N, 6.69 Per Cent; N 5,90%.

Example 10.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-1-propyl)-4-piperidineacetic acid.

A mixture of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (1.5 g, 0,0055 mol, obtained as described in example 1) and potassium iodide (5.4 g, 0,0327 mol) in methyl ethyl ketone (100 ml) was heated at boiling temperature for 2.5 hours was Added potassium carbonate (1.5 g, 0,109 mol) and ethyl ester of 4-piperidineacetic acid (1.4 g, 0,0082 mol, obtained as described in J. Am. Chem. Soc., Volume 75, 6249, 1953) and the reaction mixture was stirred at 75° With during the night. After cooled is I, the reaction mixture was filtered (Hyflo) and the solvent evaporated in vacuum. The residue was purified flash chromatography on silica gel (150 g)using a gradient of heptane and ethyl acetate (1:1→ 3:7) to obtain 0.6 g of ethyl ester of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidineacetic acid in the form of oil.

TLC: Rf=0,10 (SiO2: ethyl acetate/heptane = 1:1).

To a solution of the above ester (0.6 g, 0,0015 mol) in ethanol (5 ml) was added 4 n sodium hydroxide (0.8 ml) and the mixture was stirred at room temperature for 2.5 h and then left overnight in the refrigerator. The cold reaction mixture was allowed to warm to room temperature over 1 h and was added 4 N. hydrochloric acid (1.2 ml) and water (10 ml). The mixture was extracted with dichloromethane (2× 100 ml). The combined organic extracts were dried (MgSO4) and the solvent evaporated in vacuum. The residue was again evaporated with a mixture of acetone and isopropylacetate and then treated with a mixture of acetone and isopropylacetate to obtain solid, which was isolated and dried in vacuum. This gave 0.33 g of the connection header.

So pl. 185-188° C.

Calculated for C24H30N2O2, HCl: 69,47%; N 7,53%; N Of 6.75%. Found: 69,21%; N 7,80%; N 6,45%.

Example 11.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenzo [a,d]cyclo-hepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid.

5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-di is Enzo[a,d]cyclohepten (3.00 g, 0,0096 mol), potassium carbonate (8,3 g to 0.060 mol), potassium iodide (3.3 grams, at 0.020 mol) and ethyl ester of 4-piperidinecarboxylic acid (3.1 ml, at 0.020 mol) were mixed in methyl ethyl ketone (100 ml) and was heated at the boiling temperature for 20 h and was stirred at room temperature for 3 days. Was added water (100 ml), the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was dried (gSO4) and evaporated in vacuo to obtain the crude product in almost quantitative yield. The crude product was treated with 1 N. hydrochloric acid and ethyl acetate, evaporated to dryness and evaporated with ethyl acetate to obtain hydrochloride of the ethyl ester of 1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid in the form of solids.

So pl. 169-170° C.

The mixture visheukazannogo ether (0,105 g, 0.27 mmol), ethanol (15 ml) and 1N sodium hydroxide (10 ml) was heated at boiling point for 3 hours and then cooled to room temperature. Was added water (75 ml) and the mixture was acidified with 5 G. hydrochloric acid (3 ml) and was extracted with dichloro-methane (3× 75 ml), dried (MgSO4) and evaporated in vacuum.

The resulting foam was led from acetone to obtain 0,080 g specified in the connection header in the form of crystals.

So pl. 224-226° C.

Calculated for C24H27NO2HCl: 72,44%; N To 7.09%; N, 3.52 Per Cent. Nage is about: 72,83%; N 7,38%; N 3,23%.

Example 12.

Hydrochloride (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperazinecarboxamide.

Hydrochloride (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid (4,96 g, 12.5 mmol, obtained as described in WO 9518793) was dissolved in NN-dimethylformamide (60 ml). Was added N-hydroxybenzotriazole (1.86 g, of 13.8 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.64 g, of 13.8 mmol) and the resulting mixture was stirred at room temperature for 20 minutes. Added ammonium bicarbonate (1.98 g, 25 mmol) and the mixture was stirred for 1 day at room temperature. Added ethyl acetate (200 ml) and the resulting mixture was extracted with water (200 ml), 5% aqueous citric acid (200 ml) and saturated sodium bicarbonate (200 ml). The combined aqueous phase is evaporated to dryness in vacuo and the residue was extracted with dichloromethane (200 ml). The obtained dichloromethane suspension was filtered and evaporated. The residue was purified column chromatography on silica gel (600 ml)using a mixture of ethyl acetate and triethylamine (95:5) as eluent. This gave 1.92 g (43%) of free base in the form of oil, which was then converted into the hydrochloride by dissolving in diethyl ether (25 ml) and add 1 N. hydrochloric acid in diethyl who Fira (5,9 ml). Filtration followed by drying in vacuum was allowed to get 1,53 g (31%) indicated in the title compound in the form of a solid substance.

TLC: Rf=0,33 (SiO2: ethyl acetate/triethylamine = 95:5).

1H NMR (400 MHz, Dl3) δ 1,38 (DK, 1H), 1,75-of 1.97 (m, 3H), 2,5-3,7 (m, 13H), 5,78 (t, 1H), 7,0-to 7.3 (m, 8H), 7,63 (1H), AND 10.8 (1H).

So pl. >250° C.

Calculated for C24H28N2O, HCl: 72,62%; N Of 7.36%; N 7,06%. Found: 72,24%; N To 7.59%; N 6,87%.

Example 13.

Hydrochloride (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-4-pyrrolidinecarbonyl acid.

5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (3,86 g, 12.3 mmol, obtained as described in WO 9518793), potassium carbonate (10.2 g, 74 mmol), potassium iodide (4,08 g, 74 mmol) and the hydrochloride of the methyl ester of D-Proline (2,45 ml of 14.8 mmol) were mixed in methyl ethyl ketone (40 ml) and heated at boiling point for 20 hours After cooling, the mixture was filtered and the filtrate evaporated in vacuum. The residue was purified column chromatography on silica gel (800 ml)using a mixture of ethyl acetate and heptane (1:3) as eluent. This gave 0.96 g (22%) of the methyl ester of (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-2-pyrrolidinecarboxylic acid in the form of oil.

TLC: Rf=0,39 (SiO2: ethyl acetate/heptane = 1:2).

The above ester rest rely in 1,4-dioxane (40 ml) was added water (5 ml). Portions were added 1 N. aqueous sodium hydroxide (2,15 ml) at room temperature for 6 hours, the Mixture was stirred over night at room temperature. Portions were added 1 N. aqueous sodium hydroxide (0,84 ml) for 20 hours was Added water (100 ml) and the mixture was washed with diethyl ether (2× 100 ml). The aqueous phase was acidified to pH=2 with 1 N. hydrochloric acid and was extracted with dichloromethane (2× 100 ml). The combined organic extracts were dried (gSO4) and evaporated in vacuo to obtain 0.29 grams (41%) indicated in the title compound as amorphous solid.

1H NMR (400 MHz, CDCl3) δ 1,95 (user. With 2H), 2,3 (m, 2H), 2.5 and 3.4 (m, 11N), 5,78 (t, 1H), 7,0-to 7.3 (m, 8H).

Calculated for C23H25O2, HCl: 71,96%; N, 6.83 Per Cent; N Of 3.65%. Found: 72,15%; N 7,37%; N 3,40%.

Example 14.

Hydrochloride (S)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-4-pyrrolidinecarbonyl

5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (2.00 g, 6.4 mmol, obtained as described in WO 9518793), potassium carbonate (5.3 g, 38.4 mmol), potassium iodide (2,12 g, 12.8 mmol) and the hydrochloride of the methyl ester of L-Proline (1,27 ml, 7.7 mmol) were mixed in methyl ethyl ketone (40 ml) and was heated at the boiling temperature for 12 hours After cooling, the mixture was filtered and the filtrate evaporated in vacuum. The residue was purified count the night chromatography on silica gel (800 ml), using a mixture of ethyl acetate and heptane (1:2) as eluent. This gave 1/64 g (71%) of methyl ester of (S)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-2-pyrrolidinecarboxylic acid in the form of oil.

TLC: Rf=0,39 (SiO2: ethyl acetate/heptane = 1:2).

The above ester (1.3 g, 3.6 mmol) was dissolved in 1,4-dioxane (50 ml) was added water (5 ml). Portions were added 1 N. aqueous sodium hydroxide (3.8 ml) at room temperature for 6 hours, the Mixture was stirred over night at room temperature. Was added water (100 ml) and the mixture was washed with diethyl ether (2× 100 ml). The aqueous phase was acidified to pH=-2 with 1 N. hydrochloric acid and was extracted with dichloromethane (2× 100 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to obtain 0,80 g (58%) indicated in the title compound as amorphous solid.

1H NMR (400 MHz, CDCl3) δ 1,95 (user. With 2H), 2,3 (m, 2H), 2.5 and 3.4 (m, 11N), 5,78 (t, 1H), 7,0-to 7.3 (m, 8H).

Calculated for C23H25NO2, HCl: 71,96%; N, 6.83 Per Cent; N Of 3.65%. Found: 72,61%; N 7,30%; N 3,34%.

Example 15.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenzo [a,d]cyclo-hepten-5-ilidene)-1-propyl)-2-piperidinecarboxylic acid.

5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (10.0 g, 22 mmol, obtained as described in WO 9518793), to rbonate potassium (18,24 g, 132 mmol) and the hydrochloride of the ethyl ester of DL-pipecolinic acid (5,40 g, 26 mmol) were mixed in ethyl acetate (50 ml) and was heated at the boiling temperature for 16 hours was Added potassium carbonate (10 g), the hydrochloride of the ethyl ester of DL-pipecolinic acid (2 g) and ethyl acetate (50 ml) and the mixture was heated at boiling point for 24 hours After cooling, the mixture was filtered and the filtrate evaporated. The residue was purified column chromatography on silica gel (500 ml), elwira first dichloromethane and then ethyl acetate. It was possible to obtain a 7.92 g (92%) of ethyl ester of 1-(3-(10/11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,54 (SiO2: ethyl acetate/heptane = 3:7).

To the above ether (7.7 g, 20 mmol) was added 1 N. hydrochloric acid (100 ml) and the mixture was heated for 1 h with simultaneous distillation of water and ethanol (drove 20 ml). Was added water (40 ml) and the mixture was heated for 5 hours with distillation of water and ethanol. After cooling, to the mixture was added toluene (100 ml). The precipitated crystals were isolated by filtration and washed with 1 N. hydrochloric acid to obtain crude product (5.3g). Part (2.0 g) was subjected to additional purification by dissolution in water (100 ml, 75° (C) and addition of 37% hydrochloric acid (6 ml). The mixture was allowed to cool to room temperature. Filtering, praiwan the e 1 N. hydrochloric acid and drying in a vacuum allowed to get 1,72 g specified in the connection header in the form of solids.

So pl. 126-127° C.

1H NMR (300 MHz, Dl3) δ 1,5-1,75 (m, 4H), 2,1 (m, 1H), and 2.5-3.5 (m, MO), 4,10 (user. With 1H), 5,80 (t, 1H), 7,05-of 7.23 (m, 8H).

Calculated for C23H26NO2, HCl, 0.5 N2O: 70,13%; N, 7.16 PER CENT; N OF 3.56%. Found: 69,74%; N 7,46%; N Is 3.08%.

Example 16.

Hydrochloride of 1-(3-(10H-phenoxazin-10-yl)-1-propyl)-4-piperidinecarboxylic acid.

Phenoxazin (10.0 g, the 54.6 mmol) was dissolved in NN-dimethylformamide (300 ml) under nitrogen atmosphere. Portions was added sodium hydride (3,27 g, or 81.9 mmol, 60% dispersion in oil) and the resulting mixture was stirred for 20 minutes at room temperature. Was added dropwise 1-bromo-3-chloropropane (21,48 g, 0,136 mmol). The mixture was stirred over night. Within 4 minutes were added ammonium chloride (5.5 g, 0.10 mol) and stirring was continued for 30 minutes. The mixture was poured into water (800 ml) and was extracted with dichloromethane (2× 600 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. It was possible to obtain 16/0 g of crude 10-(3-chlorpropyl)-10H-phenoxazine.

The above crude chloride (5,09 g of 17.4 mmol) was dissolved in acetonitrile (100 ml) was added potassium iodide (2,74 g, 16.5 mmol). Ethyl ester of 4-piperidinecarboxylic acid (6,00 g of 38.2 mmol) Rast is oral in acetonitrile (30 ml) and was added to the reaction mixture. The resulting mixture was heated at boiling point for 24 h and left to mix at room temperature for 48 hours was Added water (100 ml) followed by addition of ethyl acetate (100 ml). The aqueous phase was extracted with ethyl acetate (3× 100 ml) and the combined organic phases are washed with brine (2× 100 ml) and dried (MgSO4). After evaporation in vacuo the residue was purified column chromatography on silica gel (500 ml)using a mixture of heptane and ethyl acetate (1:1) as eluent. This gave 5,18 g (77%) of ethyl ester of 1-(3-(10H-phenoxazin-10-yl)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

TLC; Rf=0,2 (SiO2: ethyl acetate/heptane = 1:1).

The above ester (1.56 g, 4.04 mmol) was dissolved in a mixture of 96% ethanol (20 ml) and tetrahydrofuran (20 ml). Solution was added sodium hydroxide (0.95 g) in water (3 ml) and the reaction mixture was stirred at room temperature for 1.5 hours was Added 0,1M hydrochloric acid (28 ml) and the mixture was extracted with dichloromethane (3× 30 ml). The combined organic extracts washed with brine (30 ml), dried (MgSO4) and evaporated in vacuo. Twice acetone was added and the solution evaporated in vacuo. After the third addition of acetone began precipitation and the mixture was left to mix for 2 hours After filtration, the solid is again suspendido the Ali in acetone (25 ml) and left to mix overnight. The solid was filtered, washed with acetone and dried. It was possible to obtain 1.30 grams (83%) indicated in the title compound in the form of a solid substance.

So pl. 196-198° C.

Calculated for C21H24N2O3,HCl: 64,86%; N 6,48%; N 7,20%. Found: 64,82%; N Is 6.78%; N 6,77%.

Example 17.

Hydrochloride of 1-(3-(3-chloro-10,11-dihydro-5H-dibenz[b,f] azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid.

3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepin (3,82 g of 16.6 mmol) was dissolved in toluene (20 ml). Was added dropwise a solution of 3-chloropropionitrile (2,53 g to 19.9 mmol) in toluene and the resulting mixture was heated to 95° C and stirred at the same temperature for 30 minutes. The mixture was stirred over night at room temperature. Was added 3-chloropropionitrile (2,53 g to 19.9 mmol) and the mixture was heated at 95° within 1.5 hours After cooling was added a 0.2m sodium hydroxide (10 ml) and the phases were separated. The organic phase was diluted with additional toluene (50 ml) and washed first 0,2M sodium hydroxide (6× 10 ml), and then 0,2M sodium hydroxide (3× 20 ml), up until the aqueous phase became alkaline. The organic phase is washed with water (3× 15 ml), brine (25 ml) and dried (MgSO4). Evaporation in vacuo allowed to get 5,23 g (98%) of crude 3-chloro-1-(3-chlorine is -10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone in the form of oil. He was subjected to further purification by the addition of heptane and ethyl acetate (1:1). It was possible to obtain 3,14 g (59%) of product as a solid.

1.0m solution of sociallyengaged in tetrahydrofuran (18.7 ml, to 18.7 mmol) were placed in a dry three-neck round bottom flask with a capacity of 250 ml in a nitrogen atmosphere. The solution was cooled in an ice bath. Taking precautions was added dropwise concentrated sulfuric acid (0.5 ml) for 10 minutes. To compensate for the evaporation of the solvent was added dry tetrahydrofuran (20 ml) and the mixture was stirred for 15 minutes. Was added tetrahydrofuran (20 ml) and the ice bath was removed. The mixture was stirred for 75 minutes at room temperature. The above amide was dissolved in dry tetrahydrofuran (25 ml) and added dropwise within 20 minutes. The reaction mixture was stirred for 1 h was Added water (0.7 ml) followed by addition of 4 n sodium hydroxide (0.7 ml) and water (2.1 ml). Stirring was continued for 30 minutes. The mixture was filtered (Hyflo) and evaporated in vacuo to obtain 2.70 g (95%) of 3-chloro-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f] azepine in the form of oil.

The above chloride (1.50 g, 4,91 mmol) was dissolved in acetonitrile (10 ml) was added ethyl ester 4-piperidinecarboxylic acid (1.70 g, the 10.8 mmol) in acetonitrile (4 ml) followed by the addition of potassium iodide (,76 g, 4.6 mmol). The resulting mixture was heated at boiling point for 24 hours was Added water (50 ml) followed by addition of ethyl acetate (50 ml). The aqueous phase was extracted with ethyl acetate (3× 30 ml) and the combined organic phases are washed with brine (2× 25 ml) and dried (MgSO4). After evaporation in vacuo the residue was purified column chromatography on silica gel (150 ml)using a mixture of heptane and ethyl acetate (1:1) as eluent. It was possible to obtain 1.78 g (85%) of ethyl ester of 1-(3-(3-chloro-10,11-dihydro-5H-dibenz[b,f] azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,21 (SiO2: ethyl acetate/heptane = 1:1).

The above ester (1.70 g, 3,98 mmol) was dissolved in 99% ethanol (20 ml). Solution was added sodium hydroxide (0,92 g) in water (2.5 ml) and the reaction mixture was stirred at room temperature for 1 h was Added 1 N. hydrochloric acid (23 ml) and the mixture was extracted with dichloromethane (3× 25 ml). The combined organic extracts washed with brine (25 ml) and water (20 ml), dried (MgSO4) and evaporated in vacuo. Added dichloromethane and the solution evaporated again. To the resulting foam was added isopropylacetate and the precipitated solid was filtered and washed. It was possible to obtain 1.28 g (74%) of crude specified in the connection header. The product was re-dissolved is in isopropanol, the solution decantation and evaporated in vacuum. Added dichloromethane and the solution is evaporated in vacuum. To the resulting foam was added isopropylacetate and the precipitated solid was filtered and washed. The procedure was repeated once more.

MS(EI) 398 (M+-HCl, 18%).

The retention time according to GHUR = 24,14 minutes (column 4× 250 mm 5 μm C18, elution by a gradient of 20-80% 0,1% triperoxonane acid/acetonitrile and 0.1% triperoxonane acid/water over 30 minutes at 35°).

Example 18.

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

A suspension of 3-piperidineacetic acid (4.5 g, to 0.032 mol, described in J. Org. Chem., 28, 602, 1963) in a mixture of dry hydrogen chloride (in excess) in ethanol was stirred at ambient temperature. When the solid had dissolved, the solution was stirred for 2 days. The solvent is evaporated in vacuum and the residue was re-evaporated with diethyl ether (25 ml) and then stirred with diethyl ether (35 ml) for 20 minutes. The solid was isolated by filtration and dried. This allowed us to get to 6.1 g of the hydrochloride of the ethyl ester of 3-piperidineacetic acid in the form of solids.

So pl. 111-113° C.

A mixture of potassium iodide (19.2 g, 0.12 mol) and methyl ethyl ketone (180 ml) was heated at boiling point in ECENA 1 h Was added a solution of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (5,2 g, 0.019 mol, obtained as described in example 1) in methyl ethyl ketone (25 ml) and heated at the boiling temperature was continued for 3 hours was Added potassium carbonate (9.3 g, 0,067 mol) and ethyl ester hydrochloride 3-piperidineacetic acid (5.6 g, or 0.027 mol) and the reaction mixture was heated at boiling point for 2 hours the Temperature was reduced to slightly less than the boiling point and the mixture was left to mix overnight. After cooling, the reaction mixture was filtered (Hyflo) and the solvent evaporated in vacuum. The residue was purified flash chromatography on silica gel (225 g)using a mixture of heptane and ethyl acetate (1:1) as eluent to obtain 5.0 g of ethyl ester of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidineacetic acid in the form of oil.

TCX: Rf=0,19 (SiO2: ethyl acetate/heptane = 1:1).

To a solution of the above ester (2.5 g, 0,0062 mol) in ethanol (10 ml) was added 4 n sodium hydroxide (2.3 ml) and the mixture was stirred at room temperature for 3 hours was Added 4 N. hydrochloric acid (3.8 ml) and water (10 ml). The mixture was extracted with dichloromethane (2× 250 ml). The combined organic extracts were dried (gSO4) and the solvent evaporated in vacuum. The residue is twice re-evaporated with acetone and some time lane is massively in acetone. The solid was isolated by filtration and dried. It was possible to obtain 2.4 g of the specified header connection in the form of solids.

So pl. 233-235° C.

Calculated for C24H30N2About2, HCl: 69,47%; N 7,53%; N Of 6.75%. Found: 69,59%; N 7,78%; N 6,50%.

Example 19.

Hydrochloride of 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-methyl-3-piperidinecarboxylic acid.

Methyl ester 2-methylnicotinic acid (4.0 g, was 0.026 mol) was dissolved in 1 N. hydrochloric acid (30 ml) was added 10% palladium on coal (0.8 g). The resulting mixture was first made at 200 pounds per square inch (~ 14,065 kg/cm2within 10 days. The reaction mixture was filtered and the solid washed with dichloromethane (100 ml) and water (50 ml). The combined filtrates evaporated in vacuo to obtain a residue, which was re-evaporated with dichloromethane (2× 30 ml). It was possible to obtain a 5.1 g of crude methyl ester hydrochloride of 2-methyl-3-piperidinecarboxylic acid, which was used in further reactions without purification.

A mixture of potassium iodide (17.5 g, 0.11 mol) and methyl ethyl ketone (180 ml) was heated at boiling point for 1 h was Added a solution of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (4.8 g, 0.019 mol, obtained as described in example 1) in methyl ethyl ketone (25 ml) and heated at a temperature which e boiling was continued for 2 hours Was added potassium carbonate (8.5 g, 0.061 mol) and the hydrochloride of the methyl ester of 2-methyl-C-piperidinecarboxylic acid (5.1 g, 0,026 mol) and the reaction mixture was heated at a temperature slightly less than boiling temperature. After cooling, the reaction mixture was filtered (Hyflo) and the solvent evaporated in vacuum. The residue was purified flash chromatography on silica gel (275 g)using a mixture of heptane and ethyl acetate (1:1) as eluent to obtain 3.4 g of methyl ester 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-methyl-3-piperidinecarboxylic acid in the form of oil.

To a solution of the above ester (3.4 g, 0,0087 mol) in 96% ethanol (15 ml) was added 4 n sodium hydroxide (4.4 ml) and the mixture was stirred at room temperature for 4 h and then left overnight in the refrigerator. Stirring was continued at room temperature for 5 h and was added 4 N. hydrochloric acid (6 ml). The solvent is evaporated and the residue triturated with acetone (30 ml) for 10 minutes. The solid was isolated by filtration, washed with acetone and dried in vacuum. The solid is suspended in a mixture of water (35 ml) and dichloromethane (800 ml). Was added a saturated solution of sodium bicarbonate until then, until the pH value became equal to 8-9, and the solid did not dissolve. The phases were separated and the aqueous phase was extracted with dichloromethane (250 ml). About yedinenye the organic extracts were combined and the volume reduced by evaporation. Added an excess of concentrated hydrochloric acid and the mixture is evaporated to dryness. The residue is twice re-evaporated with dichloromethane and then triturated with acetone. The solid was isolated by filtration and dried in vacuum. It was possible to obtain 2.4 g of the specified header connection in the form of solids.

So pl. 169-170° C.

Calculated for C24H30N2O2, HCl, H2ABOUT: WITH 66,59%; N 7,63%; N 6,47%. Found: 66,64%; N 7,94%; N 6,23%.

Example 20.

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-khinuklidinilbenzilata.

5-(3-Chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepin (1.70 g, and 6.25 mmol, obtained as described in example 1) and methyl ester of Hinkley-3-carboxylic acid (0.85 grams, 5.0 mmol) was dissolved in 2-butanone (25 ml). Added dry potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.75 g, 5 mmol) and stir the mixture was heated at boiling point for 5 hours After cooling to room temperature, was added toluene (25 ml) and water (25 ml). Formed an oily residue, which was separated from solution by desantirovaniya and was dissolved in dichloromethane (30 ml). The solution was washed with water (2× 30 ml), 1 N. hydrochloric acid, saturated sodium hydrogen carbonate solution (30 ml) and water (30 ml). The organic layer was dried over MgSO4. Evaporation in vacuum allowed in order to get to 1.15 g of hydroxide 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-methoxycarbonylmethylene. The crude product was immediately used in the next stage without additional purification.

The above ester (1,05 g of 2.50 mmol) was dissolved in ethanol (12.5 ml). Added 2 n sodium hydroxide solution of 4.1 ml, 8.25 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. Was added water (10 ml) and the ethanol evaporated in vacuo. The remaining aqueous solution was washed with diethyl ether and was extracted with 1-butanol (3× 20 ml). Butanolide phase was washed with water (10 ml) and evaporated in vacuo. The evaporation residue in n-heptane

(3× 20 ml) was allowed to get listed in the title compound (0.71 g) as a foam.

Calculated for C25H30N2O2, 3.5 N,0: 66,20%; N BY 8.22%; N 6,18%. Found: 66,52%; N 8,03%; N 5,79%.

Example 21.

Hydrochloride of 1-(3-(2,8-dibromo-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid.

2,8-Dibromo-10,11-dihydro-5H-dibenz[b,f]azepin (1,41 g, 4.0 mmol, obtained in accordance with K. Smith et al., Tetrahedron 48, 7479 (1992)) was dissolved in toluene (25 ml). To stir the solution at room temperature was added triethylamine (of 0.60 ml, 4.4 mmol) and 3-chloropropionitrile (0,50 ml, 5.2 mmol). Stirring was continued at room temperature for 1 h and at boiling temperature for 2.5 hours, the Reaction mixture was cooled, filtered and evaporated in vacuum. With the swarm 3-chloro-1-(2,8-dibromo-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propan-1-it is used in the next stage without additional purification.

The solution sociallyengaged (0,326 g, 8,56 mmol) in dry tetrahydrofuran (30 ml) was cooled in an ice bath and was added dropwise concentrated sulfuric acid (0,428 g, to 4.28 mmol). The solution was stirred at room temperature for 0.5 hour, a Solution of the above product (1.90 g, to 4.28 mmol) was added dropwise and stirring was continued for 0.5 hours the Reaction is then extinguished by careful addition of ethyl acetate (5 ml) followed by addition of water (0.8 ml). Filtration of the mixture and evaporation of the filtrate in vacuo was possible to obtain 1.51 g (82%) of 2,8-dibromo-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine in the form of a foam, which was used in the next stage without additional purification.

The above chloride (1.5 g, 3.5 mmol) and utilizedabated (0,79 g/ 5.0 mmol) was dissolved in 2-butanone (40 ml). Was added potassium carbonate (1.4 g, 10 mmol) and potassium iodide (of 0.43 g, 2.6 mmol) and stir the mixture was heated at boiling point for 60 hours, the Reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was re-dissolved in diethyl ether (50 ml). Adding dropwise 2,6M solution of hydrogen chloride in diethyl ether (2.0 ml, 5.2 mmol), the product precipitated as hydrochloride. The precipitate was collected by filtration and dried in vacuum to obtain 1.3 g (63%) of the hydrochloride of the ethyl ester of 1-(3-(2,8-dibromo-10,11-dihydro-5H-DIB is C[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid in powder form, which was used in the next stage without additional purification.

The above hydrochloride of ester (1,30 g, 2.2 mmol) was dissolved in ethanol (15 ml) was added 2 n sodium hydroxide (4.0 ml). The solution was stirred for 1.5 h at room temperature, acidified by adding 1 N. hydrochloric acid to pH 1 and the ethanol evaporated in vacuo. The aqueous suspension was washed with diethyl ether and filtered. Recrystallization of the collected solids from ethanol allowed to obtain 0.25 g (19%) of the compound specified in the header.

So pl. 165-166° C.

Calculated for C23H26N2Br2About2, HCl, 0.5 N2On, 0.5 s2H6O: 48,79%; N OF 5.29%; N 4,74%. Found: 48,64%; N 5,39%; N 4,58%.

Example 22.

Hydrochloride of 1-(3-(3,7-dichloro-10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid.

3,7-Dichloro-10,11-dihydro-5H-dibenz[b,f]azepin (4.6 g, 17 mmol) was dissolved in toluene (30 ml) was added 3-chloropropionitrile (2.3 ml, 24 mmol). The resulting mixture was heated at 95° C for 3 h, stirred at room temperature for 3 days and was heated at 90° C for 3 hours, After cooling, was added ethyl acetate (150 ml) and the mixture was washed with water (2× 100 ml). The organic phase was dried (MgSO4) and evaporated in vacuo. The residue was purified column of chromatogra what s on silica gel (600 ml), using a mixture of ethyl acetate and heptane (1:4) as eluent. It was possible to obtain 4.7 g (76%) of 3-chloro-1-(3,7-dichloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone in the form of oil.

TLC: Rf=0,14 (SiO2: ethyl acetate/heptane = 1:4).

Sociallyengaged (0,44 g, 11.6 mmol) was dissolved in dry tetrahydrofuran (15 ml) and the solution was cooled to 0° C. Slowly and precautions taken with a syringe was added concentrated sulfuric acid (0.31 g, 5.8 mmol). The suspension was stirred at room temperature for 0.5 hour, a Solution of the above amide (2.0 g, 5.8 mmol) in dry tetrahydrofuran (15 ml) was added dropwise to the suspension. The resulting mixture was stirred at room temperature for 1 h the Reaction was suppressed by addition of water (1.4 ml), 2 n sodium hydroxide (0.5 ml), water (4 ml) and potassium carbonate (5.0 g). The mixture was filtered and the filter cake was washed with dry tetrahydrofuran. The combined filtrates evaporated in vacuo to obtain 1.4 g (69%) of 5-(3-chlorpropyl)was 3.7-dichloro-10,11-dihydro-5H-dibenz[b,f]vaseline in the form of oil.

TLC: Rf=0,66 (SiO2: ethyl acetate/heptane = 1:2).

The above chloride (1.3 g, 3.8 mmol) was dissolved in methyl ethyl ketone (20 ml). Was added potassium iodide (0,63 g, 3.8 mmol), potassium carbonate (3.2 g, 23 mmol) and ethyl ester of 4-piperidinecarboxylic acid (1/2 g, 7.6 mmol) and the resulting mixture was heated at the temperature of the round boiling within 24 hours After cooling, was added ethyl acetate (100 ml) and the mixture was washed with water (2× 100 ml). The organic phase was dried (MgSO4) and evaporated in vacuo. The residue was purified column chromatography on silica gel (600 ml)using a mixture of ethyl acetate and heptane (1:2) as eluent. It was possible to obtain 0.84 g (48%) of ethyl ester of 1-(3-(3,7-dichloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidine-carboxylic acid in the form of oil.

TLC: Rf=0,22 (SiO2: ethyl acetate/heptane = 1:2).

The above ester (0.8 g, 1.7 mmol) was dissolved in ethanol (20 ml) was added water (10 ml) and 1 n sodium hydroxide (1.7 ml). The resulting mixture was stirred at room temperature for 24 h was Added water (100 ml) and the mixture was washed with diethyl ether (2× 60 ml). the pH of the aqueous phase was brought to a value of 1 through 5 N. hydrochloric acid and the aqueous phase was extracted with dichloromethane (2× 100 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to obtain an oil. Was added 2-propanol (15 ml) and the resulting precipitate was filtered and washed with 2-propanol. Drying in vacuum at 50° C for 24 h, allowed to obtain 0.33 g (41%) of the compound specified in the header.

So pl. 237-239° C.

MC(EI) (m/z): 432 (M+, 14%), 303 (43%), 142 (100%).

1H NMR (400 MHz, CDCl3): δH1,72-2,02 (m, 5H), 2,48 (m, 1H), 2,85 (m, 2H), 3,05 (m, 2H), IS 3.08 (4H), 3,39 (m/ 2N, of 3.80 (t, 2H), 7,03 (DD, 2H), 7,17 (d, 2H), 7,22 (d, 2H).

Example 23.

Hydrochloride of 1-(3-(3-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid.

5-(3-Bromo-1-propylidene)-3-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (1,05 g, 3.3 mmol, obtained as described in WO 9518793) was dissolved in methyl ethyl ketone (20 ml). Was added potassium iodide (0,44 g, 6.7 mmol), potassium carbonate (2.76 g, 20 mmol) and ethyl ester of 4-piperidinecarboxylic acid (0,77 ml, 5.0 mmol) and the resulting mixture was heated at boiling point for 1 h, After cooling, was added ethyl acetate (60 ml) and the mixture was washed with water (2× 60 ml). The organic phase was dried (MgSO4) and evaporated in vacuo. The residue (1.7 g) was purified column chromatography on silica gel (600 ml)using a mixture of ethyl acetate and heptane (1:2) as eluent. It was possible to obtain 0.97 g (73%) of ethyl ester of 1-(3-(3-methyl-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,20 (SiO2: ethyl acetate/heptane = 1:2).

The above ethyl ester (0,91 g, 1.7 mmol) was dissolved in ethanol (15 ml) was added water (5 ml) and 1 n sodium hydroxide (2.7 ml). The resulting mixture was stirred at room temperature for 24 h, the Reaction mixture was evaporated in vacuum. Was added water (100 ml) and diethyl ether (70 ml) and the phases of the divided. The pH value of the aqueous phase was set equal to 2, with 1 N. hydrochloric acid and the aqueous phase was extracted with dichloromethane (3× 200 ml). The combined organic extracts were dried (gSO4) and evaporated in vacuo to obtain 0.12 g (13%) of the compound indicated in the title. Most of the product was separated from the acidic aqueous phase upon standing. The precipitate was filtered, washed with water and dried to obtain 0.34 g (36%) of the connection header.

So pl. >250° C.

Calculated for C25H29NO2HCl: 72,89%; N 7,34%; N 3,40%. Found: 72,65%; N 7,43%; N 3,26%.

Example 24.

1-(3-(3,7-Dimethyl-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid.

To a solution of 3,7-dimethyl-10,11-dihydro-5H-dibenz[b,f]azepine (6,45 g, 0,029 mol; obtained as described in UK Patent 792615, 1958) and 3-bromo-1-Propellerheads-2-pernerova ether (8,3 g 0,037 mol) in dry benzene (80 ml) was added a suspension of sodium amide (3.2 g, 0,041 mol, 50 wt.% suspension in toluene). The reaction mixture was heated at boiling temperature for 20 h, allowed to cool and was added water (20 ml). The phases were separated, the organic phase the solvent evaporated and the residue was dissolved in a mixture of methanol (100 ml) and 5 N. Hcl (30 ml). The mixture then was heated at boiling point for 15 minutes, evaporated methanol and the mixture extragear the Wali benzene (2× 150 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent evaporated in vacuum. The residue was purified column chromatography on silica gel (50 ml), using as eluent first benzene to separate it from the original product. Then, using chloroform as eluent, provided 2.4 g of 3-(3,7-dimethyl-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol in the form of oil.

The above alcohol (2.4 g, 0,0087 mol) was dissolved in benzene (80 ml) and then was added triethylamine (3.0 ml). After adding methanesulfonanilide (1.3 ml, 0,0114 mol), the reaction mixture was stirred for 2 hours was Added water and the phases were separated. The organic phase was dried (MgSO4) and the solvent evaporated in vacuum. The residue was dissolved in acetone (50 ml). To this solution was added ethyl ester 4-piperidinecarboxylic acid (2.0 g, 0,0127 mol) and potassium carbonate (3.0 g, 0,0217 mol) and the resulting mixture was heated at boiling point for 24 hours the Mixture was allowed to cool, then filtered and the solvent evaporated in vacuo to obtain a residue, which was further purified column chromatography on silica gel (40 ml), using chloroform as eluent. It was possible to obtain 2.6 g (73%) of ethyl ester of 1-(3-(3,7-dimethyl-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

The above e is Il (2.4 g, 0,057 mol) was dissolved in ethanol (50 ml) was added 5 N. NaOH (3 ml). The mixture was stirred at 40° C for 16 h and the ethanol evaporated evaporated in vacuum to obtain a residue, which was dissolved in water (20 ml). To the resulting solution were added acetic acid (3 ml) and the mixture was extracted with dichloromethane (50 ml). The organic extract was dried (MgSO4) and the solvent evaporated in vacuum. To the residue was added diethyl ether (50 ml) to give after filtration and drying of 1.85 g (82%) indicated in the title compound in the form of a solid substance.

So pl. 207-209° C.

Calculated for C25H32N2O2, 0,25 N2O: 75,63%; N OF 8.25%; N 7,06%. Found: 75,58%; N 8,30%; N 6,89%.

Example 25.

1-(3-(3-Dimethylamino-10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid.

A suspension of sodium amide (2.6 g, 0,033 mol, 50% by weight suspension in toluene) was added to a solution of 3-dimethylamino-10,11-dihydro-5H-dibenz[b,f]azepine (6,1 g, 0,0256 mol; obtained as described in UK Patent 1040739, 1966) in dry benzene (60 ml). The reaction mixture was heated at 70° C for 1 h was Added 3-bromo-1-Propellerheads-2-pyranyloxy ether (7,35 g 0,033 mol) and the mixture was heated at boiling point for 20 hours To the cooled reaction mixture was added water (20 ml) and the phases were separated. From organises the second phase, the solvent evaporated and the residue was dissolved in a mixture of methanol (100 ml) and 5 N. HCl (30 ml). The mixture was heated at boiling point for 15 minutes and evaporated methanol. Was added water (50 ml), the pH is brought to a value of 8-9 with aqueous ammonia and the mixture was extracted with benzene (2× 150 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent evaporated in vacuum. The residue was purified column chromatography on silica gel (50 ml), using as eluent first benzene to separate it from the original product. Then, using chloroform as eluent, provided 3.5 g of 3-(3-dimethylamino-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol in the form of oil.

The above alcohol (3.5 g, 0,0118 mol) was dissolved in benzene (100 ml) was added triethylamine (4.0 ml) and methane-sulphonylchloride (1.7 ml, 0,0148 mol). The reaction mixture was stirred for 2 hours After adding water, the phases were separated. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo to obtain a residue, which was dissolved in acetone (50 ml). To this solution was added ethyl ester 4-piperidinecarboxylic acid (2.8 g, 0,0178 mol) and potassium carbonate (4,13 g, 0.03 mol) and the mixture was heated at boiling point for 24 hours the Mixture was allowed to cool, then filtered and the solvent evaporated in vacuo to obtain a residue, which was further purified column chromatography on silica gel (50 ml), using the ethyl acetate as eluent. It was possible to obtain 3.1 g of ethyl ester of 1-(3-(3-dimethylamino-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

The above ester (1,95 g, 0,0045 mol) was dissolved in ethanol (40 ml) was added 5 N. NaOH (3 ml). The mixture was stirred at 40° C for 8 h and the ethanol evaporated evaporated in vacuum. The residue was dissolved in water (20 ml). To the resulting solution were added acetic acid (3 ml) and the mixture was extracted with dichloromethane (50 ml). The organic extract was dried (MgSO4) and the solvent evaporated in vacuum. To the residue was added diethyl ether (50 ml) to give after filtration and drying rate of 1.67 g (91%) indicated in the title compound in the form of a solid substance.

So pl. 198-202° C.

Calculated for C25H33N3About2, 0,25 N2O: TO 72.87%; N 8,19%; N 10,20%. Found: 72,73%; N 8,32%; N Of 10.00%.

Example 26.

Hydrochloride (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid.

2-Piperidinylcarbonyl acid (26 g, 0,201 mol) and (+)-tartaric acid (31,2 g, 0,208 mol) suspended in a mixture of ethanol (400 ml) and water (25 ml). The mixture was heated up to 80° and the solution was allowed to cool to room temperature. The precipitated solid was filtered, washed with ethanol and dried to obtain 25.4 g (45%) of (+)-tartrate (R)-(+)-2-piperid karbonovoi acid. The mother liquor is evaporated in vacuum and the residue was dissolved in water (120 ml). Solution was added potassium hydroxide (6.5 g, 116 mmol) in water (13 ml) and dropped one-deputizing tartrate potassium was removed by filtration. Evaporation of the filtrate in vacuo was possible to obtain 19.5 g of crude (S)-(-)-2-piperidinecarboxylic acid.

Above (+)-tartrate (20 g, 72 mmol) was dissolved in water (60 ml) and the solution was added potassium hydroxide (4.0 g, 72 mmol) in water (8 ml). Besieged one substituted potassium tartrate was removed by filtration and washed with water. The mother liquor is evaporated in vacuum and the residue suspended in ethanol (100 ml) and evaporated in vacuo. The suspension in ethanol and evaporation in vacuo was repeated twice. The residue is suspended in ethanol (200 ml) and was added dropwise thionyl chloride (24 ml, 0.28 mol). The resulting mixture was heated at 70° C for 2 h, cooled to room temperature and evaporated in vacuum. Added diethyl ether (40 ml) and ethanol (1 ml) and the suspension was stirred for 30 minutes. The solid was filtered off, washed with diethyl ether and dried to obtain 11.4 g (82%) of the hydrochloride of the ethyl ester of (R)-(+)-2-piperidinecarboxylic acid.

[α ]

25
D
=10,5° (C=4.5% in water)

Gas chrom is tography N-acetyl derivative: R t=46.4 minutes. The enantiomeric excess = 97,9%.

(GC was performed on a gas chromatograph Chrompac CP 9000 with F.I.D. determination using capillary column with Chrompac CF-cyclodextrin, length 25 m, internal diameter 0.25 mm, using the flow velocity in the gap 40 ml/min 180 kPa, the linear speed of passage of the gas 27,6 cm/s, the inlet temperature and the detector 200° and the temperature in the column 120°).

5-(3-Bromo-1-propylidene)-10/11-dihydro-5H-dibenzo[a,d]cyclohepten (2.7 g, 8.6 mmol/ obtained as described in WO 9518793), potassium carbonate (7,14 g, 52 mmol), potassium iodide (1.4 g, 8.6 mmol) and the hydrochloride of the ethyl ester of (R)-(+)-2-piperidinecarboxylic acid (3.3 g, 17 mmol) were mixed in methyl ethyl ketone (50 ml) and heated at boiling point for 3 days. After cooling to room temperature was added ethyl acetate (100 ml) and the mixture was washed with water (2× 100 ml). The organic phase was dried (MgSO4) and evaporated in vacuo. The residue was purified column chromatography on silica gel (600 ml)using a mixture of ethyl acetate and heptane (1:4) as eluent. It was possible to obtain 2,62 g (78%) of ethyl ester of (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,28 (SiO2: ethyl acetate/heptane = 1:4).

The above ester (2.6 g, 6.7 mmol) was dissolved in ethanol (25 ml) and 1,4-dioxane (2 ml). Added 1 nhydroxy sodium (6,7 ml) and the mixture was stirred at room temperature for 16 hours Added 1 n sodium hydroxide (1.3 ml) and the mixture was stirred at room temperature for 4 h was Added 1 n sodium hydroxide (6.9 ml) and ethanol (10 ml) and the mixture was stirred at room temperature for 16 hours was Added 1 n sodium hydroxide (6.9 ml) and the mixture was stirred at room temperature for 16 hours was Added 1 n sodium hydroxide (6,7 ml) and the mixture was stirred at room temperature for 3 days. Was added water (100 ml) and the mixture was washed with diethyl ether (3× 100 ml). the pH of the aqueous phase was brought to 1 with 5 N. hydrochloric acid and the aqueous phase was extracted with dichloromethane (150 ml). The organic extract was dried (gSO4) and evaporated in vacuo to obtain an oil. Acetone was added (50 ml) and the solution evaporated in vacuo. Treatment with acetone was repeated. The solid is suspended in acetone and filtered. Drying in vacuum at 50° C for 24 h, allowed to obtain 1.2 g (51%) indicated in the title compound as amorphous powder.

MC(EI) (m/z): 316 (M+, 1%), 142 (100%).

1H NMR (400 MHz, CDCl3): δHof 1.45 and 1.75 (m, 5H), 2,1 (m, 1H), 2,4-by 2.55 (m, 2H), 2,75-3,4 (m, 8H), 3,90 (user. With 1H), 5,80 (t, 1H), 7,05-of 7.23 (m, 8H).

Example 27.

Hydrochloride (S)-1-(3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid.

Crude (S)-(-)-2-piperidinylcarbonyl is islote (19.5 g, obtained as described in example 26) suspended in ethanol (250 ml) and was added dropwise thionyl chloride (40 ml, 0.46 mol). After adding the resulting mixture was heated at boiling point for 2 hours the Mixture was filtered hot and the filtrate cooled to room temperature. Filtration and evaporation in vacuo gave an oil, which was led by rubbing. Was added ethanol (10 ml) followed by slow addition of diethyl ether (150 ml). Precipitated solid product was filtered off, washed with diethyl ether and dried by creating a vacuum to obtain 13.8 g (yield 35% from the nominal 2-piperidinecarboxylic acid) hydrochloride ethyl ester (S)-(-)-2-piperidinecarboxylic acid.

[α ]

25
D
=-10,7° (C=4.5% in water)

Gas chromatography (carried out as described in example 26) N-acetyl derivative: Rt=47.2 minutes. The enantiomeric excess = 96%.

5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (2.7 g, 8.6 mmol, obtained as described in WO 9518793), potassium carbonate (7,14 g, 52 mmol), potassium iodide (1.4 g, 8.6 mmol) and hydrochloride ethyl ester (3)-(-)-2-piperidinecarboxylic acid (3.3 g, 17 mmol) were mixed in methyl ethyl ketone (50 ml) and was heated at a temperature which e boiling for 3 days. After cooling to room temperature was added ethyl acetate (100 ml) and the mixture was washed with water (2× 100 ml), dried (gSO4) and evaporated in vacuo. The residue was purified column chromatography on silica gel (600 ml)using a mixture of ethyl acetate and heptane (1:4) as eluent. It was possible to obtain 2.3 g (69%) of ethyl ester of (S)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

TLC: Rf=0,22 (SiO2: ethyl acetate/heptane = 1:4).

The above ester (2.3 g, 5.9 mmol) was dissolved in ethanol (25 ml) and 1,4-dioxane (2 ml). Added 1 n sodium hydroxide (5,9 ml) and the mixture was stirred at room temperature for 16 hours was Added 1 n sodium hydroxide (1,18 ml) and the mixture was stirred at room temperature for 4 h was Added 1 n sodium hydroxide (5,9 ml) and the mixture was stirred at room temperature for 16 hours was Added 1 n sodium hydroxide (5,9 ml) and the mixture was stirred at room temperature for 16 hours was Added 1 n sodium hydroxide (5,9 ml) and the mixture was stirred at room temperature for 3 days. Was added water (100 ml) and the mixture was washed with diethyl ether (3× 100 ml). the pH of the aqueous phase was brought to 1 with 5 N. hydrochloric acid and the aqueous phase was extracted with dichloromethane (150 ml). The organic extract was dried (gSO4) and evaporated in vacuum is getting oil. Acetone was added (50 ml) and the solution evaporated in vacuo. Treatment with acetone was repeated again. The solid is suspended in acetone, filtered and dried in vacuum at 50° within 24 hours from receipt of 0.79 g (37%) indicated in the title compound as amorphous powder.

MC(EI) (m/z): 362 (M+, 1%), 142 (100%).

1H NMR (400 MHz, Dl3): δHof 1.45 and 1.75 (m, 5H), 2,1 (m, 1H), 2,4-by 2.55 (m, 2H), 2,75-3,4 (m, 8H), 3,80 (user. s, 1H), 5,80 (t, 1H), 7,05-of 7.23 (m, 8H).

Example 28

Hydrochloride (1-(2-phenothiazines-10-yl-enyl)piperidine-4-yl-acetic acid

Phenothiazines (7.5 g; of 37.6 mmol) was mixed with chloracetamide (30 m ) and stirred at room temperature overnight. The mixture was poured into a mixture of ice water (50 ml) and dichloromethane (50 ml). Was slowly added to a saturated solution of sodium bicarbonate (150 ml) and dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The organic phase was washed with water (75 ml) and saturated sodium bicarbonate solution (50 ml). To accelerate phase separation even added a saturated saline solution and ethanol. The aqueous phase was washed with dichloromethane (100 ml) and the combined organic phases were dried (MgSO4) and was evaporated in vacuum. The remaining product was filtered through silica gel using dichloromethane as eluent was evaporated and the vacuum. The residue was dissolved in toluene and was added heptane to initiate deposition. Was added toluene and the mixture was heated for dissolution. Again added heptane and the mixture was left to cool to precipitate. The precipitate was filtered and dried, obtaining 7.2 g (69%) of 2-chloro-1-(phenothiazines-10-yl)ethanone.

In a dry three-neck flask under nitrogen atmosphere was transferred via syringe 1M solution of lithium aluminum hydride in tetrahydrofuran (51,5 ml; 51,5 mmol). Added anhydrous tetrahydrofuran (20 ml) and the mixture was cooled in an ice bath. Concentrated sulfuric acid (1,37 ml; 26 mmol) was mixed with anhydrous tetrahydrofuran (10 ml) and added dropwise within 10 minutes. The resulting mixture was stirred at room temperature for 45 minutes. The above chloride (7,1 g; 26 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) and added dropwise within 10 minutes. The mixture was stirred at room temperature for 45 minutes, then was suppressed by addition of water (5 ml) under cooling with ice bath. Added tetrahydrofuran, and then water (10 ml). Was added potassium carbonate, and the mixture was stirred for 5 minutes, filtered and evaporated in vacuum to obtain oil. After adding heptane the product was deposited, to dissolve the precipitate was added toluene and the mixture was evaporated in vacuum. The residue was dissolved in warm ethanol and left to cool DL the deposition in two days. The precipitate was filtered and dried, obtaining to 4.62 g (70%) of 10-(2-chloroethyl)-10H-fenotiazina.

The above chloride (1.45 g; 5.6 mmol) was dissolved in DMF (25 ml) was added ethyl 4-piperidineacetate (1.5 g, 7.2 mmol). potassium iodide (0.88 g; 5.5 mmol) and potassium carbonate (2.3 g; of 16.7 mmol). The reaction mixture was heated for 1 hour at a temperature of 60° C, left under stirring at room temperature overnight, and was stirred and heated over night at a temperature of 60° C. After cooling, filtration and evaporation was added dichloromethane (50 ml) and then water (40 ml). The phases were separated and the organic phase was dried (MgSO4) and was evaporated in vacuum. The resulting crude product was suirable through silica using dichloromethane and methanol (95:5) as eluents. After evaporation of the fractions was given to 0.67 g of ethyl ester of (1-(2-(phenothiazines-10-yl)-ethyl)-4-piperidinyl)acetic acid.

The above ester (0.66 g, 1.7 mmol) was dissolved in ethanol (15 ml) and the solution was added sodium hydroxide (0.33 g) in water (2.5 ml). The mixture was left to stir for 3 hours and the pH is brought up to ~3 using 1M solution chloroethanol acid (9 ml). The mixture was extracted with dichloromethane (35 ml) and the organic phase was dried (MgSO4) and was evaporated. Acetone was added, then dichloromethane and the solution was evaporated. Acetone was added, then tetrahed furan and the solution was evaporated. Acetone was added (8 ml), the solution decantation and evaporated, getting 0.27 g (40%) indicated in the title compound as amorphous solid. Calculated for C21H24N2O2S· HCl· H2O,%: 59,63%; N TO 6.43%; N 6,62%.

Found, %: C 59,66%; N 6,34%; N 6,37%.

Example 29

Hydrochloride of 1-(4-(phenothiazines-10-yl)-4-piperidinecarboxylic acid

To a solution of fenotiazina (4 g, 0.02 mol) in toluene (40 ml) was added a 50%suspension of sodium amide in toluene (2,54 g, 0.03 mol) and the reaction mixture was heated in a nitrogen atmosphere for 3 hours at a temperature of 105° C. After cooling the mixture to 60° C was added 1-bromo-4-chlorobutane (6,86 g, 0.04 mol) and the reaction mixture was heated up to the boiling temperature under reflux for 7 hours. The solid was filtered and the filtrate was evaporated in vacuum, obtaining 8,58 g of crude 10-(4-chlorobutyl)-10H-fenotiazina, which was used in the next stage without additional purification.

Obtained in the previous phase chloride (8,58 g) was dissolved in methyl ethyl ketone (40 ml), was added ethyl ester 4-piperidinecarboxylic acid (of 5.82 g, 0,037 mol), potassium carbonate (13.3 g, 0,089 mol) and sodium iodide (4.44 g, 0,0296 mol)and the reaction mixture was heated at the boiling point under reflux for 8 hours. The solid was filtered and the filtrate is perivale in vacuum. The residue was mixed with benzene (250 ml) and the benzene solution was separated from the solids and filtered through celite. After evaporation in vacuo the residue was purified column chromatography on silica gel (140 g) using as eluent a mixture With 62,40%; N 6,55%; Cl Of 8.37%; N 6,61%; S 7.57 per cent. Found, %: C 62,34%; N 6,61%; Cl 8,46%; N 6,47%; S A 7.62%.

Example 30

Hydrochloride of 1-(3-(xanthene-9-ilidene)-1-propyl)-4-piperidinecarboxylic acid

To a solution of cyclopropylmagnesium (obtained from cyclopropylamine (6,05 g, 0.05 mol) and magnesium turnings (1,21 g, 0.05 mol) in anhydrous tetrahydrofuran (25 ml) in a dry nitrogen atmosphere) was added dropwise a suspension of xanthone (5.0 g, 0,025 mol) in anhydrous tetrahydrofuran (30 ml) at a temperature of 60° C. the Reaction mixture was stirred for 1 hour at a temperature of 60° C, cooled and added to chilled on ice, the mixture of saturated solution of ammonium chloride (60 ml). The layers were separated, the aqueous layer was twice extracted with ether (2× 20 ml), the combined organic extracts were washed with water (2× 30 ml), dried (gSO4) and was evaporated in vacuum. The obtained residue 6,27 g, crude 9-cyclopropylamino-9-ol was used in the next stage without additional purification.

To the solution obtained above alcohol (6.2 g) in acetic acid (100 ml) at a temperature of 10-15° C for 45 the minutes was added dropwise to a 15% solution of hydrogen bromide in acetic acid (48 ml). The mixture was stirred at 15° C for 30 minutes. After filtration the solution was diluted with water (100 ml) and cooled during the night. The precipitate was filtered, dissolved in ether (20 ml) and the solution was washed with water (20 ml), dried (Na2SO4) and was evaporated in vacuum.

The oily residue (6.2 g) was purified by chromatography on silica gel using toluene as eluent, and received 5.34 g (70%) of 9-(3-bromopropyl)xanthone.

TLC: Rf=0,88 (n-hexane/acetone = 2:1).

The mixture obtained as described above bromide (5,25 g of 0.017 mol), ethyl 4-piperidinecarboxylate (2,74 g of 0.017 mol), anhydrous potassium carbonate (of 7.23 g, 0,052 mol) and potassium iodide (2.9 g, is 0.017 mol) in 2-butanone (40 ml) was heated at a temperature of 60-70° C for 5.5 hours. After cooling, the inorganic salts were filtered off, washed with 2-butanone (10 ml) and the combined filtrates were evaporated in vacuum. Oily residue (6.6 g) was purified using chromatography on silica gel using as eluents mixtures of benzene and ethyl acetate (0-30%) with the receipt of 2.68 g (41%) of ethyl ester of 1-(3-(9-Kantelinen)-1-propyl)-4-piperidinecarboxylic acid in the form of oil.

Obtained as described above ester (2.50 g, 6/6 mmol) was dissolved in ethanol (40 ml)was added 20% sodium hydroxide (4.3 ml) and the mixture was stirred at room temperature for 6.5 hours. Ethanol viparis is whether in vacuum, the mixture was diluted with dichloromethane (300 ml) and acidified with acetic acid (pH 7). Was added water (10 ml), the phases were separated and the organic layer was dried (MgSO4) and was evaporated in vacuum. The residue was evaporated with acetone (40 ml), the resulting oil was diluted with ether (50 ml), was added a solution of hydrogen chloride in ether to achieve pH 1 and the mixture was stirred for 7 hours. The ether solution decantation from the fall precipitated hydrochloride was again added ether (50 ml) and the mixture was stirred for 3 hours. The solid product was filtered, washed with ether and dried. The result has been to 1.60 g (63%) indicated in the title compound in the form of a solid product.

So pl. 206-212° C (decomp.).

Calculated for C22H23NO3·HCl· 1/SN2CL2·1/2H2O, %:

With 64,22%; N 6,18%; N 3,37%; Cl 12,78%. Found, %:

With 64,38%; N 6,07%; N 3,28%; Cl 12,69%.

Study on the insulin resistance

Four in consciousness not to be resistant 25 gram mice-male NMRI intracervical enter histaminase (90 nmol) in accordance with the method Nishibori et al. (J.Pharmacol. Exp. Therap. 241, 582-586, 1987). The glucose content in blood was determined at time 0 and after 40 minutes after the injection of histamine. The compounds obtained according to example 11 of the present application, was administered intraperitoneally at doses of 1.0 and 10 mg/kg 30 minutes before the injection of GIS is Amina.

Connection example 11 showed a 52% inhibition % inhibition refers to the ability of the compound to inhibit the growth of the level of glucose in the blood caused by histamine. This result suggests that the compounds of the present invention can be used in the treatment of immunity to insulin.

1. N-Substituted azaheterocyclic carboxylic acids and their esters of the formula (I)

where

R1and R2independently, represent hydrogen, halogen, NR6R7or C1-6-alkyl;

Y represents-CH2or=CH2-where only the underlined atom is part of a ring system; and

X represents-O-, -S-, -CH2CH2-where R6and R7independently represent C1-6-alkyl;

r is 1, 2 or 3; and

Z represents (a)

where

R3represents -(CH2)mHE or -(CH2)pR4where m is 1, p is 0 or 1, and where R4represents-OH, -NH2or C1-6-alkoxy;

R10represents hydrogen or C1-6-alkyl; and

.... is a single bond

provided that

if R1and R2independently represent hydrogen or halogen, Y represents-CH2-, X represents-S -, and R10represents hydrogen, then R3may not be -(CH2)pR4where p is 0, and R4represents-NH2or1-6-alkoxy; and, further,

if R1and R2independently, represent hydrogen, halogen or C1-6-alkyl; X represents-O-, -S-, CH2CH2-, and R10represents hydrogen, then R3may not be -(CH2)pCOR4where p is 0 and R4is a HE or1-6-alkoxy;

or

Z is selected from (b) and (C)

and

where R3represents -(CH2)pCOR4where R is 0 or 1, and where R4is a HE or a C1-6-alkoxy;

R5represents hydrogen;

.... is a single bond;

or

Z is selected from (d), (f) and (k)

where

n = 1;

R3represents -(CH2)pR4where R is 0 or 1,

and where R4is a HE or a C1-6 -alkoxy;

R11represents hydrogen;

or

Z is a (g)

where

R3represents -(CH2)pR4where p is 0, and where

R4is a HE or1-6-alkoxy;

or Z is a (j)

where

R3represents -(CH2)pCOR4where p is 0, and where

R4is a HE or a C1-6-alkoxy;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1and R2independently, represent hydrogen, halogen, N(CH3)2or methyl.

3. The compound according to any one of the preceding paragraphs, where r is 2.

4. The compound according to claim 1, where R3represents-CH2OH, -COR4or-CH2R4where R4represents-IT or-NH2.

5. The compound according to claim 1, where R11represents hydrogen or methyl.

6. The compound according to any one of claims 1 to 5, selected from the group including:

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinecarboxylic;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-ropyl)-2-piperidinylcarbonyl acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinemethanol;

4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinylcarbonyl acid;

4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-morpholinylcarbonyl acid;

2-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1,2,3,4-tetrahydro-4-ethanolammonium acid;

(4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)piperazine-1-yl)acetic acid;

1-(3-(10,11-Dihydro-5H-dibenz[a,d]azepin-5-yl)-1-propyl)-4-piperidinyloxy acid;

1-(3-(10,11-Dihydro-5H-dibenzo[b,f]cyclohepten-5-ilidene)-1-propyl)-4-piperidinylcarbonyl acid;

(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-3-piperidinecarboxylic;

(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-pyrrolidinecarbonyl acid;

(S)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-pyrrolidinecarbonyl acid;

1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-piperidinylcarbonyl acid;

1-(3-(10H-Phenoxazin-10-yl)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-piperidinyloxy acid;

1-(3-(10,11-Dihydro-5H-dibenz[b]azepin-5-yl)-1-propyl)-2-methyl-3-piperidinylcarbonyl acid;

1-(3-(2,8-Dibromo-10,11-dihydro-5H-dibenz[a,d]azepin-5-yl)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(3,7-Dichloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(3-Methyl-10,11-dihydro-5H-dibenz[a,d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(3,7-Dimethyl-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(3-Dimethylamino-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinylcarbonyl acid;

(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-piperidinylcarbonyl acid;

(S)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-2-piperidinylcarbonyl acid;

or their pharmaceutically acceptable salts.

7. 1-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-3-khinuklidinilbenzilata or its pharmaceutically acceptable salt.

8. The compound according to any one of claims 1 to 7 as drugs having activity to inhibit neurogenic pain, inflammation and increased levels of glucose in the blood.

9. A method of obtaining a compound according to claim 1, characterized in that they are subjected to the interaction of the compound of formula (II)

where R1, R2X, Y and r are defined in claim 1, and W represents a suitable removable group, Taku is as halogen, p-toluensulfonate or mesilate, with the compound of formula (III)

HZ (III)

where Z is defined in claim 1, and, if necessary, the obtained compound of formula (I), where R4represents a C1-6-alkoxy, is subjected to hydrolysis to obtain the compounds of formula (I), where R4is a HE.

10. Pharmaceutical composition having activity to inhibit neurogenic pain, inflammation and increased levels of glucose in the blood, characterized in that as the active ingredient it contains an effective amount of a compound according to any one of claims 1 to 7 together with a pharmaceutically acceptable carrier or diluent.

11. The pharmaceutical composition of claim 10, characterized in that it contains from 0.5 to 1000 mg of the compound according to any one of claims 1 to 7 on a standard dosage form.

12. Method of inhibiting neurogenic pain, inflammation and increase the level of glucose in blood of a subject, characterized in that the specified subject is administered an effective amount of a compound according to any one of claims 1 to 7.

13. The method according to item 12, wherein the amount of compound is from 0.5 mg to 1000 mg/day on a standard dosage form.

Priority claim 1 (except for the case when R1and R2independently represent NR6R7), item 2 (except for the case when R1and R2independently denote N(The N 3)2), p.3-5, item 6 connection N 1-4, 6-8, 11-14 - 07.04.1995

Priorities on items and features:

11.09.1995 6 - 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarbonitrile acid (N10), 4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinecarboxamide acid (N5), 1-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1 propyl)-4-piperidinyloxy acid (N9);

01.04.1996 according to claim 1 (compounds in which R1and R2independently represent NR6R7), item 2 (compounds in which R1and R2independently, denote N(CH3)2item 6 - (other connections), item 7.



 

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< / BR>
where X represents the group< / BR>
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< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

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EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

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