Carboxamide of benzofuran and pharmaceutical composition

 

(57) Abstract:

Describes new connections - carboxamide of benzofuran General formula (i), where Z is CO; R1is alkoxygroup, optionally substituted by one or more halogen; R2and R3the same or different and each represents H, R6OR10, COR6C(=NOR6R6, alkyl-C(=NR6R6C(= NOH)R6, NR8R9CN, CF3, CO2H, CO2R10; R4represents H or alkyl; R5represents aryl, heteroaryl, heterocycle; R4and/or R5part aryl/heteroaryl/heterocycle optionally substituted by one or more substituents R13; R6is R10, optionally substituted in any position R14; R7represents H or alkyl; R8represents H, heteroallyl, heteroseksualci or alkoxycarbonyl; R9represents H, heteroaromatic or alkyl; R10represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci; R11represents H or alkyl; R12represents H; R13represents alkyl, optionally substituted with halogen, ALCO is UB>; R14is HE, carbonyl oxygen, OR10, NR8R9CN, CO2N, CO2R10, CONR11R12; n = 0; or its pharmaceutically acceptable salt. Also described pharmaceutical composition based on them. The compounds can be used as phosphodiesterase inhibitors in the treatment of pathological conditions associated with proteins that mediainput cellular activity. 2 C. and 18 h.p. f-crystals, 2 PL.

The scope of the invention

The present invention relates to new carboxamides and thioamides of benzofuran, and also to their preparation and use as pharmaceuticals.

Background of the invention

In EP-A-0637586 described derivatives benzofuran, including 4-carboxamide, as acetylcholinesterase inhibitors.

In WO-A-9408962 described analogs of benzofuran as receptor antagonists of fibrinogen.

In WO-A-9203427 described benzofuran-2-carboxamide with the substituent in 3-position, selected from hydroxy, acyloxy, alkoxy, optionally alkyl substituted aminoethoxy, alkylsulfonyl, optionally alkyl substituted aminoalkylsilane or arylsulfonamides as a means to ensure OST

In WO-A-9603399 described dihydrobenzofuran-4-carboxamide as inhibitors of phosphodiesterase.

In WO-A-9636624 (published 21.11.96,; EP-A-0771794) describes compounds of formula (i), as defined below, some of which may be eligible attributed to the priority date of the earlier 20.05.96, such compounds with an earlier priority date and in relation to formula (i):

R1is optionally substituted alkoxy;

R2and R3each represent H, optionally substituted alkyl (for example, cycloalkylcarbonyl alkyl), aryl or heteroaryl, alkanoyl, alkoxycarbonyl or CN; and

R4is 4-pyridyl, optionally substituted in the 2 - and 6-positions with alkyl, alkoxy, COOH, alkanoyl, alkoxycarbonyl, CF3, NH2, CN, NO2or halogen; and

R5represents H, alkyl, cycloalkyl, aryl, heteroaryl or aralkyl.

Phosphodiesterase (PDE: phosphodiestherases) and tumor necrosis factor (TNF), character actions and beneficial effects of therapeutic use of inhibitors described in patents WO-A-9636595, WO-A-9636596 and in WO-A-9636611, the content of which is incorporated herein by reference. The same documents describe derivatives benzofuran with beneficial action of the new compounds, which can be used in the treatment of pathological conditions, such as pathological conditions associated with proteins that mediainput 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:

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where Z is CO or CS;

R1is alkoxygroup, optionally substituted by one or more halogen, OH or thioalkyl;

R2and R3the same or different, and each represents H, R6OR10, COR6C(= NOR6R6, alkyl-C(=NOR6R6, alkyl-C(=NOH)R6C(=NOH)R6, halogen, NR8R9, CF3CN, CO2H, CO2R10, CONH2, CONHR6or CON(R6)2;

R4represents H, arylalkyl, heteroallyl, heteroseksualci, S(O)mR10or alkyl, optionally substituted by one or more substituents selected from hydroxy, alkoxy, CO2R7, SO2NR11R12, CONR11R12CN, carbonyl oxygen, NR8R9, COR10and S(O)nR10;

R5represents aryl, heteroaryl, heterocycle, arylalkyl, heteroaryl ameena one or more alkyl substituents-R13or R13;

R6is R10, optionally substituted in any position with (one or more) R14;

R7represents H, alkyl, cycloalkyl, arylalkyl, heteroaromatic or heteroseksualci;

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

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

R9, R11and R12the same or different, each represents H, or R10;

R13represents alkyl, optionally substituted by halogen atom, alkoxy, optionally substituted with halogen, aryl, heteroaryl, heterocycle, hydroxy, aryloxy, heteroaromatic, heterocyclic, arylalkyl, heteroarylboronic, heterocyclizations, CO2R7, CONR11R12, SO2NR11R12, halogen, -CN, -NR8R9, COR10, S(O)nR10or carbonyl oxygen;

R14not only is Lee COR10;

m is 1-2; and

n is 0-2; and

their pharmaceutically acceptable salts.

Any combinations of substituents and/or variables are allowed if such combinations result in stable compounds.

Description of the invention

Suitable pharmaceutically acceptable salts are the salts of addition of pharmaceutically acceptable bases and pharmaceutically acceptable acid. Some of the compounds of formula i which contain an acid group, form salts with bases. Suitable pharmaceutically acceptable salts with bases include metal salts, such as alkali metal salts, for example sodium salt, or salts of organic amines, such as obtained with Ethylenediamine.

Some of the compounds of formula (i) which contain an amino group, form an acid additive salt. Suitable acid additive salts include pharmaceutically acceptable inorganic salts such as sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and pharmaceutically acceptable organic acid additive salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, metasulfite, - Ketoglutarate, glycerol and g is LASS="ptx2">

The person skilled in the art it is clear that some of the compounds of formula (i) can exist in more than one tautomeric form. This invention includes all tautomeric forms.

It should be noted that the compounds according to the invention can contain one or more asymmetrically substituted atoms. The presence of one or more asymmetric centers in the compound of formula (i) may lead to stereoisomers, and note that in each case, the invention extends to all such stereoisomers, including enantiomers and diastereoisomers and their mixtures, including racemic mixtures.

As used herein, the term "alkyl", regardless of use, whether separately or as part of another group includes alkyl groups of straight and branched chain containing up to 6 atoms. Alkoxy refers to the group alkyl-O-, an alkyl group which corresponds to the previously described. Aryloxy means the group aryl-O-, aryl group which corresponds to the following definition. Heteroaromatic means the group heteroaryl-O-, and heterocyclic means a group heterocycle-O-, in which heteroaryl and heterocycle group correspond to the following definition. Harilal is alkyloxy means a group heterocycle alkyl-O-. Alkylamino means the group alkyl-N-alkyl group which corresponds to the particular above, arylamino means the group aryl-N-, and heteroarenes means the group heteroaryl-N- (aryl or heteroaryl defined below). Thioalkyl means the group alkyl-s Cycloalkyl includes non-aromatic cyclic or polycyclic system of rings with the number of carbon atoms from 3 to 10. Cyclic alkyl optionally may be partially unsaturated. Aryl denotes a carbocyclic radicals containing from 6 to 10 carbon atoms. Arylalkyl means arylalkyl group, where the aryl and alkyl such as described here. Heteroaromatic means heteroaryl-alkyl group, and heteroseksualci means geterotsyklicescoe group. Alkylsulphonyl means the group alkyl-CO-, an alkyl group which corresponds to the previously described. Arylcarbamoyl means the group aryl-CO-, in which the aryl group described previously. Heteroarylboronic means the group heteroaryl-CO-, and heterocyclicamines means a group heterocycle-CO-. Arylsulfonyl means the group aryl-SO2in which the aryl group described previously. Heteroarylboronic means the group heteroaryl-SO2and heterozygosity correspond described previously. Alkylsulfonyl means the group alkyl-SO2- in which the alkyl group described previously. Carbonyl oxygen means a group of-CO-. It will be clear that the carbonyl oxygen cannot be a Deputy on the aryl or heteroaryl ring. Carbocyclic ring means a 5-10 membered monocyclic or polycyclic system of rings which may be saturated or partially unsaturated. Heterocyclic ring means a 5-10 membered monocyclic or polycyclic system of rings (which may be saturated or partially unsaturated), where one or more atoms in the cyclic system is not carbon and another element selected from nitrogen atoms, oxygen or sulfur. Heteroaryl means a 5-10 membered aromatic monocyclic or polycyclic hydrocarbon cyclic system in which one or more atoms in the cyclic system is not carbon and another element selected from nitrogen atoms, oxygen or sulfur; if necessary, the N atom may be in the form of N-oxide. Heterocycle means a 5 - to 10-membered saturated or partially saturated monocyclic or polycyclic hydrocarbon cyclic system, one or more of the atoms in the cyclic system which is not carbon, and d is">

Compounds according to this invention can be used for the treatment of TNF-mediated pathologies. "TNF-mediated disease or pathological condition" means any and all pathological conditions in which plays the role of TNF, or by the production of TNF, or by action of TNF, leading to the release of other cytokines, such as IL-1 or IL-6 is not limited, however, only them. A pathological condition in which the cytokine IL-1, for example, is the main component and the production or effect of which is amplified or which is secreted in response to TNF, will, therefore, be considered as TNF-mediated pathological condition. Because TNF - a (also known as lymphotoxin) has structural homology, similar to TNF - a (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-and TNF - are treated as objects of inhibition by the compounds of the present invention and are therefore treated here collectively as "TNF" unless, in particular, is different.

This invention relates to a method of mediation or suppression of enzymatic aktivnaya TNF in a mammal, in need thereof, which provides for the introduction of this mammal an effective amount of the compounds of formula (i) or its pharmaceutically acceptable salt.

Inhibitors of PDE IV can be used in the treatment of various kinds of allergic and inflammatory diseases, including: asthma, chronic bronchitis, chronic obstructive airway disease, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eye irritation, allergic reactions of the eyes, the eosinophilic granulomas, psoriasis, Bechet disease, erythematous, anaphylactoid purple jade, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, sepsis, ulcerative colitis, Crohn's disease, reperfusion lesion of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and respiratory distress syndrome in adults. In addition, inhibitors of PDE IV applicable in the treatment of diabetes and conditions associated with the suppression of cerebral metabolism, such as stilnoct brain, senile dementia (Alzheimer's disease), lack of memory in the deposits, improve the neuroprotective activity funds, such as cardiac arrest, stroke, or intermittent claudication. Inhibitors of PDE IV can be used in the treatment of tardive dyskinesia, ischemia and Huntington disease. In addition, inhibitors of PDE IV can be used as gastronomiche funds. Special practical embodiment of therapeutic methods of the present invention is the treatment of asthma.

The viruses described here for treatment, are viruses that are the result of infection produce TNF, or viruses, which are sensitive to inhibition, such as by reducing replication, directly or indirectly, by the TNF-inhibitors of formula (i). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus, and the group of herpes viruses, such as Herpes zoster and Herpes simplex (not limited to).

More specifically, this invention relates to a method of treatment of a mammal infected by human immunodeficiency virus (HIV), which provides for the introduction to such mammal an effective inhibition of TNF amount of the compounds of formula (i) or its pharmaceutically acceptable salt.

Connection annoushka in suppressing the production of TNF. TNF-mediated diseases that may be the object held in therapeutic or prophylactic treatment of animals include pathological conditions, such as pathological conditions mentioned above, but in particular viral infections. Examples of such viruses include, but are not limited to): feline immunodeficiency virus (FIV) or other retroviral infection, such as virus infectious anemia of horses, the virus arthritis goats, virus visna, maedi virus and other lentiviruses.

The compounds of this invention are applicable also for the treatment of parasitic, yeast and fungal infections, where such yeast and fungal pathogens sensitive to regulatory effect of TNF or will cause the production of TNF in vivo. Preferred pathological condition as the object of treatment is fungal meningitis.

The compounds of this invention can also inhibit neurogenic inflammation through increasing the level of cyclic adenosine monophosphate (camp) in sensitive neurons. They have, therefore, analgesic, antitussive and protivogribkovym effect in inflammatory diseases accompanied by irritation and pain.

With the form meant, among other things, the connection pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as solvents and carriers, and not including material considered toxic at normal dosage levels. Pharmaceutically acceptable level of purity should generally be at least 50%, excluding standard pharmaceutical additives, preferably 75%, more preferably 90% and even more preferably 95%.

The invention further provides a method of obtaining compounds of formula (i) in which the radicals R1and other, m and n are such as defined above. It should be clear that functional groups such as amino, hydroxyl or carboxyl groups that are present in different compounds, described below, and which it is desirable to protect, may need to turn them in protected form, before you started any reaction. In such cases, the removal of the protective group may be the final stage in a specific sequence of reactions. Suitable protective groups for such functional groups must be known to the skilled in the art. Specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Green. So, the way to get seadragons or hydrolysis of the compounds of formula (i), in which R4contains a suitable group-OP, where P represents a suitable protective group (for example, benzyl or acetyl).

It should be clear that where a particular stereoisomer of formula (i) can be obtained using the techniques of separation (splitting), such as, for example, high performance liquid chromatography, or may be implemented as described here, the methods of synthesis using the appropriate homochiral starting material.

The method of obtaining the compounds of formula (i) where Z represents CO, contains reaction of the corresponding carboxylic acid of formula (ii) with a suitable amine of formula (iii):

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where R1ais R1by the definition of the formula (i) or a group, turn in the R1, a R2a-R5alikewise represent R2-R5or group into R2-R5respectively; and further, if required, converting any group R1ain R1and/or R2ain R2and/or P3ain R3and/or R4ain R4and/or R5ain R5; and further, if required, converting any group R1ain R1and/or R2ain R2and/or R3ain R3and/or R4a

Carboxylic acids of formula (ii) and amines of formula (ii) are either commercially available, previously described compounds or get them using standard methods known to practitioners. Carboxylic acid of the formula (ii), for example, conveniently be obtained from the corresponding benzofuran formula (v) using well-known practitioners of standard methods. Benzofuran formula (v), for example, can be applied to obtain the aldehyde of formula (iv), which you can then oxidize to obtain the corresponding acid of formula (ii). Alternatively, you can bronirovat benzofuran formula (v), receiving the bromide of formula (vi), which can then be converted into carbon is such as catalyzed by palladium reaction.

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The compound of formula (ia) can also be obtained by reaction of the carboxylic acid of formula (ii) with the amine (iii) with the formation of the compounds of formula (ia) in which R4arepresents H, followed by reaction with a reagent R4aY (vii) in which Y represents a suitable leaving group such as halogen. The first reaction may be carried out as described above. Carboxylic acid is preferably converted into the acid chloride, mixed anhydride or other activated intermediate product prior to reaction with the amine (iii). The reaction with the reagent (vii) can be performed in any known practitioners of suitable conditions. It can be carried out in the presence of a suitable base such as sodium hydride, preferably in a suitable solvent, such as dimethylformamide. Reagents (vii) are known compounds or are commercially available or are obtained using the well-known practitioners of standard methods. Such compounds include alkylating agents, such as propyl bromide, alleluya agents, such as benzoyl chloride and sulfonylurea agents, such as methanesulfonate.

The compounds of formula (i) can be also obtained by the can be obtained the corresponding alkylation of compounds in which R4contains a hydroxy-group. The compounds of formula (i) in which Z represents CS, can be obtained from compounds of formula (i) in which Z represents, using any known practitioners of suitable conditions, for example using reagent Lesson (Lawesson''s reagent).

Using a different connection method, in which R2and/or R3contain the oxime may be obtained from the compounds in which R2and/or R3contain a carbonyl group. This transformation can be performed using any suitable conditions known practitioners. The compounds of formula (i) in which R2and/or R3contain a carbonyl group, can be recovered using well-known practitioners standard conditions (e.g. using sodium borohydride in a suitable solvent) to obtain compounds in which R2and/or R3contain an alcohol group. Compounds in which R2and/or R3are alkyl, can be obtained by reduction of compounds in which R2and/or R3are CO-alkyl, using well-known practitioners of the standard is to be conducted and other transformations of the compounds of formula (i), R2and/or R3which contain a carbonyl group. Such transformations include, but are not limited to, reductive amination and alkylation. Compounds in which R2and/or R3contain CO-alkyl, CO-aryl, CO-heteroaryl, CO-alcylaryl, CO-Alkylglucoside or CO-alkylglycerols group can be obtained from the compounds in which R2and/or R3contain a CN-group, by adding a suitable ORGANOMETALLIC reagent such as a Grignard reagent). Any of the above transformations can be performed either at the end of the synthesis, either at the stage of a suitable intermediate product.

The compound of formula (i) or, where this is appropriate, its pharmaceutical salt and/or its corresponding pharmaceutically acceptable MES, you can type per se (in pure form or, preferably, in the form of a pharmaceutical composition containing pharmaceutically acceptable carrier.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or, where appropriate, its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES and pharmaceutically priemium by, moreover, the preferred route of administration depends on disorders for which treatment is required, preferably in the form of a uniform dosage form or in a form that as a single dose of the patient-the person can't take himself. Conveniently, when the composition is suitable for oral, rectal, local, parenteral administration or for administration via the respiratory tract. Drugs can be designed to achieve prolonged release of the active ingredient.

The term "parenteral" as used here, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats and others, compounds of the present invention is effective in the treatment of people.

The compositions of this invention can be in the form of tablets, capsules, sachets, vials, powders, granules, large tablets, suppositories, tonic powders or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Provided, where this corresponds to the destination, local preparative form.

Examples of standardized dosage forms for oral administration may be tablets and capsules, they may contain conventional carriers such as binding agents, for example syrup, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, such as microcrystalline cellulose, lactose, corn starch, sucrose, calcium phosphate, sorbitol or glycine; tabletiruemye lubricants, for example magnesium stearate; dezintegriruetsja agents, for example starch, polyvinylpyrrolidone, sodium salt glycolate starch or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid oral formulations may be obtained by conventional methods of blending, filling, tabletting or the like. For the purposes of distribution of the active substance in the weight of these compositions, which use large quantities of fillers, you can re-apply the blending operation.

Such operations, of course, not beyond the traditional techniques. Tablets can be provided with a casing in accordance with methods well known in standard formats the t to be in shape, for example, emulsions, syrups or Alexiou, or can be presented as a dry product, diluted to the desired volume with water or other suitable media before use. Such liquid preparations may contain conventional additives such as suspendisse agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel, aluminum stearate, hydrogenated edible fats; emulsifying agents, for example lecithin, monooleate sorbitan or Arabian gum, non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, ester oils, such as esters of glycerine, propylene glycol or ethyl alcohol; preservatives, for example methyl - or propyl-p - hydroxybenzoate or sorbic acid; and, if this is desirable, traditional corrigentov or dyes.

The compositions can be conveniently presented for introduction into the respiratory tract in the form of the medicinal powder for inhalation through the nose or an aerosol or solution for a nebulizer, or fine powder for insufflation, alone or in combination with an inert carrier, such as La who μm, preferably less than 10 μm, for example from 1 to 10 μm, from 1 to 5 microns, or from 2 to 5 μm. If appropriate, may be included a small number of other anti-asthma and bronchodilatory agents, e.g. sympathomimetic amines, such as izoprenalin, isoetharine, salbutamol, phenylephrine or ephedrine, and corticosteroids, such as prednisone and adrenal stimulants such as ACTH.

For injecting liquid unified dosage forms prepared using the compounds and sterile media, and the connection, depending on the concentration, can be suspended or dissolved in the carrier. Upon receipt of the solutions the compound can be dissolved in water for injection and sterilized by filtration before filling into a suitable vial or ampoule and sealing.

Conveniently, when adjuvants such as local anesthetics, preservatives or buffering agents can be dissolved in the carrier. To increase the stability of the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in generally the same way, except that instead of dissolving the compound suspend is receiving its effects of ethylene oxide before suspendirovanie in sterile media. To achieve a uniform distribution of the compounds useful in the composition include surface-active or wetting agent.

Depending on the method of administration of the composition may contain from 0.1% to 99% by weight, preferably 10-60% by weight, of active material.

The compound of formula (i) or, where appropriate, its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES, you can also enter local ready formulation in combination with traditional media for local use.

Local ready preparative forms can be represented in the form of, for example, ointments, creams or lotions, impregnated bandages, gels, gel pencils, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents, facilitating the penetration of drugs, and emollients (softeners) in ointments and creams. The finished formulation may also contain compatible conventional carriers, such as bases for creams or ointments and ethyl or alerby alcohol for lotions.

Suitable ready preparative forms of creams, lotions, gels, sticks, sprays or aerosols, which Olya, are conventional and well known in practice, for example as described in standard textbooks, such as book Harry called "Cosmeticology", published by Leonard Hill Books, book Remington called "Pharmaceutical Sciences", and in the pharmacopoeias of England and the United States (British and US Pharmacopoeias).

Acceptable, when the content of the compounds of formula (i) or, if appropriate, its pharmaceutically acceptable salt is from 0.5 to 20% by weight, preferably from 1 to 10%, for example from 2 to 5%, of the finished formulation.

The dose of a compound used in the invention, the treatment may vary, as is usually the case, depending on the gravity of the violations, the severity of the patient and on the relative effectiveness of the connection. General guiding rule, however, is the use of appropriate standard uniform doses from 0.1 to 1000 mg, such as from 0.5 to 200, from 0.5 to 100, or from 0.5 to 10 mg, for example of 0.5, 1, 2, 3, 4, or 5 mg; and such uniform dose can be entered 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, to the total daily dose for an adult weighing 70 kg was in the range of from about 0.1 to 1000 mg, i.e. in the range from 0.001 to 20 mg/kg to 0.2 mg/kg/day, and this therapy may continue for several weeks or months.

Used herein, the term "pharmaceutically acceptable" refers to materials suitable for use for the treatment of humans and in veterinary practice.

The invention is illustrated by the examples below.

THE INTERMEDIATE CONNECTION 1

2-Acetyl-7-methoxybenzophenone-4-carbonylchloride

2-Acetyl-7-methoxybenzophenone-4-carboxylic acid (0.12 g) suspended in anhydrous dichloromethane (4 ml) at room temperature under nitrogen atmosphere was added oxalicacid (0.1 ml) and then 3 drops of N,N-dimethylformamide. Evaporation in vacuum 2 hours gives specified in the title compound as a yellow solid product (~0.5 g).

TCX: Rf0,60 (50% ethyl acetate in hexane)

INTERMEDIATE COMPOUND 2

2-Acetyl-7-methoxybenzophenone-4-carboxylic acid

A mixture of 2-acetyl-4-bromo-7-methoxybenzophenone (5 g), triphenylphosphine (98 mg), bis(triphenylphosphine)palladium(II)chloride (261 mg), triethylamine (2,85 ml) and water (1 ml) in tetrahydrofuran (25 ml) was saturated with carbon monoxide in the reactor Parra at 7,73 at (110 psi). Was heated to 110oC (now under pressure 15,47 at (220 psi)) and left for a week. Visit by using aqueous sodium hydroxide (1M). The separated aqueous phase was acidified to pH 1 with dilute hydrochloric acid (1M) and extracted the resulting suspension dichloromethane (3 x 100 ml), then ethyl acetate (100 ml). These combined organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining a yellow solid product (2.58 g).

TCX: Rf0,61 (ethyl acetate).

INTERMEDIATE COMPOUND 3

2-Acetyl-4-bromo-7-methoxybenzophenone

At a temperature of 0oC to a suspension of 2-acetyl-7-methoxybenzophenone (20 g) in methanol (300 ml) was introduced dropwise a solution of bromine (5.5 ml) in methanol (100 ml). The ice bath was immediately removed and the mixture was left to warm to room temperature. 1 hour later the transformation was incomplete, so I added bromine (0.75 ml) in methanol (25 ml) and the mixture was stirred over night. The reaction was suppressed using an aqueous solution meta sodium bisulfite (300 ml) to give the precipitate, which was filtered and dried in vacuum, obtaining a brown solid product (17,4 g).

TCX: Rf0,90 (ethyl acetate).

INTERMEDIATE COMPOUND 4

2-Ethyl-7-methoxybenzophenone-4-carboxylic acid

To a solution of 2-ethyl-7-methoxybenzenesulfonamide (5 g) in I (20.7 g) in water (15 ml), then made chlorite sodium (11,05 g). The resulting heterogeneous mixture was vigorously stirred for 30 minutes and then was diluted with water (125 ml). the pH of the mixture was adjusted to 4 by addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 200 ml) and the combined organic extracts were washed with water (2 x 200 ml). The organic solution was concentrated to approximately 100 ml and then cooled to 10oC. the resulting precipitate was collected by filtration and dried at 50oC in vacuum, obtaining a solid product colors beige (4 g).

T. pl. 215-216oC.

The following compound was obtained according to the aforementioned method.

THE INTERMEDIATE COMPOUND 5

1-[1- (2,2-Dimethylpropyl)]-7-methoxybenzophenone-4-carboxylic acid

Was obtained from 2-[1-(2,2-dimethylpropyl)] -7-methoxybenzophenone - 4-carboxaldehyde (2.14 g). Specified in the title compound (1,81 g) was obtained as a pale-yellow solid product.

T. pl. 173-174oC.

THE INTERMEDIATE COMPOUND 6

4-Amino-3-chloropyridin

A solution of 4-aminopyridine (4.0 g) in concentrated hydrochloric acid (50 ml) at 80-85oC was treated with an aqueous solution of hydrogen peroxide (13,5% of the mass. /about.). The cooling solution), keeping the temperature below 15oC. the Resulting white solid product was isolated by filtration and dried in the air, getting a white solid product (4.9 g).

Rfof 0.36 (ethyl acetate).

T. pl. 65-67oC.

INTERMEDIATE COMPOUND 7

4-N-Bromo-(propylamino)pyridine

4-Aminopyridine (0,499 g) and Propionaldehyde (0.5 g) in dichloromethane (50 ml) under inert atmosphere was stirred at room temperature for 1.5 hours. Added triacetoxyborohydride sodium (2.7 g) and the mixture was left overnight. The reaction mixture is washed with aqueous sodium bicarbonate (2 x 40 ml) and was extracted with dilute hydrochloric acid (2 x 40 ml). These acid extracts were podslushivaet using pellets of potassium hydroxide and was extracted into dichloromethane (2 x 80 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum, obtaining an oily residue (0.11 g).

TCX: Rf0,49 (10% methanol in ethyl acetate).

INTERMEDIATE COMPOUND 8

2-Ethyl-7-methoxy-4-N-(3-carboethoxy)benzofuroxan

At room temperature in an inert atmosphere, 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (1.0 g) was added to the solution over night. The mixture was poured into dilute aqueous hydrochloric acid and was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated in vacuum, obtaining mentioned in the title compound (1.39 g) as a white solid product.

T. pl. 159-161oC.

The following compound was obtained according to the aforementioned method.

INTERMEDIATE COMPOUND 9

2-Ethyl-7-methoxy-4-N-(4-carboethoxy)benzofuroxan

Was obtained from 2-ethyl-7-methoxybenzophenone-4-carbonylchloride (1.3 g) and ethyl 4-aminobenzoate (1.0 g). Specified in the title compound (0,76 g) was obtained as a white solid product.

TCX: Rf0,18 (25% ethyl acetate in hexane).

INTERMEDIATE COMPOUND 10

2-[1-(2,2-Dimethylpropyl)]-7-methoxybenzophenone-4-carboxaldehyde

At 0oC in nitrogen atmosphere to a DMF (N,N-dimethylformamide) (1 ml) was added dropwise phosphorus oxychloride (1,64 ml) and was stirred for 10 minutes. Then was added a solution of 2-[1-(2,2 - dimethylpropyl)] -7-methoxybenzophenone (1.92 g) in DMF (3.5 ml). Formed solid product is pale yellow and the reaction mixture was heated to 100oC for 2 hours Left to cool dratha sodium acetate (20 ml) and the resultant mixture was extracted with MTBE (3 x 25 ml). The combined organic phases were washed with water (2 x 20 ml), saturated aqueous acidic sodium carbonate (20 ml) and brine (30 ml). The solution was dried (magnesium sulfate) and concentrated in vacuum, obtaining mentioned in the title compound (2.14 g) as a light brown oil.

TCX: Rf0,25 (5% ethyl acetate in hexane).

INTERMEDIATE COMPOUND 11

2-[1-(2,2-Dimethylpropyl)]-7-methoxybenzophenone

When 40oC to a solution of o-vanillin (10 g) in ethanol (230 ml) was added sodium hydroxide (2,89 g). After 10 minutes, was added 1 - bromopinacolone (9.7 ml) and the resulting mixture was heated at 60oC for 4 h, and then boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature, and then concentrated in vacuum. The residue was separated between ethyl acetate (100 ml) and 0.2% aqueous solution of sodium hydroxide (100 ml). Were extracted aqueous layer with ethyl acetate (2 x 75 ml) and the combined organic extracts were washed with water (100 ml) and brine (100 ml). The solution was dried (magnesium sulfate) and concentrated in vacuum, obtaining 2-[1-(2,2-dimethyl-1 - oxopropyl)]-7-methoxybenzophenone in the form of a brown oil.

To a stirred suspension of 2-[1-(2,2-dimethyl-1-oxopropyl)] and up to 65oC for 1 hour, then boiled under reflux for 1.75 hours, getting a yellow solution. After cooling to room temperature was added water (50 ml) and the mixture was extracted with dichloromethane (3 x 50 ml). The combined organic extracts washed with 2M aqueous hydrochloric acid (15 ml), water (3 x 20 ml) and brine (50 ml). The solution was dried (magnesium sulfate) and concentrated in vacuum. Purification using column chromatography on silica with elution with 5% ethyl acetate in hexane gave specified in the title compound (1.92 g) as a colourless oil.

TCX: Rf0,35 (5% ethyl acetate in hexane).

INTERMEDIATE COMPOUND 12

2-Ethyl-7-methoxybenzophenone-carbonylchloride

2-Ethyl-7-methoxybenzophenone-4-carboxylic acid (of 4.05 g) was heated in dry toluene (100 ml) with thionyl chloride (14 ml) under nitrogen atmosphere at 90oC for 2 hours the Solution is evaporated to dryness in a vacuum and subjected to azeotropic distillation with dry toluene (2 x 50 ml), getting mentioned in the title compound (4.4 g) in the form of a whitish solid product.

T. pl. 100-102oC.

INTERMEDIATE COMPOUND 13

Methyl 7-methoxybenzophenone-2-carboxylate

In nitrogen atmosphere were mixed 7 is ethylchloride (11 ml), continued stirring for 18 hours After removal of solvent received whitish crystalline solid product (10.7 g).

TCX: Rf0,94 (10% methanol in dichloromethane).

INTERMEDIATE COMPOUND 14

Methyl 4-formyl-7-methoxybenzophenone-2-carboxylate

At 0oC to a suspension of intermediate compound 13 (1 g) in dichloromethane (14 ml) was added titanium tetrachloride (1M solution in dichloromethane, 5,3 ml), then dichlorodimethyl ether (of 0.44 ml) in solution in dichloromethane (3 ml). The reaction mixture was slowly heated to room temperature, then was heated to 35oC for 18 hours. After cooling, the reaction mixture was poured into a mixture of ice and water and the aqueous phase is extracted with dichloromethane. The combined organic layers were washed with water, dried and concentrated, obtaining the solid product is a light brown color (0.97 g).

TCX: Rf0,86 (10% methanol in dichloromethane).

INTERMEDIATE COMPOUND 15

Methyl 4-carboxy-7-methoxybenzophenone-2-carboxylate

To a stirred suspension of intermediate 14 (0.97 g) in tert-butanol (115 ml) was added 2-methyl-2-butene (3 ml) and then sodium phosphate (5.7 g in 28 ml water) and sodium chlorite (3,74 g in 28 ml of water). Paramashiva what astora hydrochloric acid. The organic layers was dried and concentrated, obtaining a solid product color beige. Was purified by trituration with simple ether, obtaining a pale yellow solid product (0,62 g).

TCX: Rf0,64 (10% methanol in dichloromethane).

THE INTERMEDIATE CONNECTION 16

7-Methoxy-2-methoxycarbonylmethyl-4-carbonylchloride

In a nitrogen atmosphere at 90oC intermediate compound 15 (of 0.62 g) was heated in dry toluene (23 ml) with thionyl chloride (2 ml) for 2 hours the Solution is evaporated to dryness in a vacuum and subjected to azeotropic distillation with dry toluene (2 x 50 ml), getting mentioned in the title compound (0.51 g) as a pale brown solid product.

TCX: Rf0,0 (10% methanol in dichloromethane).

INTERMEDIATE COMPOUND 17

2-(1-(tert-Butyldimethylsilyloxy)aminoethyl)-7-methoxy - 4-[N-(3,5-dichlorine-4-yl)]benzofuroxan

To a solution of 2-acetyl-7-methoxy-4-[N-(3,5-dichlorine-4-yl)] benzoperoxide (0.5 g) in toluene (50 ml) was added O- (tert-butyldimethylsilyl)hydroxylamine (0.39 g). The reaction mixture was heated for 3 days in an atmosphere of nitrogen under conditions of Dean-stark, then 2 days left under stirring at room temperature. The reaction mixture is evaporated to dryness, the floor is om in hexane gave a white solid product (0,22 g).

TCX: Rf0,53 (50% ethyl acetate in hexane).

INTERMEDIATE COMPOUND 18

Hydrochloride of 2-((pyridin-4-yl)carbonyl] -7-methoxybenzophenone-4-carbonylchloride

Specified in the title compound was obtained by similar intermediate connection 1.

INTERMEDIATE COMPOUND 19

7-Methoxy-2-[(pyridin-4-yl)carbonyl]benzofuran-4-carboxylic acid

In working under pressure Parr reactor was mixed 2- [(pyridin-4-yl)carbonyl]-4-bromo-7-methoxybenzophenone (3.3 grams), triphenylphosphine (1 g), chloride bis(triphenylphosphine) palladium (II) (0,47 g), triethylamine (14 ml), tetrahydrofuran (150 ml) and H2O (57 ml). The vessel was purged with carbon monoxide, loaded carbon monoxide to a pressure of 12,66 at (180 psi) and heated to 80oC with stirring for 3 days. After cooling and pressure relief tetrahydrofuran was removed in vacuum. The remaining aqueous mixture was podslushivaet to pH 14 1 N. NaOH solution (250 ml) and washed with ethyl acetate (200 ml). The aqueous layer was then acidified to pH 5 with acetic acid while cooling in an ice bath. The resulting precipitate was collected by filtration and dried, obtaining a solid product color beige (2,97 g).

Mass spectrometry; observed M+N.

The following intermediate acarboni)benzofuran-4-carboxylic acid

Specified in the title compound was obtained in the form of a solid cream color (625 mg).

Mass spectrometry: observed [M+H].

THE INTERMEDIATE CONNECTION 21

4-Bromo-7-methoxy-2-[(- perigee-4-yl)carbonyl]benzofuran

To a mixture of 2-[(pyridin-4-yl)carbonyl]-7-methoxybenzophenone (0.1 g) in methanol (7 ml), cooled to -78oC, in an atmosphere of nitrogen was added bromine (0,02 ml). The reaction mixture was left for 2.5 hours to warm to room temperature. The reaction mixture then was diluted with ethyl acetate (40 ml), washed with 5% solution of meta sodium bisulfite (2 × 20 ml), saturated sodium bicarbonate solution (40 ml), dried over MgSO4and concentrated to dryness, obtaining a pale yellow solid product (0.05 g) in a mixture of 2:1 product/starting material (according to NMR).

TCX: Rfof 0.65 (10% methanol in ethyl acetate).

INTERMEDIATE COMPOUND 22

4-Bromo-7-methoxy-2-(2-thiazoleethanol)benzofuran

Mix a solution of 7-methoxy-2-(2-thiazoleethanol) benzofuran (3,09 g) in methanol (160 ml) was cooled to 0oC in an inert atmosphere was added dropwise bromine (0,61 ml). Stirring was continued at room temperature for 18 h and the solvent was then removed in vacuum. the l). The aqueous phase was extracted with ethyl acetate (3 x 60 ml), dried (magnesium sulfate) and evaporated in vacuum, obtaining mentioned in the title compound in the form of a solid product color beige (2.83 g).

TCX: Rfof 0.55 (10% acetate in hexane).

INTERMEDIATE COMPOUND 23

7-Methoxy-2-[(pyridin-4-yl)carbonyl]benzofuran

The reaction hydrobromide 4-(bromoacetyl) pyridine (5 g) and o-vanillin (2,11 g) were similar to how to conduct the reaction in the case of the intermediate compound (11), receiving specified in the title compound as a yellow solid (0.95 g).

TCX: Rfof 0.53 (ethyl acetate).

INTERMEDIATE COMPOUND 24

7-Methoxy-2-(2-thiazoleethanol)benzofuran

When 55oC to a stirred solution of o-vanillin (2,95 g) in ethanol (70 ml) was added sodium hydroxide (1.7 g) and continued stirring for 10 minutes. Then added portions of the hydrobromide of 2-bromoacetate (5,57 g) and continued heating for 5 hours the Solution was allowed to cool and concentrated in vacuum. The residue was distributed between water (200 ml) and ethyl acetate (100 ml) and was extracted with ethyl acetate (3 x 70 ml), the combined organic phases were dried over magnesium sulfate and evaporated in vacuum, obtaining the bark gave specified in the title compound as an orange needle-shaped crystals (3,09 g).

TCX: Rf0,55 (50% ethyl acetate in hexane).

INTERMEDIATE COMPOUND 25

The hydrobromide of 4-(bromoacetyl)pyridine

4-Acetylpyridine (10 g) was mixed with 48% HBr solution (18 ml) and heated to 70oC. was Added dropwise bromine (4,7 ml), dissolved in 48% HBr solution (5 ml) and then continued heating for 2.5 hours the Precipitate that formed was collected by filtration, washed with a mixture of 1:1 methanol/hexane (20 ml) and dried, obtaining a solid cream color (19.5 g) in a mixture of 2:1 product/starting material (according to NMR).

The following intermediate compound was obtained in the same way.

THE INTERMEDIATE CONNECTION 26

The hydrobromide of 2-bromoacetate

Specified in the title compound was obtained as a pale yellow solid product (5,57 g).

1H NMR (d6-DMSO) 5.00 (2H, CH2), 8.2 (1H, aromatic), 8.4 (1H, aromatic).

INTERMEDIATE COMPOUND 27

4-Nitrophenyl 7-methoxy-2-(2-thiazoleethanol) benzofuran-4-carboxylate

To a stirred solution of 7-methoxy-2-(2-thiazoleethanol) benzofuran-4-carboxylic acid (625 mg) in dichloromethane (40 ml) was added the hydrochloride of 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide (593 mg), 4-nitem precipitate was filtered, washed with dichloromethane and dried in vacuum, obtaining mentioned in the title compound as a white solid (720 mg).

1H NMR (CDCl3) 4.2 (3H, OCH3), 7.1 (1H, aromatic), 7.6 (2H, aromatic), 7.8 (1H, aromatic), 8.2 (1H, aromatic), 8.3 (1H, aromatic), 8.5 (2H, aromatic), 9.2 (2H, aromatic).

The following intermediate compound was obtained in the same way.

THE INTERMEDIATE CONNECTION 28

4-Nitrophenyl 2-ethyl-7-methoxybenzophenone-4-carboxylate

Specified in the title compound (1.26 g) was obtained as a white solid product.

TCX: Rf0,3 (50% ethyl acetate in hexane).

INTERMEDIATE COMPOUND 29

tert-Butyl 2-acetyl-7-methoxybenzophenone-4-carboxylate

A solution of 2-acetyl-7-methoxybenzophenone-4-carboxylic acid (100 mg) in dichloromethane (4 ml) was stirred at room temperature under nitrogen atmosphere. Added tert-butyl-2,2,2-trichloroacetimidate (0.16 ml), and then athirat of boron TRIFLUORIDE (0,012 ml) and the mixture was stirred at room temperature for 2 hours the Reaction was suppressed by the addition of saturated sodium bicarbonate solution (1 ml). The mixture was extracted with dichloromethane (3 x 10 ml) and the combined organic phases were dried over lake gave a white solid product (130 mg).

TCX: Rfof 0.25 (dichloromethane)

THE INTERMEDIATE CONNECTION 30

(Z)-tert-Butyl 2-(1-methoxymethyl)-7-methoxybenzophenone-4-carboxylate

A mixture of (Z)-tert-butyl 2-acetyl-7-methoxybenzophenone-4 - carboxylate (0.54 g), methoxylamine (0.31 g), pyridine (0,46 ml) and toluene (50 ml) was boiled under reflux in the conditions of a Dean-stark during the night. The mixture was then cooled and the toluene was removed in vacuum. The residue was dissolved in acetylacetone (100 ml) and washed with water (50 ml), then brine (50 ml). Drying over magnesium sulfate, and then removing the solvent in vacuo and purification by flash chromatography by elution with dichloromethane gave the product as colourless oil.

TCX: Rf0,52 (dichloromethane).

THE INTERMEDIATE CONNECTION 31

(Z)-2-(1-Methoxymethyl)-7-methoxybenzophenone-4-carboxylic acid.

A solution of (Z)-tert-butyl-2-(1-methoxymethyl)-7-methoxybenzophenone-4-carboxylate (100 mg) and triperoxonane acid (0.05 ml) in dichloromethane (5 ml) was stirred at room temperature for 4 h were Added the following Olkiluoto triperoxonane acid (0.1 ml) and continued stirring overnight. The solvent was removed in vacuo and the residue evaporated in vacuo from toluene (2 x 5 ml) and dichlor> TCX: Rf0,22 (dichloromethane).

T. pl. 233-234oC.

THE INTERMEDIATE CONNECTION 32

(Z)-4-Nitrophenyl 2-(1-methoxymethyl)-7-methoxybenzophenone-4-carboxylate

A solution of (Z)-2-(1-methoxymethyl)-7-methoxybenzophenone-4 - carboxylic acid (70 mg), 4-NITROPHENOL (41 mg), hydrochloride of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (56 mg) and 4 - dimethylaminopyridine (catalytic amount) (20 ml) was stirred at room temperature for 6 h under nitrogen atmosphere. The reaction mixture was diluted with dichloromethane (20 ml) and washed with water (3 x 20 ml). Drying over magnesium sulfate and then concentrated to dryness in vacuo gave a pale yellow solid product. Purification by flash chromatography by elution with dichloromethane gave a white solid product (53 mg).

TCX: Rf0,42 (dichloromethane).

T. pl. 195-196oC.

EXAMPLE 1. 2-Acetyl-7-methoxy-4-[N-(3,5-dichlorine-4-yl)] benzofuroxan (Method A)

At room temperature in a nitrogen atmosphere sodium hydride (0.03 g) was added to a solution of 4-amino-3,5-dichloropyridine (0.08 g) in anhydrous N,N-dimethylformamide (1 ml). This stir the mixture was heated to 60oC for 1 hour before addition of 2-acetyl-7 - methoxybenzophenone-4-carbontetrachloride (2 ml). This brown mixture was heated at 60oC for 4 hours, left to cool, poured into water (100 ml) and was extracted into ethyl acetate (2 x 50 ml). These organic extracts were washed with water (50 ml) and saturated brine (50 ml), then dried over magnesium sulfate, filtered and evaporated in vacuum to give crude residue (0.17 g). Purification of column chromatography on silica with gradient elution 20-80% ethyl acetate in hexane gave a white solid product (0.04 g).

TCX: Rf0,20 (50% ethyl acetate in hexane).

T. pl. 252-254oC.

EXAMPLE 2. 2-Ethyl-7-methoxy-4-[N-(3,5-dichlorine-4-yl)] benzofuroxan] (Method)

In an inert atmosphere a suspension of 2-ethyl-7-methoxybenzophenone - 4-carboxylic acid (300 mg) in dry toluene (50 ml) was treated with thionyl chloride (2 ml) and heated under reflux for 2 hours. The cooled reaction mixture is evaporated in vacuum and the residue was subjected to azeotropic distillation with dry toluene (2 x 10 ml) to give the acid chloride as a white solid (325 mg). In an inert atmosphere at room temperature for 30 minutes 4-amino-3,5-dichloropyridine (230 mg) in dry N,N - dimethylformamide (20 ml) was treated with bis(trimethylsilyl)amide is after heating at 50oC for 3 hours left to cool over night. It is evaporated under vacuum, was added saturated aqueous sodium bicarbonate (50 ml) and was extracted into dichloromethane (2 x 50 ml). The extracts were dried over magnesium sulfate, filtered and evaporated in vacuum to give crude residue. Purification of column chromatography on silica with elution with 50% ethyl acetate in hexane gave a white solid product (210 mg).

TCX: Rf0,15 (25% ethyl acetate in hexane).

T. pl. 199-200oC.

EXAMPLE 3. 2-Acetyl-7-methoxy-4-[N-(pyrid-4-yl)] benzofuroxan (Way WITH)

In a nitrogen atmosphere at 0oC solution of 2-acetyl-7-methoxybenzophenone-4 - carbonylchloride (164 mg) in anhydrous dichloromethane (10 ml) was treated with 4-aminopyridine (0.07 g), triethylamine (0.12 g) and 4-dimethylaminopyridine (2 mg). This solution was left to warm to room temperature and was stirred overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate (10 ml), water and saturated brine (10 ml), then dried over magnesium sulfate, filtered and evaporated in vacuum to give crude residue. Purification by column chromatography on silica with elution with 5% methanol in Dane).

T. pl. 247-248oC (decomposition).

EXAMPLE 4. 2-Acetyl-7-methoxy-4-[N-(pyrid-4-yl)-N-propyl] benzofuroxan

4-[N-(Propylamino)] pyridine (0.08 g) was treated with 2-acetyl - 7-methoxybenzophenone-4-carbonylchloride (0.15 g), as in the Method, receiving a pale yellow foam (129 mg).

TCX: Rf0,57 (5% methanol in dichloromethane).

IR (film): 1292, 1587, 1647, 1685 cm-1.

EXAMPLE 5. 2-Acetyl-7-methoxy-4-[N-(2-chlorophenyl)] benzofuroxan

2-Chloroaniline (0,42 ml) was treated with 2-acetyl-7-methoxybenzophenone-4-carbonylchloride (1 g), as in Method C. Purification by column chromatography on silica with elution with 50% ethyl acetate in hexane gave a solid product (137 mg).

T. pl. 179-181oC.

EXAMPLE 6. 2-Acetyl-7-methoxy-4-[N-(2,6-dimetilfenil)] benzofuroxan

2,6-Dimethylaniline (0,49 ml) was treated with 2-acetyl-7-methoxybenzophenone-4-carbonylchloride (1 g), as in Method C. Purification by column chromatography on silica with elution with 50% ethyl acetate in hexane gave a solid (255 mg).

TCX: Rf0,23 (50% ethyl acetate in hexane).

T. pl. 225-226oC.

EXAMPLE 7. 2-Acetyl-7-methoxy-4-[N-(4-methoxyphenyl)] benzo is,19 g), as in Method C. Purification by column chromatography on silica with elution with 50% ethyl acetate in heptane gave a solid product (103 mg).

TCX: Rf0,26 (50% ethyl acetate in heptane).

EXAMPLE 8. 2-Acetyl-7-methoxy-4-[N-(3-bromo-5-methylpiperid-2 - yl)]benzofuroxan (Method D)

In an inert atmosphere at room temperature for 15 minutes, 2-amino-3-bromo-5-methylpyridin (0.64 g) in dry tetrahydrofurane (20 ml) was treated with sodium hydride (0.15 g; 60% dispersion in oil). Was added a solution of 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (0,86 g) in dry tetrahydrofuran (10 ml) and then stirred over night before evaporation in a vacuum. Was added aqueous sodium bicarbonate (50 ml) and the mixture was extracted with ethyl acetate (2 x 50 ml). These extracts were dried over magnesium sulfate, filtered and evaporated in vacuum. The crude residue was purified by column chromatography on silica with elution with 50% ethyl acetate in hexane, obtaining a pale yellow powder (95 mg).

TCX: Rfof 0.5 (50% ethyl acetate in hexane).

EXAMPLE 9. 2-Acetyl-7-methoxy-4-[N-were)]benzofuroxan

m-Toluidine (0,42 ml) was treated with 2-acetyl-7-methoxybenzophenone-4 - carbonylchloride in hexane gave a yellow solid product (200 mg).

TCX: Rfof 0.5 (50% ethyl acetate in hexane).

T. pl. 193-195oC.

EXAMPLE 10. 2-Acetyl-7-methoxy-4-[N-(3,5-dichlorine - 2 - yl)]benzofuroxan

2-Amino-3,5-dichloropyridine (0,758 g) was treated with 2-acetyl - 7-methoxybenzophenone-4-carbonylchloride (1,17 g), as in Method D, using N, N-dimethylformamide as a co-solvent. Purification by column chromatography on silica 3% methanol in dichloromethane gave a yellow solid product (13 mg).

TCX: Rfof 0.5 (50% ethyl acetate in hexane).

EXAMPLE 11. 2-Acetyl-7-methoxy-4-[N-(2-were)] benzofuroxan

2-Methylaniline (0,21 ml) was treated with 2-acetyl-7-methoxybenzophenone - 4-carbonylchloride (0.5 g) as in Method C. Purification by column chromatography on silica with elution with 50% ethyl acetate in hexane gave a yellow solid product (128 mg).

TCX: Rf0,24 (50% ethyl acetate in hexane).

T. pl. 174-175oC.

EXAMPLE 12. 2-Acetyl-7-methoxy-4-[N-(4-methoxy-2-methyl - phenyl)]benzofuroxan

4-Methoxy-2-methylaniline (of 0.56 ml) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (1.0 g) as in Method C. Purification by column chromatography dioxide as the/SUB> 0,25 (50% ethyl acetate in hexane).

T. pl. 217-218oC.

EXAMPLE 13. 2-Acetyl-7-methoxy-4-[N-(pyrimidine-4-yl)] benzofuroxan

4-Aminopyrimidine (0,376 ml) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (1 g), as in Method C. Purification by column chromatography on silica with elution 0-10% methanol in a gradient of ethyl acetate gave a yellow solid product (0.14 g).

TCX: Rf0,49 (10% methanol in ethyl acetate).

T. pl. 212-214oC.

EXAMPLE 14. 2-Acetyl-7-methoxy-4-[N-(2-triptoreline)] benzofuroxan

2-Aminobenzotrifluoride (0.5 ml) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (1.0 g) as in Method D. Purification by column chromatography on silica with elution with 50% ethyl acetate in hexane gave a yellow solid product (0.12 g).

T. pl. 164-166oC.

EXAMPLE 15. 2-Acetyl-7-methoxy-4-[N-(3-chloropyrid-4-yl)] benzofuroxan

4-Amino-3-chloropyridin (0,26 ml) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (0.5 g) as in Method A, except that the initial generation of the anion was carried out at room temperature using 15-crown-5 (0,90 g). Purification by Cordy product (0.08 g).

TCX: Rf0,65 (5% methanol in dichloromethane).

T. pl. 197-200oC.

EXAMPLE 16. 2-Acetyl-7-methoxy-4-(N-(2-trifloromethyl)] benzofuroxan

2-Cryptomaterial (0,49 ml) was treated with 2-acetyl-7-methoxybenzophenone-4-carbonylchloride (0.7 g) as in Method C. Purification by column chromatography on silica with elution with 50% ethyl acetate in hexane gave a yellow solid product (0,065 g).

TCX: Rf0,49 (50% ethyl acetate in hexane).

T. pl. 163-165oC.

EXAMPLE 17. 2-Acetyl-7-methoxy-4-[N-(2-ethylphenyl)] benzofuroxan

2-Ethylaniline (of 0.48 ml) was treated with 2-acetyl-7-methoxybenzophenone-4-carbonylchloride (1.0 g) as in Method C. Purification by column chromatography on silica with elution 25% ethyl acetate in hexane gave a whitish solid product (310 mg).

TCX: Rf0,13 (25% ethyl acetate in hexane).

T. pl. 174 - 175oC.

EXAMPLE 18. 2-Acetyl-7-methoxy-4-[N-(3-methylpiperid-2-yl)] benzofuroxan

2-Amino-3-picoline (0,32 ml) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (0.73 g) as in Method C. Purification by column chromatography on silica with elution with 5% normative).

EXAMPLE 19. 2-Ethyl-7-methoxy-4-[N-(2-chloropyrid-3-yl)] benzofuroxan

3-Amino-2-chloropyridine (0.88 g) was treated with 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (1.8 g) as in Method A, except that the generation of the anion produced at room temperature for 1.5 hours. Purification by flash chromatography on silica with elution with hot ethyl acetate, followed by rubbing with diethyl simple ether gave a solid product color beige (0,53 g).

TCX: Rf0,35 (50% ethyl acetate in hexane).

T. pl. 124-125oC.

EXAMPLE 20. 2-Acetyl-7-methoxy-4-[N-(2-methoxyphenyl)] benzofuroxan

o-anisidine (0,49 ml) was treated with 2-acetyl-7-methoxybenzophenone-4 - carbonylchloride (1 g), as in Method C. Purification by column chromatography on silica with elution 30% ethyl acetate in hexane gave a solid yellow product (160 mg).

EXAMPLE 21. 2-Acetyl-7-methoxy-4-[N-(2-chloropyrid-3-yl)] benzofuroxan

3-Amino-2-chloropyridine (509 mg) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (1.0 g) as in Method D. Purification by column chromatography on silica with elution 25% ethyl acetate in hexane gave t boxlid

2-Chloro-6-methylaniline (of 0.56 ml) was treated with 2-acetyl-7 - methoxybenzophenone-4-carbonylchloride (1 g), as in Method C. Purification by recrystallization from dichloromethane gave a brown solid product (160 mg).

TCX: Rfof 0.4 (5% methanol in dichloromethane).

EXAMPLE 23. 2-(l-Hydroxyethyl)-7-methoxy-4-[N-(3,5 - dichlorine-4-yl)benzofuroxan

2-Acetyl-7-methoxy-4-[N-(3,5-dichlorine-4-yl)] benzofuroxan (0.50 g) suspended in dry methanol (20 ml) and treated with sodium borohydride (196 mg) at room temperature. Needed some cooling externally with ice. The suspension was then stirred over night. The reaction mixture was poured into water and was extracted into ethyl acetate. In the evaporation in vacuum was obtained a solid product, which was purified by column chromatography and elution with 5% methanol in dichloromethane, getting a white solid product (400 mg).

TCX: Rf0,52 (80% ethyl acetate in heptane).

T. pl. 229-231oC.

EXAMPLE 24. 2- [3- (Pyrid-3-yl)-1-oxopropyl]-7-methoxy-4- [N-(3,5-dichlorine-4-yl)]benzofuroxan

In an inert atmosphere a solution of 2-acetyl-7-methoxy-4-[N-(3,5 - dichlorine-4-yl)] benzoperoxide (0.40 g) in dry N,N - Dimethylol After 1 hour at -10oC was added the hydrochloride of 3-picolylamine (0.20 g) and the mixture was stirred for 2 hours and then left it to warm to room temperature over night. It was poured into water and was extracted into ethyl acetate. These extracts were washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuum. The resulting residue was purified by column chromatography with elution 3-10% gradient of methanol in dichloromethane, then triturated with diethyl simple ether, receiving powder colour beige (15,5 mg).

TCX: Rfa 0.27 (10% methanol in dichloromethane).

EXAMPLE 25. 2-(1-benzylamino)ethyl-7-methoxy-4-[N- (3,5-dichlorine-4-yl)]benzofuroxan

2-Acetyl-7-methoxy-4-[N-(3,5-dichlorine-4-yl)] benzofuroxan (100 mg) in dry toluene (40 ml) containing dry pyridine (64 μm) and the hydrochloride of O-benzylhydroxylamine (126 mg) was boiled under reflux in the conditions of a Dean-stark in an inert atmosphere. After 2 hours the mixture was left to cool and was stirred overnight. Adding methanol and acetone resulted in the formation of sludge. It was filtered and obtained solid product (26 mg).

TCX: Rfto 0.45 (50% ethyl is-7-methoxy-4- [N- (3-carboethoxy)]benzofuroxan (0,78 g) in THF (25 ml) was treated with a solution of the monohydrate of lithium hydroxide (0.18 g) in water (25 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum, diluted with water (100 ml) and acidified using dilute aqueous hydrochloric acid. The resulting white precipitate was collected, washed with water and dried in vacuum, obtaining mentioned in the title compound (0.68 g) as a white solid product.

TCX: Rf0,35 (5% methanol in dichloromethane).

T. pl. 265-267oC.

In accordance with the above technique has received the following connection:

Example 27. 2-Ethyl-7-methoxy-4-[N-(4-carboxyphenyl)] benzofuroxan

Specified in the title compound (0,59 g) as a white solid product was obtained from 2-ethyl-7-methoxy-4-[N-(4-carboethoxy)] benzoperoxide (0,67 g).

TCX: Rfof 0.4 (5% methanol in dichloromethane).

T. pl. 279-280oC.

EXAMPLE 28. 2-[l-(2,2-Deleteprofile)]-7-methoxy-4-[N- (3,5-dichlorine-4-yl)]benzofuroxan

To a suspension of 2-[1-(2,2-dimethylpropyl)] -7-methoxybenzeneboronic acid (0,59 g) in toluene (10 ml) was added thionyl chloride (1.65 ml) and the mixture is boiled under reflux for 3 hours, the Mixture was stirred at room temperature overnight and concentrated in vacuum. The residue was repeatedly subjected to azeotropic paragons is Aramina-pyridine(0.74 g) in dry DMF (2 ml) at room temperature under nitrogen atmosphere was made hexamethyldisilazide sodium (1M solution in THF, a 4.5 ml). The reaction mixture was stirred at room temperature for 0.5 h, then was heated to 50oC. was Added a solution of 2-[1-(2,2 - dimethylpropyl)]-7-methoxybenzophenone-4-carbonylchloride (0,63 g) in DMF and the reaction mixture was stirred for another 3 h and then at room temperature for 16 hours was Added water (20 ml) and the resulting precipitate was collected and dried in vacuum. Purification by column chromatography on silica with elution 25% ethyl acetate in hexane gave specified in the title compound (0.29 grams) as a pale-yellow solid product.

TCX: Rf0,4 (50% ethyl acetate in hexane).

T. pl. 164-165oC

EXAMPLE 29. 2-(1-Methoxymethyl)-7-methoxybenzophenone-4- [N-(3,5-dichlorine-4-yl)]carboxamide

To a suspension of 2-acetyl-7-methoxy-4-[N-(3,5-dichlorine-4 - yl)]benzoperoxide (0.07 g) in dry toluene (40 ml) was added pyridine (0,09 ml) and hydrochloride methoxylamine (0,056 g) and the mixture was heated under conditions of Dean-stark within 24 hours Evaporation of the solvent and purification by flash chromatography on silica with elution with dichloromethane and then 5% methanol in dichloromethane and subsequent preparative TCX (5% methanol in dichloromethane) gave white Tersane).

EXAMPLE 30. N-(3,5-Dichlorine-4-yl)-2-carboxy-7 - methoxybenzophenone-4-carboxamid

4-Amino-3,5-chloropyridin (0.31 g) was treated with methyl 7 - methoxy-2-methoxycarbonylmethyl-4-carbonylchloride as in Example 19. Purification by flash chromatography on silica with elution 10% methanol in dichloromethane gave a pale yellow solid product (0.15 g).

TCX: Rf0,1 (10% methanol in dichloromethane).

T. pl. above 350oC.

EXAMPLE 31. 2-Ethyl-7-methoxy-4-[N-(2,5-dimethylpyridin-4-yl)] benzofuroxan

4-Amino-2,5-dimethylpyridin (0.3 g) was treated with 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (0,59 g) as in Example 19. Purification by flash chromatography on silica with elution 10% methanol in dichloromethane and subsequent rubbing with hexane gave a whitish solid product (0.11 g).

TCX: Rf0,33 (10% methanol in dichloromethane).

T. pl. 164-165oC.

EXAMPLE 32. N-(5-Chloropyrimidine-4-yl)-2-ethyl-7-methoxybenzophenone-4-carboxamid

4-Amino-5-chloropyrimidine (0.25 g) was treated with 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (0,46 g), as in Method C. Purification by recrystallization gave a whitish solid product (0.12 g).

TCX: Rfthe ine-5-yl)] benzofuroxan

5-Amino-3-methylcitrate (0.3 g) was treated with 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (0.50 g) as in Example 19. Purification by flash chromatography on silica with elution with 50% ethyl acetate in hexane gave a solid cream color (0.1 g).

TCX: Rf0,47 (50% ethyl acetate in hexane).

Mass spectrometry: observed [M+H].

EXAMPLE 34. 2-Ethyl-7-methoxy-4-[N-(4-aminopyrido[3,2-b] pyridinyl)]benzofuroxan

4 Aminopyrido[3,2-b] pyridine (0.36 g) was treated with 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (0,59 g) as in Example 21. Purification by flash chromatography on silica with elution 10% methanol in ethyl acetate followed by rubbing with hexane gave pale-yellow solid product (0,23 g).

TCX; Rf0,52 (10% methanol in ethyl acetate).

T. pl. 155-157oC.

EXAMPLE 35. 2-Ethyl-7-methoxy-4-[N-(3-forperiod-4-yl)] benzofuroxan

4-Amino-3-herperidin (0.25 g) was treated with 2-ethyl-7 - methoxybenzophenone-4-carbonylchloride (0,53 g), as in Method C. Purification by flash chromatography on silica with elution with 50% ethyl acetate in hexane gave a whitish solid product (0,13 g).

TCX: Rf0,15 (50% E. the reed-4-yl)] -7 - methoxybenzeneboronic

To a suspension of 2-acetyl-7-methoxy-4-[N-(3,5-dichlorine-4-yl)] benzoperoxide (0.5 g) in dry toluene (30 ml) was added pyridine (1 g) and hydroxylamine (0.9 g) and the mixture was heated under conditions of Dean-stark within 48 hours Evaporation of the solvent and washing with water gave a whitish solid product (0.2 g).

TCX: Rf0,22 (50% ethyl acetate in hexane).

T. pl. 250oC (decomposition).

EXAMPLE 37. 2-Ethyl-7-methoxy-4-[N-(2-chloro-5-carboxyl)phenyl] benzofuroxan

5-Carboxymethyl-2-Chloroaniline (0,566 g) was treated with 2-ethyl - 7-methoxybenzophenone-4-carbonylchloride (0.50 g) as in Example 19. Purification by flash chromatography on silica with elution with 50% ethyl acetate in hexane gave 2-ethyl-7 - methoxy-4-[N-(2-chloro-5-methoxycarbonyl)phenyl]benzofuroxan in the form of a white solid product (0,497 g; TCX: Rfof 0.5 (50% ethyl acetate in hexane); so pl. 174-176oC). This product (0.31 g) was treated as in Example 26, receiving specified in the title compound (0,282 g) as a white solid product.

TCX: Rf0.6 (ethyl acetate)

T. pl. 278-279oC.

EXAMPLE 38. Z-2-(1-Hydroxyimino)-4-[N-methyl-N-(3,5 - dichloropyridine-4-yl)]-7-methoxybenzeneboronic

To a solution of Z-2-(1-hydrocele Bu4NI (catalytic amount), then was added a NaOH solution (6 mg) in H2O (1 ml). The whole mixture was stirred for 20 minutes, then was added MeI (45 mg) and stirring was continued for 12 hours. The mixture was concentrated to dryness, diluted with EtOAc (20 ml), washed with H2O (10 ml), brine (10 ml), dried over MgSO4and again concentrated to dryness, to give crude product. Purification by flash chromatography on silica with elution with 50% ethyl acetate in hexane gave a white solid product (24 mg).

TCX: Rf0,37 (50% ethyl acetate in hexane).

T. pl. 97-98oC.

EXAMPLE 39. Z-2-(1-(4-Pyridyloxy)aminoethyl)-7 - methoxybenzophenone-4-[N-(3,5-dichlorine-4-yl)]carboxamide

To a solution of Z-2-(1-hydroxyimino)-4-[N-(3,5-dichloropyridine-4-yl)] -7-methoxybenzenesulfonamide (50 mg) in tetrahydrofuran (10 ml) was added Bu4NI (catalytic amount), then NaOH solution (17 mg) in H2O (1 ml). The whole mixture was stirred for 20 min, then was added the hydrochloride of 4-chloromethylpyridine (46 mg) and continued stirring for 48 hours. The mixture was concentrated to dryness, diluted with EtOAc (20 ml), washed2O (10 ml), brine (10 ml), dried over MgSO4and again concentrated to dryness, obtaining si is e gave a whitish solid product (10 mg).

TCX: Rfof 0.26 (ethyl acetate).

T. pl. 217-218oC.

EXAMPLE 40. 2-(1-Hydroxyimino)-4-[N-(3,5-dichloropyridine-4-yl)] -7-methoxybenzeneboronic

In a nitrogen atmosphere to a solution of 2-(1-tert-butyldimethylsilyloxy) aminoethyl)-7-methoxy-4-[N-(3,5-dichlorine-4-yl)]benzoperoxide in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran) (0,48 ml). Stirring was continued for 20 min, then the reaction mixture was concentrated to dryness, to give crude product. Purification by flash chromatography on silica with elution with 50% ethyl acetate in hexane gave a whitish solid product (0.1 g) in a mixture of 2:1 isomers (E:Z (according to NMR).

TCX: Rf0,22 (50% ethyl acetate in hexane).

T. pl. 280oC (decomposition).

EXAMPLE 41. 2-[(Pyridin-4-yl)carbonyl]-7-methoxybenzophenone-4-[N- (3,5-dichloropyridine-4-yl)]carboxamide

In a nitrogen atmosphere to a solution of 4-amino-3,5-dichloropyridine (0.56 g) in dimethylformamide (10 ml) was added sodium hydride (0.3 g). The reaction mixture was heated to 55oC for 1 h, then one portion was added 2-[(pyridin-4-yl)carbonyl] -7-methoxybenzophenone-4 - carbonylchloride. Heating at 55oC continued teenadult. Purification by flash chromatography on silica by elution with ethyl acetate and then 20% methanol in ethyl acetate gave a solid cream color (0.3 g).

TCX: Rfof 0.36 (ethyl acetate).

T. pl. 250-252oC

EXAMPLE 42. 2-[Methoxyimino(4-pyridyl)methyl]-7-methoxybenzophenone-4- [N-(3,5-dichloropyridine-4-yl)]carboxamide

2-[(Pyridin-4-yl)carbonyl] -7-methoxybenzophenone-4-[N-(3,5 - dichloropyridine-4-yl)]carboxamide (0.25 g) was treated with the hydrochloride methoxylamine (0,165 g) as in Example 29. The crude product is washed with H2O, and then diethyl simple ether, obtaining a white solid product (0,217 g) in a mixture of 5.5:4.5 isomers (E:Z (according to NMR).

T. pl. 245-247oC.

Mass spectrometry: observed [M+H].

EXAMPLE 43. E-2-(1-(4-Pyridyloxy)aminoethyl)-7-methoxybenzophenone-4- [N-(3,5-dichlorine-4-yl)]carboxamide

In a nitrogen atmosphere to a suspension of 2-(1-hydroxyimino)-4-[N- (3,5-dichloropyridine-4-yl)] -7-methoxybenzenesulfonamide (50 g) in ethanol (2 ml) was added sodium (9 mg). After moving all solid reagents to the solution was added the hydrochloride of 4-chloromethylpyridine (21 mg) and the reaction mixture was stirred at room temperature for 3 days. Was added sodium (6 mg) and hydroblast H2O (20 ml), extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with H2O (20 ml), brine (20 ml), dried over MgSO4and concentrated to dryness give crude product. Purification by flash chromatography on silica by elution with ethyl acetate gave a whitish solid product (18 mg).

TCX: Rfof 0.43 (ethyl acetate).

T. pl. 231 - 232oC.

EXAMPLE 44. 2-(4-Morpholino)acetyl-7-methoxybenzophenone-4- [N-(3,5-dichlorine-4-yl)]carboxamide

In a nitrogen atmosphere to a solution of 2-acetyl-7-methoxy-4- [N-(3,5 - dichloropyridine-4-yl)] benzoperoxide (0.1 g) in 45% HBr/AcOH (4 ml) was added bromine (0.01 ml). The reaction mixture was stirred at room temperature for 12 h, and then extinguished H2O (20 ml) and was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (20 ml), brine (20 ml), dried over MgSO4and concentrated to dryness, to give crude 2-bromoacetyl-7 - methoxybenzophenone-4-[N-(3,5-dichlorine-4-yl)]carboxamide. Purification by flash chromatography on silica with elution with 50% ethyl acetate in hexane gave containing impurities yellow solid product (20 mg), which was used without Dalil)] carboxamide (20 mg) in dichloromethane (5 ml) was added morpholine (0,09 ml) and triethylamine (10 mg). Stirring was continued for 1.5 hours. Then the reaction mixture was diluted with additional dichloromethane, washed with H2O, dried over MgSO4and concentrated to dryness give crude product. Purification by flash chromatography on silica by elution with ethyl acetate in hexane gave a yellow solid product (10 mg).

TCX: Rfof 0.38 (ethyl acetate).

T. pl. 130oC (decomposition).

EXAMPLE 45. N-(2,6-Dichloro-4-carboxyphenyl)-2-ethyl-7-methoxybenzophenone - 4-carboxamid

Ethyl 4-amino-3,5-dichlorobenzoate (0,815 g) was treated with 2-ethyl - 7-methoxybenzophenone-4-carbonylchloride (0,754 g) as in Example 19. Purification by trituration of the crude product from dichloromethane gave N-[2,6-dichloro-4-(etoxycarbonyl)phenyl] -2-ethyl-7 - methoxybenzophenone-4-carboxamide as a white solid (338 mg; TCX: Rf0,15 (20% ethyl acetate in hexane); so pl. 165-166oC). This product (292 mg) was processed as in Example 26, receiving specified in the title compound (230 mg) as a white solid product.

TCX: Rf 0,6 (6% methanol in dichloromethane).

T. pl. 274-275oC.

EXAMPLE 46. 7-Methoxy-2-(2-diazocarbonyl)-4-[N-(5 - chloropyrimidine-4-yl)] benzofuroxan

In nitrogen atmosphere at perisphere in oil (135 mg) and stirring was continued for 3 hours Then were added 4-nitrophenyl 7-methoxy - 2-(2-diazocarbonyl)benzofuran-4-carboxylate (720 mg) and stirring continued for 18 hours the Solvent was removed in vacuo, the resulting residue triturated with ethyl acetate, and then purified by flash chromatography on silica with elution with a mixture of 2% ammonium hydroxide/20% methanol in ethyl acetate. Further rubbing with methanol gave specified in the title compound in the form of a solid cream color (165 mg).

Mass spectrometry: observed [M+H].

T. pl. 262 to 264oC.

The following compound was obtained from 4-nitrophenyl 2-ethyl-7 - methoxybenzophenone-4-carboxylate and the appropriate amine according to the aforementioned method.

EXAMPLE 47. 2-Ethyl-7-methoxy-4-[N-2,5-giftability-4-yl)] benzofuroxan

From 4-amino-2,5-giftability (190 mg) has been specified in the title compound (95 mg) in the form of a whitish solid product.

TCX: Rf0,6 (50% ethyl acetate in hexane).

T. pl. 175-176oC.

EXAMPLE 48. 2-Ethyl-7-methoxybenzophenone-4-[N-(1,3,5-trimethylpyrazole - 4-yl)]carboxamide

From 4-amino-1,3,5-trimethylpyrazole (165 mg) has been specified in the title compound (222 mg) in the form of ber CLASS="ptx2">

EXAMPLE 49. 2-[2-(4-Morpholino)-(2-methoxy)iminoethyl] -7 - methoxy-4-[N-(3,5-dichlorine-4-yl)]benzofuroxan

Was obtained from 2-(4-morpholino)acetyl-7-methoxy-4-[N-(3,5 - dichlorine-4-yl)] benzoperoxide method similar to Example 4. Purification by flash chromatography on silica by elution with ethyl acetate gave a yellow solid product in the form of a mixture of isomers 1:1 (20 mg).

TCX: Rf0.66 and of 0.53 (ethyl acetate).

T. pl. 140oC (decomposition).

EXAMPLE 50. (Z)-2-[1-(2-Methylthiazole-4-yl-methoxy)iminoethyl] -7-methoxy-4-[N-(3,5-dichlorine-4-yl)]benzofuroxan

At room temperature in a nitrogen atmosphere was stirred solution of (Z)-2-(1-hydroxyimino)-7-methoxy-4-[N- (3,5-dichloropyridine-4-yl)] benzophenoneoxymate in dimethylformamide (30 ml). Was added sodium hydride (60% dispersion in oil) (17 mg) and continued stirring for 1 h was Added 4-chloromethyl-2-methylthiazole (0.84 g) (obtained from cleaners containing hydrochloride salt using sodium bicarbonate and the mixture was stirred for 1 h the Mixture was poured into water (100 ml) and was extracted with ethyl acetate (3 x 100 ml). The combined organic washings were washed with water (100 ml) and brine (50 ml), dried over magnesium sulfate and removed dissolve reagirovanija alkylating agent and purified by flash chromatography with elution 0-10% methanol in ethyl acetate, getting a white solid product (0,69 g).

TCX: Rf0,62 (ethyl acetate).

T. pl. 221-222oC.

The following compound of the Example was obtained in a similar method.

EXAMPLE 51. (Z)-2-(1-(4-Morpholinoethoxy)iminomethyl)-7 - methoxy-4-[N-(3,5-dichlorine-4-yl)]benzofuroxan

Purification by recrystallization from a mixture of ethyl acetate/hexane gave a white solid product (0,22 g).

TCX: Rfof 0.50 (10% methanol in dichloromethane).

T. pl. 178-179oC.

EXAMPLE 52. (Z)-2-(1-Methoxymethyl)-7-methoxy-4-[N- (3,5-dichlorine-4-yl)]benzofuroxan

At room temperature in a nitrogen atmosphere was stirred solution of 4-amino-3,5-dichloropyridine (23 mg) in dimethylformamide (5 ml). Was added sodium hydride (60% dispersion in oil) (9 mg) and the resulting suspension was stirred for 1 h was Added a solution of 4-nitrophenyl 2-(1-methoxyaminomethyl)] -7-methoxybenzophenone-4 - carboxylate (50 mg) in dimethylformamide (2 ml) and stirring continued over night. The reaction was suppressed by addition of water (1 ml) and vacuum the mixture evaporated to dryness. Purification by flash chromatography by elution with 50% ethyl acetate in hexane gave a white solid product (23 mg).

TCX: Rf0,40 (50% ethyl shall confirm the inhibitory activity of the compounds of formula (i) in respect of phosphodiesterase IV, are standard experimental techniques described in the publications: Schilling et al. , Anal. Biochem., 216; 154 (1994); Thompson and Strada, Adv.Cycl. Nucl. Res., 8; 119 (1979) and Gristwood and Owen, Br.J.Pharmacol., 87: 91P (1986).

In these tests the compounds of formula (i) showed activity at levels corresponding to the levels that are considered useful in the treatment connected with phosphodiesterase IV pathological conditions.

The ability of compounds of the formula (i) to inhibit the production of TNF in managernew peripheral blood cells of people (PBMC) was measured as follows. PBMC obtained from viewsat blood or leukocyte film using standard techniques. Cells inoculated in RPMI 1640+1% fetal calf serum in the presence and in the absence of inhibitors. Add LPS (100 ng/ml), and the culture incubated for 22 h at 37oC in an atmosphere of 95% air and 5% CO2. The supernatant supernatant have TNFa ELISA method using commercially available kits.

Activity in vivo in a model of cutaneous eosinophilia determined by the methods described Hellewell et al. , Br. J. Pharmacol. 111: 811 (1994) and Br. J. Pharmacol. , 110: 416 (1993). Activity in the lung model is measured according to the methods described in Kallos and Kallos, Int. Archs. Allergy Appl. lminun and measurement of inhibition of asthmatic reactions early and late phase, as well as inhibition of hyperactivity of the Airways, described the Broadley et al: Broadley et al., Pulmonary Pharmacol., 7: 311 (1994), J. lmmunological Methods, 190: 51 (1996) and British J. Pharmacol., 116: 2351 (1995). In this model, the compounds of this invention are active.

Abbreviations:

LPS - Lipopolysaccharide (endotoxin);

ELISA enzyme - linked immunosorbent assay.

Table definitions IC50in respect of the enzyme PDE4, table of physical characteristics of some compounds according to the invention, as well as the values of R1-R14for compounds 1-20 given at the end of the description.

1. The compound of General formula (i)

< / BR>
where Z is CO;

R1is alkoxygroup, optionally substituted by one or more Halogens;

R2and R3the same or different and each represents H, R6OR10, COR6C(=NOR6R6, alkyl-C(=NOR6R6C(=NOH)R6, NR8R9CN, CF3, CO2H, CO2R10;

R4represents H or alkyl;

R5represents aryl, heteroaryl, heterocycle;

in R4and/or R5part aryl/heteroaryl/heterocycle optionally substituted by one or more substituents R13
R8represents H, heteroallyl, heteroseksualci or alkoxycarbonyl;

R9represents H, heteroaromatic or alkyl;

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

R11represents H or alkyl;

R12is N;

R13represents alkyl, optionally substituted with halogen, alkoxy, optionally substituted with halogen, heterocycle, hydroxy, CO2R7, halogen, CN, S(0)nR10;

R14imagine IT, carbonyl oxygen, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12;

n is 0;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where R2and R3the same or different and each represents H, R6, COR6C(=NOR6R6CN, CO2H, CO2R10.

3. Connection on p. 1, where R2and R3the same or different, and each represents R6aor alkyl-R6a; R6arepresents H, aryl, heteroaryl, heterocycle, hydroxy, arylalkyl or COR10; R10represents alkyl, aryl, heteroaryl, heterocycle, Arial>7
, halogen, CN, S(0)nR10.

4. Connection on p. 1, where R2and R3each independently selected from H, R6or COR6; R6represents alkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci.

5. The compound according to any one of the preceding paragraphs, where R2is not N.

6. The compound according to any one of the preceding paragraphs, where R5represents optionally substituted aryl or heteroaryl.

7. The compound according to any one of the preceding paragraphs, where R2and R3both are not H.

8. The compound according to any one of the preceding paragraphs, where both 2and R3independently represent OR10or NR8R9.

9. The compound according to any one of paragraphs.1 to 7, where R2and R3independently represent C(=NOR6R6, alkyl-C(=NOR)R6C(=NOH)R6.

10. The compound according to any one of paragraphs.1 to 7, where R2and R3independently represent heterocycle, heteroseksualci or heteroaryl, optionally substituted in any position with (one or more)R14.

11. The compound according to any one of paragraphs.1 to 7, where R2and R3independently represent alkyl, substituted the Boma of PP.1 - 7, where R2and R3independently represent alkyl, substituted by one or more COR, and R is aryl, heteroaryl or heterocycle.

13. The compound according to any one of paragraphs.1 to 7, where R2and R3independently represent COR as determined in paragraph 12, optionally substituted in any position with (one or more) R14.

14. The compound according to any one of the preceding paragraphs, where R4represents H or alkyl.

15. The compound according to any one of the preceding paragraphs, where R5represents aryl or heteroaryl, each of which may be optionally substituted by one or more substituents R13.

16. Connection on p. 1, selected from 2-acetyl-7-methoxy-4-N-(3,5-dichlorine-4-yl)benzoperoxide and 2-acetyl-7-methoxy-4-N-(pyrid-4-yl)benzoperoxide.

17. Connection on p. 1, selected from the group including

2-ethyl-7-methoxy-4-N-(3,5-dichlorine-4-yl)benzofuroxan,

2-acetyl-7-methoxy-4-[N-(pyrid-4-yl)-N-propyl]benzofuroxan,

2-acetyl-7-methoxy-4-N-(2-chlorophenyl)benzofuroxan,

2-acetyl-7-methoxy-4-N-(2,6-dimetilfenil)benzofuroxan,

2-acetyl-7-methoxy-4-N-(4-methoxyphenyl)benfuracarb ylphenyl)benzofuroxan,

2-acetyl-7-methoxy-4-N - (3,5-dichlorine-2-yl)benzofuroxan,

2-acetyl-7-methoxy-4-N-(2-were)benzofuroxan,

2-acetyl-7-methoxy-4-N - (4-methoxy-2-were)benzofuroxan,

2-acetyl-7-methoxy-4-N-(pyrimidine-4-yl)benzofuroxan

2-acetyl-7-methoxy-4-N-(2-reformational)benzofuroxan,

2-acetyl-7-methoxy-4-N-[2-(piperidine-1-yl)phenyl]benzofuroxan,

2-acetyl-7-methoxy-4-N-(3-chloropyrid-4-yl)benzofuroxan,

2-acetyl-7-methoxy-4-N - (2-trifloromethyl)benzofuroxan,

2-acetyl-7-methoxy-4-N-(2-ethylphenyl)benzofuroxan,

2-acetyl-7-methoxy-4-N-(3-methylpiperid-2-yl)benzofuroxan,

2-ethyl-7-methoxy-4-N-(2-chloropyrid-3-yl)benzofuroxan

2-acetyl-7-methoxy-4-N-(2-methoxyphenyl)benzofuroxan

2-acetyl-7-methoxy-4-N-(2-chloropyrid-3-yl)benzofuroxan,

2-acetyl-7-methoxy-4-N-(2-chloro-6-were)benzofuroxan,

2-(1-hydroxyethyl)-7-methoxy-4-N-(3,5-dichlorine-4-yl)benzofuroxan,

2-(3-pyrid-3-yl-1-oxopropyl)-7-methoxy-4-N-(3,5-dichlorine-4-yl)benzofuroxan,

2-(1-benzylamino)ethyl-7-methoxy-4-N-(3,5-dichlorine-4-yl)benzofuroxan,

2-ethyl-7-labels is R>
2-[1-(2,2-dimethylpropyl)]-7-methoxy-4-N-(3,5-dichlorine-4-yl)benzofuroxan.

18. The compound according to any one of the preceding paragraphs in the form of an enantiomer or mixture of enantiomers.

19. The compound according to any one of the preceding paragraphs, having inhibitory activity against phosphodiesterase IV or tumor necrosis factor.

20. Pharmaceutical composition having inhibitory activity against phosphodiesterase IV or tumor necrosis factor-containing compound according to any one of the preceding paragraphs, and a pharmaceutically acceptable carrier or excipient.

Priority points:

20.05.96 - PP.1 - 20;

05.12.96 - PP.1 - 20 (updating s);

22.04.97 - PP.1 - 20 (clarification of signs).

 

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

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The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to new derivatives of phenyl-oxo-alkyl-(4-piperidinyl)benzoate of formula I, their N-oxide forms, salts and steric isomer forms, where R1- halogen, R2is hydrogen, R3- C1-6-alkyl, or R2and R3form together a bivalent radical of the formula -(CH2)2- or -(CH2)3-, Alk-C1-6-alcander, R4is hydrogen or C1-6-alkoxy, R5, R6and R7is hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy or R5and R6taken together , form a bivalent radical of the formula-NR8-C(O)-NR9- or-NH-C(NH-R10)=N-, where R8and R9is hydrogen, C1-6-alkyl, R10is hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl

The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl, etc

The invention relates to substituted azetidinone General formula I listed in the description

The invention relates to benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H, Cl, Br, OH or OA;

R3denotes benzyl or itself known protective for the amine function group;

X denotes a CN, COON, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Het;

R4and R5each independently of one another denotes H, A or benzyl;

A denotes alkyl with 1-4 C-atoms;

Ph denotes phenyl;

Het represents imidazol-1-yl, triazole-1-yl or tetrazol-1-yl; and

Py denotes a pyridyl;

and their salts
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