N-substituted azaheterocyclic carboxylic acids and pharmaceutical composition

 

(57) Abstract:

The present invention relates to new N-substituted azaheterocyclic carboxylic acids of the formula I or their salts containing compositions and their use for the clinical treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, causing neurogenic pain or inflammation. 2 C. and 35 C.p. f-crystals.

The invention relates to new N-substituted azaheterocyclic carboxylic acids, in which a substituted alkyl chain forms part of the N-substituent, or their salts, processes for their preparation, containing compositions, to the use of compounds with the aim of obtaining compositions for clinical treatment of painful conditions, increased pain sensitivity, and inflammatory conditions, in which the pathophysiological role of C-fibers, causing neurogenic pain or inflammation, and methods of treatment for these painful conditions, increased pain sensitivity, and inflammatory conditions. This invention relates also to the use of compounds for lowering blood glucose and/or inhibition of secretion, circulation is soedineniya interact with containing neuropeptides C-fibers. Therefore, these compounds can be used in the treatment of immunity to insulin in non-insulin-dependent diabetes mellitus (NIDDM) to improve glucose tolerance, as well as age-related obesity.

The nervous system has a profound impact on the inflammatory response. Antidrama stimulation of sensory nerves gives a limited expansion of blood vessels and increased permeability of blood vessels (Janecso and other Br. Pharmacol. 1967, 31, 138-151), a similar reaction is observed and after injection of the peptides, which are known to be present in the sensitive nerves. From these and other data it is concluded that the peptides selected from the endings of sensory nerves that mediate many of the inflammatory reaction in tissues such as skin, joints, urinary tract, eye, brain, gastrointestinal tract and respiratory tract. Therefore, inhibition of allocation and/or activity of the peptides sensory nerves may be useful in therapy, for example, arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombophlebitis, glaucoma, gastrointestinal disease or migraine.

In addition, the strong effect of CGRP on the activity glikogensintetazy skeletal muscle and glucose metabolism muscle t the RP may play a physiological role in glucose metabolism in skeletal muscle, directing phosphorylated glucose away from the storage of glycogen in the glycolytic and oxidative pathways (Rosetti and other Am. J. Physiol. 264, E1-E10, 1993). The peptide may be an important physiological modulator of intracellular transport of glucose in physiological conditions, such as exercise, and can also contribute to the weakening of the action of insulin and glikogensintetazy skeletal muscles in pathophysiological conditions, such as NIDDM age or obesity (Melnyk and other Obesity Res. 3, 337-344, 1995), when markedly reduced levels of CGRP in the circulating plasma. Therefore, inhibition of allocation and/or activity of the neuropeptide CGRP may be useful in the treatment of immunity to insulin that is associated with type 2 diabetes or aging.

In U.S. Patent 4383999 and 4514414 and European Patents EP 236342, and EP 231996 claimed some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids as inhibitors of GABA uptake. In the European Patents EP 342635 and EP 374801 as inhibitors of GABA uptake declared N-substituted azaheterocyclic carboxylic acids, in which oximetery group and the vinyl ester group respectively form part of the N-substituent. In addition to that is the notes. European Patent EP 221572 declares that 1-aryloxyalkyl-3-carboxylic acid are inhibitors of GABA uptake.

WO 9518793, published on 13 July 1995, WO 9631498 and WO 9631499, both published October 10, 1996, disclose N-substituted azaheterocyclic carboxylic acids and their esters. Collect. Czech. Chem. Commun., so 59, 1994, pp. 667-674, discloses tricyclic analogues of N-(4,4-diphenyl-3-butene-1-yl)nicotinebuy acid and related compounds, some of these compounds exhibit antihistaminic and anti-ulcer activity. WO 9722338 published on June 26, 1997, discloses the use of N-substituted azaheterocyclic carboxylic acids and their esters to reduce blood glucose and/or inhibition of secretion, circulation or actions of the insulin-antagonistic peptides. However, in the above-mentioned documents do not specifically disclosed, none of the compounds of this invention.

The present invention relates to compounds of General formula I, where X, Y, Z, R1, R2and r such as defined in the detailed description of the present invention.

These compounds are useful for the treatment, prevention, elimination, mitigation or improvement of symptoms related to painful conditions, REP C-fibers, for example, neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as symptoms caused by or related to the secretion and circulation of insulin-antagonistic peptides, such as non-insulin dependent diabetes mellitus (NIDDM) and age-related obesity.

The purpose of this invention is to provide pharmaceutical compositions containing as active ingredient at least one of the compounds of General formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent.

Another objective of the present invention is to provide a method for treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, such as neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, and treatment of symptoms caused by or related to the secretion and circulation of insulin-antagonistic peptides, such as non-insulin dependent diabetes mellitus (NIDDM) and age-related obesity. The method of treatment can be described as the treatment of one of the above symptoms in need of receivedany of the present invention or its pharmaceutically acceptable salt.

Another aspect of this invention concerns the use of compounds of this invention, for preparing a pharmaceutical composition for the treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, such as neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis and for the treatment of symptoms caused by or related to the secretion and circulation of insulin-antagonistic peptides, such as non-insulin dependent diabetes mellitus (NIDDM) and age-related obesity.

Additional objectives will become clear from the following description.

Thus, the present invention relates to new N-substituted azaheterocyclic carboxylic acids of the formula I

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where R1and R2independently are hydrogen, halogen or C1-C6-alkyl;

Y is or where only the underlined atom participates in the ring system;

X is-S-, -CH2CH2-, -O-CH2-, -CH2-OH, -S-CH2-, -CH2-S;

r is 1 or 2;

Z is selected from

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< / BR>
where R3is -(CH2)pCOOH, where R is 0 or 1,

ileka or optical isomers, and all the selected isomers, pure and partially purified stereoisomers or racemic mixtures are included in the scope of this invention. The isomers can be distinguished by standard methods, such as chromatographic or fractional crystallization of suitable salts.

Preferred compounds of formula I in the form of individual geometric or optical isomers.

Compounds corresponding to the present invention may not necessarily exist in the form of pharmaceutically acceptable salts of joining acids, metal salts or optionally alkyl ammonium salts.

Examples of such salts include inorganic and organic salts of joining acids, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable salt accession inorganic or organic acids, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), which are known to experts.

Also includes hydrates of the above salts accession acids, which can form a real connection.

Salt prisoediniyates base in a suitable solvent, containing the appropriate acid and excrete salt through evaporation of the solvent or by precipitation or crystallization.

The compounds of formula I can be introduced in the form of a pharmaceutically acceptable salt accession acid or in the form of a metal salt, or (lower alkyl)ammonium salt. Such salts exhibit approximately the same order of activity as the free base.

The following terms shall have the specified value in the above structural formulas and throughout the present description.

Used here, the term "C1-C6-alkyl", alone or in combination, refers to a linear or branched saturated hydrocarbon chain, having 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-trimethylpropyl.

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

Illustrative examples of the compounds included in the present invention include:

1-(2-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-ethyl)-3-piperidinylcarbonyl to the 1-dihydrobenzo[b, e] thiepin-11-ilidene)-1-ethyl)-3-piperidinylcarbonyl acid;

1-(2-(2-chloro-6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid;

(R)-1-(2-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-ethyl)-3-piperidinylcarbonyl acid;

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

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

1-(3-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-propyl)-4-piperidinylcarbonyl acid;

1-(3-(2-fluoro-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-4-piperidinylcarbonyl acid;

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

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

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

1-(2-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid;

1-(2-(6,11-dihydrobenzo[b, e] oxepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid,

or their pharmaceutically acceptable salts.

It is shown that the new compounds of formula I inhibit neurogenic inflammation, which vklla this can be demonstrated in animal models of histamine-induced paw edema (Amann and others, Europ. J. Pharmacol. 279, 227-231, 1995), where the new compounds of formula I demonstrate a strong inhibitory effect. The compounds of formula I can be used to treat all painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, causing neurogenic pain or inflammation, namely: acute painful conditions, examples of which include migraine, postoperative pain, burns, bruises, post herpetic pain (shingles) and pain, usually due to acute inflammation; chronic painful and/or inflammatory conditions, examples of which include various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, cough, asthma, itching, chronic pancreatitis, inflammatory skin diseases, including psoriasis and autoimmune dermatosis, pain in osteoporosis.

In addition, it is shown that the compounds of General formula I improves glucose tolerance in diabetic ob/ob mice and that this may be due to the reduced allocation of CGRP from peripheral not the tion of obesity. Experimentally this is illustrated by subcutaneous injection of glucose ob/ob mice with pre orally administered compounds of General formula I (or without it).

Compounds of General formula I can be obtained in the following way:

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The compound of formula II, where R1, R2X, Y and r such as defined above, and W is a suitable leaving group such as halogen, pair-toluensulfonate or mesilate may react with uzasadnienie formula III where Z is as defined above. This alkylation reaction can 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 such as sodium hydride or potassium carbonate, and a catalyst, such as alkali metal iodide, at temperatures up to the boiling point of the used solvent under reflux for 1-120 hours.

The compounds of formula II and III can be easily obtained by methods known to experts.

Under certain circumstances it may be necessary to protect the intermediate products used in the above methods, for example the compound of formula III, suitable protection in "Protective Groups in Organic Chemistry", J. F. W. McOrnie and others (New York, 1973).

PHARMACOLOGICAL METHODS

I. Histamine-induced swelling feet

Study of histamine-induced paw edema in rats carried out mainly as described by Amann and others (Europ. J. Pharmacol. 279, 227-231, 1995). Briefly, male Sprague-Dawley rats weighing 250-300 g are anaesthesia pentobarbital sodium and placed them on the table, heated to 32oC. After 10 minutes in the right hind paw injected histamine (50 μl, 3 mg/ml) and after 20 min then determine swollen feet by plethysmography combined with water (Ugo Basile). The compounds administered intraperitoneally 15 minutes before anesthetic.

Inhibition of histamine-induced edema at 1 mg/kg:

Example % inhibition of edema

2 - 51

12 - 49

II. Reduced allocation of CGRP

Female ob/ob mice (age 16 weeks) make subcutaneous injection of glucose (2 g/kg). Then determine the glucose in the blood from the tail vein by means of glucoseoxidase (glucose oxidase method). At the end of the study decapitate animals and collect the blood of the body. Define immunoreactive CGRP in plasma by radioimmunoassay studies. Study two groups of animals. One group is treated with a filler, while the other gretcheskije SONGS

The present invention relates also to pharmaceutical compositions comprising a compound of formula I or its pharmaceutically acceptable salt, typically, such compositions also contain a pharmaceutical carrier or diluent. Compositions containing the compounds of this invention can be obtained in the usual way and present in the form of conventional forms, such as capsules, tablets, solutions or suspensions.

Used in the pharmaceutical carrier can be well-known solid or liquid carrier. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, agar, pectin, Arabic gum (acacia), magnesium stearate and stearic acid. Examples of liquid carriers are syrup, oil of groundnuts, olive oil and water.

Similarly, the carrier or diluent may include any material that slows the release, known in the art, such as glycerylmonostearate or glycerylmonostearate, alone or in a mixture with paraffin.

The route of administration may be by any method, which effectively transports the active compound to the appropriate or desired site of action, such as oral, through the nose, lung or PA is th, intravenous, be as ophthalmic solution or an ointment, the preferred oral route of administration.

If you use a solid carrier for oral administration, the drug can be tablet, placed in a hard gelatin capsule, in the form of powders or granules, or you can get a toffee or a cake.

The amount of solid carrier will vary widely but is typically from about 25 mg to 1 year If used carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsule or sterile water for injection such as aqueous or non-aqueous liquid suspension or solution.

Preparation for nasal injection may contain the compound of formula I dissolved or suspended in a liquid carrier, in particular in aqueous media for aerosols. The carrier may contain additives such as solubilizing agents, for example propylene glycol, surface-active compounds, amplifiers absorption, such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, such as parabens.

For parenteral use are especially suitable solutions or suspensions for injection, preference is ASS="ptx2">

Tablets, coated tablets or capsules with talc and/or Carbo-hydrate as a carrier or binder or the like, particularly suitable for oral administration. Preferred carriers for tablets, coated tablets or capsules include lactose, corn starch and/or potato starch. In cases where you can use sweetened media, you can use syrup or elixir.

A typical tablet which can be prepared in the usual way tabletting, may contain:

Core:

The active compound (as free compound or its salt) 100 mg

Colloidal silicon dioxide (Aerosil) 1.5 mg

Microcrystalline cellulose (Avicel) - 70 mg

Modified cellulose resin (Ac-Di-Sol) - 7.5 mg

Magnesium stearate

Shell:

A receiver array is approximately 9 mg

* Mywacett 9-40 T approximately - 0.9 mg

*The acylated monoglyceride used as plasticizer for film coating.

The compounds of this invention can enter a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or improvement of symptoms related to all painful conditions, increased pain sensitivity and/or inflammation migraine, neuropathy, itching and rheumatoid arthritis, as well as symptoms caused by or related to the secretion and circulation of insulin-antagonistic peptides, such as non-insulin dependent diabetes mellitus (NIDDM) or age-related obesity. Such mammals include animals and domestic animals, such as animals kept in the apartment, and nadomestnih animals, such as wild animals.

The compounds of this invention can be introduced in the form of their salts with alkali or alkaline earth metals together, in turns or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of pharmaceutical compositions in an effective amount.

For the above symptoms dosage depends strongly on the used compounds of the formula I, route of administration and the necessary treatment. However, in General, satisfactory results are obtained at a dose of about 0.5 to 1000 mg, preferably about 1 to 500 mg, of the compounds of formula I, taken usually 1-5 times a day, not necessarily in the form of the drug with prolonged release of active component. Usually, dosage forms suitable for oral administration comprise from about 0.5 to 1 what vitalem.

Suitable dosage ranges are usually changing, as indicated above, depending on the specific route of administration, accepted forms, symptoms, targeted admission, the patient and his weight and the preference and experience of the attending physician or veterinarian.

Typically, the compounds of this invention are divided into standard dosage forms, including 50-200 mg of active ingredient per dose in a pharmaceutically acceptable carrier.

Usually, dosage forms suitable for oral, nasal, pulmonary or transdermal application include from about 0.5 to 1000 mg, preferably from 1 to 500 mg, of the compounds of formula I in a mixture with a pharmaceutically acceptable carrier or diluent.

Any described herein distinctive characteristics or combinations of distinctive features is considered an integral part of this invention.

EXAMPLES

The method of obtaining compounds of formula I and containing products is additionally illustrated in the following examples, which, however, do not limit the scope of the invention.

Further reduction in TLC means thin layer chromatography, CDCl3- deuterochloroform, a DMSO-d6- hexadecyltrimethylammonium to the characteristic protons indicated in the title compounds, correspond to the structures. Chemical shifts1H NMR (n) are given in ppm (M. D. ). So pl. is the melting temperature, is given inoAnd was not specified. Column chromatography was performed using the method described by W. C. Still and others, J. Org. Chem. (1978), 43, 2923-2925, on silica gel Merck silica gel 60 (Art. 9385). The compounds used as starting materials are either known compounds or compounds that can easily be obtained by known methods.

EXAMPLE 1

Hydrochloride of 1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-3-piperidinecarboxylic acid

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To a solution of 11-(2-bromation)-6,11-dihydrobenzo[b,e]tiepin (3.33 g, 0,0105 mol, obtained similarly as described in the Coil. Czech. Chem. Comm. 52, 1566, 1987) in dimethyl sulfoxide (60 ml) is added potassium carbonate (2.0 g, of 0.02 mol), ethyl ester of 3-piperidinecarboxylic acid (1.65 g, 0,0105 mol) and sodium iodide (50 mg) and the mixture was stirred at 50oC for 4 hours. The reaction mixture was diluted with chloroform (100 ml), filtered off solid, and the filtrate washed with water (3 x 80 ml). Dried chloroform solution (MgSO4) and remove the solvent in vacuo. Oily residue (5.6 g) was dissolved in acetone and treated with ethanol process. who gives 3,81 g(75%) 1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-3-piperidinecarboxylic acid of monoethylene ester of oxalic acid (EtOOCCOOH).

The above ester (2,95 g of the base obtained from hydroarsenate, 0,0075 mole) is dissolved in ethanol (50 ml) and add a 15% sodium hydroxide (11 ml). The reaction mixture was stirred at room temperature for 10 hours, then poured into dichloromethane (500 ml) and acidified with concentrated hydrochloric acid. The dichloromethane layer is separated, dried (MgSO4) and evaporated in vacuo. The residue is crystallized from a mixture of 95% ethanol and ether, obtaining 2.7 g (90%) specified in the connection header. So pl. 227-240oC.

Calculated for C22H23NO2S HCl:

With 65,74%; N 6,02%; CL 8,82%; N 3,49%; S 7,98%.

Found: 65,53%; N 6,18%; Cl 8,76%; N 3,44%; S Of 7.82%.

EXAMPLE 2

Hydrochloride of 1- (2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid

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To a solution of 11-(2-bromation)-6,11-dihydrogen-zo[b,e]tiepin (4,76 g 0,015 mol, obtained similarly as described in the Coil. Czech. Chem. Comm. 52, 1566, 1987) in dimethyl sulfoxide (90 ml) is added potassium carbonate (3.1 g, 0,0225 mol), ethyl ester of 4-piperidinecarboxylic acid (2,36 g 0,015 mol) and sodium iodide (50 mg) agree solid, and the filtrate washed with water (4 x 60 ml). Dried benzene solution (MgS04) and remove the solvent in vacuo. Oily residue (6,34 g) is dissolved in acetone and treated with ethanolic oxalic acid. The precipitate is filtered off and washed with a hot mixture of ethanol and acetone, getting 5,2 g(72%) 1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid of monoethylene ester of oxalic acid.

The above ester (3,95 g of the base obtained from hydroarsenate, of 0.01 mole) is dissolved in ethanol (30 ml) and added 4N sodium hydroxide (8 ml). The reaction mixture was stirred at room temperature for 15 hours, then poured into dichloromethane (250 ml) and acidified with concentrated hydrochloric acid. The dichloromethane layer is separated, dried (MgSO4) and evaporated in vacuo. The residue is evaporated twice with acetone (15 ml) and the crude product is dissolved in acetone (30 ml). The product is filtered and washed with diethyl ether. After drying, this gives 3,71 g (92%) specified in the connection header. So pl. 227-240oC.

Calculated for C22H23NO2SH:

With 65,74%; N 6,02%; CL 8,82%; N 3,49%; S 7,98%.

Found: 65,39%; N 6,15%; Cl 8,55%; N 3,34%; S 7,63%.

EXAMPLE 3

Gigny (4.94 g, 0,203 mol) in tetrahydrofuran (15 ml) activate a crystal of iodine and 1,2-dibromoethane (0.4 ml). After the reaction type (refrigerator with a dry ice-ethanol, nitrogen atmosphere) 10% solution of vinylboronate (21,4 g of 0.2 mol) in tetrahydrofuran (70 ml). The reaction begins immediately, and the remaining part of the solution vinylboronic added dropwise with stirring so fast (over 45 min) to maintain the temperature 58-62oC. the Mixture is heated for 30 minutes at boiling temperature under reflux and then cooled to 30oC. After 1 hour is added dropwise with stirring (30-35oC) a solution of 2-chloro-6,11-dihydrobenzo[b, e]tiepin (28,9 g of 0.1 mol, obtained as described in the Es. farmacie 11, 451, 1962) in tetrahydrofuran (70 ml). The mixture is left to stand overnight at room temperature and then quenched by cooling (ice and sodium chloride) solution of ammonium chloride (21 g) in water (100 ml). Add toluene (100 ml) and the mixture is filtered, the aqueous layer was extracted with toluene (3 x 100 ml). Toluene solutions combine, dried (gSO4) and evaporated. The residue is crystallized from a mixture of benzene (50 ml) and hexane (100 ml), receiving a 27.4 g (95%) of 2-chloro-11-vinyl-6,11-dihydrobenzo[b,e]thiepin-11-ol.

The suspension obtained above alcohol is one of the acid in acetic acid (48 ml) for 30 minutes. The mixture was stirred at 15oC for 1 hour, then filtered, washed the solid with water (3 x 60 ml), acetic acid (100 ml) and dried. Exit 11-(2-bromation)-2-chloro-6,11-dihydrobenzo[b, e] tiepin is 25.6 g (83%).

To the solution obtained above bromide (1,76 g of 0.005 mole) in dimethyl sulfoxide (30 ml) is added potassium carbonate (0,82 g 0,006 mol), ethyl ester of 3-piperidinecarboxylic acid (0,86 g, 0,0055 mol) and sodium iodide (20 mg) and the mixture was stirred at 50oC for 4 hours. The reaction mixture was diluted with chloroform (100 ml), filtered off the solid and the filtrate washed with water (3 x 40 ml). The chloroform solution is dried (gSO4) and the solvent is evaporated in vacuum. Oily residue (2,53 g) is dissolved in acetone and treated with ethanolic oxalic acid. Osadovskaya crude salt hydroarsenate (2.55 g) is recrystallized from aqueous ethanol, getting 1.84 g(71%) 1-(2-(2-chloro-6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-3-piperidinecarboxylic acid of monoethylene ester of oxalic acid.

The above ester (1.0 g of the base obtained from hydroarsenate, 0,0025 mole) is dissolved in ethanol (25 ml) and add 20% sodium hydroxide (10 ml). The reaction mixture is stirred at to what Laney acid. The dichloromethane layer is separated, dried (MgSO4) and evaporated in vacuo. The residue is crystallized from a mixture of 95% ethanol and acetone, getting to 0.47 g (43%) specified in the connection header. So pl. 235-250oC (decomposes).

Calculated for C22H22ClNO2SHCl:

With 60,55%; N 5,31%; CL 16,25%; N 3,21%; S 7,33%.

Found: 60,74%; N 5,33%; Cl 16,47%; N 2,93%; S 7,28%.

EXAMPLE 4

Hydrochloride of 1-(2-(2-chloro-6,11-dihydrobenzo[b, e]thiepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid

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To a solution of 11-(2-bromation)-2-chloro-6,11-dihydrobenzo[b, e]tiepin (1,76 g of 0.005 mole), obtained as described in Example 3, N,N-dimethylformamide (20 ml) is added potassium carbonate (2,33 g 0,006 mole) and ethyl ester of 4-piperidinecarboxylic acid (0,86 g, 0,0055 mol) and the mixture was stirred at 50oC for 3 hours. The reaction mixture was diluted with dichloromethane (80 ml), filtered off solid, and the filtrate washed with water (4 x 30 ml). Dried dichloromethane solution (MgSO4) and remove the solvent in vacuo. Oily residue (2,34 g) is dissolved in acetone and treated with ethanolic oxalic acid. Osadovskaya crude salt hydroarsenate (5.8 g) is recrystallized from aqueous ethanol, receiving 1.12 g(87%) 1-(2-(2-chloro-6,11-Digi the CLASS="ptx2">

The above ester (0,70 g of the base obtained from hydroarsenate, 0,0017 mole) is dissolved in ethanol (25 ml) and add 40% sodium hydroxide (6 ml). The reaction mixture is stirred and heated at boiling temperature under reflux for 1 hour, cooled and poured into dichloromethane (150 ml). The solution is acidified with concentrated hydrochloric acid, dichloromethane layer is separated, dried (MgS04) and evaporated in vacuo. This gives 0.71 g (96%) of the crude hydrochloride is indicated in the title compound, which is recrystallized from a mixture of acetone and diethyl ether. So pl. 230-250oC.

Calculated for C22H22ClNO2SHCl:

With 60,55%; N 5,31%; CL 16,25%; N 3,21%; S 7,33%.

Found: 60,29%; N, 5,32%; Cl 16,09%; N 2,90%; S 7,44%.

EXAMPLE 5

Hydrochloride (R)-1-(2-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-ethyl)-3-piperidinecarboxylic acid

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To a solution of 11-(2-bromation)-6,11-dihydrobenzo[b,e]tiepin (4,43 g of 0.014 mol, Coll. Czech. Chem. Comm. 52, 1566 (1987)), in N,N-dimethylformamide (75 ml) is added potassium carbonate (19.3 g, of 0.14 mol) and ethyl ester tartrate (R)-3-piperidinecarboxylic acid (to 6.43 g, 0,0209 mol) and the mixture was stirred at 70oC for 6 hours. The reaction mixture is diluted with benzene (300 ml), Hotfile the t of the solvent in vacuo. Oily residue (6,83 g) is dissolved in acetone and treated with a solution of oxalic acid in ethanol. Separated solid matter and crude hydrocalc (g) (5.8 g) is recrystallized from a mixture of 96% ethanol and ether, receiving of 5.81 g (86%) (R)-1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)- 3-piperidinecarboxylic acid of monoethylene ester of oxalic acid. So pl. 170-173oC.

The above ester (4,70 g of the base obtained from hydroarsenate, a 0.012 mmole) is dissolved in ethanol (30 ml) and added 4N sodium hydroxide (9 ml). The reaction mixture was stirred at room temperature for 6 hours, poured into dichloromethane (400 ml) and acidified with concentrated hydrochloric acid. The dichloromethane layer is separated, dried (MgSO4) and evaporated in vacuo. Oily residue evaporated twice with acetone and then triturated with hot acetone, which gives 3,86 g (83%) specified in the connection header. So pl. 220-227oC.

Calculated for C22H23NO2S1:

With 65,74%; N 6,02%; CL 8,82%; N 3,49%; S 7,98%.

Found: 65,82%; N 6,09%; Cl 8,79%; N 3,44%; S 8.08 Per Cent.

EXAMPLE 6

Hydrochloride of 1- (3-(2-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-3-pyrrolidinyloxy acid

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HPLC time UD is 250 mm, elution with a 20-80% gradient of 0.1% triperoxonane acid/acetonitrile and 0.1% triflorum-susei acid/water for 25 minutes at 35oC).

Calculated for C24H26rNO2l0,5 H2ABOUT:

WITH 59,33%; N 5,81%; N 2,88%.

Found: 59,34%; N 5,97%; N 2,56%.

EXAMPLE 7

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

< / BR>
HPLC retention time (high performance liquid chromatography) = 18,91 and 19,06 minutes (mixture of E/Z-isomers) (column (5 μm C18, 4 x 250 mm, elution with a gradient of 20-80% 0,1% triperoxonane acid/acetonitrile and 0.1% triflorum-susei acid/water for 25 minutes at 35oC).

Calculated for C25H29NO2l0,75 H2O:

WITH 70,57%; N 7,46%; N 3,29%.

Found: 70,45%; N Of 7.36%; N, 3.04 From%.

EXAMPLE 8

Hydrochloride of 1-(3-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-propyl)-4-piperidinecarboxylic acid

< / BR>
The solution cyclopropylmagnesium in dry tetrahydrofuran obtained from cyclopropylamine (3.7 g, 0,031 mol), magnesium turnings (0.8 g, 0,033 mole) and dry tetrahydrofuran (50 ml) under nitrogen atmosphere, is added dropwise to a solution of (6,11-dihydrobenzo[b,e]tape the submission of completed the mixture is heated at 50oC for 2 hours. The reaction mixture was cooled in an ice bath and carefully add saturated ammonium chloride (50 ml) and water (50 ml). The mixture is extracted with diethyl ether (2 x 100 ml), dried (MgSO4), filtered and the solvent is evaporated in vacuum, obtaining 4.4 g of crude 11-cyclopropyl-6,11-dihydro-11N-dibenzo[b,e]thiepin-11-ol in the form of butter.

The result of the above crude alcohol (4.0 g) dissolved in dichloromethane (50 ml) and added dropwise at room temperature a solution of trimethylsilylpropyne (2.1 ml, to 0.016 mole). When the addition is complete, the mixture is stirred at room temperature for 1.5 hours and add water (50 ml). Share phase and the organic phase washed with water (50 ml), dried (gSO4) and the solvent is evaporated in vacuum, obtaining 4.1 g (83%) of crude 1-bromo-3-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)propane in the form of a solid substance.

The resulting crude mixture of the bromide (1.0 g, to 3.02 mmole), ethyl ester of 4-piperidinecarboxylic acid (1.0 g, 6,04 mmole), dry potassium carbonate (2.5 g, 18,11 mmole), potassium iodide (1.0 g, 6.02 mmole) and methyl ethyl ketone (100 ml) is heated at boiling temperature under reflux for 18 hours. The cooled reaction mixture is quenched with water (100 ml) and e x 100 ml) and washed with aqueous phase with diethyl ether (50 ml). The aqueous phase is alkalinized 50% sodium hydroxide and extracted with diethyl ether (2 x 100 ml). The combined organic extracts washed with saturated aqueous ammonium chloride (100 ml), dried (MgSO4), filtered and the solvent evaporated in vacuum. This gives 0.50 g (41%) of ethyl ester of 1-(3-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-propyl)-4-piperidinecarboxylic acid in the form of oil. TCX: Rf= 0,28 (SiO2: ethyl acetate/heptane = 1:1).

The result of the above ethyl ester (0.5 g, of 1.23 mmole) is dissolved in ethanol (10 ml) and add sodium hydroxide solution (60 mg, about 1.47 mmole) in water (5 ml). The reaction mixture was stirred at room temperature for 18 hours and remove the solvent in vacuo. Add water (75 ml) and the mixture was washed with diethyl ether (2 x 50 ml). The aqueous phase is acidified (pH 1) with concentrated hydrochloric acid and extracted with dichloromethane (3 x 50 ml). The combined organic extracts washed with water (50 ml), dried (gSO4), filtered and the solvent evaporated in vacuum. The residue is suspended in a mixture of acetone (5 ml) and diethyl ether (10 ml) and stirred for 18 hours at room temperature. The precipitate is filtered off and washed with diethyl ether, receiving 0.25 g powder. His suspek (11%) indicated in the title compound as amorphous solid.

1H NMR (400 MHz, DMSO-d6), to 1.79 (m, 2H) ; 2,00 (m, 3H) ; of 2.21 (m, 1H) ; 2,44 (m, 1H) ; 2,84 (m, 2H) ; 3,14 (m, 2H) ; to 3.36 (m, 2H) ; 3,71 (d, 1H, J=13,8 Hz); was 4.76 (d, 1H, J=13,8 Hz); of 5.89 (t, 1H); 6,98 (DD, 1H) ; 7,11 (m, 3H) ; 7,32 (m, 3H) ; was 7.45 (d, 1H); from 10.1 (broad s, 1H); and 12.5 (broad s, 1H).

MS (EI): 379 (M+, 20%).

EXAMPLE 9

Hydrochloride of 1-(3-(2-fluoro-10,11-dihydro-5H-dibenzo[a, d]cyclo-hepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid

< / BR>
The solution cyclopropylmagnesium in dry tetrahydrofuran (obtained from cyclopropylamine (10.7 g, 0,088 mol), magnesium turnings (2.14 g, 0,088 mole) and dry tetrahydrofuran (100 ml) under nitrogen atmosphere) is added dropwise to a solution of 2-fluoro-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-she (10.0 g, 0,044 mole) in dry tetrahydrofuran (100 ml). When the addition is complete, the mixture is heated at 50oC for 3 hours. The reaction mixture was cooled in an ice bath and add saturated ammonium chloride (50 ml). The mixture is extracted with diethyl ether (2 x 100 ml) and the combined organic extracts washed with saturated sodium chloride (50 ml), dried (MgSO4), filtered and the solvent is evaporated in vacuum, obtaining 11.2 g of crude 2-fluoro-5-cyclopropyl-10,11-dihydro-5H-dibenzo[a, d]Cycloheptane-5-ol in the form of butter.

Obtained above smilelaid (5,3 ml, 0,041 mol). When the addition is complete, the mixture is stirred at room temperature for 1 hour and add water (50 ml). Share phase and the organic phase washed with water (50 ml), dried (MgSO4) and the solvent is evaporated in vacuum, obtaining 11.2 g (91%) of crude 1-bromo-3-(10,11-dihydro-5H-dibenzo[a,d]Cycloheptane-5-ilidene)propane in the form of a solid substance.

The mixture obtained above crude bromide (3.0 g, 9,06 mmole), ethyl ester of 4-piperidinecarboxylic acid (1.4 g, 18,12 mmole), dry potassium carbonate (7.5 g, 54,3 mmole), potassium iodide (1.5 g, 9,06 mmole) and methyl ethyl ketone (150 ml) is heated at boiling temperature under reflux for 18 hours. The cooled reaction mixture is quenched with water (100 ml) and extracted with diethyl ether (2 x 100 ml). The combined organic extracts washed with water (2 x 100 ml) and saturated sodium chloride (100 ml), dried (MgS04), filtered and the solvent evaporated in vacuum. The remainder of the cleaning column chromatography on silica gel (1000 ml), using as eluent a mixture of ethyl acetate and heptane (1:1). This gives 1.6 g (43%) of the ethyl ester of 1-(3-(2-fluoro-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene)-1-propyl)-4-piperidinecarboxylic acid in the form of butter.

The result of the above ethyl is 5 ml). The reaction mixture was stirred at room temperature for 18 hours and remove the solvent in vacuo. Add water (100 ml) and the mixture was washed with diethyl ether (50 ml). The aqueous phase is acidified (pH 1) with concentrated hydrochloric acid and extracted with dichloromethane (375 ml). The combined organic extracts dried (MgSO4), filtered and the solvent evaporated in vacuum. The residue is suspended in acetone (25 ml) and stirred for 1 hour at room temperature. The precipitate is filtered off, washed with diethyl ether and dried, gaining 0.7 g specified in the title compound as amorphous solid.

Calculated for C24H26FNO2HCl0,25 N2ABOUT:

WITH 68,56%; N 6,59%; N TO 3.33%.

Found: 68,54%; N Of 6.71%; N 3,12%.

EXAMPLE 10

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

< / BR>
HPLC retention time (high performance liquid chromatography) = 17,27 minutes (column 5 μm C18, 4 x 250 mm, elution with a 20-80% gradient of 0.1% triperoxonane acid/acetonitrile and 0.1% triperoxonane acid/water for 25 minutes at 35oC).

Calculated for C24H30N2O2HCl0,5 H2ABOUT:

< / BR>
HPLC retention time (high performance liquid chromatography) = 20,13 minutes (column 5 μm C18, 4 x 250 mm, elution with a 20-80% gradient of 0.1% triperoxonane acid/acetonitrile and 0.1% triperoxonane acid/water over 30 minutes at 35oC).

1H NMR (400 MHz, DMSO-d6),n: of 3.94 (t, 2H) ; 7,00 (t, 2H) ; was 7.08 (d, 2H) ; 7,20 (m, 4H).

EXAMPLE 12

Hydrochloride (R)-1-(2-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-ethyl)-2-piperidinecarboxylic acid

< / BR>
To a solution of 2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)ethylbromide (2,36 g, 0,0079 mole) in dry N,N-dimethylformamide (11.8 ml) is added hydrochloride ethyl ester (R)-2-piperidinecarboxylic acid (2.30 g, 0,0119 mol) and potassium carbonate (3.28 g). The reaction mixture is heated at 74-78oC for 2.5 hours. Add water (40 ml) and benzene (40 ml) and after separation of the organic phase washed with water (2 x 40 ml), dried (MgSO4) and the solvent evaporated in vacuum. The remainder of the cleaning column chromatography on silica gel (50 g) using chloroform as eluent. This gives 3.11 g of ethyl ester of (R)-1-(2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-ethyl)-2-piperidinecarboxylic acid in the form of oil. TLC: Rf=0,5 (SiO2: n-hexane/Atila (8,8 ml). The mixture is stirred at room temperature for six days. Add concentrated hydrochloric acid (4.5 ml) and then dichloromethane (445 ml). The phases are separated, the organic phase is dried (MgSO4) and evaporated in vacuo. The residue (foam) is stirred overnight with diethyl ether (50 ml). This gives after drying, 2.2 g (73%) indicated in the title compound in the form of crystals. So pl. 185-190oC.

Calculated for C23H25NOHCl:

WITH 71,95%; N, 6.83 PER CENT; N OF 3.65%.

Found: 71,84%; N 6,84%; N 3,32%.

EXAMPLE 13

Hydrochloride of 1-(2-(10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinecarboxylic acid

< / BR>
To a solution of 2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)ethylbromide (2,99 g of 0.01 mol) in dry N,N-dimethylformamide (15 ml) is added ethyl ether 4-piperidinecarboxylic acid (2,36 g 0,015 mol) and potassium carbonate (2,07 g, 0,0149 mol). The reaction mixture is heated at 74-80oC for 2.5 hours. Add water (50 ml) and benzene (50 ml) and after separation of the layers the organic phase is washed with water (3 x 20 ml), dried (MgSO4) and the solvent evaporated in vacuum. The remainder of the cleaning column chromatography on silica gel (50 g) using chloroform as eluent. This gives 2.17 g (58%) of ethyl is.

The above ester (2.0 g, 0,0053 mole) is dissolved in ethanol (45 ml) and added 4N sodium hydroxide solution (6 ml). The mixture is left at room temperature for 24 hours. Add concentrated hydrochloric acid (3.0 ml) and then dichloromethane (300 ml). The phases are separated, the organic phase is dried (MgSO4) and the solvent evaporated in vacuum. Oily residue is evaporated with acetone (20 ml) and the solution is kept at room temperature for two days. The crystalline product is filtered and washed with acetone and n-hexane. This gives after drying, 1.18 g (58%) specified in the connection header. So pl. 219-227oC.

Calculated for C23H25NO2HCl:

With 71,95%; N 6,83%; CL 9,23%; N 3,65%.

Found: 71,54%; N 6,87%; CL 8,94%; N Of 3.80%.

EXAMPLE 14

Hydrochloride of 1-(2-(6,11-dihydrobenzo[b, e]oxepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid

< / BR>
To a solution of 11-(2-bromation)-6,11-dihydrobenzo[b, e]oxepin (4,55 g 0,015 mol) in dimethyl sulfoxide (90 ml) is added potassium carbonate (3.1 g, 0,0225 mol), ethyl ester of 4-piperidinecarboxylic acid (2,36 g 0,015 mol) and sodium iodide (50 mg) and the mixture was stirred at 70-80oC for 5 hours. The reaction mixture is diluted with benzene (250 ml), filtered off firmly the ü in vacuum. Oily residue (4.94 g) was dissolved in acetone and treated with ethanolic oxalic acid. Precipitated crude hydrocalc filtered off and washed with hot acetone. Yield 4.15 g(59%) 1-(2-(6,11-dihydrobenzo[b,e]oxepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid of monoethylene ester of oxalic acid. So pl. 209-213oC.

The above ester (of 3.32 g of the base obtained from hydroarsenate, 0,0088 mole) is dissolved in ethanol (17 ml) and added 4N sodium hydroxide (5 ml). The reaction mixture was stirred at room temperature for 18 hours, then poured into dichloromethane (350 ml) and acidified with concentrated hydrochloric acid. The dichloromethane layer is separated, dried (gSO4) and evaporated in vacuo. The residue is evaporated twice with acetone (15 ml) and dissolved in acetone (30 ml). The crystalline product is filtered and washed with acetone. This gives after drying 1.85 g (55%) indicated in the title compound as a crystalline product. So pl. 210-218oC (decomposes).

Calculated for C22H23NO3HCl:

With 68,48%; N 6,27%; CL 9,19%; N 3.63 Percent.

Found: 65,14%; N 6,24%; CL 8,93%; N 3,57%.

1. N-Substituted azaheterocyclic carboxylic acids, predstavlyayushie[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or 1-(2-(2-chloro-6,11-dihydro-dibenzo[b, e] thiepin-11-ilidene)-1-ethyl)-3-piperidinylcarbonyl acid or 1-(2-(2-chloro-6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or (R)-1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-3-piperidinylcarbonyl acid or 1-(3-(2-fluoro-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl)-4-piperidinylcarbonyl acid or 1-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-2-piperidinyloxy acid or 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinylcarbonyl acid or (R)-1-(2-(10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene)-1-ethyl)-2-piperidinylcarbonyl acid or 1-(2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or 1-(2-(6,11-dihydrobenzo[b, e]oxepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid 1-(3-(2-bromo-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene)-1-propyl)-3-pyrrolidinyloxy acid or 1-(3-(3-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ilidene)-1-propyl-3-pyrrolidinyloxy acid or 1-(3-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-propyl)-4-piperidinylcarbonyl acid or their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that it is a 1-(2-(6,11-dihydrobenzo[b, e]thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl to the hat is 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

4. Connection on p. 1, characterized in that it is a 1-(2-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

5. Connection on p. 1, characterized in that it is a hydrochloride of 1-(2-(6,11-dihydrobenzo[b, e]thiepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid.

6. Connection on p. 1, characterized in that it is a hydrochloride of 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinecarboxylic acid.

7. Connection on p. 1, characterized in that it is a hydrochloride of 1-(2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinecarboxylic acid.

8. Connection on p. 1 as an active ingredient for a pharmaceutical composition intended for the treatment of neurogenic inflammation.

9. Connection on p. 1 as an active ingredient for a pharmaceutical composition intended for the treatment of neuropathy.

10. Connection on p. 1 as an active ingredient for a pharmaceutical composition intended for the treatment of rheumatoid arthritis.

11. Connection on p. 1 as tx2">

12. Connection on p. 1 as an active ingredient for a pharmaceutical composition intended for the treatment of itching.

13. The compound according to any one of paragraphs.8-12, characterized in that it is a 1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

14. The compound according to any one of paragraphs.8-12, characterized in that it is a 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

15. The compound according to any one of paragraphs.8-12, characterized in that it is a 1-(2-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

16. The compound according to any one of paragraphs.8-12, characterized in that it is a hydrochloride of 1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid.

17. The compound according to any one of paragraphs.8-12, characterized in that it is a hydrochloride of 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinecarboxylic acid.

18. The compound according to any one of paragraphs.8-12, characterized in that it is a hydrochloride of 1-(2-(10,11-Digue composition, with antihistaminic activity, comprising an active component and a pharmaceutically acceptable carrier or diluent, wherein the active component using N-substituted azaheterocyclic carboxylic acids under item 1.

20. The pharmaceutical composition according to p. 19, characterized in that as the active component using 1-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

21. The pharmaceutical composition according to p. 19, characterized in that as the active component using 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

22. The pharmaceutical composition according to p. 19, characterized in that as the active component using 1-(2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

23. The pharmaceutical composition according to p. 19, characterized in that as the active component using the hydrochloride of 1-(2-(6,11-dihydrobenzo[b, e]thiepin-11-ilidene)-1-ethyl-4-piperidinecarboxylic acid.

24. The pharmaceutical composition drank)-4-piperidinecarboxylic acid.

25. The pharmaceutical composition according to p. 19, characterized in that as the active component using the hydrochloride of 1-(2-(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinecarboxylic acid.

26. The pharmaceutical composition according to any one of paragraphs.19-25, characterized in that it is intended for the treatment of neurogenic inflammation.

27. The pharmaceutical composition according to any one of paragraphs.19-25, characterized in that it is intended for the treatment of neuropathy.

28. The pharmaceutical composition according to any one of paragraphs.19-25, characterized in that it is intended for the treatment of rheumatoid arthritis.

29. The pharmaceutical composition according to any one of paragraphs.19-25, characterized in that it is intended for the treatment of migraine.

30. The pharmaceutical composition according to any one of paragraphs.19-25, characterized in that it is intended for the treatment of itching.

31. The pharmaceutical composition according to any one of paragraphs.19-25, characterized in that it comprises from 0.5 to 1000 mg of the compounds according to paragraphs.1-7 in the standard dose.

32. The pharmaceutical composition according to p. 31, characterized in that it comprises 1-(2-(6,11-dihydrobenzo[b, e]thiepin-11-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically pickup is in-10-yl)-1-propyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

34. The pharmaceutical composition according to p. 31, characterized in that it comprises 1-(2-(10,11-dihydro-5H-dibenzo-[a, d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinylcarbonyl acid or its pharmaceutically acceptable salt.

35. The pharmaceutical composition according to p. 31, characterized in that it includes the hydrochloride of 1-(2-(6,11-dihydrobenzo[b, e]thiepin-11-ilidene)-1-ethyl)-4-piperidinecarboxylic acid.

36. The pharmaceutical composition according to p. 31, characterized in that it includes the hydrochloride of 1-(3-(phenothiazines-10-yl)-1-propyl)-4-piperidinecarboxylic acid.

37. The pharmaceutical composition according to p. 31, characterized in that it includes the hydrochloride of 1-(2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-ethyl)-4-piperidinecarboxylic acid.

 

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< / BR>
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< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts
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