Derivatives of dibenzo[d, g][1,3]dioxazine and dibenzo-[d,g][1, 3,6]doxazocin, the method of production thereof, pharmaceutical composition and method of treating neurogenic inflammation, neuropathy and rheumatoid arthritis

 

(57) Abstract:

The present invention relates to new compounds of the formula

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where R1and R2independently are hydrogen, halogen, R3- hydrogen AND - C1-3-alkylene, Y - where only the underlined atom participates in the ring system, and Z are selected from

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where R12- hydrogen R13- hydrogen R14- (CH2)tCOR15where t = 0 or 1, R15HE, WITH1-6-alkoxy; - optional single bond or a double bond; or their pharmaceutically acceptable salts, and method of production thereof, pharmaceutical compositions and methods for treating neurogenic inflammation, neuropathy and rheumatoid arthritis. The technical result is to provide new compounds for the treatment of painful conditions in which C-fibers play a pathophysiological role, causing neurogenic pain or inflammation. 4 C. and 13 C. p. F.-ly, 1 table.

The invention relates to new N-substituted the aminoalcohols, amino acids and derived their acids, where substituted alkyl chain forms part of the M-Deputy, or their salts, to processes for their preparation, to compositions containing them and their use for the clinical treatment TEW), and/or inflammatory conditions in which C-fibers play a pathophysiological role, causing neurogenic pain or inflammation.

This invention relates to the use of these compounds for the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM, NIDDM) or aging, and data connections, as is known, harm containing neuropeptide C-fibers and, therefore, inhibit the secretion and circulation of insulin antagonizers peptides, such CGRP or anilino.

The nervous system has a profound effect on the response of inflammation (inflammatory response). Interamna (oppositely directed) stimulation of sensory nerves leads to localized vasodilation (widening of blood vessels) and increased vascular permeability (Janecso et al. , Br. J. Pharmacol. , 1967, 31, 138-151), and a similar response is observed after injection of peptides known to be present in the sensitive nerves. These and other studies postulate that the peptides released from the endings of sensory nerves that mediate many of the inflammatory reaction in tissues such as skin tissues, joints, urinary tract, eye, and tissue membranes of the brain (meninges), gastro-kichen/or activity can be used in the treatment, for example, arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombophlebitis, glaucoma, gastrointestinal disease or migraine,

Further, a strong effect of CGRP on the activity glikogensintetazy skeletal muscle and muscle glucose metabolism, as well as taking into account that this peptide is released from the neuromuscular junction (junction) with nervous excitement, confirm that CGRP may play a physiological role in glucose metabolism of skeletal muscle, directing phosphorylated glucose by store (depositing) of glycogen and glycolytic and oxidative pathways (Rossetti et al. , Am. J. Physiol. , 254, E1-E10, 1993). This peptide may represent an important physiological modulator of intracellular movement of glucose in physiological conditions, such as physical activity, may also contribute to the reduction of insulin action and glikogensintetazy skeletal muscle in pathophysiological conditions, such NIDDM, or aging related to obesity (Melnyk et al. , Obesity Res. , 3, 337-344, 1995), when circulating plasma levels of CGRP significantly increased. Therefore, inhibition of allocation and/or activity of the neuropeptide CGRP can be used in the treatment of insulin resistance associated with Diab N-(4,4-disubstituted-3-butenyl) azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801 N-substituted azaheterocyclic carboxylic acids, in which the oxime-ether group and vinyl ether group form part of the N-substituent, respectively, are claimed as inhibitors of GABA uptake. In addition, in WO 9107389 and WO 9220658 N-substituted usacycling karbonovy acid are claimed as inhibitors of GABA uptake. In EP 221572 States that 1-aryloxyalkyl-3-carboxylic acid are inhibitors of GABA uptake.

In DE 2833892 claimed some derivatives N-dibenzo [d, g] [1,3,6] doxazosin as local anesthetics or to treat Parkinson's disease.

This invention relates to new N-substituted the aminoalcohols, amino acids and derivatives, their acid formula I:

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where R1and R2independently are hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy;

R3is hydrogen or C1-3-alkyl;

And is C1-3-alkylene;

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

Z is selected from

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< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where n= 1 or 2;

R11is hydrogen or C1-6-alkyl;

R12is hydrogen or CC1-6-alkyl or C1-6-alkoxy;

R13is hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy;

R14represents -(CH2)mHE or - (CH2)tCOR15where m= 0, 1, 2, 3, 4, 5 or 6, and t= 0 or 1, and where R15is HE, NH2, -NHOH or C1-6-alkoxy;

R16represents C1-6-alkyl or-B-COR15where In represents C1-6-alkylen,2-6-albaniles or2-6-akinyan,

R15is the same as above;

- optional single bond or a double bond;

or their pharmaceutically acceptable salts.

The compounds of formula I can exist as geometric and optical isomers, and all isomers and mixtures thereof are included in the scope of the invention. The isomers can be separated using standard methods, such as chromatographic techniques or fractional crystallization of suitable salts.

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

Compounds according to the invention may not necessarily exist in the form of pharmaceutically acceptable salts of joining acids and optionally alkyl ammonium salts.

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

Used herein, the term "C1-6-alkyl", alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1-6 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.

Used herein, the term "C1-6-alkoxy", alone or in combination, refers to a straight or branched, monovalent Deputy, including C1-6is an alkyl group linked through an ether oxygen having a free valence bond from the ether oxygen and having 1-6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentek is s, covered by this invention include:

2-Chloro-12-(3-dimethylamino)propylidene-N-dibenzo[d, g] [1,3] dioxin

2,10-Dichloro-12-(2-dimethylamino)ethoxy-N-dibenzo[d, g] [1,3] dioxin

2,10-Dichloro-12-(3-dimethylamino)propyl-N-dibenzo[d, g] [1,3] dioxin

2,10-Dichloro-12-(3-dimethylamino-1-methyl)ethoxy-N-dibenzo[d, g] [1,3] dioxin

3-Chloro-12-(2-dimethylaminopropyl)-N-dibenzo[d, g] [1,3] dioxin

3-Chloro-12-(3-dimethylamino)propylidene-N-dibenzo[d, g] [1,3] dioxin

3-Chloro-12-(3-dimethylamino-1-methylpiperidin)-N-dibenzo[d, g] [1,3] dioxin

2-Fluoro-12-(3-dimethylamino)propylidene-N-dibenzo[d, g] [1,3] dioxin

2-Methyl-12-(3-(4-methyl-1-piperazinil)propylidene-N-dibenzo [d, g] [1,3] dioxin

2-Chloro-12-(3-(4-methyl-1-piperazinil)propylidene-N-dibenzo [d, g] [1,3] dioxin

3-Chloro-12-(3-(4-methyl-1-piperazinil)propylidene-N-dibenzo-[d, g] [1,3] dioxin

Ethyl Efir-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)propyl)-3-piperidinecarboxylic acid 1-(3-(N-Dibenzo [d, g] [1,3] dioxin-12-ilidene)propyl)-3-piperidinecarboxylate acid

or their pharmaceutically acceptable salt.

Used herein, the term "patient" includes any mammal that would benefit from treatment of neurogenic pain or the t to limit in this way.

It was demonstrated 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 induced by formalin pain or swelling of the legs. (Wheeler and Cowan, Agents Actions 1991, 34, 264-269), in which the new compounds of formula I demonstrate a strong inhibitory effect. The compounds of formula I can be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role, causing neurogenic pain or inflammation, i.e.:

acutely painful conditions, examples of which are migraine, postoperative pain, burns, bruises, post herpetic pain (Zoster) and pain as such, usually associated with acute inflammation, chronic, painful and/or inflammatory conditions, examples of which are the various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondaic, gout, inflammatory bowel disease, prostatitis, pain and cancer pain, chronic headache, cough, asthma, chronic pancr the ASS="ptx2">

In addition, it was demonstrated 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 and obesity associated with aging. Experimentally it has been demonstrated by subcutaneous injection of glucose ob/ob mice subjected to preliminary oral treatment with compound of General formula I or not subjected to this treatment.

The compounds of formula I can be obtained in the following way:

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The compound of formula II, where R1, R2, R3And Y are such as defined above, and W represents a suitable tsepliaeva group, such as halogen, p-toluensulfonate or mesilate may interact with azaheterocyclic compound of formula III where Z is as defined above. This alkylation reaction may be performed in a solvent such as acetone, disutility ether, 2-butanone, metaldetector, ethyl acetate, tetrahydrofuran (THF) or toluene, in the presence of a base such as sodium hydride and a catalyst, such as iodide selecing the example, 1-120 hours If received esters in which R15is alkoxy, then the compounds of formula I, where R15is 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 for 0.5-6 hours

Compounds of formulas II and III can be easily obtained by methods well known to specialists in this field.

In some cases it is necessary to protect the intermediates used in the above methods, for example the compound of formula III, suitable protecting groups. The group of carboxylic acids, for example, you can atrificial. The introduction and removal of such groups described in "Protective Groups in Organic Chemistry", J. F. W. McOrnie ed (New York, 1973).

Pharmacological methods

I. Caused by formalin pain or swelling feet

Values in vivo inhibition caused by formalin pain or swelling of the legs of the compounds of this invention evaluated in mice mainly by the method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).

NMRI mice-females weighing about 20 g injected 20 ml of 1% formalin in the left hind paw. Then the animals are placed on a heated (31o(C) the table and assess the ECE between the legs is used as a criterion (reading) edematous response paws, injected formalin.

II. Caused by histamine swelling feet

Values in vivo inhibition caused by histamine swelling of the compounds of this invention evaluated in rats essentially as described by Amann et al. , (Europ. J. Pharmacol. , 279, 227-231, 1995).

Briefly, Sprague-Dawley rats (males) weighing 250-300 g anaesthetize pentobarbital sodium and put it on the table, heated to 32 degrees. After ten minutes in the right hind paw injected histamine (50 microlitres, 3 mg/ml) and after 20 minutes determine the swelling of the legs with water plethysmography (Ugo Basile). Compound is administered intraperitoneally 15 minutes before anesthetics (see tab. 1).

III. Reduced release of CGRP

ob/ob mice-females at the age of 16 weeks is injected glucose (2 g/kg) subcutaneously. In the future, after a certain time determine the levels of glucose in blood from the tail vein glucose oxydase method. At the end of the study animals decapitate and blood collected from the body. Immunoreactive CGRP determined in plasma using radioimmunoassay analysis. Use two groups of animals. One group is treated with a solvent, while the other group receives a compound of formula I with drinking water (100 mg/l) for five days to test the BA introduction and correct treatment. However, generally satisfactory results are obtained with a dose from about 0.5 mg to 1000 mg, preferably 1 mg to about 500 mg, of the compounds of formula I, usually given from 1 to 5 times a day, not necessarily in the form of extended (long) release. Usually, dosage forms suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula 1, mixed with a pharmaceutical carrier or diluent.

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

In addition, this invention also relates to pharmaceutical compositions comprising a compound of formula I or its pharmaceutically acceptable salt, and usually such compositions also contain a pharmaceutical carrier or diluent. Compositions containing the compounds of this invention can be obtained using conventional methods and can be performed in conventional forms, for example capsules, tablets, solutions ielem. Examples of solid carriers are lactose, magnesium oxide, sucrose, talc, gelatin, agar, pectin, gum Arabic, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

Similarly, the carrier or diluent may include any substance that promotes prolongation (retention time), known in the field, such as glyceryl the monostearate or glyceryl distearate, alone or mixed with resin.

If for oral administration use solid media, the preparation can be tableted, placed in a hard gelatin capsule in powder form or granules, or it may be in the form of tablets or cakes. The amount of solid carrier may vary, but typically ranges from about 25 mg to about 1 g If you use a carrier liquid, the preparation 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.

Typically, the compounds of this invention are released in a single dosage form comprising 50-200 mg of the active ingredient or together with a pharmaceutically PR mg/day, for example about 100 mg per dose, when administered to patients, such as people, as a medicinal product.

A typical tablet, which can be obtained using standard tabletting techniques, contains mg:

Core:

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

Colloidal silicon dioxide (Aerosil) and 1.5

Cellulose, microcryst. (Avicel) - 70

Modified cellulose resin (Ac-Di-Sol) - 7, 5

Magnesium stearate

Coverage:

A receiver array, approx. - 9

*Mywacett 9-40T, approx. - 0, 9

* The acylated monoglyceride used as plasticizer for film coating

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, vnutrenniy, intramuscular, local, intravenous, be, ophthalmic solution or an ointment, and oral route is preferred.

EXAMPLES

The method of obtaining compounds of formula (I) and preparations containing them in the future is illustrated by the following examples, which, however, is not to be considered is atiu and Dl3- deuterated chloroform and (DMSO-d6) (DMSO-d6) - hexadeuterated dimethyl sulfoxide. Structures of the compounds are confirmed by either using elemental analysis or NMR (nuclear magnetic resonance (NMR), where, when appropriate, presents peaks attributed to the characteristic protons in these compounds. 1H-NMR shifts (N) are presented in ppm M. D. (ppm). So pl. (M. p. ) - melting point, and it is expressed inoAnd not corrected. Column chromatography is carried out using the method described by W. C. Still et al. , J. Org. Chem. , (1978), 43, 2923-2925, on Merck silica gel 60 (Art. 9385). The compounds used as starting compounds are either known compounds, or compounds that can be easily obtained by methods known per se.

Example 1

1-(3-(N-Dibenzo [d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid hydrochloride

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2,2'-Dihydroxybenzophenone (10.0 g, to 46.7 mmol) and diiodomethane (13,1 g, 49 mmol) was dissolved in dry dimethylformamide (180 ml). Add dried finely ground powdered potassium carbonate (9.2 grams, from 66.7 mmol) and the mixture is heated at 105oC for 16 h, After cooling to room temperature the reaction mixture in the mixture of ethanol (80 ml) and 4N sodium hydroxide (20 ml). The solution is stirred at the boiling temperature of phlegmy for 1 h, 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-2-it is in the form of a solid (9.5 g, 90% yield).

So pl. 93-95oWITH

Bromide solution cyclopropylamine in dry tetrahydrofuran (obtained from cyclopropylamine (24.2 g, 0.2 mol), magnesium turnings (a 4.86 g, 0.2 mol) and dry tetrahydrofuran (70 ml) was placed in a nitrogen atmosphere. Added dropwise 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 h, cooled and added to ice a mixture of saturated ammonium chloride (400 ml) and ether (200 ml). The organic layer is separated, the aqueous phase is extracted with ether (50 ml), the combined organic extracts washed with water (2100 ml) and brine (50 ml), dried over MgSO4, evaporated in vacuum and released from the light fractions (desorbed) toluene (225 ml) to give 11.2 g of 12-cyclopropyl-N-dibenzo[d, g] [1,3] dioxin-12-ol.

1H NMR (200 MHz, CDCl3): 0,50 (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 a solution of ol). The reaction mixture was stirred at room temperature for 1 h and poured on ice, the acidic solution of saturated sodium carbonate (75 ml). The organic phase is separated, washed with ice water (275 ml) and brine (75 ml), dried over gSO4and evaporated in vacuum, obtaining of 7.95 g of the crude 12-(3-bromo-1-propylidene) -N-dibenzo [d, g] [1,3] dioxazine, which is used in the next stage without additional purification.

A mixture of the above crude bromide (1,83 g, 5.5 mmol), ethyl 3-piperidinecarboxylate (0,865 g, 5.5 mmol), dried potassium carbonate (2.28 g, 16.5 mmol), sodium iodide (0,82 g, 5.5 mmol) and 2-butanone (25 ml) is heated at the boiling temperature of phlegmy within 3 hours After cooling to room temperature, to the reaction mixture is added diethyl ether (50 ml) and water (50 ml). The organic layer was separated, washed with water (250 ml) and acidified by adding 2 N hydrochloric acid. The aqueous layer was separated and the organic phase is extracted twice with water (50 ml). The combined aqueous extracts are adjusted to pH 8.5 with saturated sodium bicarbonate solution and extracted with dichloromethane (225 ml). The organic extract was washed with water (50 ml). Dried over MgSO4and evaporated in vacuum, obtaining at%).

The above ester (1.66 g, 4.0 mmol) dissolved in ethanol (20 ml) and added 2N sodium hydroxide (6.6 ml, 13,2 mmol). The mixture is stirred at room temperature for 1.5 hours, the Ethanol is evaporated in vacuo and the residue diluted with water (25 ml). Add 1 N hydrochloric acid (17.6 ml) and the solution washed with diethyl ether (25 ml). The aqueous phase is extracted with dichloromethane (330 ml). The combined organic extracts dried over MgSO4and evaporated in vacuum, obtaining 1.1 g of the above compound in the form of foam, which was triturated with ethyl acetate, filtered and dried.

So pl. 190-192oC, decomp.

Calculated for C23H25NO4HCI0,25 C4H8O2:

With, 65,82%; H, 6.44% of the; N, 3,20%; Found:

WITH, 65,76%; N TO 6.58%; N, 3,05%.

Example 2

(R)-1-(3-(N-Dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid hydrochloride

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A mixture of 12-(3-bromo-1-propylidene)-N-dibenzo[d, g] [1,3] dioxazine (of 7.90 g, 22 mmol, obtained as described in example 1), (L)-tartrate ethyl ester (R)-3-piperidinecarboxylic acid (6.60 g, 22 mol), powdered potassium carbonate (12.2 g, 88 mmol), sodium iodide (3.5 g, 22 mmol) and 2-butanone (100 ml) heated at boiling temperature under reflux in t the cue layer is separated, washed with water (250 ml) and acidified by addition of 2 N hydrochloric acid. The aqueous layer was separated and the organic phase is extracted twice with water (50 ml). The combined aqueous extracts are adjusted to pH 8.5 using a saturated solution of sodium bicarbonate and extracted with dichloromethane (225 ml). The organic extract was washed with water (50 ml), dried over MgSO4and evaporated in vacuum. The obtained residue (6,21 g) purified by chromatography on silica gel using a mixture of toluene and ethyl acetate as eluent, obtaining the ethyl ester of (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl} -3-piperidinecarboxylic acid in the form of oil (3,96 g, 41%).

The above ester (a 3.06 g, 7.5 mmol) dissolved in ethanol (40 ml) and add 2 N sodium hydroxide (12,4 ml of 24.8 mmol). The mixture is stirred at room temperature for 1.0 hours, the Ethanol is evaporated in vacuo and the residue diluted with water (25 ml). the pH is brought to 6 by addition of 1 N hydrochloric acid and the solution washed with diethyl ether (25 ml). The aqueous phase is extracted with dichloromethane (330 ml). The combined organic extracts dried over gSO4and evaporated in vacuum, obtaining a 2.75 g of a foam which was dissolved in tetrahydrofuran (75 ml). Added dropwise an excess chloris%).

So pl. 227-228oC, decomp.

Calculated for C23H25NO4HCl:

With, 66,42%; N, 6.30%, And; N, 3,37%; Found:

WITH, 66,50%; N 6,61%; N, 3,14%.

Example 3

Hydrochloride ethyl ester (R)-1-(3-(N-dibenzo-[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylic acid

Ethyl ester of (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-ilidene)-1-propyl)-3-piperidinecarboxylic acid (0,86 g, 2.1 mmol, obtained as described in example 2) dissolved in tetrahydrofuran (10 ml) and added dropwise 2.6 N solution of hydrogen chloride in ether (0,97 ml, 2,52 mmol). The solution is evaporated in vacuum and the residue is treated with ether (20 ml). The precipitate is filtered off, washed with ether and dried in vacuum, obtaining a named connection in the form of powder.

Calculated for C25H29NO4HCl0,5 H2O:

With, 66,29%; N, 6,90%; N, 3.09% Of; Found:

WITH, 65,97%; N 7,03%; N, 2.87% OF.

Example 4

1-(3-(N-Dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-4-piperidinecarbonitrile acid hydrochloride

< / BR>
A mixture of 12-(3-bromo-1-propylidene)-N-dibenzo[d, g] [1,3] dioxazine (4.0 g, 12 mmol, obtained as described in example 1), ethyl ester of 4-piperidinecarboxylic acid (1.9 g, 12 mmol ), anhydrous potassium carbonate (5.0 g) and sodium iodide (0.2 g) in N, N-DIMET the Ute and washed with benzene (40 ml) and the filtrate is diluted with additional benzene (120 ml). The benzene solution washed with water (350 ml), dried over gSO4and evaporated in vacuum. The oily residue (4.8 g) purified by chromatography on silica gel using a mixture of benzene - ethyl acetate as eluent, obtaining the ethyl ester of 1-(3-(N-dibenzo [d, g] [1,3] dioxin-12-ilidene)-1-propyl)-4-piperidinecarboxylic acid in the form of an oil (2.3 g, 47%).

The above ester (2.30 g, 5.6 mmol) was dissolved in ethanol (30 ml), add 20% sodium hydroxide solution (3.5 ml) and the mixture is stirred at room temperature for 7 hours, the Solution was diluted with dichloromethane (240 ml) and acidified with concentrated hydrochloric acid (3 ml). The mixture was washed with water (10 ml), the organic phase is dried over MgSO4and evaporated in vacuum. The solid residue is washed with acetone, filtered and dried in vacuum, obtaining the titled compound (1.8 g, 73%).

So pl. 239-245oWITH,

Calculated for C23H25NO4NS,5 C2H5OH:

With, 65,67%; N, 6,66%; Cl, 8.08 per cent; N, 3,19%;

Found:

With, 65,51%; N 6,35%; C1, 8,78%; N, 3.27 Per Cent.

Example 5

(R)-1-(3-(2,10-Dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid hydrochloride

< / BR>
2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0,042 mol, obtained an is dimethylformamide (226 ml). Add the dried powdered potassium carbonate (8,3 g) and the mixture is heated at 105oC for 5 h and left overnight at room temperature. The reaction mixture was poured on ice (220 g). After 0.5 h the precipitate is collected by filtration and dissolved in diethyl ether (500 ml). The organic layer was washed with 5% sodium hydroxide (50 ml), dried over MgSO4and evaporated in vacuum, obtaining 12 g (96%) 2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-2-it is in the form of a solid substance.

To a solution of bromide cyclopropylamine in dry tetrahydrofuran (obtained from cyclopropylamine (15.7 g, 0,130 mol), magnesium turnings (3,15 g, 0,130 mol) and dry tetrahydrofuran (45 ml) under cooling for 5 minutes, add a solution of the above ketone (of 7.65 g, was 0.026 mol) in dry tetrahydrofuran (30 ml). The reaction mixture was stirred at 38-42oC for 3 h, cooled in a bath with ice and add a mixture of saturated ammonium chloride (260 ml) and diethyl ether (130 ml). The reaction mixture is filtered, the organic layer is separated, the aqueous phase is extracted with diethyl ether (35 ml). The combined organic extracts washed with water (270 ml) and brine (70 ml), dried over MgSO4and evaporated in vacuum. The crude product is purified colonics ropyl-N-dibenzo[d, g] [1,3] dioxin-12-ol in the form of a solid substance. To a solution of the 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 was stirred at room temperature for 1 h and poured onto cooled ice saturated solution of acid sodium carbonate (80 ml). The organic phase is separated, washed with water (280 ml) and brine (80 ml), dried over MgSO4and evaporated in vacuum. This gives 9,12 g of oil, which is purified column chromatography on silica gel (250 g) using a mixture of cyclohexane: benzene (3: 1) as eluent. It gives of 6.61 g (62%) 2,10-dichloro-12-(3-bromo-1-propylidene)-N-dibenzo[d, g] [1,3] dioxazine in the form of an oil which crystallizes upon standing.

A mixture of the above bromide (3.0 g, 0,0075 mol), ethyl ester tartrate (R)-3-piperidinecarboxylic acid (3,45 g, 0,0112 mol), dried potassium carbonate (10,35 g of 0.075 mol) and N, N-dimethylformamide (42 ml) is heated at 60oC for 12 hours After cooling to room temperature, add water (150 ml) and benzene (75 ml). The organic layer was separated, washed with water (360 ml), dried over gSO4and evaporated in vacuum. The crude oil is purified column chromatography on silica gel (65 g), use the-12-ilidene)-1-propyl)-3-piperidinecarboxylic acid in the form of butter.

The above ester (1.44 g, of 0.003 mol) is dissolved in ethanol (25 ml) and add 4 N sodium hydroxide (3,36 g of 0.013 mol). The mixture is left at room temperature over night. Add concentrated hydrochloric acid (1,68 ml) and then dichloromethane (170 ml), the organic layer is separated, dried over gSO4and evaporated. Evaporation is repeated with dichloromethane (120 ml) and acetone (20 ml). The oily residue is dissolved in acetone (10 ml) to give after 12 h at room temperature 0,54 g (37%) of the named compound in the form of crystals.

1H-NMR (250 MHz, DMSO-d6):N =7,49 (d, J= 2.5 Hz, 1H); to 7.32 (DD, J= 2.5 Hz and 8.8 Hz, 1H); 7,26 (DD, J= 2.5 Hz and 8.8 Hz, 1H); 7,19 (d, J= 2.5 Hz, 1H); to 7.09 (d, J= 8,8 Hz, 1H); 6,97 (d, J= 8,8 Hz, 1H); 6,09 (t, J= 7.2 Hz, 1H); of 5.84 (s, 2H); 2,43 (K, J= 7.2 Hz, 2H); 3.15 in (t, J= 7.2 Hz).

Calculated for C23H23CL2NO2l0,53H6ABOUT:

With, 57,26%; N, And 5.30%; N, 2.73 Percent; Cl, 20,70%;

Found:

With, 56,95%; N 5,31%; N, 2,53%; Cl, 20,75%.

Example 6

1-(3-(N-Dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinyloxy acid hydrochloride

< / BR>
A mixture of 12-(3-bromo-1-propylidene)-N-dibenzo [d, g] [l, 3] dioxazine (5,00 g, 15 mmol), obtained as described in example 1), methyl 3-pyrrolidineethanol (3, 04 g, 15 nipania under reflux for 5 hours The reaction mixture is cooled and water is added (140 ml) and ether (140 ml). The mixture is vigorously stirred for 5 minutes, the organic layer separated, washed with water (250 ml) and dried over MgSO4. The solvent is evaporated in vacuum and the residue (4,34 g) is subjected to column chromatography on silica gel (100 g) using a mixture of dichloromethane: methanol (10: 1) as eluent. It gives of 1.05 g of methyl ester 1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinyloxy acid.

To the above solution of ester of 0.85 g, 2.1 mmol) in ethanol (16 ml) was added 20% sodium hydroxide (1.3 ml), the mixture is stirred at room temperature for 2 h and left to stand overnight. The solution was poured into dichloromethane (100 ml), cooled in a bath with ice, acidified with 2N hydrochloric acid and stirred for 10 minutes. Add water (5 ml). The organic layer is dried over gSO4partially discolor activated charcoal and evaporated in vacuum. The hydrochloride of the above compound is isolated in the form of a hygroscopic amorphous solid (0.64 g, 77%).

So pl. 70-90oC.

1H NMR (250 MHz, CDCl3): Nto 7.15 (m, 8H); 5,95 (t, J= 7.2 Hz, 1H); to 5.85 (s, 2H); 3,36-1,51 (BL, 13H).

Calculated for S="ptx2">

Example 7

1- (3-(2,10-Dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinyloxy acid hydrochloride

< / BR>
A mixture of 2,10-dichloro-12-(3-bromo-1-propylidene)-N-dibenzo [d, g] [1,3] dioxazine (4.0 g, 0.01 mol, obtained as described in example 5), acetate methyl ester 3-pyrrolidinyloxy acid (2,23 g to 0.011 mol), potassium carbonate (4.5 g, 0,0325 mol) and sodium iodide (1.1 g, 7,3 mmol) in 2-butanone (60 ml) heated at boiling temperature under reflux for 6 hours After cooling to room temperature the reaction mixture is diluted with acetone, filtered and evaporated in vacuum. The crude product is purified column chromatography on silica gel (200 g) using a mixture of chloroform (95%) and ethanol (5%) as eluent. This gives 0.8 g of methyl ester 1-(3-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinyloxy acid in the form of butter.

To the above-mentioned ether complex (0.8 g, 1.78 mmol) in ethanol (11,6 ml) add a solution of sodium hydroxide (in 0.288 g) in water (1.08 ml) and the reaction mixture was stirred at room temperature for 16 hours Add concentrated hydrochloric acid (1.08 ml) and then dichloromethane (80 ml). After stirring for 10 minutes the organic is re-evaporation with acetone was repeated twice. The residue is again dissolved in acetone (40 ml) and left at 0oC for 4 h This gives 300 mg (36%) of the named compound as a solid substance.

So pl. 183-193oC, decomp.

Calculated for C23H23CL2NO4HCl:

WITH, 56,98%; N, 4,99%; N, 2,89%;

Found:

WITH, 56,92%; N 5,02%; N, 3.16 PER CENT.

Example 8

(R) -1- (2-(N-Dibenzo[d, g] [1,3] dioxin-12 yloxy) -1-ethyl)-3-piperidinecarboxylate acid acetate

< / BR>
To a suspension N-dibenzo[d, g] [1,3] dioxin-12-she (9,05 g, 40 mmol) in ethanol (140 ml) is added dropwise at 40oWith a solution of sodium borohydride (0.8 g, 21 mmol) in water (5 ml) containing 2 drops of 10% sodium hydroxide and the reaction mixture was stirred at 70oC for 5 hours Add small portions additionally solid borohydride sodium (1.0 g, 2.6 mmol) and the reaction mixture is heated to 70oC for 2 h Cloudy solution is filtered and the solvent is removed in vacuum. Add toluene (150 ml) and water (80 ml), the layers separated and the aqueous layer was extracted with toluene (50 ml). The combined toluene extracts are washed with water (50 ml), dried over MgSO4and vypaivajut in vacuum. The residue (9,03 g),

which crystallizes after standing, triturated with cyclohexane and hoteltravel the Oh cleanup.

So pl. 80-90oC.

To a solution of the above alcohol (5.0 g, 22 mmol) in benzene (85 ml), add triethylamine (5.5 g, 54 mmol) and the solution methanesulfonanilide (3.2 g, 28 mmol) in benzene (25 ml) is added dropwise at 15-20oC for 20 minutes under cooling in a bath of cold water. After the addition, the reaction mixture was stirred for 2 h at room temperature. Add water (35 ml) and the organic layer was separated, washed with water (25 ml), dried over MgSO4and evaporated in vacuum. To the oil residue (5.8 g) is added anhydrous potassium carbonate (8.6 g, 62 mmol) and 2-bromoethanol (to 13.6 ml, 191 mmol). The reaction mixture is stirred for 17 h at room temperature, diluted with dichloromethane (60 ml), filtered and evaporated in vacuum. Solid 12-(2-bromoethoxy)-N-dibenzo[d, g] [1,3] dioxin (5.0 g, 68%) is separated from the residue after standing at room temperature and is filtered and washed with petroleum ether.

So pl. 112-114oWITH

The solution of the above bromide (1.7 g, 5 mmol), ethyl ester tartrate (R)-3-piperidinecarboxylic acid (2.1 g, 6.7 mmol) and potassium carbonate (1.1 g, 8 mmol) is stirred for 22 h at room temperature. The inorganic salt is filtered off and the filter is ml), dried over MgSO4and evaporated in vacuum. Oily residue, the crude ester (R)-1-(2-(N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylic acid is used in the next stage without additional purification.

The above ester (1.6 g, 3.9 mmol) dissolved in ethanol (16 ml) and add 20% sodium hydroxide (2.1 ml). The reaction mixture was stirred at room temperature for 18 h, poured into dichloromethane (320 ml) and acidified with concentrated acetic acid (5.3 ml). The organic phase is washed with water (50 ml), dried over MgSO4and evaporated in vacuum. Oily residue re-evaporated (2) with benzene, then triturated with acetone, obtaining crystals of the above compound (0.96 g, 55%).

So pl. 120-128oC.

Calculated for C24H29NO7:

With that 65,00%; N, 6,59%; N, 3,16%; Found:

WITH, 65,21%; N 6,70%; N, 3.06 PER CENT.

Example 9

(R)-1-(2-(2,10-Dichloro-N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylate acid hydrochloride

< / BR>
Bis-(5-chloro-2-hydroxyphenyl)methane (25,0 g of 92.9 mmol) is dissolved in N, N-dimethylformamide (350 ml) and add diazomethane (7.8 ml, 97.5 mmol) and potassium carbonate (18.6 g, 135 mmol). The mixture is heated to 105oWith over new for 30 minutes, the solid is filtered off and washed with a small amount of water. The solid is suspended in a mixture (80: 20) of ethanol and 4N sodium hydroxide and the resulting mixture was heated at 80oC for 1 h After cooling, the mixture was poured into water (600 ml) and the precipitate filtered off. After drying receive 2,10-dichloro-N-dibenzo [d, g] [1,3] dioxin (24.8 g, 95%), which is used for further reaction without purification.

The above dioxin (7.7 g, 27 mmol) and N-bromosuccinimide (5.4 g, 30 mmol) is suspended in carbon tetrachloride (100 ml). Azobisisobutyronitrile (50 mg) added and the mixture is heated at boiling temperature under reflux. During the first 7 h every second hour add portions more azobisisobutyronitrile (50 mg). The heat continue throughout the night. Then add two additional portions of azobisisobutyronitrile (50 mg) and heated at the boiling point under reflux continued for 24 hours in General. After cooling, the reaction mixture is filtered and evaporated. Add dichloromethane (10 ml) and diethyl ether (15 ml) and the solid is filtered off, getting after drying, 12-bromo-2,10 - dichloro-N-dibenzo[d, g] [1,3] dioxin (3,37 g, 11%).

The above bromide (3,37 g, 9,36 mmol) is mixed with 2-bromoethanol (8.0 ml, 110 mmol) and potassium carbonate (3.9 g, 28 MK mix and stirring is continued over night at room temperature. The mixture is heated at 120oWith within 24 hours After cooling, the mixture is evaporated and add ethyl acetate (100 ml) and water (100 ml). The phases are separated and the organic phase washed with water (100 ml). The combined aqueous phase is extracted with ethyl acetate (100 ml). The organic extracts are dried (MgSO4) and evaporated, receiving untreated 12-(2-bromoethoxy)-2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin (4,34 g). The product is used for further reaction without purification.

Above bromoethoxy connection (4,25 g, 10.5 mmol) are suspended in dimethyl sulfoxide (50 ml). Add tartrate ethyl ester (R)-3-piperidinecarboxylic acid (4.1 g, 13.7 mmol) and potassium carbonate (3.2 g, 23 mmol). The reaction mixture was stirred at 50oWith throughout the night. After cooling and filtering, add water (250 ml) and the mixture extracted with diethyl ether (2100 ml). The organic extracts washed with water (75 ml), dried (gSO4) and evaporated. The oily residue purified column chromatography on silica gel (600 ml) using a mixture of heptane: ethyl acetate (2: 1) as eluent. This gives ethyl ester (R)-1-(2-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylate the e sodium hydroxide (0.54 g, 13.5 mmol) in ethanol (40 ml) and water (5 ml) was stirred at room temperature for 3.5 hours the pH of the mixture was adjusted to 4 by adding 1N hydrochloric acid (14 ml). The mixture is extracted with dichloromethane (260 ml), the combined organic phases are washed with brine (75 ml), dried over MgSO4and the solvent is removed in vacuum. The residue is stirred with acetone (10 ml) for 2.5 h, the solid product is filtered and dried, obtaining the titled compound (0.56 g, 71%).

So pl. 218-220oC.

Calculated for C22H23Cl2NO5HCl:

With, 54,06%; N, Of 4.95%; N, 2.87% Of; Found:

WITH, 56,9%; N, 4.8%, OF N, 2,6%.

Example 10

(R)-1-(3-(2-Chlorine-N-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-3-piperidinecarboxylate acid hydrochloride

< / BR>
A suspension of 2-chloro-N-dibenzo [d, g] [1,3] doxazosin (10,65 g, 43 mmol, obtained as described in Journal of Molecular Structures, 131, 1985, 131-140) and 3-chloropropionyl chloride (6,55 g, 51.6 mmol) in dry toluene (100 ml) is heated at the boiling point under reflux for 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-chloropropionate (3.0 g, 79 mmol) suspended in dry tetrahydrofuran (80 ml), cooled in a bath with ice and add concentrated sulfuric acid (a 3.87 g of 39.5 mmol) dropwise at a speed such as to maintain the temperature < 12oC. the Solution was stirred at room temperature for 1.5 h the Solution of the above chloride (12.8 g, 37.8 mmol) in dry tetrahydrofuran (80 ml) is added dropwise and continue stirring for 2 h the Reaction is quenched by careful addition of ethyl acetate (100 ml) followed by addition of water (5.7 ml). Filtration of the mixture and evaporation of the filtrate in vacuo yield 2-chloro-12(3-chlorpropyl)-N-dibenzo[d, g] [1,3,6] doxazosin in the form of foam.

A mixture of the above crude chloride (1,14 g, 3.5 mmol), (L)-tartrate ethyl ester (R)-3-piperidinecarboxylic acid (1,05 g, 3.5 mmol), dried potassium carbonate (1,94 g, 14 mmol), sodium iodide (of 0.53 g, 3.5 mmol) and 2-butanol (15 ml) is heated at boiling temperature under reflux for 60 hours, the Reaction mixture is filtered, the filtrate is washed with 2-butanone (10 ml) and the combined filtrates evaporated in vacuo. The crude product is purified column chromatography on silica gel using a mixture of ethyl acetate and heptane (1: 3),2-yl)-1-propyl)-3-piperidinecarboxylic acid (0,77 g, 49%) as oil.

The above ester (0,77 g of 1.73 mmol) dissolved in ethanol (7.5 ml) and added 2N sodium hydroxide (2,86 ml, 5,71 mmol). The mixture is stirred at room temperature for 16 hours, the Ethanol is evaporated in vacuo and the residue diluted with water (25 ml). the pH is brought to b, adding 6N hydrochloric acid, and the aqueous solution extracted with dichloromethane (315 ml). The combined organic extracts dried over gSO4and evaporated in vacuum. The residue is dissolved in tetrahydrofuran (15 ml) and added dropwise to 2.5 N hydrogen chloride in ether (0,59 ml of 1.47 mmol). Add ether (30 ml) and the mixture stirred for 3 h, the precipitate filtered and dried, obtaining of 0.53 g (68%) of the named compound in powder form. So pl. 177-180oC.

Calculated for C22H25ClN2O4HCl:

With, 58,28%; H, 5.78 Percent; N, 6,18%; Found:

WITH A 58.3%; N, 5.9 PER CENT, N, 6,1%.

Example 11

1- (3- (N-Dibenzo[d, g] [1, 3, 6] doxazosin-12-yl) -1-propyl)-4-piperidinecarbonitrile acid hydrochloride

< / 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 dropwise over 30 minutes. The resulting mixture was stirred for 30 m is ateenyi 15 minutes. The reaction mixture was stirred for 2.5 h at room temperature, heated at boiling temperature under reflux for 2 h and stirred at room temperature over night. The mixture is filtered and 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 drying receive the product N-(2-(2-bromperoxidase)phenyl)formamide (14.1 g, 37%).

The above formamide (6.8 g, 21 mmol) is suspended in Dowtherm (75 ml), 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 throughout the night. After cooling, the mixture is filtered. And the filter cake washed with dichloromethane. Dowtherm and the solvent is distilled off and the ethanol (200 ml) is added to the residue, which is left for the night. 4 M sodium hydroxide (14 ml) is added and the mixture is heated at the boiling point under reflux for 1 h After cooling, the mixture is filtered and evaporated. The residue is suspended in ethyl acetate (200 ml) and water (100 ml). The organic phase is washed with water (275 ml). Dirout in a warm cyclohexane (100 ml) and cooled with stirring. Landed solid is filtered off, getting after drying, the product 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). Sodium hydride (1.13 g, 28 mmol, 60% dispersion in oil) are added in portions and the resulting mixture is stirred for 30 minutes at room temperature. 1-Bromo-3-chloropropane (4.6 ml, 47 mmol) is slowly added dropwise and the reaction mixture was stirred at room temperature over night. Add sodium hydride (0.56 g, 14 mmol) and stirring is continued for 6 hours Add sodium hydride (0.56 g, 14 mmol) and stirring is continued over night. Added aluminium chloride (3.2 g) and the mixture is stirred for 30 minutes. Add water (300 ml) and the mixture extracted with dichloromethane (2250 ml). The organic extracts are dried (MgSO4) and evaporated. The residue is purified column chromatography on silica gel using a mixture of heptane: ethyl acetate (6: 1) as eluent. This gives the product, 12-(3-chlorpropyl)-N-dibenzo[d, g] [1,3,6] -doxazosin (2,18 g, 40%).

The above chloride and potassium iodide (3.7 g, 22 mmol) in methyl ethyl ketone (110 ml) is heated at the boiling point under reflux in t the keys, and then add potassium carbonate (1.2 g, 8.6 mmol). The reaction mixture is heated at the boiling point under reflux for 48 hours After cooling, the mixture is filtered, the filter cake washed with ethyl ketone and the filtrate is evaporated. The oily residue is purified column chromatography on silica gel (500 ml) using ethyl acetate as eluent. This gives the ethyl ester of 1-(3-(N-dibenzo [d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-4-piperidinecarboxylic acid (0,80 g, 57%) as oil.

The above ester (0.50 g, 1.22 mmol), dissolved in sodium hydroxide solution (0.24 g, 6 mmol) in ethanol (30 ml) and water (3 ml), stirred at room temperature for 3 hours the pH of the mixture was adjusted to 3 by adding 1 N hydrochloric acid (5 ml). The mixture is extracted with dichloromethane (240 ml), the combined organic phases are washed with brine (50 ml), dried over MgSO4and the solvent is removed in vacuum. The residue is triturated with acetone (20 ml) and the solid product is filtered and dried, obtaining a named connection with a quantitative yield (0.52 g).

So pl. 180-187oC.

Calculated for C22H26N2O4HCl1,25 HzO:

With, 59,85%; N, 6,74%; N, 6,35%; Found:

WITH, 59,85%; N 6,60%, N 6,00%.
R3is hydrogen;

A - C1-3-alkylene;

Y - where only the underlined atom participates in the ring system;

Z is selected from

< / BR>
< / BR>
< / BR>
where R12is hydrogen;

R13is hydrogen;

R14represents -(CH2)tCOR15where t = 0 or 1, R15is HE, C1-6-alkoxy;

- optional single bond or a double bond,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where Z is selected from

< / BR>
< / BR>
< / BR>
where R14- -(CH2)tCOR15where t = 0 or 1, R15is HE.

3. Connection under item 1 or 2, selected from the following compounds:

1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid,

(R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid,

ethyl ester of (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylic acid,

1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-4-piperidinecarbonitrile acid,

(R)-1-(3-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid,

1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinecarbonyl>(R)-1-(2-(N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylate acid,

(R)-1-(2-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylate acid,

(R)-1-(3-(2-chlorine-N-dibenzo[d, g] [1,3,6] doxazosin-12 yloxy)-1-propyl)-3-piperidinecarboxylate acid,

1-(3-(N-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-4-piperidinecarbonitrile acid,

or its pharmaceutically acceptable salt.

4. The compound according to any one of paragraphs. 1-3, representing the (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinylcarbonyl acid.

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

< / BR>
where R1, R2, R3And Y are such as defined above,

W represents a suitable tsepliaeva group, such as halogen, p-toluensulfonate or mesilate,

subjected to interaction with azaheterocyclic compound of formula III

HZ,

where Z is as defined above.

6. The method according to p. 5, where the compound of formula I is (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinylcarbonyl acid.

7. Pharmaceutical composition comprising as an active component. farmacevticheskaja composition under item 1, with inhibitory activity against neurogenic inflammation.

9. The pharmaceutical composition according to p. 7, having inhibitory activity against neurogenic pain or inflammation associated with diabetic neuropathy.

10. The pharmaceutical composition according to p. 7, having inhibitory activity against neurogenic pain or inflammation associated with rheumatoid arthritis.

11. The pharmaceutical composition according to p. 7, suitable for the treatment of neurogenic inflammation comprising an effective amount of a compound according to any one of paragraphs. 1-4 together with a pharmaceutically acceptable carrier or diluent.

12. The pharmaceutical composition according to p. 7, suitable for the treatment of neuropathy, comprising an effective amount of a compound according to any one of paragraphs. 1-4 together with a pharmaceutically acceptable carrier or diluent.

13. The pharmaceutical composition according to p. 7, suitable for the treatment of rheumatoid arthritis comprising an effective amount of a compound according to any one of paragraphs. 1-4 together with a pharmaceutically acceptable carrier or diluent.

14. The pharmaceutical composition according to any one of paragraphs. 7-13, including otruba of PP. 7-14, comprising as an active ingredient (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinylcarbonyl acid.

16. A method of treating neurogenic inflammation, neuropathy or rheumatoid arthritis in a subject in need of such treatment, comprising the introduction of a specified subject an effective amount of a compound according to any one of paragraphs. 1-4, including 2-{ 4-[3-(N-dibenzo[d, g] [1,3,6] doxazosin-1-propyl] piperazine-1-yl} ethanol and case when a in the formula (I) optionally, R1and R2independently represent hydrogen, halogen or trifluoromethyl, and Y is >N-CH2- when R16in the group Z, is represented by the formula-NR11R16represents a C1-4-alkyl, and R11is hydrogen or C1-6-alkyl.

17. The method of treatment according to p. 16, where the specified subject is administered (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinylcarbonyl acid.

Priority points and features:

19.09.1995 on PP. 1, 2, 4-13 except for the value of Y is>N-CH2; under item 3 for the following connections:

1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid;

Ethyl ester of (R)-1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidin is-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid,

1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-4-piperidinecarbonitrile acid,

(R)-1-(3-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-piperidinecarboxylate acid,

1-(3-(N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinecarbonyl acid,

1-(3-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12-ilidene)-1-propyl)-3-pyrrolidinecarbonyl acid,

(R)-1-(2-(N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylate acid,

(R)-1-(2-(2,10-dichloro-N-dibenzo[d, g] [1,3] dioxin-12 yloxy)-1-ethyl)-3-piperidinecarboxylate acid,

(R)-1-(3-(2-chlorine-N-dibenzo[d, g] [1,3,6] doxazosin-12 yloxy)-1-propyl)-3-piperidinecarboxylate acid,

1-(3-(N-dibenzo[d, g] [1,3,6] doxazosin-12-yl)-1-propyl)-4-piperidinecarbonitrile acid.

 

Same patents:

The invention relates to new derivatives of piperidineacetate-2-it General formula I, where R1and R2each independently from each other represents an unsubstituted or once substituted phenyl residues, substituents which may be OA, Hal, NH2, OTHER3; R3denotes-CO-alkyl, where alkyl has 1 to 7 carbon atoms; And indicates WITH1-C6alkyl; Hal denotes F, CL, Br or J

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to an improved process for the preparation of substituted indole derivatives useful in the treatment and prevention of migraine

The invention relates to a derivative of oxazolidin-2-it General formula (I):

< / BR>
where X is O,

Y denotesor

< / BR>
R1indicatesor< / BR>
R2and R3each, independently of one another, denotes H, A or benzyl;

A denotes alkyl with 1-6 C-atoms;

D denotes amidinopropane, aminomethyl, aminohydrocinnamic, 5-methyl-1,2,4-oxadiazolidine-3-yl or guanidinate;

r and s independently of one another denote 0, 1, 2, 3 or 4;

however, if necessary, free amino - or amidinopropane can be protected partially or fully protective for the amino function groups, as well as their enantiomers, diastereomers and physiologically acceptable salts

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to substituted chromalusion (thio)ureas of the formula (I):

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where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;

R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;

Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

A denotes the residue of a saturated or unsaturated lactam of the formula:

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where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

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and their physiologically acceptable salts

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis

-alaninemia and their derivatives, method for the treatment glycolipoprotein diseases, the prevention of ischemic myocardial damage, the pharmaceutical composition" target="_blank">

The invention relates to derivatives of indole-2-carboxamide that can be used as inhibitors of glycogen phosphorylase, and to methods of treatment of glycogenolysis-dependent diseases or conditions using these compounds and pharmaceutical compositions containing these compounds

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)
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