1,4-disubstituted piperazines, the method of production thereof, pharmaceutical composition and method of treating neurogenic inflammation

 

(57) Abstract:

The invention relates to 1,4-disubstituted the piperazines of General formula I, the method of production thereof, 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. 4 C. and 30 C.p. f-crystals, 1 PL.

The invention relates to new N-substituted azaheterocyclic compounds 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 therapy painful condition, 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 these compounds for lowering blood glucose and/or inhibition of secretion, circulation or actions of insulin-auliana containing C-fibers, containing neuropeptides. 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 effect 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. J. 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. Thus, the peptides released 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 release 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 m the Institute nerve, suggest that CGRP may play a physiological role in glucose metabolism of skeletal muscles, directing phosphorylated glucose away from the storage of glycogen and glycolytic and oxidative pathways (Rossetti and other Am. J. Physiol. 264, E1-E10, 1993). This 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 or age obesity {lnyk and other Obesity Res. 3, 337-344, 1995), when markedly reduced levels of CGRP in the circulating plasma. Therefore, inhibition of release 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 4,383,999 and 4,514,414 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 is th, in WO 9107389 and WO 9220658 as inhibitors of GABA uptake declared N-substituted usacycling carboxylic acid. European Patent EP 221572 discloses 1-aryloxyalkyl-3-carboxylic acids as inhibitors of GABA uptake.

The present invention relates to compounds of General formula I, where X, Y, Z, M1, M2, R1-R12, r and m are 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, 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, 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.

In another aspect of the scope of the present invention is included a pharmaceutical composition containing as active ingredient at least one of the compounds of General formula I or its pharmaceutically the present invention provides a method 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, as well as a method of treatment of symptoms caused by or related to the secretion and circulation of insulin-antagonistic peptides such as CGRP or Amylin, 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 treatment of a patient, which includes an introduction to the specified neurological patient an effective amount of the compounds of this invention or its pharmaceutically suitable salts.

Another aspect of this invention relates to the use of the compounds of this invention for the preparation of pharmaceutical compositions for the treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, for example, 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 the texts.

Additional tasks will be clear from the following description.

The present invention relates to new 1,4-disubstituted the piperazines of formula I:

< / BR>
where R1and R2independently are hydrogen, halogen, trifluoromethyl, hydroxyl, C1-6-alkyl or C1-6-alkoxy group; and

X is ortho-phenylene, -O-, -S-, -C(R6R7)-, -CH2CH2-, -CH=CH-CH2-, -CH2-CH= CH-, -CH2-(C=O)-, -(C=O)-CH2-, -CH2CH2CH2-, -CH=CH-, -N(R3)-(C=O)-, -(CO)-N(R8)-, -O-CH2-, -CH2-O-, -OCH2-O, -S,-CH2-, -CH2-S-, -(CH2)N(R8)-, -N(R8) (CH2)-, -N(CH3)SO2-, -SO2N(CH3)-, -CH (R10) (CH2)-, -CH2CH(R10)-, -(C= O)-, -N(R9)- or -(S=O)-, where R6, R7, R8and R9independently are hydrogen or C1-6-alkyl; and R10is C1-6-alkyl or phenyl; and

Y is where only the underlined atom participates in the ring system, and r is 1, 2 or 3; and Z is selected from

< / BR>
< / BR>
where M1and M2independently are C or N; and

R5is hydrogen, C1-6-alkyl, phenyl or benzyl; and

R3is hydrogen, halogen, trift what agropol, by cyano, (CH2)mCOR11, (CH2)mHE or (CH2)mSO2R11where

R11is hydroxyl, C1-6-alkoxy group or other12where

R12is hydrogen or C1-6-alkyl; and m is 0, 1 or 2; or

R4choose from

< / BR>
< / BR>
< / BR>
or their pharmaceutically suitable salts.

The compounds of formula I can exist as geometric and optical isomers, and all the 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 a pharmaceutically suitable salts accession acids, or (when the carboxylic acid group is not etherification) in the form of a pharmaceutically suitable salts of the metals, or optionally alkyl ammonium salts.

Examples of such salts of vkluchat, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically suitable salt accession inorganic or organic acids, and include the pharmaceutically suitable 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 accession acids can be obtained as the direct products of the synthesis of compounds. Alternatively, you can dissolve the free 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 used in the form of a pharmaceutically suitable salt accession acid or in the form of a metal salt or (lower alkyl)ammonium. 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 herein, the term "C1-6-alkyl", alone or in combin, who, what aka as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1,2,2-trimethylpropyl.

Used herein, the term "C1-6-alkoxy-group, single or in combination, refers to a linear or branched monovalent Deputy, which includes the C1-6is an alkyl group attached through ether oxygen, has a free valence from the ether oxygen and from 1 to 6 carbon atoms, for example methoxy-, ethoxy-, propoxy-, isopropoxy, butoxy, intoxi-groups.

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

In the preferred embodiment of this invention R1and R2selected from hydrogen, halogen, trifloromethyl or C1-6-alkyl. Preferably, R1and R2represented hydrogen, chlorine or methyl.

In another preferred embodiment of this invention X is chosen from-CH2CH2-, -CH= CH-, -O-CH2-, -CH2-O-, -OCH2O-, -S-CH2- or-CH2-S-. Preferably choose X-CH2CH2-, -OCH2O-, -S-CH2- or-CH2-S-.

Still on the system rings.

In another preferred embodiment of this invention r is 1 or 2.

In another preferred embodiment of the present invention Z is selected from

< / BR>
where M1and M2independently are C or n

In another preferred embodiment of this invention R3is hydrogen, trifluoromethyl, nitro-group or cyano.

In another preferred embodiment of this invention R4is hydrogen, trifluoromethyl, nitro-group, a cyano or (CH2)mCOR11.

In another preferred embodiment of the present invention m is 0 or 1.

In another preferred embodiment of this invention R11is hydroxyl.

Preferred compounds of the present invention include:

2-(4-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-piperazine-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-piperazine-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(N-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(2-chlorine-N-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-3-Piri is BR>
2-(4-(3-(10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene)-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

2-(4-(2-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1 - ethyl)-1-piperazinil)-3-pyridylcarbonyl acid;

6-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-2-pyridylcarbonyl acid;

2-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

2-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-5-pyridylcarbonyl acid;

2-(4-(3-(3-chloro-10,11-dihydro-5H-dibenzo[b, f]azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

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

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

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

1-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-4-(3-trifluoromethyl-2-pyridyl)piperazine;

2-(4-(2-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)ethyl)piperazine-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

2-(4-(2-(6,11-�benzo[a, d] cyclohepten-5-ilidene)-1-propyl)piperazine-1-yl)-2-pyridylcarbonyl acid;

2-(4-(3-(3-methyl-10,11-dihydro-5H-dibenzo[b, f]azepin-5 - yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

6-(4-(3-(dibenzo[d, g] [1,3,6]doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-pyridine-2-carboxylic acid

or their pharmaceutically suitable salts.

It is shown that the new compounds of formula I inhibit neurogenic inflammation, which includes the release of neuropeptides from peripheral and Central endings sensitive C-fibers. Experimentally this can be demonstrated in animal models of histamine-induced paw edema (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; hronicheskaya, 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 release of CGRP from peripheral nerve endings. Therefore, compounds of General formula I can be used in the treatment of NIDDM, as well as age-related obesity. Experimentally this is illustrated by subcutaneous injection of glucose ob/ob mice with advanced oral introduction of the compounds of General formula I (or without it).

The compounds of 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 convenient removable group, such as halogen, paratoluenesulfonyl or mesilate may react with uzasadnienie formula III where Z is as defined above. This alkylation reaction can be carried out in restoril, in the presence of a base such as sodium hydride 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. If the resulting esters in which R11is the alkoxy group, the compounds of formula I, where R11is HE, 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, 0.5 to 6 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 protective groups. Carboxylate group can, for example, to atrificial. The introduction and removal of such groups described in "Protective Groups in Organic Chemistry", editor J. F. W. McOrnie (New York, 1973).

PHARMACOLOGICAL METHODS

I. Histamine-induced swelling feet

Study of histamine-induced paw edema in rats carried out mainly as described in the work thawed sodium and placed them on the table, heated to the 32oC. After ten minutes in the right hind paw injected histamine (50 microlitres, 3 mg/ml) and 20 minutes after that determine swollen feet by plethysmography combined with water (Uqo Basile). The compounds administered intraperitoneally 15 minutes before anesthetic.

II. Reduced release 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 method using glucoseoxidase (glucose oxidase method). At the end of the study decapitate animals and collect the blood. Define immunoreactive CGRP in plasma by radioimmunoassay studies. Study two groups of animals. One group is treated with a filler, while the other group given drinking water compound of formula I (100 mg/l) for five days prior to the test.

The table shows the values of the reaction inhibiting histamine-induced swelling for some common compounds.

PHAMACEUTICALLY SONGS

The present invention relates also to pharmaceutical compositions comprising a compound of formula I or its pharmaceutically suitable salt, typically, such compositions also contain headlamp shall be in the usual ways and to be in conventional forms, for example in the form of capsules, tablets, solutions or suspensions.

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

In a similar case, the carrier or diluent may include any material that slows the release of the active ingredient, known from the prior 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, pulmonary or parenteral e.g. rectal, depot, transdermal, subcutaneous, intranasal, intramuscular, local, intravenous, be in the form of an ophthalmic solution or ointment, the preferred oral route of administration.

If you use a solid carrier for oral administration, the drug can TableRow Peski. 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 application 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 Soubirous agents, for example propylene glycol, surface-active compounds, amplifiers absorption, such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, such as parabens.

For parenteral application, particularly suitable solvents or suspension for injection, preferably aqueous solutions with the active compound dissolved in polyhydroxyalkane castor oil.

Tablets, coated tablets or capsules containing talc and/or carbohydrate as a carrier or binder or the like, particularly suitable for oral administration. Preferred carriers for tablets, coated tablets or capsules include lactose, kukur is with 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

*Mywacett9-40 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 inflammatory conditions in which the pathophysiological role of C-fibers, such as 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) or loiasis in the apartment, and of nadomestnih animals, such as wild animals.

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

For the above symptoms dosage largely depends on the compounds of formula T, route of administration and the necessary treatment. However, in General satisfactory results are obtained with a dose from about 0.5 mg to 1000 mg, preferably from about 1 mg 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 mg to 1000 mg, preferably from about 1 mg to 500 mg, of the compounds of formula I in a mixture with a pharmaceutical carrier or diluent.

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 outdelay on a standard dosage forms, including 50-200 mg of active ingredient/per dose in a pharmaceutically suitable carrier or together with him.

Usually, dosage forms suitable for oral, nasal, pulmonary or transdermal application include from about 0.5 mg to 1000 mg, preferably 1 mg to 500 mg, of the compounds of formula I in a mixture with a pharmaceutically suitable 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, Dl3- deuterochloroform, DMSO-d6- hexadecene-sulfoxide. Structures of the compounds are confirmed by either elemental analysis or NMR, which shows the peaks attributed to the characteristic protons indicated in the header of the compounds correspond to the structures. Chemical shifts1H NMR (n) are given in ppm (M. D.). So pl. is the melting temperature, is given ino 2923-2925, on silica gel Merck silica gel 60 (Art. 9385). Compounds used as starting materials are either known compounds or compounds that can easily be obtained by known methods.

EXAMPLE 1

Hydrochloride of 2-(4-(3-(N-dibenzo[d, g] [1,3] dioxin-12-or-den)-1-propyl)-piperazine-1-yl)-3-pyridineboronic acid

< / BR>
2,2'-Dihydroxybenzophenone (10.0 g, 46,7 mmole) and died-methane (13,1 g, 49 mmol) dissolved in dry N,N-dimethyl-formamide (180 ml). Add the dried fine powder of potassium carbonate (9.2 grams, 66.7 mmole) and the mixture is heated at 105oC for 16 hours. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate is collected by filtration through a 0.5 hour, washed with water on a filter and dissolved in a mixture of ethanol (80 ml) and 4N sodium hydroxide (20 ml). The solution is stirred at the boiling point under reflux for 1 hour, cooled and diluted with water (300 ml). The resulting crystalline precipitate is filtered off, washed with water (50 ml) and dried in vacuum, obtaining N-dibenzo[d, g] [1,3] -dioxin-12-it is in the form of a solid (9.5 g, 90%). So pl. 93-95oC.

The solution cyclopropylmagnesium dry tetrahydrofuran (70 ml) was placed in a nitrogen atmosphere. Add drop by drop a solution of the above ketone (9,05 g, 40 mmol) in dry tetrahydrofuran (50 ml). The reaction mixture was stirred at 40oC for 1.5 hours, cooled and added to ice a mixture of saturated ammonium chloride (400 ml) and ether (200 ml). The organic layer is separated and the aqueous phase is extracted with ether (50 ml). The combined organic extracts washed with water (2100 ml) and with brine (50 ml), dried (gSO4), evaporated in vacuo and distilled with toluene (2 x 25 ml). This gives 11.2 g 12-cyclopropyl-N-dibenzo[d,g][1,3]dioxin-12-ol.

1H NMR (200 MHz, CDCl3):n0,50 (d, 2H); 0.75 in (d, 2H); 2,00 (m, 1H); 5,14 (s, 2H); from 6.9 to 7.4 (m, 6N); 7,81 (d, 2H).

To the solution obtained above alcohol (6,21 g, 22 mmole) in dry dichloromethane (225 ml) add trimethylsilylpropyne (3,71 g, and 24.2 mmole). The reaction mixture is stirred for 1 hour at room temperature and poured into ice saturated solution of sodium bicarbonate (75 ml). The organic phase is separated, washed with ice water (275 ml) and with brine (75 ml), dried (gSO4) and evaporated in vacuo. It gives of 7.95 g of crude 12-(3-bromo-1-propylidene)-N-dibenzo[d, g] [1,3] dioxazine, which is used in the next stage without additional is arbonboy acid (3.54 in) 15 mmol, obtained as described in J. Med. Chem. 31, 618-624 (1988)), sodium iodide (2,23 g, 15 mmol) and potassium carbonate (5.1 g, 37 mmol) in 2-butanone (70 ml) is heated at the boiling point under reflux for 5 hours. After cooling, the mixture was poured into diethyl ether (170 ml) and water (170 ml). The organic layer was separated, washed with water (2100 ml), acidified with 2N hydrochloric acid and washed with water (250 ml). The combined aqueous layers alkalinized using a saturated solution of sodium bicarbonate, and extracted with dichloromethane (200 ml). The organic extract is dried (MgSO4) and evaporated in vacuo. The residue (4.35 g) clean chromatography on silica gel, using as eluent a mixture of benzene and ethyl acetate and getting ethyl ester 2-(4-(3-(N-dibenzo[d, g][1,3]dioxin-12-ilidene)-1-propyl)piperazine-1-yl)-3-pyridineboronic acid (3,71 g, 51%).

The mixture obtained above ester (0,99 g, 2 mmole) and 20% sodium hydroxide (1.5 ml) in ethanol (13 ml) was stirred at room temperature for 4 hours. Pour mixture in dichloromethane (100 ml), acidified with 2N hydrochloric acid and washed with water (10 ml). The organic solution is dried (MgSO4and add activated carbon. The mixture is stirred for 10 minutes, filtered and remove R the minutes, filtered and washed with ethyl acetate. After drying receive specified in the header connection (0,80 g, 74%). So pl. 225-229oC.

Calculated for C27H27N3O4, HCl, 0.25 to C4H8O2, 0.25 S2H5HE: 64,89%; N 6,02%; C1 6,72%; N OF 7.96%;

Found: 64,95%; N 5,86%; C1 Of 6.73%: N 7,94%.

EXAMPLE 2

The dihydrochloride 2-(4-(3-(2,10-dichloro-12H-dibenzo[d, g] [1, 3]-doxepin-12-ilidene)-1-propyl)-piperazine-1-yl)-3-pyridineboronic acid.

< / BR>
2,2'-Dihydroxy-5,5'-benzophenone (12.1 g, 0,042 mol, obtained as described in JACS 77, 543 (1955)) and diameter (11.9 g, 0,044 mol) dissolved in dry N,N-dimethylformamide (226 ml). Dry and add a powder of potassium carbonate (8,3 g) and the mixture is heated at 105oC for 5 hours and left overnight at room temperature. The reaction mixture was poured on ice (220 g). The precipitate is collected by filtration and dissolved in diethyl ether (500 ml). The organic solution was washed with 5% sodium hydroxide (50 ml), dried (gS4) and evaporated in vacuo. This gives 12 g (96%) 2,10-dichloro-N-dibenzo[d,g]-[1,3]dioxin-12-it is in the form of a solid substance.

To a solution of cyclopropylmagnesium in dry tetrahydrofuran (obtained from cyclopropylamine (15.7 g, 0,130 mol), magnesium strutton (of 7.65 g, 0,026 mol) in dry tetrahydrofuran (30 ml). The reaction mixture was stirred at 38-42oC for 3 hours, cooled in an ice bath and add a mixture of saturated ammonium chloride (260 ml) and diethyl ether (130 ml). Then the reaction mixture is filtered and separated the organic layer and the aqueous phase extracted with diethyl ether (35 ml). The combined organic extracts washed with water (270 ml) and with brine (70 ml), dried (MgSO4) and evaporated in vacuo. The crude product is clean column chromatography on silica gel (140 g), using as eluent benzene. This gives a rate of 8.75 g (98%) 2,10-dichloro-12-cyclopropyl-N-dibenzo[d,g][1,3]dioxin-12-ol in the form of a solid substance.

To the solution obtained above alcohol (8,75 g, or 0.027 mol) in dry dichloromethane (245 ml) is added trimethylsilyl-bromide (as 4.02 g, 0,026 mol). The reaction mixture is stirred for 1 hour at room temperature and poured into ice saturated solution of sodium bicarbonate (80 ml). The organic phase is separated, washed with water (280 ml) and with brine (80 ml), dried (MgSO4) and evaporated in vacuo. This gives 9,12 g of oil, which clean by way of column chromatography on silica gel (250 g) using as eluent a mixture of cyclopetane crystallizes upon standing.

The mixture obtained above bromide (3 g, 0,008 mol), ethyl ester of 2-(1-piperazinil)-3-pyridineboronic acid (1,76 g, 0,0075 mole), potassium carbonate (3.1 g, of 0.022 mole) and sodium iodide (1.1 g, 7.3 mmol) in 2-butanone (35 ml) is heated at the boiling point under reflux for 6 hours. After cooling to room temperature the mixture is diluted with acetone, filtered and evaporated in vacuum. The solid residue is cleaned column chromatography on silica gel (100 g) using chloroform as eluent. This gives 2.7 g (65%) ethyl ester 2-( 4-(3-(2,10-dichloro-N-dibenzo [d, g] [1,3] dioxin-12-ilidene)-1-propyl) piperazine-1-yl;-3-pyridineboronic acid in the form of butter.

The above ester (2.7 g, 4,87 mmole) is dissolved in ethanol (30 ml) and add a solution of sodium hydroxide (0.74 g) in water (2.8 ml). The mixture is stirred at room temperature for 48 hours. Add concentrated hydrochloric acid (2.8 ml) and then dichloromethane (100 ml). The organic layer is separated, dried (MgSO4) and evaporated in vacuo. The resulting foam was stirred with hot acetone (150 ml), filtered the product and washed with acetone, obtaining 1.8 g (62%) specified in the connection header.

1H NMR (250 MHZ, DMSO-d6):n8,31 ( J=2,5 Hz, 1H); 7,10 (d, J= 8.5 Hz, 1H); 6,97 (d, J=8.5 Hz); 6,95 (DD, J=4,7 Hz and 7.5 Hz, 2H); x 6.15 (t, J=7.5 Hz, 1H); 5,86 (s, 2H); to 3.73 (sh.s, 4H); 3.25 to (sh.C, 6N); 2,50 (kV, J=7.5 Hz, 2H).

Calculated for C27H25Cl2N3O4, 2 Hcl, 0.5 H2O: 53,30%; N With 4.64%; N 6,91%; Cl 23,31%;

Found: 53,41%; N 4,60%: N Of 6.73%: Cl 22,71%.

EXAMPLE 3

The dihydrochloride of 2-(4-(3-(N-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)piperazine-1-yl)-3-pyridineboronic acid

< / BR>
N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mmol) is dissolved in 99.9% ethanol (65 ml). The sodium methylate (7.0 g, 130 mmol) is suspended in 99.9% ethanol (70 ml) and added drop by drop in 30 minutes. The resulting mixture was stirred for 30 minutes. Add drop by drop within 15 minutes, 1-bromo-2-chloromethoxy-benzene (26,1 g, 118 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974, 331-337). The reaction mixture is stirred for 2.5 hours at room temperature, heated at boiling temperature under reflux for 2 hours and stirred at room temperature overnight. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in toluene (500 ml) and washed with a saturated solution of sodium carbonate (2200 ml). The organic phase is dried (MgSO4) and evaporated. The residue is suspended in ethanol (40 ml), filtered and washed with ethanol (310 ml). After mole) is suspended in duterme (75 ml) and add potassium carbonate (3.9 g, 28 mmol), and then copper (1.1 g, 17 mmol) and copper bromide (1.5 g, 11 mmol). The reaction mixture is heated at 180oWith during the night. After cooling, the mixture is filtered and washed precipitate on the filter with dichloromethane. Distilled of Dowtherm and the solvent and add to the residue ethanol (200 ml), the mixture is left overnight. Add 4M sodium hydroxide (14 ml) and the mixture is heated at boiling temperature under reflux for 1 hour. After cooling, the mixture is filtered and evaporated. The residue is suspended in ethyl acetate (200 ml) and water (100 ml). The phases are separated and the organic phase washed with water (275 ml). The aqueous phase is extracted with ethyl acetate (100 ml) and the combined organic extracts evaporated. The residue is suspended in a warm cyclohexane (100 ml) and allowed to cool under stirring. Saducees the solid is filtered off and dried, obtaining N-dibenzo[d,g][1,3,6]doxazosin (of 4.57 g, 50%).

The above doxazosin (4.0 g, 19 mmol) was dissolved in dry N,N-dimethylformamide (150 ml). Add parts sodium hydride (1.13 g, 28 mmol, 60% dispersion in oil) and the resulting mixture is stirred for 30 minutes at room temperature. Slowly drop by drop add 1-bromo-3-chloropropane (4.6 ml, 47 mmol) and stirred reacceleration within 6 hours. Add sodium hydride (0.56 g, 14 mmol) and continue stirring overnight. Add ammonium chloride (3.2 g) and the mixture is stirred for 30 minutes. Add water (300 ml) and extracted with a mixture of dichloromethane (2250 ml). The combined organic extracts dried (MgSO4) and evaporated. The remainder of the cleaning column chromatography on silica gel, using as eluent a mixture of heptane and ethyl acetate (6: 1). This gives 12-(3-chlorpropyl)-N-dibenzo[d,g] [1,3,6]-doxazosin (2,18 g, 40%).

The above chloride (135 g, 4,66 mmole) and potassium iodide (5.0 g, 30 mmol) in methyl ethyl ketone (150 ml) is heated at boiling temperature under reflux for 4.5 hours. Add ethyl ester 2-(1-piperazinil)-3 - pyridineboronic acid (3.0 g, 12 mmol) and then potassium carbonate (2.25 g, 16.3 mmole). The reaction mixture is heated at the boiling point under reflux for 19 hours. After cooling, the mixture is filtered, the filter cake washed with ethyl ketone and the filtrate is evaporated. The remaining oil clean column chromatography on silica gel (800 ml), using as eluent a mixture of heptane and ethyl acetate (1:3). This gives the ethyl ester of 2-(4-(3-(N-dibenzo-[d,g][1,3,6]doxazosin-12-yl)-1-propyl)piperazine-1-yl)-3-p is the solution of sodium hydroxide (0.24 g, 6 mmol) in ethanol (30 ml) and water (3 ml), stirred at room temperature for 25 hours. Bring the pH of the mixture to 3 by adding IN hydrochloric acid (6 ml). The mixture is extracted with dichloromethane (240 ml), the combined organic phases are washed with brine (50 ml), dried (MgSO4) and the solvent evaporated in vacuum. The residue is triturated with isopropylacetate (15 ml) and filtered off the solid product. Part of the product (275 mg) is suspended in acetone (160 ml), evaporated in vacuo and dried, obtaining mentioned in the title compound (0,23 g, 75%).

Calculated for C26H28N4O4, 2 Hcl, 0.5 H2O, 0.5 S5H10ABOUT2: 57,67%; N 6,07%; N 9,44%;

Found: 57,78%; N 6,02%; N, 9.42 Per Cent.

HPLC retention time (high performance liquid

chromatography) =18,42 minutes (column 5 μm S mm), elution with a 20-80% gradient of 0.1% triperoxonane acid/acetonitrile and 0.1% triperoxonane acid/water over 30 minutes at 30oC.

EXAMPLE 4

The dihydrochloride 2-(4-(3-(2-chlorine-N-dibenzo[d, g][1,3,6] doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-3-pyridineboronic acid

< / BR>
A suspension of 2-chloro-N-dibenzo[d,g][1,3,6]doxazosin (10,65 g, 43 mmole, described in J. Mol. Struct., 131, 1985, 131-140) and 3-chloropropionate 5 hours. After cooling to room temperature the reaction mixture is washed with saturated sodium bicarbonate solution (50 ml). The organic layer is dried (gSO4) and is evaporated in vacuum, obtaining 2-chloro-12-(3-chloropropionyl)-N-dibenzo[d, g][1,3,6]doxazosin (12,85 g, 88%).

To a chilled suspension of sociallyengaged (3.0 g, 79 mmol) in dry tetrahydrofuran (80 ml) was added one drop of concentrated sulfuric acid (a 3.87 g of 39.5 mmole) with such a rate as to maintain the temperature of <12C. the Mixture is stirred at room temperature for 1.5 hours. Add drop by drop a solution of the above amide (12.8 g, of 37.8 mmole) in dry tetrahydrofuran (80 ml) and continue stirring for 2 hours. The reaction is quenched carefully by adding ethyl acetate (100 ml) and then water (5.7 ml). Filtration and evaporation of the mixture in vacuum to give 2-chloro-12-(3-chlorpropyl)-N-dibenzo[d,g][1,3,6]doxazosin in the form of foam.

The mixture obtained above chloride (1,14 g, 3.5 mmole), methyl ester of 2-(1-piperazinil)-3-pyridineboronic acid (0,78 g, 3.5 mmole), dry potassium carbonate (1.45 g, 10.5 mmole), sodium iodide (of 0.53 g, 3.5 mmole) and 2-butanone (15 ml) is heated at boiling temperature under reflux for 48 hours. The reaction mixture is evaporated in Waco is Yat column chromatography on silica gel, using as eluent a mixture of ethyl acetate and toluene (1:1) containing triethylamine (2.5 percent). This gives methyl ester 2-(4-(3-(2-chlorine-N-dibenzo[d,g] [1,3,6]doxazosin-12-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid (1.10 g, 62%) as oil.

The above ester (1.10 g, of 2.16 mmole) is dissolved in ethanol (10 ml) and added 2N sodium hydroxide (3,37 ml, 7,13 mmole). The mixture is stirred at room temperature for 16 hours. The ethanol is evaporated in vacuo and the residue diluted with water (25 ml). Bring the pH to 6 by adding 6N hydrochloric acid and extracted with an aqueous solution of dichloromethane (315 ml). The combined organic extracts dried (MgSO4) and evaporated in vacuo. The residue is dissolved in tetrahydrofuran (25 ml) and add one drop of 2.5 N solution of hydrogen chloride in ether (1,67 ml, 4,18 mmole). The mixture is stirred for 3 hours, the precipitate is filtered off and dried, obtaining 0,86 g (75%) specified in the connection header. So pl. 165-173oC.

Calculated for C26H27ClN4O4, 2 MODEL HC1: 54,99%; N 5,15%; N 9,87%;

Found: With 54.8%; N 5,2%; N 9,65%.

EXAMPLE 5

The dihydrochloride of 1-(3-(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ilidene)-1-propyl)-4-(2-pyridyl)piperazine

< / BR>
A mixture of 5-(3-bromo-1-propylidene)-10,11-digit the lei, (described in J. Org. Chem. 1953, 18, 1484), potassium carbonate (2.8 g, 20 mmol) and N,N-dimethylformamide (40 ml) was stirred at room temperature for 16 hours and at 50-55oC for 8 hours. After cooling, the mixture is diluted with benzene (150 ml) and washed with water (3100 ml). The organic layer is extracted with 3N hydrochloric acid (100 ml). The acidic aqueous layer was alkalinized 5N sodium hydroxide (60 ml) to pH 12 and extracted with benzene (100 ml). The benzene solution is dried (K2CO3) and filtered through silica gel (12 g). Evaporation in vacuo gives an oil (2,98 g, 75%). It is dissolved in ethanol (20 ml), acidified by means of hydrogen chloride in diethyl ether (3 mmole/ml, 8 ml) and precipitated in diethyl ether (20 ml). The precipitate is filtered off, washed with diethyl ether and dried, obtaining 2.1 g (44%) specified in the connection header. So pl. 152-155oC.

Calculated for C27H29N3, 2HCl, N2About: 66,66%; N 6,84%; N 8,64%; Cl 14,58%;

Found: 67,27%; N 6,52%; N 8,76%; Cl 14,19%.

EXAMPLE 6

Hydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-1-piperazinil)-3-pyridineboronic acid

< / BR>
A mixture of ethyl ester of 2-(1-piperazinil)-3-pyridineboronic acid (4.6 g, 0,019 mol), 3-(10,11-dihydro-5H-dibenzo[a,d]cyclo is ewout 60oC for 5 hours. After standing over night, filtered the solid and washed with benzene. The filtrate is diluted with benzene (200 ml) and washed with water (4100 ml). The organic solution is dried (MgSO4) and the solvent evaporated in vacuum. The residue (7,8 g) clean column chromatography on silica gel, using as eluents benzene and a mixture of benzene-ethyl acetate and getting ethyl ester 2-(4-(3-(10,11-dihydro-5H-1-dibenzo [a, d] cyclohepten-5-ilidene; -1-propyl)-1-piperazinil)-3-pyridineboronic acid (3.4 g, 48%) as oil.

The mixture obtained above ester (2.1 g, 4.5 mmole) and 20% sodium hydroxide (3.0 ml) in ethanol (21 ml) was stirred at room temperature for 16 hours. The solution was poured into dichloromethane (250 ml) and acidified with 2N hydrochloric acid. The organic phase is washed with water (10 ml), dried (MgS4) and the solvent evaporated in vacuum. The remainder in the form of foam is distilled off with acetone and crystallized from acetone, receiving 1.5 g (70%) specified in the connection header. So pl. 224-230oC.

Calculated for C28H29N3ABOUT2, MODEL HC1, 0,25 N2ON, 0.5 S3H6About: With 69,53%; N 6,63%; C1 6.96 per cent; N OF 8.25%;

Found: 69,76%; N 6,76%; C1 7,00%; N 8,17%.

EXAMPLE 7

Hydrochloride 2-(4-(2-(10,11-dihydrogen-5H-dibenzo[b, f] azepin (2.5 g, 0,0104 mol, obtained as described in Fr. Pat. 1,215 599) and triethylamine (2.8 g, 0,028 mole) dissolved in benzene (90 ml). Add drop by drop within 10 minutes a solution of methanesulfonamide (1.66 g, 0,0145 mole) in benzene (10 ml) at 15-20oWith cooling in a bath of cold water. When the addition was completed, the reaction mixture is stirred for 1 hour at room temperature. Add water (35 ml), the organic layer separated, washed with water (25 ml), dried (gSO4) and evaporated in vacuo. Dissolved in acetone (55 ml) methanesulfonate (3.2 g, 97%) and add ethyl ester 2-(1-piperazinil)-3-pyridineboronic acid (2.64 g, 0,0112 mol) and potassium carbonate (4.0 g). The reaction mixture is heated at 50-55oC for 28 hours. The mixture is filtered and removed solvent by evaporation in vacuum. The crude residue (5.7 g) clean column chromatography on silica gel (65 g), using as eluent a mixture of benzene and chloroform. This gives 2.0 g (43%) ethyl ester 2-(4-(2-(10,11- dihydro-5H-dibenzo[b, f]azepin-5-yl)-1-ethyl)-1-piperazinil)-3-pyridineboronic acid in the form of butter.

The above ester was dissolved in ethanol (5 ml) and added 4N sodium hydroxide (5 ml). Add dichloromethane (200 ml), then concentrated hydrochloric acid (3 ml). T is one. The crude product is dissolved in warm N,N-dimethylformamide, add benzene and the mixture is cooled during the night. The precipitate is filtered off, washed with benzene and dried, obtaining 0.9 g (44%) specified in the connection header.

So pl. 240-245oC.

Calculated for C26H28N4O2, HCl, 0.5 H2O: 65,87%; N 6,38%; N 11,82%; Cl of 7.48%;

Found: 65,82%; N 6,23%; N 11,66%; Cl Of 7.90%.

EXAMPLE 8

Hydrochloride 6-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-2-pyridineboronic acid

< / BR>
To a suspension of 6-chloropyridin-2-carboxylic acid (8,3 g, 0,0525 mol, obtained as described in hm. Weg. 45, 2456 (1912)) in dioxane (25 ml) is added thionyl chloride (9.4 ml of 0.13 mol) and the resulting mixture was stirred at 70oC for 4 hours. The reaction mixture was concentrated in vacuo and add a mixture of dioxane (8,3 ml) and ethanol (16.6 ml). The reaction mixture is heated to 70oC for 2 hours, add triethylamine (8,3 ml), ethanol (4,1 ml) and water (8,3 ml) and the reaction mixture is again concentrated. The residue is partitioned between diethyl ether (28 ml) and water (18 ml) and the phases are separated. The aqueous layer was extracted with diethyl ether (30 ml) and the combined organic layers dried (gS4) and evaporated in vacuo.th above ester (8.6 g, 0,046 mole), anhydrous piperazine (41 g, 0,476 mol) and sodium iodide (0,46 g) in toluene (145 ml) is heated at boiling temperature under reflux for 2.5 hours. After cooling to about 80oWith filtered piperazine, and the filtrate is mixed with water (250 ml) and diethyl ether (100 ml). The organic layer is separated and washed ash (250 ml) and with brine (50 ml), dried (MgSO4) and evaporated, obtaining 4.6 g of oil. The aqueous layer was extracted with chloroform (550 ml), the combined organic phases are washed with water and saline solution (as above), dried and evaporated, receiving a further 3.2 g of oil. Both the compounds obtained clean column chromatography on silica gel (200 g), using as eluent a mixture of chloroform and ethanol (9:1). This gives 5 g (46%) of the ethyl ester of 6-(1-piperazinil)-2-pyridineboronic acid in the form of butter.

The mixture obtained above ester (2.20 g, 9,35 mmole), (10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)methane sulfonate (2,82 g, 8,51 mmole) and potassium carbonate (3.3 g, 0,0239 mol) in acetone (47 ml) is heated at boiling temperature under reflux for 16 hours. The reaction mixture was filtered and concentrated in vacuo. The remainder of the cleaning column chromatography on silica gel (100 g), use the sawdust)-1-piperazinil)-2-pyridineboronic acid in the form of butter.

The mixture obtained above ester (1.06 g, 2.25 mmole), ethanol (10 ml), sodium hydroxide solution (0,342 g) and water (1.3 ml) was stirred at room temperature for 48 hours. Add concentrated hydrochloric acid (1.25 ml) and then dichloromethane (60 ml). The phases are separated and the organic phase is dried (gSO4) and evaporated in vacuo. The residue re-evaporated with acetone (30 ml) and stirred with hot ethanol (30 ml). After drying, this gives 0.45 g (42%) specified in the connection header.

Calculated for C27H30N4ABOUT2, HCl: 67,70%; N 6,52%; N 11,70%; Cl 7,40%;

Found: 67,26%; N 6,70%; N 11,63%; Cl 7,31%.

EXAMPLE 9

The dihydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid

< / BR>
A mixture of 5-(3-chlorpropyl)-10,11-dihydro-5H-dibenzo [b,f]-azepine (4,54 g, 16.7 mmole), methyl ester 2-piperidinemethanol acid (3.7 g, 16.7 mmole), dry potassium carbonate (6,92 g, 50,1 mmole), sodium iodide (2.5 g, 16.7 mmole) and 2-butanone (50 ml) heated at boiling temperature under reflux for 60 hours. After cooling to room temperature, add toluene (100 ml) and water (100 ml). The organic layer was separated, washed with water (250 ml) and evaporated in vacuo. Raw pData (3:1), containing triethylamine (2.5 percent). This gives 2.3 g (30%) methyl ester 2-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid in the form of butter.

The above ester (2.3 g, 5,04 mmole), dissolved in a mixture of 2N sodium hydroxide (8,32 ml, 16,63 mmole) and ethanol (25 ml), stirred at room temperature for 16 hours. The ethanol is evaporated in vacuo and the residue diluted with water (50 ml). Added 2N hydrochloric acid (20 ml) and washed with a solution of diethyl ether (25 ml). The aqueous phase is extracted with dichloromethane (330 ml). The combined organic extracts dried (gSO4) and is evaporated in vacuum, obtaining a foam. It crystallized from tetrahydrofuran, filtered and dried, obtaining 1.20 g (50%) specified in the connection header. So pl. 168-171oC.

Calculated for C27H30N4ABOUT2, 1,75 model HC1: 64,04%; N 6,32%; N 11,06%; Cl 12,25%;

Found: 63,72%; N, 6.42 Per Cent; N Is 10.68%; Cl 11,99%.

EXAMPLE 10

Hydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-5-pyridineboronic acid

< / BR>
A mixture of methyl ester of 2-bromopyridin-5-carboxylic acid (1.40 g, 6.5 mmole) and piperazine (5,59 g, 65 mmol) dissolved in acetonitrile (50 ml) and heated at boiling temperature with Ohe (50 ml) and extracted with water (350 ml). The organic solution is dried (MgSO4) and is evaporated in vacuum, obtaining 0,80 g (56%) of methyl ester of 2- (1-piperazinil)-5-pyridineboronic acid. So pl. 91-92oC.

The mixture obtained above ester (0.73 g, 3.3 mmole), 5-(3-chlorpropyl)-10,11-dihydro-5H-dibenzo[b, f] azepine (0.9 g, 3.3 mmole), dry potassium carbonate (1,37 g of 9.9 mmole), sodium iodide (0.5 g, 3.3 mmole) and 2-butanone (10 ml) is heated at boiling temperature under reflux for 24 hours. After cooling to room temperature, to the reaction mixture was added dichloromethane (25 ml) and water (25 ml). The organic layer was separated, washed with water (210 ml) and evaporated in vacuo, the crude residue clean column chromatography on silica gel, using as eluent a mixture of toluene and ethyl acetate (1:1) containing triethylamine (2.5 percent). This gives 0.65 g (43%) methyl ester 2-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinil)-5-pyridineboronic acid in the form of butter.

The above ester (0.65 g, 1.25 mmole), dissolved in a mixture of 2N sodium hydroxide (to 2.06 ml, 4,13 mmole) and ethanol (10 ml), stirred at room temperature for 16 hours. The ethanol is evaporated in vacuo and the residue diluted with water (30 ml). Added 2N hydrochloric acid (20 ml) and washed reacti dried (gSO4) and concentrated in vacuo to 20 ml of the Precipitate is filtered off and dried, obtaining 0.33 g (60%) specified in the connection header.

So pl. 240-244oC.

Calculated for C27H30N4ABOUT2, HCl, 0.5 N2O: 66,45%; N 6,61%; N 11,48%; Cl 7,26%;

Found: 66,39%; N 6,64%; N 11,22%; Cl 7,08%.

EXAMPLE 11

The dihydrochloride 2-(4-(3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid

< / BR>
To a solution of 3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepine (5.0 g, 22 mmole) in toluene (20 ml; add one drop of 3-chloropropionitrile (of 3.32 g, 26 mmol) in toluene (8 ml). The reaction mixture was stirred at 95oC for 2 hours and allowed to mix at room temperature over night. Added 2N sodium hydroxide (25 ml) and then toluene (50 ml) and separated phases. Toluene phase is washed with 2N sodium hydroxide (225 ml), water (330 ml) and with brine (30 ml). The organic phase is dried (gSO4) and evaporated in vacuo. The residue is distilled with methanol (30 ml) and the residue suspended in ethyl acetate (8 ml), stirred and filtered.The solid is washed with ethyl acetate (10 ml) and dried. This gives 4.0 g (57%) of 3-chloro-1-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)propan-1-it.

Potassium iodide (2.8 g, 17 mmol) and methyl ethyl ketone (70 ml) is heated at 80oC for 1 hour. The above chloride (0.8 g, 3 mmole) dissolved in methyl ethyl ketone (10 ml) and add. The mixture is heated at the boiling point under reflux for 50 minutes. Add potassium carbonate (1.25 g, 9 mmol) and then methyl ester 2-(1-piperazinil)-3-pyridineboronic acid (1.0 g, 4 mmole) in methyl ethyl ketone (10 ml). The reaction mixture was stirred at 78oWith during the night. After cooling, the mixture was filtered (hyflo) and evaporated. The remainder of the cleaning column chromatography on si-Lika the on-5H-dibenzo [b,f] azepin-5-yl) -1-Pro saws) -1-piperazinil)-3-pyridineboronic acid.

TLC: Rf=0,17 (SiO2the ethyl acetate/heptane = 1:1).

The result of the above ethyl ester (0.33 g, 0.67 mmole) is dissolved in ethanol (8 ml). Add 4N sodium hydroxide (0,34 ml) and the reaction mixture is stirred for 2 hours at room temperature and stored in the refrigerator overnight. Continue stirring at room temperature for 24 hours. Add 4N sodium hydroxide (0,34 ml), stirring is continued for 2 hours, add 4N sodium hydroxide (0,34 ml) and stirring is continued for 3.5 hours. Add 4N hydrochloric acid (1,18 ml) and then water (20 ml) and dichloromethane (100 ml). The phases are separated and the organic phase is dried (gSO4) and evaporated. The residue is evaporated with acetone (230 ml), stirred with isopropylacetate (3-5 ml) for 5 minutes, filtered and dried. Yield 0.18 g (51%) indicated in the title compound as amorphous powder.

Calculated for C27H29ClN4O2, 2HCl, 0,25 C5H9O2: 62,98%; N 6,03%; N THE 10.40%;

Found: 63,31%: N 6,36%; N, 10.16 Per Cent.

HPLC retention time (high performance liquid chromatography)= 23,82 minutes (column 5 μm S mm), elution with a 20-80% gradient of 0.1% triperoxonane acid/acetonitrile and 0.1% trihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene)-1-propyl)-4-(2-nitrophenyl)piperazine

< / BR>
2-Ftorirovannom (11.4 g, 81 mmol) was dissolved in dimethyl sulfoxide (200 ml) and added piperazine (of 56.4 g of 0.65 mol) and sodium carbonate (20.6 g, 0,2 mol). The mixture is stirred at 130oC for 16 hours. After cooling, add toluene (300 ml) and washed with a mixture of water (3300 ml) and 1N sodium hydroxide (300 ml). The organic phase is dried (gSO4) and concentrated in vacuo. The remainder of the clean flash chromatography on silica gel, elwira first with a mixture of ethyl acetate, heptane and triethylamine (5:5:0,25), then a mixture of ethyl acetate and triethylamine (9:1) and finally with a mixture of methanol and triethylamine (40: 1). This gives 1-(2-nitrophenyl)-piperazine (8,08 g, 48%).

TLC: Rf=0,27 (SiO2: ethyl acetate/methanol/triethylamine 1:1:0,25).

The above piperazine (1.51 g, 7.3 mmole) dissolved in methyl ethyl ketone (50 ml), add 5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo [a,d] cyclohepten (2.28 g, 7.3 mmole), potassium iodide (0.96 g, 15 mmol) and potassium carbonate (6.0 g, 44 mmole) and the resulting mixture is stirred at the boiling temperature under reflux for 24 hours. After cooling, add ethyl acetate (100 ml) and the mixture washed with water (2100 ml), dried (gSO4) and concentrated in Vacu is that a mixture of ethyl acetate and heptane (1:2), and receiving of 2.18 g (68%) of free base. It is dissolved in diethyl ether (30 ml) and add 1N hydrochloric acid in diethyl ether (5 ml). Saducees solid allocate by filtration and dried in vacuum, obtaining of 1.83 g (53%) specified in the connection header.

So pl. 204-206oC.

Calculated for C28H29N3O2HCl: 70,65%; N 6,35%; N 8,83%;

Found: 70,50%; N 6,51%; N 8,61%.

EXAMPLE 13

2-(4-(3-(10,11-Dihydro-5H-dibenzo[a, d]cyclohepten-5-ilidene; 1-propyl)-1-piperazinil)benzonitrile

< / BR>
Piperazine (6.0 g, 69 mmol) was dissolved in dimethyl sulfoxide (50 ml), add 2-perbenzoate (0.95 ml, 9 mmol) and potassium carbonate (2.2 g, 17 mmol) and the mixture stirred at room temperature for 16 hours. Add water and extracted with a mixture of toluene (2100 ml). The combined organic extracts are washed with 1N sodium hydroxide (375 ml), dried (gSO4) and concentrated in vacuo, receiving 1.48 g (88%) of 2-(1-piperazinil)benzonitrile in the form of oil. TLC: Rf=0,12 (SiO2: ethyl acetate/triethylamine = 4:1).

The above benzonitrile (4,89 g, 26 mmol) dissolved in methyl ethyl ketone (100 ml) and add potassium carbonate (21,7 g, 157 mmol), potassium iodide (3,45 g, 52 mmole) and 5-(3-bromo-1-propylidene;-10,11-dihydro-5H-dibenzo[a, d] cyclohepten (8,18 g, 26 molality to room temperature, add ethyl acetate (200 ml) and the mixture washed with water (2150 ml), dried (gSO4)and concentrated in vacuo. The remainder of the clean flash chromatography on silica gel, elwira first with a mixture of ethyl acetate and heptane (1:4) and then a mixture of ethyl acetate and heptane (1:2). This gives the ceiling of 5.60 g specified in the connection header in the form of a solid substance.

So pl. 112-114oC.

Calculated for C29H29N3: 83,02%; N 6,97%; N 10,02%;

Found: 83,25%; N 7,14%; N To 9.93%.

EXAMPLE 14

Hydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-1-piperazinil benzoic acid

< / BR>
2-(4-(3-(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ilidene)-1-propyl)-1-piperazine)benzonitrile (0,30 g, 0.72 mmole, obtained as described in example 13) are added to a mixture of water (0.6 ml), sulfuric acid (0.6 ml) and acetic acid (0.6 ml). The resulting mixture is heated at boiling temperature under reflux for 24 hours and stirred for 3 days at room temperature. Added 1N sodium hydroxide (20 ml) and washed with diethyl ether (320 ml). The aqueous phase is acidified with 5N hydrochloric acid to pH 1. The mixture is extracted with dichloromethane (250 ml), the combined extracts dried (gSO4) and is evaporated in vacuum, obtaining 0.21 g (56%) indicated in the title compound as amorphous twerdok,58%;

Found: 69,69%; N, 6.69 Per Cent; N Is 5.06%.

Mass spectrometry with electron ionization (70 eV):

m/e=438 (M+,0, 1%).

EXAMPLE 15

The dihydrochloride of 1-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-4-(3-trifluoromethyl-2-pyridyl)piperazine

< / BR>
A mixture of 5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo-[a, d] cycloheptene (1.10 g, 3.5 mmole, obtained as described in WO 9518793), 1-(3-(trifluoromethyl)-2-pyridyl)piperazine (0,81 g, 3.5 mmole), potassium carbonate (1.45 g, 10.5 mmole) and sodium iodide (of 0.53 g, 3.5 mmole) in dry 2-butanone (10 ml) heated at boiling temperature under reflux for 40 hours. The solvent is removed in vacuo, and the residue is dissolved in toluene (25 ml) and water (25 ml). The organic layer is separated, dried (gSO4) and concentrated in vacuo. The residue is cleaned by a chromatography method with instant evaporation on silica gel, using as eluent a mixture of toluene and ethyl acetate (3:1) containing 2.5% triethylamine, and getting 1.54 g (95%) of free base. It is dissolved in tetrahydrofuran (25 ml) and add 1N hydrogen chloride in diethyl ether (7 ml). Saducees solid allocate by filtration and dried in vacuum, obtaining 1.45 g (77%) indicated in the title compound in the form of a solid vase,64%; N 7,83%;

Found: 61,99%; N Of 5.82%; N 7,60%.

EXAMPLE 16

The dihydrochloride 2-(4-(2-(6,11-dihydrobenzo[b,e]thiepin-11-ilidene)ethyl)-piperazine-1-yl)-3-pyridineboronic acid

< / BR>
A mixture of 11-(2-bromation)-6,11-dihydrobenzo[b, e] tiepin (2.5 g, of 7.9 mmole, obtained as described in Coll. Czech. Chem. Comm. 52, 1566 (1987)), ethyl 2-(1-piperazinil)-3-pyridinecarboxylic (1.86 g, of 7.9 mmole), potassium carbonate (1.45 g, 10.5 mmole) and N,N-dimethylformamide (15 ml) is stirred and heated at 150oC for 10 hours. The mixture is diluted with water and extracted with benzene (50 ml). The organic phase is dried (potassium carbonate), filtered and the solvent evaporated in vacuum. The oily residue is purified silica gel (50 g), using ethyl acetate as eluent and receiving base, which was dissolved in diethyl ether and neutralized with oxalic acid in acetone. This gives 2.7 g (54%) of ethyl hemihydrate 2-(4-(2-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)ethyl)-1-piperazinil)-3-pyridine carboxylate of hydroarsenate.

TLC: Rf=0,5 (SiO2: chloroform/ethanol/ammonia = 40:2:1).

The above ester (2.25 g, of 4.77 mmole) is dissolved in ethanol (40 ml) and added 5N sodium hydroxide (3 ml). The mixture was stirred at 40oC for 20 hours, the ethanol is evaporated in vacuumize dried (gSO4) and the solvent evaporated in vacuum. The residue is dissolved in acetone and neutralized hydrogen chloride in diethyl ether, receiving 2,13 g (85%) indicated in the title compound in the form of a hemihydrate.

So pl. 188-195oC.

Calculated for C26H25N3O2S, 0.5 H2O 2HCl:

With 59,42%; N 5.37 Percent; N 8,00%; Cl 13,49%; S 6,10%;

Found: 56,94%; N 5,23%; N 8,10%; Cl 13,44%; S 5,80%.

EXAMPLE 17

The dihydrochloride 2-(4-(3-(6,11-dihydrothieno[b, e] thiepin-11-ilidene)-1-propyl)-1-piperazinil)-3-pyridineboronic 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 drop by drop to a solution of 6,11-dihydrobenzo[b,e]thiepin-11-she (3.5 g, to 0.016 mol, obtained similarly as described in Chem. Pharm. Bull. 39, 1991, 2564) in dry tetrahydrofuran (50 ml). When the addition is complete, the mixture is heated at 50oC for 2 hours. The reaction mixture was cooled in an ice bath and carefully add ammonium chloride (50 ml) and water (50 ml). The mixture is extracted with diethyl ether (2100 ml), dried (gSO4), filtered and the solvent is evaporated in vacuum, obtaining 4.4 g cirulatory in dichloromethane (50 ml) and added drop by drop at room temperature the solution 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). The phases are separated 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.

TLC: Rf=0,55 (SiO2: benzene/cyclohexane = 1:3).

The mixture obtained above bromide (3,65 g to 0.011 mol), ethyl ester 2-piperazinil-3-pyridineboronic acid (3.11 g, 0,0132 mole), potassium carbonate (4,55 g, 0,033 mol) and sodium iodide (1,61 g to 0.011 mol) in 2-butanone (53 ml) is heated at the boiling point under reflux for 6 hours. After standing overnight, the reaction mixture was filtered and the filtrate is evaporated in vacuum. Oily residue clean column chromatography on silica gel (70 g) using chloroform as eluent. This gives 4,87 g (91%) of ethyl ester 2-(4-(3-(6,11-dihydro-dibenzo[b,e]thiepin-11-ilidene)-1-propyl)-1-piperazinil)-3-pyridineboronic acid in the form of butter.

TLC: Rf=0,42 (SiO2: ethyl acetate/n-hexane = 1:1).

The above ester (2,77 g, 0,0057 mole) is dissolved in ethanol (46 ml) and added dropwise 4N hydroxide NAT is islote (4,76 ml) and dichloromethane (300 ml) and the organic layer is separated, dried (gSO4) and evaporated in vacuo. The residue is evaporated with dichloromethane (380 ml). After stirring with a mixture of acetone (100 ml) and diethyl ether (100 ml) to obtain 0.75 g (24%) specified in the connection header.

So pl. 161-166oC.

Calculated for C27H27N3ABOUT2S, 2hcl, N2O:

WITH 59,12%; N 5,70%; N 7,66%; S 5,85%;

Found: 59,27%: N 5,61%; N 7,54%; S 6,13%.

EXAMPLE 18

2-(4-(2-(6,11-dihydrobenzo[b, e] thiepin-11 yloxy)ethyl)-1-piperazinil)-3-piridinkarbonovaya acid

< / BR>
6,11-Dihydrobenzo[b, e] thiepin-11-ol (13,2 g, 0,0578 mol, obtained similarly as described in Ceskoslov. Farm. 11, 404 (1962)) was dissolved in benzene (160 ml) and add 2-bromoethanol (10.8 g, 0,086 mole) and concentrated sulfuric acid (2 ml). The mixture is stirred at room temperature for 2 hours, after standing over night add ice water and separated phases. The organic phase is washed with 5% sodium bicarbonate, dried (gSO4), the solvent is evaporated in vacuum, obtaining a residue which is crystallized from a mixture of benzene and cyclohexane. This gives 13.5 g (70%) 11-(2-bromoethoxy)-6,11-dihydrobenzo-[b,e]tiepin in the form of a solid substance.

TLC: Rf=0,08 (SiO2: cyclohexane/ethyl acetate = 5:1).

Nata potassium (1.65 g, 12 mmol) and N,N-dimethylformamide (15 ml) is stirred and heated at 150oC for 10 hours. The mixture is diluted with water and extracted with benzene (50 ml). The organic phase is dried (potassium carbonate), filtered and the solvent evaporated in vacuum. The oily residue is purified silica gel (50 g), using ethyl acetate as eluent and getting free base which was dissolved in diethyl ether and neutralized with oxalic acid in acetone, receiving 3.75 g (74%) hydrate ethyl 2-(4-(6,11-dihydrobenzo[b,e]thiepin-11-laxity)-1-piperazinil)-3-pyridinecarboxylic of hydroarsenate in the form of crystals. Using aqueous ammonia from the above oxalate extract free base and allocate it by extraction with diethyl ether. TLC: Rf=0,55 (SiO2: chloroform/ethanol/ammonia = 40:2:1).

The above free ester (2.65 g, 5.4 mmole) is dissolved in ethanol (40 ml) and added 5N sodium hydroxide (4 ml). The mixture was stirred at 40oC for 20 hours, the ethanol is evaporated in vacuo and water is added (40 ml) and then acetic acid (3 ml). The mixture is extracted with dichloromethane (50 ml). Filtered the product, crystallized from this solution. From the mother liquor is evaporated with dichloromethane and by rubbing with AC is S="ptx2">

So pl. 217-218,5oC.

Calculated for C26H27N3ABOUT3S, 0,25 N2ABOUT: 67,00%; N 5,95%; N 9,02%; S 6,88%;

Found: 67,18%; N Of 5.84%; N 8,99%; S 6,64%.

EXAMPLE 19

Hydrochloride 6-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene; -1-propyl)piperazine-1-yl-2-pyridineboronic acid

< / BR>
To a solution of ethyl ester of 6-piperazinil-2-pyridine-carboxylic acid (7.0 g, of 0.03 mol) in 2-butanone (150 ml) is added 3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl of methansulfonate (6.8 g, 0,0207 mol) and potassium carbonate (8.0 g). The reaction mixture is heated at 40oC for 3 hours. After standing overnight at room temperature, continue heating for 9 hours at 60oS and 9 hours at the boiling temperature under reflux. The solid is filtered off, washed with acetone and the filtrate is evaporated in vacuum. The remainder of the cleaning column chromatography on silica gel (200 g) using chloroform as eluent. This gives 6,63 g (68%) ethyl ester 6-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-propyl)-piperazine-1-yl)-2-pyridineboronic acid in the form of butter.

TCX: Rf=0,32 (SiO2: petroleum ether/ethyl acetate = 3:2).

To a solution of poluchayut the reaction mixture at room temperature for 60 hours. Add concentrated hydrochloric acid (4.9 ml) and then dichloromethane (230 ml). The mixture is stirred for 5 minutes, split phase and the organic phase is dried (gSO4) and evaporated in vacuo. Foaming the residue is dissolved in acetone (500 ml) and evaporated to one-third of its volume. The formed solid is filtered off, receiving 1.8 g (47%) specified in the connection header.

So pl. 233-243oC.

Calculated for C28H29N3O2, HCl, 0.25 N2About: With 69,98%; N 6,40%; CL, a total of 8.74%; N 7,38%;

Found: 69,90%; N, 6.42 Per Cent; CL Of 8.47%; N 7,52%.

EXAMPLE 20

Hydrochloride 2-(4-(3-(3-methyl-10,11-dihydro-5H-dibenzo[b, f] -azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid

< / BR>
Under nitrogen and under stirring with a magnetic stirrer in an oil bath heated sodium (3,14 g, 0,136 mol) at 120-130oWith up to melting point and then add one drop of methanol (6,1 ml of 0.15 mol). As is a certain amount of unreacted sodium, add methanol (1 ml). The alcoholate is heated at the same temperature for one hour and cooled white friable solid material in a bath of ice and salt to 10-15oC. Add one drop of a mixture of diethyl 2-bromo-phenylmethylsulfonyl (of 27.94 g 0,091 mol) and 4-methyl-2-nitrobenzaldehyde (60 ml). When the addition was completed, the reaction mixture was stirred another 20 minutes at the same temperature, incubated for another 1 hour at room temperature under light while cooling in a water bath and leave overnight in the refrigerator. Add water (150 ml) under cooling in an ice bath, the reaction mixture is still diluted with water (450 ml) and extracted with ethyl acetate (5100 ml). The organic layer was washed with water (100 ml) and dried (gSO4). The residue (32,5 g) is stirred with cyclohexane, the solid is filtered off, dissolved in warm cyclohexane and the hot solution is decanted from the oil which is separated in the flask, and cooled. Saducees the solid is filtered off, washed with cyclohexane and dried (8,9 g) (product A).

The filtrate is combined with the previously separated oil, the mixture is evaporated in vacuum and the residue (19,25 g) clean column chromatography on silica gel (200 g), using as eluent a mixture of cyclohexane and benzene (10:1) and obtaining as a by-product 1,2-bis-(2-bromophenyl)ethylene (3,26 g, 21%).

Changing eluent a mixture of cyclohexane and benzene (1:1) receive an additional portion (6,70 g) solids, identical product. Total output is selected, as shown above, from the reaction cm>=0,75 (SiO2: cyclohexane/ethyl acetate = 5:1).

The solution obtained above nitrobenzene (9,68 g of 30.3 mmole) in ethanol (110 ml) and methanol (40 ml) hydronaut 2 hours at 3 MPa in the presence of the research (0.6 ml) and catalyst Rh/C (CR 319) (2 g). The catalyst is filtered off, the filtrate is evaporated in vacuum and the residue is distilled with toluene (320 ml). After standing at room temperature oily residue crystallizes. After washing the solids with petroleum ether and drying receive 2-(2-(2-bromophenyl)ethyl)-5-methylaniline (8,15 g, 92%).

So pl. 67-69oC.

Calculated for C15H16BrN: 62,08%; N 5,56%; VG 27,54; N A 4.83%;

Found: 62,45%; N 5,70%; VG 27,25; N Is 5.06%.

The mixture obtained above amine (10.4 g, being 0.036 mole) and sodium formate (4.9 g, 0,072 mol) in formic acid (70 ml) is heated at the boiling point under reflux for 3 hours and left to stand overnight.

The reaction mixture was poured into water (500 ml) and stirred for 30 minutes. The solid is filtered off, washed with water and then ethanol. After air drying receive N-(2-(2-(2-bromophenyl)ethyl)-5-were)formamid of 8.3 g, 72%). So pl. 167-169oC.

The mixture obtained above formyl derivative (6.50 g, 20 s (40 ml) is heated to 160oWith, cool, add 20% sodium hydroxide (4 ml) and heat the mixture to 75oWith in 30 minutes. The mixture was poured into water (400 ml) and ethyl acetate (500 ml), filtered off solid, separate the organic layer, washed with 1N hydrochloric acid, 10% hidrocarbonetos of sodium and water (2100 ml) and dried (gSO4). The residue (4,88 g) clean column chromatography on silica gel, using as eluent a mixture of cyclohexane and benzene (1:1). It gives of 2.26 g (54%) of 3-methyl-10,11-dihydro-5H-dibenzo [b,f] azepine. TLC: Rf=0,75 (SiO2: cyclohexane/ethyl acetate = 5:1).

To the solution obtained above azepine (2,09 g of 0.01 mol) in benzene (25 ml) is added a suspension of sodium amide (1.01 g, 0,013 mol, 50% suspension in toluene, diluted with 5 ml of benzene and the mixture is heated to 70oC for 1.5 hours in a nitrogen atmosphere. Then add 1-tetrahydropyranyl-3-bromopropane (2,90 g of 0.013 mol) and the mixture is heated to 70oC for 19 hours. After cooling, the reaction quenched with water (20 ml), add benzene (10 ml), divide the layers and the organic layer dried (gSO4). The remainder (of 3.73 g) was dissolved in methanol (20 ml), added 6N hydrochloric acid (6 ml) and heated the mixture at the boiling point under reflux for 30 minutes. Then methanol is evaporated in vacuua benzene extracts are dried (gSO4). The solvent is evaporated in vacuum and the residue (2.65 g) clean column chromatography on silica gel (50 g), using as eluent a mixture of benzene and ethyl acetate (10:1). This gives 1,83 g (68%) of 5-(3-hydroxypropyl)-3-methyl-10,11-dihydro-5H-dibenzo[b,f]azepine in the form of butter.

TLC: Rf=0,25 (SiO2: chloroform).

To the solution obtained above alcohol (1.70 g, 6.3 mmole) and triethylamine (1.9 g, 18 mmol) in benzene (25 ml) is added drop by drop within 15 minutes a solution of methanesulfonamide (0,91 g of 7.9 mmole) in benzene (8 ml) at 18-20oWith cooling in an ice bath. The reaction mixture was stirred at room temperature for 2 hours. Spin-off the triethylamine hydrochloride is filtered off, washed with benzene (15 ml), the combined benzene layers are washed with water (225 ml) and then brine (20 ml) and dried (gSO4). After evaporation of the solvent in vacuo use oily methanesulfonate (2,07 g, 94%) in the next stage without further purification.

TCX: Rf=0,50 (SiO2: chloroform).

The mixture obtained above methanesulfonate (2,07 g, 6 mmol), ethyl 2-(1-piperazinil)-3-pyridinecarboxylic (1,41 g, 6 mmol), potassium iodide (1,00 g, 6 mmol) and potassium carbonate (2,49 g, 18 mmol) in 2-butanone (40 ml) Nagl) and ether (75 ml), the organic phase is washed with water (20 ml) and dried (gSO4). The solvent is removed in vacuum, obtaining the ethyl ester specified in the connection header (of 3.07 g) as oil. TCX: Rf=0,35 (SiO2: saturated with ammonia in chloroform/ethanol =50:1).

To the solution obtained above ester (2,90 g) in 2-propanol (15 ml; add a solution of oxalic acid dihydrate (0.85 grams) in 2-propanol (5 ml), the mixture is gently heated and then cooled. Separated salt is filtered off, another washed with 2-propanol and ether and dried in vacuum, obtaining of 2.97 g (83%) of ethyl ester oxalate 2-(4-(3-(3-methyl-10,11-dihydro-5H-dibenzo[b,f]-azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid.

From the above oxalate (2.85 g) release the free ether (1,91 g) in dichloromethane suspension with ammonium hydroxide and get it in the form of butter.

To the solution obtained above ester (1,83 g, 3.8 mmole) in ethanol (22 ml) was added 20% sodium hydroxide (2.5 ml) and the mixture is stirred for 5 hours at room temperature. The major part of the methanol is removed in vacuo, the residue is dissolved in dichloromethane (180 ml) and acidified with 2N hydrochloric acid, the aqueous layer was separated, the organic layer washed with water (10 ml), dried (gSO4and remove R is(1,81 g) in acetone. Using the receive filtering crystalline insoluble in acetone the connection specified in the header and saducees from solution (1.26 g, 67%).

So pl. 200-206oC.

Calculated for C28H32N4O2HCl: 68,21%; N 6,75%; CL 7,19%; N 11,36%;

Found: 68,05%; N 6,83%; CL 7,28%; N 10,95%.

EXAMPLE 21

The hydrochloride of 6-(4-(3-(dibenzo[d, g][1,3,6]doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-pyridine-2-carboxylic acid

< / BR>
N-Dibenzo[d, g] [1,3,6] doxazosin (1.7 g, 8 mmole, obtained similarly as described in Example 3) is dissolved in dry benzene (25 ml) at 45oC. In an atmosphere of nitrogen was added a suspension of sodium amide in toluene (1.1 g, 50%, 14 mmol) and the mixture was stirred at 70oC for 2.5 hours. Add fresh 1 tetrahydropyranyloxy-3-bromopropane (2,88 g, 13 mmol, 72oC/70 PA) and the mixture is heated at boiling temperature under reflux for 14 hours and left overnight at room temperature. To the reaction mixture are added benzene (25 ml) and water (25 ml), stirred for 15 minutes and separated. The organic extract is dried (sodium sulfate) and the solvent evaporated in vacuum. The residue (4.9 g) was dissolved in methanol (20 ml), added 6N hydrochloric acid (6,7 ml, 40 metrahit benzene (80 ml), the organic phase is washed with water (30 ml), dried (sodium sulfate) and evaporated in vacuum (3.5 g). The crude product is cleaned chromatography on silica gel (80 g), using as eluent a mixture of benzene and ethyl acetate (10:1). Get 12-(3-hydroxypropyl)dibenzo[d, g][1,3,6]doxazosin (1,36 g, 47%) as oil.

TLC: Rf=0,45 (SiO2: benzene/ethyl acetate = 10:1).

The solution methanesulfonanilide (0,98 g, 8.6 mmole) in dry toluene (10 ml) is added drop by drop for 20 minutes to mix the solution obtained above is derived propanol (1,36 g, 5 mmol) and triethylamine (1.6 g, 15 mmol) in dry toluene (40 ml) under nitrogen atmosphere at room temperature. Is slightly exothermic reaction. The reaction mixture is stirred at 24oC for 3 hours and then at the 36oC for 1.5 hours. Dilute the reaction mixture with toluene (50 ml), washed with water (430 ml) and with brine (25 ml), dried (sodium sulfate) and evaporated in vacuo. Oily mesilate (1.8 g, 100%) used in the next stage without additional purification.

TLC: Rf=0,36 (SiO2: benzene/ethyl acetate = 10:1).

Obtained above mesilate (1.8 g, 5 mmol), ethyl 6-(piperazine-1-yl)pyridine-2-carboxylate (1.9 g, 8 mmol), dry carveout at the boiling point under reflux for 5 hours. Distilled acetone, the residue is dissolved in benzene (150 ml) and washed with water (450 ml) and with brine (30 ml), dried (sodium sulfate) and evaporated in vacuo. Oily residue is cleaned chromatography on silica gel (70 g) using as eluents first benzene and then ethyl acetate. This gives ethyl ester indicated in the title compound (1.44 g, 59%) as oil.

TLC: Rf=0,62 (SiO2: benzene/ethyl acetate = 10:1).

The solution obtained above ester (1.44 g, 2,95 mmole) in ethanol (15 ml) and 5N sodium hydroxide (20 ml) is stirred for 15 minutes at 50-55oAnd then 21 hours at 22oTo add dichloromethane (200 ml) and the mixture is acidified to pH 1 with 2.5 N hydrochloric acid. The organic layer is separated, dried (sodium sulfate) and evaporated in vacuo, getting to 1.14 g of the solid residue, which is triturated with a mixture of acetone (15 ml) and ether (20 ml). The product is filtered and washed with a mixture of acetone-ether (2:3,310 ml) and ether (5 ml) to give 0.9 g (79%) specified in the connection header.

So pl. 224-227oC.

Calculated for C26H29N4ABOUT4, HCl, 0.5 H2O: 61,71%; N 5,98%; N 11,07%;

Found: 61,60%; N 6,05%; N 10,70%.

1. 1,4-Disubstituted piperazines of General formula I

< / BR>
where R1and R2O-, -SCH2-, -CH2-S-;

Y is >C=CH-, >CH-O-, where only the underlined atom participates in the ring system;

r=1, 2, or 3;

Z is selected from

< / BR>
where M1and M2independently are C or N;

R3is hydrogen;

R4is hydrogen or (CH2)mR11where R11is hydroxyl,1-6alkoxy group or other12where R12is hydrogen or C1-6the alkyl and m=0, 1, 2,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1and R2independently are hydrogen, halogen or1-6the alkyl, preferably hydrogen, halogen or stands.

3. The compound according to any one of the preceding paragraphs, in which Y is where only the underlined atom participates in the ring system.

4. The compound according to any one of the preceding paragraphs, in which r=1, 2.

5. The compound according to any one of the preceding paragraphs, in which Z is chosen from

< / BR>
where M1and M2independently are C or n

6. The compound according to any one of the preceding paragraphs, in which m=0, 1.

7. The compound according to any one of the preceding paragraphs, in which R11is hydroxyl.<(3-(12H-dibenzo[d, q] [1,3] dioxin-12-ilidene)-1-propyl)-piperazine-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(2,10-dichloro-N-, dibenzo[d, q](1,3)dioxit-12-ilidene)-1-propyl)-piperazin-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(N-dibenzo[d, q)(1,3,6] doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(2-chlorine-N-dibenzo[d, q] [1,3,6] doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-3-pyridylcarbonyl acid;

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

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

2-(4-(2-10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-ethyl)-1-piperazinil)-3-pyridylcarbonyl acid;

6-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-2-pyridylcarbonyl acid;

2-(4-(3-(10,11-dihydro-5H-dibenzo(b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

2-(4-(3-(10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-5-pyridylcarbonyl acid;

2-(4-(3-3-chloro-10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

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

2-(4-(3-(10,11-dihydro-5H-diben is n-5-ilidene)-1-propyl)-1-piperazinil)benzoic acid;

1-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)-4-(3-trifluoromethyl-2-pyridyl)piperazine;

2-(4-(2-{ 6,11-dihydrobenzo(b, f] thiepin-11-ilidene)ethyl)-piperazin-1-yl)-3-pyridylcarbonyl acid;

2-(4-(3-(6,11-dihydrobenzo[b, e] thiepin-11-ilidene)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid;

2-(4-(2-(6,11-dihydrobenzo[b, e] thiepin-11 yloxy)ethyl)-1-piperazinil)-3-pyridylcarbonyl acid;

6-(4-(3-(10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5-ilidene)-1-propyl)piperazine-1-yl)-2-pyridylcarbonyl acid;

2-(4-(5-3-methyl-10,11-dihydro-5H-dibenzo[b, f] azepin-5-yl-1-propyl-1-piperidyl) -3-piridincarbonova acid;

6-(4-(3-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-piperazine-1-yl)-pyridine-2-carboxylic acid

or their pharmaceutically acceptable salts.

9. Connection on p. 1, representing 2-(4-(3-(10,11-dihydro-3H-dibenz[b, f] -azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid or its pharmaceutically acceptable salt.

10. Connection on p. 1 representing dihydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenz[b, f] -azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid.

11. The compound according to any one of the preceding paragraphs as an active ingredient for Badinerie according to any one of the preceding paragraphs as the active component of the pharmaceutical composition, intended for the treatment of neuropathy.

13. The compound according to any one of the preceding paragraphs as an active component of a pharmaceutical composition intended for the treatment of rheumatoid arthritis.

14. The compound according to any one of the preceding paragraphs as an active component of a pharmaceutical composition intended for the treatment of migraine.

15. The compound according to any one of the preceding paragraphs as an active component of a pharmaceutical composition intended for the treatment of itching.

16. The compound according to any one of paragraphs.11-15, characterized in that it is a 2-(4-(3-(10,11-dihydro-5H-dibenz[b, f] -azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid or its pharmaceutically acceptable salt.

17. The compound according to any one of paragraphs.11-15, characterized in that it is a dihydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid.

18. The method of obtaining the compounds of formula I on p. 1, consisting in the fact that it includes the interaction of the compounds of formula II

< / BR>
where R1, R2X, Y, r such as defined above;

W is the mules III

< / BR>
where Z is as defined above,

with the formation of the compounds of formula 1.

19. Pharmaceutical composition having antihistaminic activity, comprising an active component and a pharmaceutically acceptable carrier or diluent, wherein the active component is used 1,4-disubstituted piperazines according to any one of paragraphs.1-8.

20. The pharmaceutical composition according to p. 19, characterized in that as the active component use 2-(4-(3-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid or its pharmaceutically acceptable salt.

21. The pharmaceutical composition according to p. 19, characterized in that as the active component used dihydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenz[b, f] -azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid.

22. The pharmaceutical composition according to any one of paragraphs.19-21, characterized in that it is intended for the treatment of neurogenic inflammation.

23. The pharmaceutical composition according to any one of paragraphs.19-21, characterized in that it is intended for the treatment of neuropathy.

24. The pharmaceutical composition according to any one of paragraphs.19-21, characterized in that it pre is characterized in that what it is intended for the treatment of migraine.

26. The pharmaceutical composition according to any one of paragraphs.19-21, characterized in that it is intended for the treatment of itching.

27. The pharmaceutical composition according to any one of paragraphs.19-21, characterized in that it comprises from 0.5 to 1000 mg of the compounds according to paragraphs.1-8 in the standard dose.

28. The pharmaceutical composition according to p. 27, characterized in that it includes 2-(4-(3-(10,11-dihydro-5H-dibenz[b, f] -azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid or its pharmaceutically acceptable salt.

29. The pharmaceutical composition according to p. 27, characterized in that it includes dihydrochloride 2-(4-(3-(10,11-dihydro-5H-dibenz[b, f]-azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridineboronic acid.

30. A method of treating neurogenic inflammation in need of such treatment of a patient, characterized in that it includes an introduction to the specified patient an effective amount of a compound according to any one of paragraphs.1-8.

31. The method according to p. 30, characterized in that the injected 2-(4-(3-(10,11-dihydro-5H-dibenz[b, f]-azepin-5-yl)-1-propyl)-1-piperazinil)-3-pyridylcarbonyl acid or its pharmaceutically acceptable salt.

32. The method according to p. 30, wherein introducing the dihydrochloride of 2-(what about the treatment of neurogenic inflammation in need of such treatment the patient p. 30, characterized in that it includes the introduction of a given patient, the compounds of formula I in the form of pharmaceutical compositions under item 19.

34. The method according to p. 33, wherein the administered pharmaceutical composition according to paragraphs.20 and 21.

 

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