Bicyclic carboxamide and their pharmaceutically acceptable salts and pharmaceutical compositions on their basis

 

(57) Abstract:

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are R6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10is all, Y is O and n is 2-4, their pharmaceutically acceptable salts. The compounds of formula (i) have inhibitory PDE and TNF activity and can be used in medicine as an agent for inhibition of phosphodiesterase and tumor necrosis factor. 2 S. and 11 C.p. f-crystals, 2 PL.

The scope of the invention

The invention relates to new heterocyclic compounds and their pharmaceutically acceptable salts, processes for their preparation and formulation based on them and use as pharmaceuticals.

Background of the invention

2-Tiniversity with integreeruda activity described in Eur.J.Med. Chem., (1994) 29:75.

In EP-A-0116938 and J. Med.Chem. (1987) 30, 62 described heteroarylboronic as inhibitors of lipolysis, useful for treatment of ischemic heart disease and hypertriglyceridemia.

In WO-A-9406783 and WO-A-9406782 described heteroarylboronic possessing insecticidal, nematocidal, acaricidal and fungicidal activities.

In WO-A-9604251 described aryloxypropanolamine heteroaryl compounds as inhibitors of bradykinin.

Heteroaryl compounds described as antagonists of fibrinogen in WO-A-9408962.

as amplifiers animal productivity.

The benzimidazole described as antagonists of dopamine in WO-A-9422839.

DE-F-4237617 reveals the imidazoles as antiparasitics agents.

Phosphodiesterase (PDE) and tumor necrosis factor (TNF), their mode of action and therapeutic utility of their inhibitors described in WO-A-9720833 and PCT/GB 97/01361, the contents of which are incorporated in this description by reference. In the same document describes carboxamide which are useful as inhibitors of PDE and TNF.

Summary of the invention

This invention relates to the pharmaceutical use of the compounds of formula (i) below, for the treatment of painful conditions such as painful conditions associated with proteins that mediate cellular activity, for example, by inhibition of tumor necrosis factor and/or by inhibiting phosphodiesterase IV. According to the invention the new compounds have the formula (i):

< / BR>
where (1) X represents N, and (a) Z is =CR1-CR2=, and Y represents N, (b) Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= , and Y is CR2or (2) X is NR4Z represents - CR1=, and Y represents N;

Q PR>C(=NOR6R13, alkyl-C(=NOR6R13, NR8R9, CON(R6)2, halogen, CF3CN, CO2H, CO2H, R6, CO-het, where het is a heterocyclic ring (such as morpholine or piperidine), attached via the N atom in the ring and optionally substituted by one or more R14or

< / BR>
R3is HE, thioalkyl or C1-6alkoxy or cycloalkene, each of which is optionally substituted by one or more Halogens;

R4represents H or alkyl;

R5represents aryl or heteroaryl, any of which may optionally be substituted by one or more substituents selected from halogen, optionally halogen-substituted of alkyl, hydroxy, optionally halogen-substituted alkoxy, CO2H, CO2R10, CONR11R12, COR10, SO2R10, SO2NR11R12, NR9R9and CN;

each R6independently represents H or a group selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroallyl and geterotsiklicheskie, and any of these groups optionally substituted in any position by the substituent R7;

R7 or COR10;

R8represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroallyl, heteroseksualci, alkylsulphonyl, alkoxycarbonyl, arylcarbamoyl, heteroarylboronic, heterocyclicamines, alkylsulfonyl arylsulfonyl, heteroarylboronic or heterozygosity;

R9represents H, alkyl, cycloalkyl, aryl, heteroaryl heterocycle, aralkyl, heteroaromatic or heteroseksualci; or NR8R9represents a heterocyclic ring (such as morpholine or piperidine), optionally substituted R14;

R10represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci;

R11and R12are the same or different and each represent H or R10;

R13is R10, optionally substituted by one or more R7;

R14represents alkyl, arylalkyl or heteroaromatic; and

R15represents alkyl, V is O or S, and n is 2-4;

and their pharmaceutically acceptable salts.

Compounds according to the invention are bicyclic aryl nucleus. Depending on the definitions of X, Y and Z they preseminal otherwise, what compounds 1b). Preferred compounds are defined in the dependent claims.

Description of the invention

Suitable pharmaceutically acceptable salts are salts of pharmaceutically acceptable bases, and salts attaching a pharmaceutically acceptable acids. Some of the compounds of formula (i) containing an acid group, form salts with bases. Suitable pharmaceutically acceptable salts of the bases include metal salts, such as alkali metal salts, for example, sodium salt or salts with organic amines, such as with Ethylenediamine.

Some of the compounds of formula (i) containing an amino group, form salts accession acids. Suitable salts of joining acids include pharmaceutically acceptable inorganic salts such as sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable salts of the accession of organic acids, such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, metasulfite, -Ketoglutarate, glycerol and glucose-1-phosphate. Pharmaceutically acceptable salts of compounds of formula (i) is obtained using conventional methods.

For specialisterne form. This invention includes all tautomeric forms. It is obvious that the compounds according to the invention can contain one or more asimmetricheskii substituted carbon atoms. The presence of one or more of these asymmetric centers in the compound of formula (i) may lead to an increase in the number of stereoisomers, and in each case, it should be understood that the invention encompasses all such stereoisomers, including enantiomers and diastereoisomers, and their mixtures, including racemic mixtures.

When used herein, the term alkyl, as used by itself or as part of another group includes alkyl groups with linear or branched chain containing up to 6 atoms. Alkoxy means alkyl-O-group in which the alkyl group is, as described earlier. Cycloalkyl includes non-aromatic cyclic or multicyclonic ring system of about 3 to 10 carbon atoms. Cyclic alkyl may optionally be partially unsaturated. Cycloalkane means cycloalkyl-O-group in which cycloalkyl is the same as defined above. Aryl refers to aromatic monocyclic or multicyclonic carbocyclic group containing about 6-10 carbon atoms. Ari is salkil means heteroaryl-alkyl group and heteroseksualci means heterocycle-alkyl group. Alkylsulphonyl means alkyl-CO-group in which an alkyl group such as defined previously. Arylcarbamoyl means an aryl-CO-group in which the aryl group is as defined previously. Heteroarylboronic means heteroaryl-CO-group and heterocyclicamines means heterocycle-CO-group. Arylsulfonyl means aryl-SO2-the group in which the aryl group is as defined previously. Heteroarylboronic means heteroaryl-SO2group and heterozygosity means heterocycle-SO2-group. Alkoxycarbonyl means alkyloxy-CO-group in which the alkoxy group is as defined previously. Alkylsulfonyl means alkyl-SO2-the group in which an alkyl group such as defined previously. Heterocyclic ring means about 5-10 membered monocyclic or multicyclonic ring system which may be saturated or partially unsaturated), in which one or more atoms of the ring system is an element other than carbon, selected from nitrogen atoms, oxygen or sulfur. Heteroaryl means a 5-10 membered aromatic monocyclic or multicyclonic hydrocarbon ring system in which the od of the PTA, oxygen or sulfur; optionally, the N atom may be in the form of N-oxide. Heterocycle means roughly 5-10-membered saturated or partially saturated monocyclic or multicyclonic hydrocarbon ring system in which one or more atoms in the ring system represent an element other than carbon, selected from nitrogen, oxygen or sulfur. Halogen means fluorine, chlorine, bromine or iodine.

"TNF mediated disease or disease state" means any or all of the painful condition, which plays the role of TNF or by the production of TNF, or caused by TNF release of other cytokines, such as IL-1 or IL-6, but not limited to. A painful condition in which, for example, IL-1 is a major component, and whose production or action is exacerbated or secreted in response to TNF, should, therefore, be regarded as a pathological state mediated by TNF. Because TNF - a (also known as lymphotoxin) has close structural homology with TNF - a (also known as catechin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-, and TMF - inhibited the E. otherwise indicated.

This invention relates to a method of mediation or inhibition of enzymatic activity or catalytic activity of PDE IV in a mammal, in need, and to a method of inhibiting production of TNF in a mammal, in need, which includes an introduction to the specified mammal an effective amount of the compounds of formula (i) or its pharmaceutically acceptable salt.

Inhibitors of PDE IV is useful for the treatment of various allergic and inflammatory diseases, including: asthma, chronic bronchitis, chronic obstruction of the respiratory tract, chronic inflammatory lung disease, idiopathic dermatitis, idiopathic) eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic reaction in the eye, eosinophilic granuloma, psoriasis, a disease Bechet, erythematous, anafilaktichesky hemorrhagic nephritis, inflammation of joints, arthritis, rheumatoid arthritis and other arthritic diseases, such as rheumatoid spondylosis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock is diabetes and diseases related inhibition of brain metabolism, such as ageing of the brain, senile dementia (Alzheimer's disease), memory impairment caused by Parkinson's disease, depression and multi-infarct dementia. Inhibitors D IV is also useful for the treatment of diseases, the improvement which occurs due to the neuroprotective activity, such as cardiac arrest, stroke and intermittent (intermittent) lameness. In addition, inhibitors of PDE IV can be useful as gastroprotection. The preferred embodiment of therapeutic methods of the present invention is the treatment of asthma.

Viruses are proposed for treatment in this description are those that produce TNF as the result of infection, or those which are sensitive to inhibition, for example, by reducing replication, directly or indirectly, under the action of TNF inhibitors of the formula (i). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus, and viruses of herpes group, such as, but not limited to, Herpes zoster (shingles) and Negres simplex (herpes simplex).

This invention more specifically on the em introduction to such mammal an effective TNF-inhibiting amount of the compounds of formula (i) or its pharmaceutically acceptable salt.

The compounds of this invention are also useful for veterinary treatment of animals that is different from the person in need of inhibition of production of TNF. TNF-mediated diseases for treatment, therapeutically or prophylactically, in animals include painful conditions, such as the above, but in particular viral infections. Examples of such viruses include, but are not limited to, human immunodeficiency virus cats (VIC) or other retroviral infections such as virus infectious anemia of horses, the virus arthritis goats, Visna virus (causes Central nervous system in sheep), Maedi virus and other lentiviruses.

The compounds of this invention are also useful in the treatment of parasitic, fungal yeast and fungal infection, when such yeast and fungi are sensitive to positive regulation by THF or will cause the production of TNF in vivo. Preferred painful condition for treatment is fungal meningitis.

The compounds of formula (i) are preferably in pharmaceutically acceptable form. Under a pharmaceutically acceptable form meant, inter alia, a pharmaceutically acceptable level of purity, for vklyuchaemykh as toxic at normal dosage levels. Pharmaceutically acceptable level of purity is usually at least 50%, excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and even more preferably 95%.

In addition, the invention relates to a method for obtaining compounds of formula (i) in which R1-R15and Q, X, Y, and Z are as defined above. It should be borne in mind that functional groups such as amino, hydroxyl or carboxyl group is present in various compounds described below, and you want to keep, it may be necessary to translate in protected form before any reactions. In such cases, the removal of the protective groups may be the end stage of a particular reaction. Suitable protective groups for such functional groups are obvious to experts in the field. Specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greens. Thus, the method of obtaining compounds of formula (i) in which R1contains-OH, involves removal of protection (for example, by hydrogenolysis or hydrolysis) of the compounds of formula (i) in which R3contains appropriate-OP, where P represents a suitable protective group (e.g. benzyl).


< / BR>
where R3ais R3as defined in relation to formula (i), or a group capable of being converted into R3and R4aand R5alikewise represent R4and R5or group into R4and R5respectively, and X', Y' and Z' represent the X, Y and Z or a group, turn in X, Y and Z, respectively; and, thereafter, if desired, converting any group R3ain R3and/or R4ain R4and/or R5ain R5and/or X' in X and/or Y' in Y and/or Z' in Z. the Interaction of carboxylic acids of the formula (ii) with the amine of formula (iii) can be performed under any suitable conditions known to the specialist. Preferably, before the interaction with the amine of formula (iii) carboxylic acid is converted into the acid chloride acid, mixed anhydride or other activated intermediate product. Preferably, the interaction with the amine of formula (iii) is carried out in the presence of a suitable base, e.g. an amine base such as triethylamine, preferably in a suitable solvent such as dichloromethane. In some cases, may require a stronger base such as sodium hydride, and a polar solvent, such as dimethylformamide.

Formirovanie the compounds of formula (iv) can be carried out under standard conditions known to specialists in this field, for example, using phosphorus oxychloride and dimethylformamide at elevated temperature. Oxidation of the aldehyde of formula (v) may be carried out using appropriate conditions known to the experts in this field, for example, with the use of sodium chlorite and sodium phosphate in water/tert-butanol in the presence of the absorber acid, such as 2-methyl-2-butene. Bromination of compounds of formula (iv) can be carried out using standard conditions, for example, using bromine in a suitable solvent, such as methanol. The carboxylation of the bromide of formula (vi) can usually be accomplished using the ORGANOMETALLIC catalyst is 2">

The compound of formula (iv) may be commercially available, previously described connection, or it can be obtained using standard conditions known to specialists in this field. For example, the methods described in EP-A-0701907, EP-A-0116938, DE-A-4237417, J. Med.Chem. (1987) 30, 62, J. Chem. Soc. Perkin Trans.I (1982) 357 and J. Chem.Soc. Perkin Trans.I (1949) 3012, J. Chem.Soc. (1928) 2393 and J. Chem.Soc. (1964) 4645.

Amines of formula (iii) are either commercially available, previously described compounds, or get them using standard conditions known to specialists in this field.

The compound of formula (i) can also be obtained by interconversion of other compounds of formula (i). For example, the compound in which R1contains alcohol function can be obtained by reduction of compounds of formula (i) in which R1contains a carbonyl function.

As another example, compounds in which R1and/or R2contains the oxime can be obtained from the compounds in which R1and/or R2contains a carbonyl group. This conversion may be performed using any appropriate standard conditions known to specialists in this field. The compounds of formula (i), in which conditions, well-known experts in this field (for example, sodium borohydride in a suitable solvent) to obtain compounds in which R1and/or R2contain an alcohol group. Compounds in which R1and/or R2are alkilani, can be obtained by reduction of compounds in which R1and/or R2are CO-alkyl, using conventional conditions known to the experts in this field (for example, hydrazine hydrate in the presence of a suitable base in an appropriate solvent). Other transformations can be carried out for compounds of formula (i) in which R1and/or R2contain a carbonyl group. Such transformations include, but are not limited to, reductive amination and alkylation. Any of the above transformations can be executed or at the end of the synthesis, or any suitable intermediate product. The compounds of formula (i) in which Z represents CS, can be obtained from compounds of formula (i) in which Z represents CO, using any suitable conditions known to the experts in this field, for example, using a reagent of Lawson.

It should be borne in mind that when it is necessary to indiv effektivnaya liquid chromatography, or are there ways of synthesis performed using the corresponding homochiral educt.

The compound of formula (i), or a corresponding pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES can be entered by themselves or, preferably, in the form of a pharmaceutical composition that also includes a pharmaceutically acceptable carrier.

Accordingly, the present invention relates to pharmaceutical compositions comprising a compound of formula (i), or a corresponding pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES and a pharmaceutically acceptable carrier.

The active compound may be incorporated into the formulations for administration by any suitable route, the preferred route of administration depends on the disease that requires treatment, and preferably it is in the form of a single dosage form or in the form of that person-the patient can enter yourself as a single dose. Mainly the composition is suitable for oral, rectal, local, parenteral administration or administration via the respiratory tract. Preparations can be made for the floor is here includes subcutaneous injections, intravenous, intramuscular, vnutrigrudne injection or infusion methods. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats and so on, the compounds according to the invention is effective in the treatment of people.

The composition of the invention can be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, recovered powders or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Agents for local injection is used, where this is appropriate.

To achieve consistency in imposing preferably, the composition according to the invention were in the form of single dose.

An example of a single dose for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, gum Arabic, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example, microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricating agents for tablets, for example, magnesium stearate; razlichiya the Uzzah; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid compositions for oral administration can be obtained by conventional methods of blending, filling, tabletting or the like. The subsequent mixing can be used for uniform distribution of the active agent in compositions where there are large quantities of fillers.

Of course, such operations are conventional in the art. Tablets may be coated by methods well known in normal pharmaceutical practice, in particular, shell dissolution in the intestine.

Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or they can be presented as a dry product, reconstituted with water or other suitable solvents before use. Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel, aluminum stearate, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or hummurabi the e coconut oil, esters of oils, such as esters of glycerine, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p - hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring agents or dyes.

The composition may also eligible to be submitted for introduction into the respiratory tract in the form of snuff powder or an aerosol or solution for spraying or in the form of a fine powder for insufflation, alone or in combination with an inert carrier such as lactose. In this case, suitable particles of active compound, which has a diameter less than 50 microns, from 0.1 to 50 microns, preferably less than 10 microns, for example, from 1 to 10 microns, from 1 to 5 microns, or from 2 to 5 microns. When possible, the composition can be included a small number of other protivoastmatichesky and bronchodilatation, for example, amines sympathomimetics, such as izoprenalin, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids, such as prednisone and adrenal stimulants such as ACTH.

For parenteral administration are the liquid unit dosage forms using connection and sterile solvent and, depending on the use of the ditch compound can be dissolved in water for injection and sterilized by filtration before filling into suitable vials or ampoules and hermetically sealed. Mainly, the solvent can be dissolved with an adjuvant, such as local anesthetics, preservatives and buferiruemoi agents. To increase the stability of the composition can be frozen after filling bubbles and the water removed under vacuum. Suspensions for parenteral administration receive essentially the same way, except that the compound is suspended in a solvent instead of dissolution, and in addition sterilization cannot be accomplished by filtration. The connection can be sterilized by exposure to ethylene oxide before suspendirovanie in a sterile solvent. Mainly, surfactant or wetting agent is included in the composition to facilitate uniform distribution of the connection.

The compositions may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of active substance, depending on the method of administration.

The compounds of formula (i) or, if appropriate, their pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES can also be administered in the form of formulations for topical use in combination with suitable excipients for topical application.

The recipe is th bandages, gels, gel pencils, sprays and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to facilitate penetration of medications and softening means in ointments and creams. The formulations may also contain compatible conventional carriers, such as Foundation creams and ointments and ethanol or alerby alcohol lotions.

Suitable formulations of cream, lotion, gel, pencil, ointment, spray or aerosol, which can be used for compounds of formula (i) or, if appropriate, their pharmaceutically acceptable salts are conventional formulations well known in this field, for example as described in standard reference books, such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences and the British and US Pharmacopoeias (USP Britain and the United States).

Suitably, the compound of formula (i) or, if appropriate, its pharmaceutically acceptable salt, approximately from 0.5 to 20% by weight of the formulation, preferably from about 1 to 10%, for example from 2 to 5%. The dose of a compound according to the invention, useful for the treatment will vary in the usual way, depending on the severity of the disease, weight of patient and relative efficiency soedinenii, 0.5 to 100, or from 0.5 to 10 mg, for example, 0,5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times a day, so that the total daily dose for an adult patient weighing 70 kg was in the range from 0.1 to 1000 mg, i.e. in the range of from about 0.001 to 20 mg/kg/day, as, for example, from 0,007 to 3, from 0,007 to 1.4, from being 0.007 to 0.14 or from 0.01 to 0.5 mg/kg/day, for example, 0,01, 0,02, 0,04, 0,05, 0,06, 0,08, 0,1 or 0.2 mg/kg/day, and this therapy may continue for several weeks or months.

When used in this description, the term "pharmaceutically acceptable" includes materials that are suitable both for human and for veterinary use.

The following examples illustrate the invention

The intermediate connection 1

2-Amino-3-nitroanisole

To 2-amino-3-NITROPHENOL (4.0 g) dissolved in tetrahydrofuran (80 ml) at ambient temperature was added tetrabutylammonium iodide (0.4 g), sodium hydroxide (4.0 g) in water (40 ml) and itmean (3.4 ml). This mixture was stirred overnight and then concentrated in vacuum. The residue was poured into water (200 ml) and was extracted with ethyl acetate (CH ml), then washed with water bicarbonate and was evaporated in vacuum, getting listed in the title compound as a dark solid (4.4 g).

TLC Rf0,7 (50% ethyl acetate in hexane)

Intermediate compound 2

2,3-Diaminoanisole

2-Amino-3-nitroanisole (4.3 g) was first made in ethyl acetate (200 ml) using as the catalyst 10% palladium on coal in an atmosphere of hydrogen at ambient temperature. After completion, the reaction mixture was filtered through celite and the filtrate was evaporated in vacuum, obtaining mentioned in the title compound as a brown liquid (3,60 g)

TLC Rfof 0.65 (ethyl acetate)

Intermediate compound 3

5-Methoxyphenoxy

Hydrate glyoxal bisulfite sodium (10.0 g) in water (80 ml) was heated to 60oC, then solution was added 2,3-diaminoanisole (3,40 g) in ethanol (40 ml). Then stir the mixture was heated at 80oC for 1 hour before adding concentrated hydrochloric acid (6 drops). Heating was continued for 1 hour. The mixture was left to cool overnight, concentrated in vacuo and poured into aqueous potassium carbonate solution (40 ml). An ethyl acetate extracts (g ml) washed with water (100 ml) and saturated saline (50 ml), then dried over anhydrous sulfate is about the substance (of 3.07 g).

TLC Rfof 0.40 (ethyl acetate)

Intermediate compound 4

8-Methoxyaniline-5-carboxylic acid

To 5-methoxykynuramine (2.3 g) in methanol (50 ml) at -20oC in an atmosphere of inert gas was added during 15 minutes a solution of bromine (from 0.76 ml) in methanol (10 ml). After stirring for 4 h the reaction mixture was left at -20oC at night. The mixture was poured into an aqueous solution of sodium metabisulfite (100 ml), podslushannyy sodium bicarbonate and was extracted with ethyl acetate (CH ml). These extracts were washed with water (100 ml) and saturated saline (50 ml), then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining a brown solid (2,45 g). Purification of column chromatography using as eluent 50% ethyl acetate in hexane resulted in not quite a white solid substance (0,46 g) in a mixture of 5-bromo - 5,6-dibromsalan products. It's solid, triphenylphosphine (0.5 g), bis (triphenylphosphine) palladium (II) chloride (1.0 g) and triethylamine (6 ml) was dissolved in tetrahydrofuran (200 ml) and was heated at 80oC in a Parr apparatus in a gaseous atmosphere of carbon monoxide at 1380 kPa (200 psig). After 6 days, the mixture was cooled to theatre and were extracted with ethyl acetate (CH ml). These extracts are re-extracted with 1 M sodium hydroxide solution (g ml) and the combined aqueous phase was acidified to pH 5 glacial acetic acid. An ethyl acetate extracts (g ml) and the acidic aqueous phase was washed with water (100 ml) and saturated saline (50 ml), then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining mentioned in the title compound as a solid (0,19 g).

TLC Rfof 0.20 (ethyl acetate)

The intermediate compound 5

4-Methoxy-2-triftoratsetata

A solution of 2,3-diaminoanisole (1.0 g) in triperoxonane acid (15 ml) was boiled under reflux for 5 hours and then stirred at room temperature overnight. Excess triperoxonane acid was removed in vacuo, and the residue was distributed between ethyl acetate (50 ml) and water (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (50 ml) and water (50 ml). Drying over anhydrous sodium sulfate and removal of solvent in vacuo resulted in a brown residue. Cleaning column chromatography, elwira 50% ethyl acetate in hexane, got mentioned in the title compound as a yellow solid (1.4 g).

TLC Rf
2,3-Diaminoanisole (5,88 g) and lactic acid (5.6 ml) were combined, treated with concentrated hydrochloric acid (45 ml) and heated at 100oC for 18 hours. The reaction mixture was cooled to 0oC, neutralized with ammonium hydroxide solution and was extracted with ethyl acetate (CH ml). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo and the residue was purified flash chromatography on silica, elwira with ethyl acetate, obtaining the desired product as a reddish brown solid (4,91 g).

TLC Rf0,125 (ethyl acetate)

Intermediate compound 7

2-Acetyl-4-methoxybenzimidazole

A solution of 2-(1-hydroxyethyl)-4-methoxybenzimidazole (2,18 g) in acetic acid (8.5 ml) was heated at 100oC and treated with a solution of chromium trioxide (0.85 grams) in water (3 ml). After 10 minutes the reaction mixture was poured into water (110 ml), the precipitate was removed by filtration through a layer of celite and the product was extracted with dichloromethane (I ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining the desired product as light brown solid (1.4 g).

TLC Rf0.6 (ethyl acetate) is-2-triftoratsetata (1.4 g) in tetrahydrofuran (40 ml) under nitrogen was added sodium hydride (0.32 g; 60% dispersion in oil). The mixture was stirred for 20 minutes at room temperature before adding methyliodide (1.35 g). Stirring was continued over night. The reaction was stopped by adding water (10 ml) and the solvent was evaporated in vacuum. Added ethyl acetate (50 ml) and the organic layer was washed with saturated sodium bicarbonate solution (20 ml), water (20 ml) and brine (20 ml). After drying over anhydrous magnesium sulfate, followed by removal of solvent in vacuum has been specified in the header connection (1/6 g) in the form of oil, which upon standing turned into a solid substance.

TLC Ra0,75 (50% ethyl acetate in hexane)

The following compounds were obtained in the same way.

Intermediate compound 9

2-Acetyl-7-methoxy-3-methylbenzimidazole

Was obtained from 2-acetyl-7-methoxybenzimidazole (0.5 g). Purification with flash chromatography on silica with elution with 50% ethyl acetate in hexane gave specified in the title compound as a white solid (0.24 g).

TLC Rf0,38 (50% ethyl acetate in hexane)

Intermediate compound 10

7-Methoxy-3-propyl-2-triftoratsetata

Was obtained from 4-methoxy-2-triptorelin is 15% ethyl acetate in hexane gave specified in the title compound as a white solid (2,03 g).

TLC Rf0,4 (20% ethyl acetate in hexane)

Intermediate compound 11

4-Bromo-7-methoxy-3-methyl-2-triftoratsetata

To a solution of 7-methoxy-3-methyl-2-triftoratsetata (1.4 g) in chloroform (50 ml) under nitrogen atmosphere was added N - bromosuccinimide (1.2 g). The mixture was stirred for 20 minutes and then the reaction was stopped by adding 5% solution of sodium metabisulfite (50 ml) and the organic layer was separated. Washing with water (50 ml), drying over anhydrous magnesium sulfate and removal of solvent in vacuo resulted in an orange oil. Purification with flash chromatography with elution with 50% ethyl acetate in hexane gave specified in the title compound as an orange solid (1.73 g)

TLC Rf0,79 (50% ethyl acetate in hexane)

The following compounds were obtained according to a similar method.

Intermediate compound 12

2-Acetyl-4-bromo-7-methoxy-3-methylbenzimidazole

Was obtained from 2-acetyl-7-methoxy-3-methylbenzimidazole (0.24 g). Purification with flash chromatography on silica with elution with 50% ethyl acetate in hexane gave the desired product as a white solid (0,23 g).

TLC Rfof 0.5 (50% ethyl acetate in hexane)

Premeiotic-2-triftoratsetata (2,03 g). Purification with flash chromatography on silica with elution 15% ethyl acetate in hexane gave specified in the title compound as a white solid (0,69 g).

TLC Rf0,4 (20% ethyl acetate in hexane)

Intermediate compound 14

7-Methoxy-3-methyl-2-triftoratsetata-4-carboxylic acid

A mixture of 4-bromo-7-methoxy-3-methyl-2-triftoratsetata (1.7 g), bis(triphenylphosphine) palladium (II) chloride (0.26 g), triphenylphosphine (0,48 g) and triethylamine (7.7 ml) in tetrahydrofuran (30 ml) and water (10 ml) was heated at 80oC in a Parr apparatus in a gaseous atmosphere of carbon monoxide at 1240 kPa (180 psi). After 3 days the mixture was cooled to ambient temperature and concentrated in vacuum. The mixture was podslushivaet to pH 14 1 M sodium hydroxide solution and was extracted with ethyl acetate (CH ml). The aqueous phase was acidified to pH 5 glacial acetic acid. The precipitate was filtered and washed with water, getting mentioned in the title compound (0,81 g) in the form of a pure white solid.

TLC Rf0,37 (50% ethyl acetate in hexane)

The following compounds were obtained in the same way.

Intermediate compound 15

2-ACET is Azola. Purification with flash chromatography on silica with elution with 50% ethyl acetate in hexane gave the desired product as a white solid (1.38 in).

TLC Rf0,75 (50% ethyl acetate in hexane)

The intermediate connection 16

7-Methoxy-3-propyl-2-triftoratsetata-4-carboxylic acid

Was obtained from 4-bromo-7-methoxy-3-propyl-2-triftoratsetata (0,69 g). Rubbing with tert-butylmethylamine ether gave specified in the title compound as a white solid (0.29 grams).

TLC Rf0,4 (50% ethyl acetate in hexane)

Intermediate compound 17

4-Bromo-7-methoxy-2-triftoratsetata

A solution of 7-methoxy-2-triftoratsetata (5.0 g) in chloroform (100 ml) was cooled to 0oC was added N-bromosuccinimide (4.5 g). The mixture was stirred for 2 hours Then washed with 5% aqueous sodium metabisulfite (50 ml), dried over magnesium sulfate, evaporated in vacuo, and purified flash chromatography, elwira 25% ethyl acetate in hexane, getting mentioned in the title compound as a white solid (1.0 g).

TLC Rf0,29 (20% ethyl acetate in hexane)

Intermediate compound 18

4-Bromo-7-methoxy-3-(4-methox ethylformate (20 ml) was added sodium hydride (0.16 g; 60% dispersion in oil). The mixture was stirred at room temperature for 10 minutes, and then were added 4-methoxybenzylamine high (0.56 ml) and a catalytic amount of tetrabutylammonium iodide. The reaction mixture was heated at 90oC for 6 h, then poured into water (100 ml) and was extracted with ethyl acetate (CH ml). United

the organic phase was washed with water (100 ml) and saturated saline (50 ml), dried over magnesium sulfate, evaporated in vacuo, and purified flash chromatography, elwira 33% ethyl acetate in hexane, getting mentioned in the title compound as a white solid (0.52 g).

TLC Rf0,31 (201-hydrated ethyl acetate in hexane)

Intermediate compound 19

7-Methoxy-3-(4-methoxybenzyl)-2-triftoratsetata-4-carboxylic acid

A mixture of 4-bromo-7-methoxy-3-(4-methoxybenzyl)-2-triftoratsetata (520 mg), bis(triphenylphosphine)palladium (II) chloride (90 mg), triphenylphosphine (110 mg) and triethylamine (1.8 ml) in tetrahydrofuran (50 ml) and water (15 ml) was heated at 80oC in a Parr apparatus in a gaseous atmosphere of carbon monoxide at 1240 kPa (180 psi). After 5 days the mixture was cooled to ambient temperature and concentrated in HAC is tkilyle to pH 6 glacial acetic acid and was extracted with ethyl acetate (CH ml). The combined extracts were dried over magnesium sulfate and evaporated in vacuum, obtaining mentioned in the title compound as a cream solid (310 mg).

TLC Rf0,12 (50% ethyl acetate in hexane)

Intermediate compound 20

2-Ethyl-4-hydroxybenzoate

A mixture of the hydrochloride of 2-aminotetralin (5.0 g) and triethylorthoformate (13,7 ml) was heated at 150oC for 2 h, and then poured into a mixture of water (140 ml) and ethanol (35 ml). The mixture was intensively stirred for 30 minutes at room temperature, the precipitate was removed by filtration and dried, obtaining mentioned in the title compound as a beige solid (4.11 g).

TLC Rf0,40 (50% ethyl acetate in hexane)

The intermediate connection 21

4-Hydroxybenzotriazol

Hydrochloride of 2-aminotetralin (2 g) and triethylgallium (4,5 ml) was boiled under reflux in nitrogen atmosphere for 3 hours After cooling to room temperature the reaction mixture was poured into a mixture of water (70 ml) and ethanol (20 ml). The mixture was intensively stirred for 30 minutes, then left overnight at room temperature. The resulting beige precipitate was filtered and was dried by azeotropic distillation with tatoonie connection 22

2-Ethyl-4-methoxybenzoate

2-Ethyl-4-hydroxybenzoate (4,17 g) was dissolved in tetrahydrofuran (73 ml) at room temperature. Added tetrabutylammonium iodide (0.4 g), and then sodium hydroxide solution (to 3.89 g) in water (40 ml). The mixture was stirred for 10 minutes before adding iodomethane (3,13 ml). Then the stirring was continued over night. The crude mixture was evaporated onto silica gel and purified flash chromatography, elwira 25% and then 50% ethyl acetate in hexane, getting mentioned in the title compound in the form of liquid color straw (3,05 g).

TLC Rfof 0.50 (50% ethyl acetate in hexane)

The following compound was obtained in the same way

Intermediate compound 23

4-Methoxybenzoate

Was obtained from 4-hydroxybenzotriazole, getting mentioned in the title compound (90 mg) as a brown solid.

TLC Rf0,41 (50% ethyl acetate in hexane)

Intermediate compound 24

2-(1-Hydroxyethyl)-4-methoxybenzoate

4-Methoxybenzoate (6.0 g) was dissolved in tetrahydrofuran (225 ml) and cooled to -78oC in nitrogen atmosphere. Was added n-utility (26.5 ml, 1.6 M solution in hexano) and the mixture was stirred at -78oC for 30 minutes is 15 minutes, and then was cooled to -78oC. From a pre-cooled (syringe solution was added acetaldehyde (2.3 ml). The mixture was stirred at -78oC for 3 h, it was allowed to warm to room temperature and was stirred overnight. The reaction was stopped aqueous sodium bicarbonate (50 ml, gradually) and the tetrahydrofuran was evaporated in vacuum. The residue was extracted with dichloromethane (I ml). The combined organic phases were dried over magnesium sulfate, evaporated in vacuo, and purified flash chromatography, elwira 30%-50% ethyl acetate in hexane, getting mentioned in the title compound as a brown solid (6.25 g)

TLC Rf0,14 (30% ethyl acetate in hexane)

Intermediate compound 25

2-Acetyl-4-methoxybenzoate

The solution oxalicacid (0.25 ml) in dichloromethane (6.5 ml) was cooled to -55oC in nitrogen atmosphere. Was added dropwise a solution of dimethylsulfoxide (of 0.44 ml) in dichloromethane (1.3 ml) and the mixture was stirred for 5 minutes at -55oC before adding a solution of 2-(1-hydroxyethyl)-4-methoxybenzoate (0.5 g) in dichloromethane (2.5 ml). Stirring was continued for 15 minutes at -55oC, then added triethylamine (1.8 ml). The mixture was stirred at -55oC sdelali. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were dried over magnesium sulfate, evaporated in vacuo, and purified flash chromatography, elwira 30% ethyl acetate in hexane, to obtain specified in the title compound as a white solid (350 mg).

TLC Rfto 0.45 (50% ethyl acetate in hexane)

The intermediate connection 26

4-Methoxy-2-(2-methyl-[1,3]-dioxolane-2-yl)benzoxazol

2-Acetyl-4-methoxybenzoate (200 mg), p-toluensulfonate acid (239 mg), ethylene glycol (0,29 ml) and toluene (10 ml) was boiled under reflux in the conditions of a Dean-stark within 2 hours After cooling to room temperature, the toluene was evaporated and the residue was distributed between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (40 ml), aqueous sodium bicarbonate (2x40 ml) and water (40 ml), dried over magnesium sulfate, evaporated in vacuo, and purified flash chromatography, elwira 30% ethyl acetate in hexane to obtain specified in the title compound as a white solid (129 mg).

TLC Rf0,32 (30% ethyl acetate in hexane)

Intermediate compound 27

7-Bromo-2-ethyl-4-the solution was cooled to -78oC. was added dropwise bromine (0,73 ml). The mixture was gradually heated to room temperature and was stirred for 3.5 hours, the Methanol was evaporated in vacuum and the residue was distributed between ethyl acetate and aqueous sodium bicarbonate. The combined organic phases are washed with 5% aqueous sodium metabisulfite, was evaporated on silica and purified flash chromatography, elwira 25%-50% ethyl acetate in hexane, to obtain the mixture specified in the title compound and 2-ethyl-4-methoxybenzoate in the form of a pale yellow liquid (2.28 g).

TCX Rfof 0.50 (50% ethyl acetate in hexane)

The intermediate connection 28

2-Ethyl-4-methoxybenzimidazole-7-carboxylic acid

A mixture of 7-bromo-2-ethyl-4-methoxybenzoate (0.7 g), triphenylphosphine (0,273 g), bis(triphenylphosphine)palladium (II) chloride (0.125 g) and triethylamine (3.9 ml) in tetrahydrofuran (19 ml) and water (6.2 ml) was heated at 80oC in a Parr apparatus in a gaseous atmosphere of carbon monoxide at a pressure of 140 pounds per square inch (965,3 kPa) for 3 days. Then the mixture was cooled to ambient temperature and concentrated in vacuum. The mixture was podslushivaet to pH 14 1 M sodium hydroxide solution and was extracted with ethyl acetate (CH ml). The aqueous phase was acidified who sewed (MgSO4) and was evaporated in vacuum, obtaining mentioned in the title compound as a beige solid (0.40 g).

TCX Rf0,30 (50% ethyl acetate in hexane)

Intermediate compound 29

7-Bromo-4-methoxy-2-(2-methyl-[1,3]-dioxolane-2-yl)benzoxazol

4-Methoxy-2-(2-methyl-[1,3] -dioxolane-2-yl)benzoxazole (129 mg), N-bromosuccinimide (107 mg) and acetonitrile (5 ml) were combined and stirred at room temperature under nitrogen atmosphere for 4 hours the Mixture was distributed between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (I ml), dried over magnesium sulfate, evaporated in vacuo and was purified column chromatography, elwira 30% ethyl acetate in hexane, to obtain specified in the title compound as a white solid (95 mg).

TLC Rf0,41 (30% ethyl acetate in hexane)

The following compound was obtained in the same way.

The intermediate connection 30

7-Bromo-4-methoxybenzoate

Was obtained from 4-methoxybenzothiazole, highlighting specified in the title compound (635 mg).

TLC Rfof 0.51 (30% ethyl acetate in hexane)

The intermediate connection 31

4-Methox benzoxazol (480 mg), the palladium acetate (34 mg), 1,3-bis(diphenylphosphino)propane (126 mg), triethylamine (0,21 ml), water (15 ml) and tetrahydrofuran (30 ml) were combined and heated for 3 days at 90oC in a Parr apparatus under a pressure of 1035 kPa (150 psi) of carbon monoxide. After cooling to room temperature, the tetrahydrofuran was evaporated in vacuo, the residue was distributed between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic extracts were dried over magnesium sulfate, evaporated in vacuo, and purified flash chromatography, elwira with ethyl acetate, to obtain specified in the title compound as white solid (190 mg).

TLC Rfof 0.51 (ethyl acetate)

The intermediate connection 32

4-Methoxybenzothiazole-7-carboxylic acid

7-Bromo-4-methoxybenzoate (630 mg), triethylamine (3,85 ml), triphenylphosphine (290 mg), bis (triphenylphosphine) palladium chloride (88 mg), water (20 ml) and tetrahydrofuran (40 ml) were combined and heated at 90oC in a Parr apparatus under a pressure of 1035 kPa (150 psi) of carbon monoxide for 3 days. After cooling to room temperature, the tetrahydrofuran was evaporated. The residue was distributed between etelaat is ovali with ethyl acetate (CH ml), and then dichloromethane (I ml). The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. Purification of the residue with flash chromatography with elution by ethyl acetate and rubbing with diethyl ether resulted specified in the title compound as a white solid (125 mg). When standing from aqueous layer was deposited white solid, which was removed by filtration, and dried in vacuum at 45oC for 1 hour, receiving an additional portion specified in the title compound as a white solid (49 mg).

TLC Rfof 0.50 (ethyl acetate)

Example 1

8-Methoxyaniline-5-[N-(3,5-dichlorine-4-yl)]carboxamide

8-Methoxyaniline-5-carboxylic acid (0,19 g) dissolved in dichloromethane (16 ml), was treated in an inert atmosphere by oxalylamino (0.3 ml), then added 2 drops of N,N-dimethylformamide and stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo and carried out the azeotropic distillation with dry toluene (g ml) to give the dihydrochloride of the carboxylic acid as a brown solid (0.3 g). The solution of this solid in dry N,N-dimethylformamide (10 ml) was added at 60oC to a mixture of 4-the ed it already was stirred at ambient temperature for 1 hour. After 2 hours the mixture was left to cool over night before evaporation in a vacuum. The residue was filtered through a layer of silicon dioxide with hot ethyl acetate and the filtrate was evaporated in vacuum, obtaining the following residue. It was purified column chromatography using as eluent 10% methanol in ethyl acetate, getting mentioned in the title compound in the form of not-quite-white solid (0.09 g)

TLC Rfof 0.65 (10% methanol in ethyl acetate)

So pl. 205-208oC

The following compound was obtained according to a similar method.

Example 2

2-Acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(pyridine-4-yl)] carboxamide

Was obtained from 2-acetyl-7-methoxy-3-methylbenzimidazole-4-carboxylic acid (0.50 g) and 4-aminopyridine (0.18 g). Purification with flash chromatography on silica with elution 10% methanol in ethyl acetate gave specified in the title compound in the form of not-quite-white solid (0.10 g)

TLC Rf0,31 (10% methanol in ethyl acetate)

So pl. 274-275oC

Example 3

7-Methoxy-3-methyl-2-triftoratsetata-4- [N-(3,5-dichlorine-4-yl)]carboxamide

7-Methoxy-3-methyl-2-triftoratsetata-4-carboxylic acid (0.40 g), is able N,N-dimethylformamide and stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuum, obtaining hydrochloride carboxylic acid as a brown solid product. The solution of this solid product in dry N, N-dimethylformamide (10 ml) was added at ambient temperature to a mixture of 4-amino-3,5-dichloropyridine (0.29 grams), sodium hydride (0,30 g, 60% dispersion) and N, N-dimethylformamide (10 ml), which before this was stirred for 1 h at ambient temperature. After 2 h the mixture was left to cool overnight, then evaporated in vacuum. The residue was purified column chromatography using as eluent 50% ethyl acetate in hexane, getting mentioned in the title compound as a white solid (0.16 g).

TLC Rf0,34 (50% ethyl acetate in hexane)

So pl. 228-229oC

The following compounds were obtained in the same way.

Example 4

7-Methoxy-3-propyl-2-triftoratsetata-4-[N-(3,5-dichloropyridine-4-yl)]carboxamide

Obtained from 7-methoxy-3-propyl-2-triftoratsetata-4-carboxylic acid (0.28 g) and 4-amino-3,5-dichloropyridine (0.18 g). Purification with flash chromatography on silica with elution with 40% ethyl acetate in hexane gave specified in the header connection in vieC

Example 5

2-Acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dichlorine-4-yl)] carboxamide

Was obtained from 2-acetyl-7-methoxy-3-methylbenzimidazole-4-carboxylic acid (1.38 in). Purification with flash chromatography with elution 10% methanol in dichloromethane led to headline the compound (0.75 g) as a beige solid.

TLC Rf0,5 (10% methanol in dichloromethane)

So pl. 290-291oC

Example 6

2-Ethyl-4-methoxybenzimidazole-7-[N-(4-pyridyl)]carboxamide

To a solution of 2-ethyl-4-methoxybenzimidazole-7-carboxylate (0.40 g) in dichloromethane (20 ml) at room temperature under nitrogen atmosphere was added oxalicacid (0,32 ml). After stirring for 10 minutes was added dry N, N-dimethylformamide (2 drops). Stirring is continued throughout the night, getting a yellow solution, which was evaporated to dryness in vacuum. The residue was dissolved in dichloromethane (20 ml). Was added triethylamine (0,53 ml), then 4-aminopyridine (0.20 g) and the mixture was stirred at room temperature overnight. The mixture is evaporated on silica and purified flash chromatography, elwira dichloromethane, and then 10% methanol in dichloromethane, getting mentioned in the title compound in the form of solid veshestvaC

Example 7

2-Ethyl-4-methoxybenzimidazole-7-[N-(3,5-dichlorine-4-yl)] carboxamide

2-Ethyl-4-methoxybenzimidazole-7-carboxylate (1.24 g), 4-dimethylaminopyridine (catalytic amount), 4-NITROPHENOL (1,17 g) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g) in dichloromethane (60 ml) was stirred at room temperature for 48 hours the Mixture was evaporated on the silicon dioxide and chromatographically, elwira 50% ethyl acetate in hexane, receiving 4-nitrophenyl 2-ethyl-4-methoxybenzimidazole-7-carboxylate. 4-Amino-3,5-dichloropyridine (0,57 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature under nitrogen atmosphere. Was added sodium hydride (0.20 g, 60% dispersion) and the mixture was stirred for 5 h, and then were added 4-nitrophenyloctyl ester (1.2 g) and stirred additional 18 hours, the Reaction mixture was evaporated on silica and purified flash chromatography, elwira 50% ethyl acetate in hexane with the allocation specified in the title compounds as white solids (0,44 g).

TLC Rf0,20 (40% ethyl acetate in hexane)

Mass spectrum (CI): observed peak [M+H]+< / BR>
Example 8

2-Ethyl-4-methoxybenzimidazole-7-[N-(3,5-dichloropyridine-4-yl-N-oxide)] carboxamide

A solution of 2-ethyl-4-my acid in acetic acid (0,03 ml) and was stirred for 14 days at room temperature. The reaction mixture was distributed between dichloromethane (20 ml) and water (20 ml). The organic layer was separated, dried over dry magnesium sulfate, filtered and the filtrate was evaporated in vacuum. Purification with flash chromatography on silica with elution 10% methanol in ethyl acetate gave the desired product as a white solid (0,018 g).

TLC Rf0,38 (10% methanol in ethyl acetate)

So pl. 201-203oC

Example 9

4-Methoxybenzothiazole-7-[N-(3,5-dichloropyridine-4-yl)]carboxamide

A mixture of 4-methoxybenzothiazole-7-carboxylic acid (0.16 g), dimethylaminopyridine (catalytic amount), 4-NITROPHENOL (0.17 g), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.17 g) in dichloromethane (30 ml) was stirred under nitrogen atmosphere at room temperature overnight. The mixture was diluted with dichloromethane (20 ml) and washed with water (I ml). The combined organic phases were dried over magnesium sulfate and evaporated in vacuum to obtain 4-nitrophenyl 4-methoxybenzothiazole-7-carboxylate. 4-Amino-3,5-dichloropyridine (0.15 g) was dissolved in N,N-dimethylformamide (5 ml) at room temperature in nitrogen. Was added sodium hydride (40 mg, 60% dispersion in oil) and the mixture was stirred for 1 h before adding 4-formamide was evaporated in vacuum and the residue was distributed between ethyl acetate (40 ml) and water (40 ml). The combined organic phases were washed with water (2x40 ml), dried over magnesium sulfate, was evaporated on silica and purified flash chromatography with elution with 50% ethyl acetate in hexane, getting mentioned in the title compound as a white solid (51 mg).

TLC Rf0,19 (50% ethyl acetate in hexane)

So pl. 193-194,5oC

The following compounds were obtained in the same way.

Example 10

7-Methoxy-3-(4-methoxybenzyl)-2-triftoratsetata-4-[N-(3,5-dichloropyridine-4-yl)]carboxamide

Obtained from 7-methoxy-3-(4-methoxybenzyl)-2 - triftoratsetata-4-carboxylic acid, allocating specified in the title compound (140 mg) as a white solid.

TLC Rf0,35 (50% ethyl acetate in hexane)

So pl. 184,5-186oC

Example 11

2-(2-Methyl-[1,3] dioxolane-2-yl)-4-methoxybenzoate-7-[N-(3,5-dichloropyridine-4-yl)]carboxylate

Was obtained from 2-(2-methyl-[1,3] dioxolane-2-yl)-4-methoxybenzoate-7-carboxylic acid, allocating specified in the title compound (58 mg) as a white solid.

TLC Rf0,61 (ethyl acetate)

So pl. 155-157oC

Example 12

N-(3,5-Dichlorphenol-4-yl)-7-methoxy-2-triphtalocyaninine (50 mg) was stirred triperoxonane acid (3 ml) for 2 h at room temperature. Excess triperoxonane acid was removed in vacuo and the residue was distributed between ethyl acetate (25 ml) and aqueous sodium bicarbonate (25 ml). The aqueous phase was extracted with ethyl acetate (25 ml). The combined organic phases were dried over magnesium sulfate and evaporated in vacuum, obtaining a solid, which is triturated with diethyl ether, obtaining mentioned in the title compound as a cream solid (19 mg).

TLC Rf0,30 (50% ethyl acetate in hexane)

So pl. 300-301oC

Example 13

2-(1-Hydroxyimino)ethyl-7-methoxy-3-methyl-benzimidazole-4-[N-(3,5-dichloropyridine)]carboxamide

A mixture of 2-acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dichlorine - 4-yl)] carboxamide (0,60 g), hydroxylamine hydrochloride (1,05 g) and pyridine (1,22 ml) in toluene (40 ml) was boiled under conditions of Dean-stark for 21 hours, the Solvent was evaporated in vacuo and the residue triturated with water and filtered. The precipitate was dried in vacuum, highlighting specified in the header of the connection (or 0.57 g) as a beige solid.

So pl. 272-273oC

Mass spectrum: observed peak [M+H]+< / BR>
Example 14

3-Methyl-2-(1-(2-methylthiazole-4-ylethoxy)aminoethyl)-7-methoxybenzimidazole-4-[N-(3,5-dichlorine-4-yl-)]carboxamide

telharmonic (20 ml) at room temperature in the inert gas atmosphere was added sodium hydride (60%, 43 mg). After 1 h was added 4-chloromethyl-2-methylthiazole (217 mg) and dimethylformamide (5 ml) and stirring continued at room temperature for 18 hours the Reaction was stopped by addition of water (25 ml) and was extracted with ethyl acetate (CH ml). The combined organic phases were dried (magnesium sulfate), filtered and evaporated on silica gel. Purification with flash chromatography with elution by ethyl acetate gave specified in the title compound as a white solid (28 mg).

So pl. 220-221oC

Mass spectrum: observed peak [M+H]+< / BR>
The following compound was obtained in the same way.

Example 15

3-Methyl-2-[1-(3-dimethylaminopropoxy)aminoethyl] -7-methoxybenzimidazole-4-[N-(3,5-dichlorine-4-yl)carboxamid

Was obtained using 2-(1-hydroxyimino)ethyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dichloropyridine)] carboxamide (330 mg), and hydrochloride of N, N-dimethylaminopropylamine (383 mg). Purification with flash chromatography with elution of 20% methanol in dichloromethane led to headline the compound (96 mg) in the form of not-quite-white solid.

TLC Rf0,25 (20% methanol in dichloromethane)

So pl. 186-187oC

Methods of analysis

The analyses used the represent the conventional methods of analysis, described in Schilling et al. , Anal. Biochem., 216:154 (1994), Thompson and Strada, Adv. Cycl. Nuci. Res., 8:119 (1979) and Gristwood and Owen, Br.J. Pharmacol., 87:91P (1986).

The compounds of formula (i) expressed in these assays the activity at a level comparable to that expected useful in the treatment of painful conditions associated with phosphodiesterase IV.

The ability of compounds of the formula (i) to inhibit the production of TNF in human monocytes measured as follows. Menagerie cells peripheral blood was obtained by standard methods from their blood samples. The cells were placed in RPMI1640 + 1% fetal calf serum in the presence and in the absence of inhibitors. Added LPS (100 ng/ml) and the culture incubated for 22 h at 37oC in an atmosphere of 95% air/5% CO2. The supernatant liquid was studied on F using ELISA (enzyme-linked immunosorbent assay) using commercially available kits for analysis.

Activity in vivo at the cellular eosinophilic model was determined using the methods described in Hellewell et al., Br.J. Pharmacol., 11:811 (1994) and Br.J. Pharmacol., 110:416 (1993). Activity in the lung model was measured using the methods described in Kallos and Kallos, Int. Archs. Allergy Appl. lmmunol., 73:77 (1984) and Sa asthmatic responses to early and late phase, as well as inhibition of hyperresponsiveness of the Airways, described in Broadley et al. Pulmonary Pharmacol., 7:311 (1994), J. Immunological Methods 190:51 (1996) and British J. Pharmacol., 116:2351 (1995). Compounds according to the invention showed activity in this model.

Additional experimental data are presented in table. 1.

Data on biological activity are presented in table. 2.

1. Bicyclic carboxamide General formula (i)

< / BR>
in which (1) X represents N, and (a) Z is =CR1-CR2= and Y represents N, (b) Z is =CR1and Y represents O, S or NR4or (C) Z is =CR1-N= and Y represents CR2or (2) X is NR4Z is- (CR1= and Y represents N;

Q represents O;

R1and R2are the same or different and each represent COR6, C(=NOR6R13, alkyl-C(=NR6R13, NR8R9, CF3, R6or cyclic group

< / BR>
R3represents C1-6alkoxygroup, optionally substituted with halogen;

R4represents H or alkyl;

R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted the substituted R7, cycloalkyl, aryl, heteroaryl, optionally substituted R7, heterocycle, optionally substituted R7, arylalkyl, substituted R7, heteroallyl and geterotsiklicheskie;

R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12;

R8and R9each represents H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14;

R10represents alkyl, heterocycle;

R11and R12are the same and each represents H;

R13is alkyl;

R14is alkyl;

R15is alkyl;

V is ABOUT;

n=2-4;

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R3represents methoxy.

3. Connection under item 1 or 2, in which R4is N.

4. The compound according to any one of the preceding paragraphs, in which R5is optionally substituted 4-pyridyl or optionally substituted 4-pyridyl-N-oxide.

5. The compound according to any one of the preceding paragraphs, in which X represents n

6
C(=NOR6R13, CF3CN, R6or specified cyclic group.

7. The compound according to any one of the preceding paragraphs, in which R1and R2are the same or different and each represent COR6C(=NOR6R13, alkyl-C(= NR6R13, NR8R9, CF3and R3is optionally substituted alkoxy; R5is heteroaryl, which may be substituted with halogen, alkyl, CONR11R12, CF3or CN; R7is not alkyl; and R8and R9each represents hydrogen or alkyl.

8. Connection on p. 7, in which Q represents O; R1and R2are the same or different and each represents a COR13, C (=NOR10R13or R6; R3represents C1-6alkoxy, optionally substituted with halogen; R6represents H or a group selected from alkyl, optionally substituted R7, aryl, heteroaryl, optionally substituted R7, heterocycle, optionally substituted R7, arylalkyl, substituted R7, heteroallyl or geterotsiklicheskie; R10represents alkyl, heterocycle; R11and R12are the same and CAID-4-yl)]carboxamide.

10. Connection on p. 1, selected from 2-trifluoromethyl-3-methyl-7-methoxybenzimidazole-4-[N-(3,5-dichlorine-4-yl)] carboxamide; 2-ethyl-4-methoxybenzimidazole-7-[N-(4-pyridyl)] carboxamide; and 2-ethyl-7-methoxybenzimidazole-4-[N-(3,5-dichlorine-4-yl)]carboxamide.

11. Connection on p. 1, selected from

2-acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(pyridine-4-yl)]carboxamide,

7-methoxy-3-propyl-2-triftoratsetata-4-[N-(3,5-dichloropyridine-4-yl)]carboxamide,

2-acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dichlorine-4-yl)]carboxamide,

2-ethyl-4-methoxybenzimidazole-7-[N-(3,5-dichlorine-4-yl)]carboxamide,

2-ethyl-7-methoxybenzimidazole-4-[N-(3,5-dichloropyridine-4-yl-N-oxide)]carboxamide,

4-methoxybenzothiazole-7-[N-(3,5-dichloropyridine-4-yl)]carboxamide,

7-methoxy-3-(4-methoxybenzyl)-2-triftoratsetata-4-[N-(3,5-dichloropyridine-4-yl)]carboxamide,

2-(2-methyl-[1,3] dioxolane-2-yl)-4-methoxybenzoate-7-[N-(3,5-dichloropyridine-4-yl)carboxylate,

N-(3,5-dichlorine-4-yl)-7-methoxy-2-triftoratsetata-4-carboxamide,

2-(1-hydroxyimino)ethyl-7-methoxy-3-methyl-benzimidazole-4-[N-(3,5-dichloropyridine)]carboxamide,

3-methyl-2-(1-(2-methylthiazole-4-ylethoxy)aminoethyl)-7-methoxybenzimidazole-4-[N-(3,5-dichlorine-4-the ID-4-yl)]carboxamide.

12. Pharmaceutical composition having inhibitory PDE and TNF activity, comprising a compound according to any one of the preceding paragraphs and a pharmaceutically acceptable carrier or excipient.

13. The compound according to any one of paragraphs.1-11 as an agent for inhibition of phosphodiesterase and tumor necrosis factor.

Priority points:

15.11.1996 on PP.8 and 9;

22.04.1997 on PP.7 and 10;

17.11.1997 on PP.1-6 and 11-13.

 

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< / BR>
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