N-oxides of heterocyclic compounds with inhibitory activity against tnf and pde-iv

 

The invention relates to N-oxides of heterocyclic compounds of the formula (I), where R1is CH3CH2F, CHF2, CF3; R2is CH3, CF3; R3represents F, Cl, Br, CH3; R4represents H, F, Cl, Br, CH3. The invention can be used in medicine as a therapeutic agent for the treatment of asthma, eosinophilia, neutrophilia, chronic bronchitis, chronic lung disease and chronic obstructive Airways disease. 1 s and 5 C.p. f-crystals, 1 Il., table 2.

The invention relates to new heterocyclic compounds and their preparations, and their use as pharmaceuticals.

Background of the invention the European Patent application EP-A-0498722 describes quinoline derivatives as inhibitors of angiotensin And2and endothelin.

Model of the action of phosphodiesterase (PDE), as well as factors tumor necrosis (TNF) and therapeutic utility of their inhibitors described in WO-A-9744036 and U.S. Patent 5804588, the contents of which are incorporated herein as references. These publications explore in detail chinainternational, obuobie connection therapeutically useful, in particular, for the treatment of painful conditions associated with proteins that mediate cellular activity, for example, by inhibiting TNF and/or PDE IV. According to this invention, these compounds are compounds of formula (i):where R1represents CH3CH2F, CHF2or CF3; R2represents CH3or CF3; R3represents F, Cl, Br, CN or CH3; and R4represents H, F, Cl, Br, CN or CH3; or their pharmaceutically acceptable salts.

Briefly, the compounds of this invention are N-oxides of the respective bases, which are described (some specifically) in WO-A-9744036. These new compounds have excellent solubility, and improved metabolic stability and pharmacokinetic profile. Particularly preferred is the compound of Example 8.

The present invention also offers a method of mediation or inhibition of enzymatic activity, catalytic activity of PDE IV in a mammal in need and inhibiting production of TNF in need of this mammal, which includes the introduction of the specified melicope the description of the drawing the Attached drawing is a graph which shows the data of the RK after oral administration to rats of a particular dose of the compounds of this invention and the known compounds (for comparison).

Description of the invention
Certain compounds of formula (i) which contain a basic 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) are obtained using well-known techniques.

The compounds of this invention can be obtained by N-oxidation of the corresponding free bases. Such free base is known, or can be easily obtained by the method disclosed in WO-A-9744036. For example, the compound of formula (i) can be obtained by treating the free base of peracetic acid in acetic acid in a suitable solvent, such as chloroform, or peroxide in any or painful conditions, which mean any and all painful conditions involving TNF, or by the production of TNF, or when TNF triggers the release of other cytokines, such as interleukin-1 (IL-1) or interleukin-6 (IL-6), but is not limited to them. Consequently, a painful condition mediated by TNF, consider a painful condition in which, for example, IL-1 is a major component, and its production or effect, or is in response to TNF. Because TNF-(also known as lymphotoxin) is a close structural homologue of TNF-(also known as, cachectin), and each of them induces similar biologic responses and binds to the same cellular receptor, both TNF-and TNF-that is inhibited by compounds of the present invention, and therefore have here a generic term "TNF" unless specifically stated otherwise.

Inhibitors of PDE IV is useful in the treatment of many allergic and inflammatory diseases, including asthma, chronic bronchitis, atopic dermatitis, endogenous eczema, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjuncti, sitemates, allergic hemorrhagic nephritis (anaphylactoid purpura nephritis, inflammation of joints, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease (Crohne''s disease), myocardial damage and brain damage due to repeated perfusion (reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and respiratory distress syndrome in adults. In addition, inhibitors of PDE IV useful in the treatment of diabetes and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia (multi-infarct dementia dementia). Inhibitors of PDE IV is also applicable in the States in which it is shown neuroprotective agents, such as cardiac arrest, seizure and intermittent claudication. In addition, inhibitors of PDE IV can be useful as gastronomicznych agents. A special variant of therapeutic methods of the present invention is the treatment of asthma.

Proposed for treatment in this way viruses are those viruses that probatio, the direct or indirect) with TNF inhibitors of the formula (i). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the viruses of herpes group, such as Herpes zoster and Herpes simplex (but not limited).

In more detail, this invention relates to a method of treatment of a mammal infected by human immunodeficiency virus (HIV), which includes an 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 can also be used in comprehensive veterinary care for animals other than human in need of inhibition of production of TNF. Subject to treatment, therapeutic or prophylactic mediated TNF disease include painful conditions, such as those listed above, but, in particular viral infections. Examples of such viruses include, but are not limited to) feline immunodeficiency virus (FIV) or other retroviral infections such as virus, equine infectious anemia virus goat arthritis, visna virus, maedi virus and other lentiviruses.

The compounds of this invention are also useful in the treatment of p is edstam TNF, or induce the production of TNF in vivo. Preferred for such treatment a painful condition is fungal meningitis.

Preferably, the compounds of formula (i) was in pharmaceutically acceptable form. Under a pharmaceutically acceptable form see, inter alia, a pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and carriers, and not including any materials that are considered toxic at normal dosage. Pharmaceutically acceptable level of purity is usually at least 50%, excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and even more preferably 95%. Used herein, the expression "pharmaceutically acceptable" includes substances that are suitable for human use and for veterinary use.

The compound of formula (i) or, where appropriate, its pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES you can enter in the body by themselves, or preferably in the form of a pharmaceutical composition that also includes a pharmaceutically acceptable carrier.

Thus, the present invention provides a pharmaceutical composition comprising the compound MES and a pharmaceutically acceptable carrier.

The active compound can be prepared to receive any convenient way, the preferred method depends on requiring treatment, and the preferred drug is a standard dosage form or a form that people can accept himself as a single dose. Mainly the composition is suitable for oral, rectal, local, parenteral administration or administration via the respiratory tract. Drugs can be designed for slow release of the active component.

Used herein, the term " parenteral includes subcutaneous injections, intravenous, intramuscular, vnutrigrudne injection or infusion. 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 for the treatment of humans.

The compositions of this invention can be in the form of tablets, capsules, sachets, vials, powders, granules, pellets, suppositories, powders to obtain a desired composition or liquid preparations such as solutions or suspensions for oral administration or in sterile solutions or suspensions for parenteral administration. When it is convenient, preparationto) receiving preferably, to the composition of this invention was the standard dose. Standard dosage forms for oral administration may be tablets and capsules and may contain conventional fillers (excipients such as binding agents, for example syrup, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers (fillers), for example, microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants to obtain tablets, for example, magnesium stearate; disintegrating agents, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable moisturizing agents, such as sodium lauryl sulfate.

Solid compositions for oral administration can be obtained by ordinary methods of blending, filling, tabletting or the like. Re-stage mixing can be used for distribution of the active ingredient in the compositions with the use of large quantities of fillers.

Such techniques, of course, well known to specialists. The tablets may be coated according to methods well known in normal pharmaceutical item which may be for example, in the form of emulsions, syrups or elixirs, or may be a dry product to obtain before applying the desired composition with water or other suitable solvent. Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate, food, hydrogenated fats; emulsifying agents, for example lecithin, servicemanual or Arabian gum; non-aqueous solvents (which may include edible oils), for example, almond oil, coconut oil, esters butyric acids, such as esters of glycerine, propylene glycol or ethyl alcohol; preservatives, for example methyl - or propyl-para-hydroxybenzoate or sorbic acid; and, if required, conventional flavoring or tinted agents.

The compositions may also be suitable for introduction into the respiratory tract in the form of a powder for inhalation through the nose, or an aerosol or solution for a nebulizer, or microdispersed powder for insufflation, alone or in combination with an inert carrier such as lactose. In this case, it is convenient to the particles of active compound had a diameter is 5 microns. In suitable cases, you can include small quantities of other asthma or bronchodilators, for example, sympathomimetic amines, such as izoprenalin, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids, such as prednisone and adrenal stimulants such as ACTH.

For parenteral administration is prepared standard liquid dosage forms, using the compound of the invention and a sterile carrier, and depending on the resulting concentration of the compound can be suspended or dissolved in this medium. Upon receipt of the solutions of this compound can be dissolved in water for injection and sterilized by filtration before filling in suitable vials or ampoules and clogging.

It is useful to dissolve in the carrier adjuvants such as local anesthetics actions, preservatives and buffering agents. To improve stability after filling vials composition can be frozen and to remove the water in the vacuum. Suspension for parenteral use are essentially the same manner except that the compound is suspended in the carrier, and are not dissolved and sterilization cannot be applied filtering. Connect the knowledge to include in the composition of the surface-active compound or a wetting agent to facilitate uniform distribution of the connection.

These compositions may contain from 0.1 to 99 wt.%, preferably from 10 to 60 wt.% active compounds, depending on the method of administration.

The compound of formula (i) or a suitable pharmaceutically acceptable salt and/or its pharmaceutically acceptable MES can also be applied in the preparation of local action in combination with conventional fillers for preparations of local action.

Drugs local actions may constitute, for example, ointments, creams or lotions, bandages impregnated, gels, gel sticks, sprays and aerosols, and may contain the usual useful additives, such as preservatives, solvents, facilitating the penetration of drugs, and softening agents in ointments and creams. These preparations may contain conventional compatible media, such as bases for creams and ointments and ethanol or alerby alcohol for lotions.

Suitable formulations of creams, lotions, gels, sticks, ointments, sprays or aerosols that can be applied to compounds of formula (i) or, where appropriate, their pharmaceutically acceptable salts, are the usual well-known specialists preparations, for example as described in standard works, such as Harry's Cosmeticology, in appropriate cases, its pharmaceutically acceptable salt contains from about 0.5 to 20 wt.% drug preferably about 1 to 10 wt.%, for example, from 2 to 5%.

The dose used in the treatment of the compounds of this invention generally depends on the severity of the disease, the patient's weight and the relative efficiency of the connection. However, generally, a suitable dose may be from 0.1 to 1000 mg, namely, from 0.5 to 200 mg, from 0.5 to 100 mg, or from 0.5 to 10 mg, for example, 0,5, 1, 2, 3, 4 or 5 mg; and such standard dose can be taken 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 the total daily dose for an adult weighing 70 kg is from about 0.1 to 1000 mg, or about 0.001 to 20 mg/kg/day, namely, 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 such treatment may continue for several weeks or months.

Methods of research
Studies used to confirm the inhibitory activity of compounds of the formula (i) as phosphodiesterase IV represent the standard of research methodology, described in Schilling and others, 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 studies, the compounds of formula is less States, associated with phosphodiesterase IV.

The ability of compounds of the formula (i) to inhibit the production of TNF in managernew cells in human peripheral blood (PBMC's) is measured as follows. PBMC's is obtained from vegetarianas blood or Buffy coats" (leucocytes films) standard methods. Cells were seeded in RPMI1640 + 1% fetal calf serum in the presence or in the absence of inhibitors. Add LPS (lipopolysaccharide (endotoxin); 100 ng/ml) and the culture incubated for 22 h at 37oC in an atmosphere of 95% air/5% CO2. Supernatant tested for TNFthrough research ELISA (research immunosorbent associated with the enzyme), using commercially available kits.

Definition
The activity determined on the model of the lungs of Guinea pigs, using the techniques described in the works of Mauser and others, Am. Rev. Respir. Dis. 148:1623 (1993) and Am. J. Respir. Crit. Care Med. 152:467 (1995).

The pharmacokinetic profile of the compounds of the present invention determined in rats, which in the right carotid artery entered the cannula for blood collection. Connection for intravenous infusion is prepared in the form of a suitable composition, for example, 10% (vol/vol) dimethyl sulfoxide, 50% (vol/vol) PEG 400 (polyethylene glycol 400) in water, and to, and 8 h after dose. Connection for oral administration is prepared in the form of a suitable composition, for example, 0.4% (wt/vol) methylcellulose in water. Blood samples taken after 0.5, 1, 2, 4, 6 and 8 h after dose. In some cases, samples are taken within 12 hours after a dose. By centrifuging each sample of blood are plasma, and then determine the concentration of drugs using standard methods such as liquid chromatography - mass spectrometry with subsequent precipitation of the protein.

The results are presented below in table. 1 and also shown on the attached drawing. The drawing is a graph showing data of the RK after oral administration to rats dose compounds; the dependence of PC (concentration in plasma; ng/ml) from time t (time clock).Represents the connection of example 8, andfree base. Obviously the advantage of the new connection.

The solubility of the compound of example 8 in water at pH 7 is 0.2 mg/ml solubility of the corresponding free base under the same conditions is 0.002 mg/ml presented in Other examples, the compounds also exhibit suitable solubility.

In the following table. 2 PR PDE4, isolated from human U937 cells. The test was conducted in accordance with the methodology described above.

The data obtained in vivo in a model of the lungs of Guinea pigs, using the techniques described above, and represent % suppression of eosinophilia. This model corresponds to the asthma.

In addition, the compound from example 8 was also evaluated on the model of neutrophilia in rats, which corresponds COPD - chronic obstructive lung disease. Inhibition of the influx of neutrophils compound of example 8 in this model accounted for 62% of the oral dose of 3 mg/kg. Model in rats is described in detail in Pulmonary Pharmacology & Therapeuticals (2001) 14, 157-164, Spond et al.

Compounds according to the invention appears to exhibit low toxicity, since none of the tests was not detected any noticeable toxicity.

The following Examples illustrate the invention.

The intermediate product 1 - 2-Trifloromethyl-8-ol.

A solution of 8-methoxy-2-triptoreline (10.0 g) in 48% Hydrobromic acid (40 ml) is stirred while boiling under reflux overnight. The reaction mixture was poured into water (200 ml) and adjusted pH to 12.5 using 46-48% sodium hydroxide solution. After extraction with dichloromethane the feature is extracted with dichloromethane (2100 ml) and the combined organic extracts washed with water, dried over sodium sulfate, filter and remove the solvent in vacuo, obtaining the product (9.3 g) as a white solid.

The mass spectrum of the [M+H] 214
The intermediate product 2 - 8-(tert-Butyldimethylsilyloxy)-2-trifloromethyl
A solution of 2-trifloromethyl-8-ol (11.5 g), tert-butyldimethylsilyloxy in (8.9 g) and triethylamine (6.5 g) in dichloromethane (60 ml) is stirred overnight at room temperature. The reaction mixture was washed with water (250 ml), dried over sodium sulfate, filter and remove the solvent in vacuo, obtaining the product (17.9 g) as a white solid.

The mass spectrum of the [M+H] 328.

Next, the intermediate product is obtained according to a similar method.

The intermediate product 3 - 8-(tert-Butyldimethylsilyloxy)-2-IU tinhinan
Prepared from 8-hydroxyquinoline solution (10 g) to give the product (17 g) as an orange oil.

Thin layer chromatography (TLC) Rfof 0.90 (10% methanol in ethyl acetate).

The intermediate product 4 - 5-Bromo-8-(tert-butyldimethylsilyloxy)-2-trifloromethyl
A solution of 8-(tert-butyldimethylsilyloxy)-2-triptoreline (17.5 g) in dichloromethane (100 ml) obrabativaem sodium sulfate (100 ml) and water (50 ml). The organic layer is separated, dried over magnesium sulfate, filter and remove the solvent in vacuo, obtaining the product (21,4 g) as a dark oil.

The mass spectrum of the [M+H] 406.

Next, the intermediate product is obtained according to a similar method.

The intermediate product 5 - 5-Bromo-8-(tert-butyldimethylsilyloxy)-2-methylinosine
Prepared from 8-(tert-butyldimethylsilyloxy)-2-methylinosine (0,63 g) to give the product (0.66 g) as a yellow oil.

TLC Rf0,90 (dichloromethane).

The intermediate product 6 - 5-Bromo-2-trifloromethyl-8-ol.

A solution of 5-bromo-8-(tert-butyldimethylsilyloxy)-2-triptoreline (21 g) in methanol (150 ml) is treated with 37% hydrochloric acid (5 ml) and water (5 ml). The mixture is stirred at room temperature for 12 h at 45oC for 2 hours, the Methanol is removed in vacuo and the residue partitioned between 10% sodium hydroxide solution (100 ml) and dichloromethane (50 ml). The aqueous layer was neutralized with 37% hydrochloric acid to a pH of 7.2 and extracted with dichloromethane (450 ml). The combined organic extracts are dried over magnesium sulfate, filter and remove the solvent in vacuo, obtaining the product (12 g) as a cream solid color.

Mass yloxy)-2-methylinosine (16.3 g) in tetrahydrofuran (500 ml) was treated dropwise with a solution of tetrabutylammonium (1.0 M in tetrahydrofuran, 54 ml). The mixture is stirred for 10 min, diluted with dichloromethane (750 ml) and washed with water (3250 ml). The organic solution is dried over magnesium sulfate, filter and remove the solvent in vacuo, obtaining an orange oil. Recrystallization from aqueous methanol gives the product of 7.65 g) as a white solid.

TLC Rf0,58 (10% methanol in dichloromethane).

The intermediate product 8 - 5-Bromo-8-deformedarse-2-trifloromethyl
To a stirred solution of 5-bromo-2-trifloromethyl-8-ol (12.0 g) in dioxane (120 ml) was added 47% aqueous sodium hydroxide solution (12 ml). The mixture is heated to 78oWith and pass through it Chlorodifluoromethane (7,4 g) within 3 hours After cooling, the mixture was diluted with water (80 ml) and remove the solvent in vacuo. The resulting suspension is filtered and the filter residue is washed with dichloromethane (50 ml) and then water (50 ml). The organic layer is separated and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts washed with 0.5% sodium hydroxide solution (100 ml), dried over magnesium sulfate and remove the solvent in vacuo. The residue is transferred in tert-butyl methyl ether (100 ml), turbid solution is filtered and removed solvent in vacuo, recip what the product is obtained according to a similar method.

The intermediate product 9 - 5-Bromo-8-deformedarse-2-methylinosine
Prepared from 5-bromo-2-methylinosine-8-ol (1.0 g) to give a brown solid. Purification by recrystallization from methanol gives the product (0.96 g) as off-white solid.

TLC Rf0,86 (50% ethyl acetate in hexane).

The intermediate product 10 - 8-Deformedarse-2-trifloromethyl-5-carboxylic acid
A mixture of 5-bromo-8-deformedarse-2-triptoreline (6.0 g), triphenylphosphine (0.3 g), bis(triphenylphosphine)palladium(II) chloride (0.15 g), 47% solution of sodium hydroxide (4.5 g) and water (12 ml) in tetrahydrofuran (50 ml), rinsed with gaseous carbon monoxide in the Parr reactor (Parr pressure reactor at a pressure of 7 bar. The mixture is heated to 100oWith within 24 hours After cooling and venting, the reaction mixture was partitioned between a solution of sodium hydroxide (1.5 g in 50 ml) and tert-butylmethylamine ether (100 ml). The organic solution is extracted with sodium hydroxide solution (21.5 g in 50 ml). The combined aqueous extracts are stirred with activated charcoal (1.5 g) for 15 min and then filtered. The filtrate is acidified to pH 4 using 37% solution of hydrochloric acid, and the resulting cream-colored precipitate is separated Phil g) as a cream solid color.

The mass spectrum of the [M+H] 308.

Next, the intermediate product is obtained according to a similar method.

The intermediate product 11 - 8-Deformedarse-2-methylinosine-5-carboxylic acid
Prepared from 5-bromo-8-deformedarse-2-methylinosine (5,72 g) to give the product (2,88 g) as a brown solid.

TLC Rfof 0.60 (10% methanol in dichloromethane).

The intermediate product 12 - 4-Nitrophenyloctyl ether 8 deformedarse-2-trifloromethyl-5-carboxylic acid
A solution of 8-deformedarse-2-trifloromethyl-5-carboxylic acid (0.5 g) in dichloromethane (50 ml) is treated with 4-NITROPHENOL (0.25 g), 4-dimethylaminopyridine (catalytic amount) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (0.35 g) and the mixture is stirred at room temperature for 12 hours, the Reaction mixture was washed with water (50 ml), dried over sodium sulfate, filter and remove the solvent in vacuo. The residue is purified column chromatography on silica, elwira dichloromethane, and get the product of 0.47 g) as a cream solid color.

TLC Rf0,75 (5% ethyl acetate in dichloromethane).

The following intermediate products are obtained according to a similar method.

The intermediate product 13 - 4-Nitrophenyloctyl ether 8-ditty (0.50 g). Purification of column chromatography on silica with elution with 50% ethyl acetate in hexane gives the product (0,63 g) as a yellow solid.

TLC Rf0,73 (10% methanol in dichloromethane).

The intermediate product 14 - 4-Nitrophenyloctyl ester 8-methoxy-2-trifloromethyl-5-carboxylic acid.

Prepared from 8-methoxy-2-trifloromethyl-5-carboxylic acid (0,60 g), getting mentioned in the title compound (0.75 g) as a yellow solid.

TLC Rf0,64 (50% ethyl acetate in hexane).

The intermediate product 15 - (3-Chloropyridin-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid.

To a stirred solution of 4-amino-3-chloropyridine (136 mg) in N,N-dimethylformamide (2 ml) in an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 42 mg). The reaction mixture was stirred at room temperature for 1 h Then add 4-nitrophenyloctyl ether 8 deformedarse-2-methylinosine-5-carboxylic acid (200 mg) and continue stirring for 18 hours to Remove the solvent in vacuo, and the resulting residue is purified column chromatography on silica, elwira 50% ethyl acetate in hexane, and receive the product (155 mg) as a white solid.

TCX Rf0,3 (50% of these is the first product 16 - (3-Methylpyridin-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid
Prepared from 4-nitrophenylamino ether 8 deformedarse-2-methylinosine-5-carboxylic acid (500 mg) and 4-amino-3-methylpyridine (170 mg). Purification of column chromatography on silica with elution with 10% methanol in dichloromethane gives the product (200 mg) as a pale yellow solid.

TCX Rfof 0.55 (10% methanol in ethyl acetate).

The intermediate product 17 - (3-Chloropyridin-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Prepared from 4-nitrophenylamino ether 8 deformedarse-2-trifloromethyl-5-carboxylic acid (466 mg) and 4-amino-3-chloropyridine (283 mg). Purification of column chromatography on silica with elution with 15% ethyl acetate in dichloromethane gives the product (297 mg) as a white solid.

TCX Rf0,26 (15% ethyl acetate in dichloromethane).

The intermediate product 18 - (3,5-Dichloropyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Prepared from 4-nitrophenylamino ether 8 deformedarse-2-trifloromethyl-5-carboxylic acid (480 mg) and 4-amino-3,5-dichloropyridine (360 mg). Purification of column chromatography on silica with elution with 20% ethyl acetate in g is megalocnus product 19 - (3,5-Differencein-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Prepared from 4-nitrophenylamino ether 8 deformedarse-2-trifloromethyl-5-carboxylic acid (390 mg) and 4-amino-3,5-diphereline (120 mg). Purification of column chromatography on silica with elution with 10% ethyl acetate in dichloromethane gives the product (180 mg) as a white solid.

TCX Rf0,27 (15% ethyl acetate in dichloromethane).

The intermediate product 20 - (3,5-Differencein-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
Prepared from 4-nitrophenylthio ester 8-methoxy-2-trifloromethyl-5-carboxylic acid (425 mg) and 4-amino-3,5-diphereline (282 mg). Purification of column chromatography on silica with elution with 5% methanol in dichloromethane gives the product (162 mg) as a white solid.

TCX Rf0,34 (5% methanol in dichloromethane).

The intermediate product 21 - (3-Chloropyridin-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
To a stirred solution of 4-amino-3-chloropyridine (124 mg) in N,N-dimethylformamide (5 ml) in an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 52 mg). The reaction mixture was stirred at room temperature for 1 h Seedalot the solvent in vacuo and the resulting residue is distributed between ethyl acetate (250 ml) and water (50 ml). The organic layer is separated, dried over magnesium sulfate, filter and remove the solvent in vacuo. Purification of column chromatography on silica by elution with ethyl acetate gives the product (330 mg) as a pale pink solid.

TLC Rf0,41 (ethyl acetate).

So pl. 192-194oC.

Next, the intermediate product is obtained according to a similar method.

The intermediate product 22 - 3-(Methylpyridin-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
Prepared from 8-methoxy-2-trifloromethyl-4-carbonylchloride (430 mg) and 4-amino-3-methylpyridine (170 mg). Purification of column chromatography with elution with 10% methanol in ethyl acetate to give the product (160 mg) as a white solid.

TLC Rf0,29 (10% methanol in ethyl acetate).

The intermediate product 23 - (3-Methylpyridin-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
A solution of 8-deformedarse-2-trifloromethyl-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) was stirred at room temperature under nitrogen atmosphere. Add oxalicacid (0,28 ml) and then N,N-dimethylformamide (1 drop) and continue stirring overnight. Remove the solvent in vacuo, receive the mixed solution of 8-deformedarse-2-trifloromethyl-4-carbonylchloride (650 mg) in dichloromethane (40 ml) in an atmosphere of nitrogen was added triethylamine (0.68 ml) and 4-amino-3-methylpyridin (352 mg). The reaction mixture is stirred for 18 hours to Remove the solvent in vacuo, and the resulting residue is purified column chromatography on silica with elution with 5% methanol in dichloromethane and receive the product (563 mg) in the form of not-quite-white solid.

TLC Rfof 0.53 (10% methanol in dichloromethane).

Next, the intermediate product is obtained according to a similar method.

The intermediate product 24 - (3,5-Dimethylpyridin-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
Prepared from 8-methoxy-2-trifloromethyl-4-carbonylchloride (500 mg) and 4-amino-3,5-dimethylpyridine (210 mg). Purification by trituration with acetone and ether gives the product (82 mg) as a pale yellow solid.

TLC Rf0,42 (10% methanol in dichloromethane with 1% ammonium hydroxide).

Example 1 (3-chloro-1-oxypyridine-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid
Peracetic acid (36-40% in acetic acid, 0.1 ml) are added to a solution of (3-chloropyridin-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid (50 mg) in chloroform (10 ml) at room temperature. After stirring over night the reaction mixture was diluted with dichloromethane (20 ml) and washed with water (10 ml). Organicheskoi chromatography with elution with 10% methanol in ethyl acetate to give the product (25 mg) as a white solid.

TLC Rf0,2 (10% methanol in ethyl acetate).

Compounds of the following Examples, get the same methodology.

Example 2 (3-Chloro-1-oxypyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Prepared from (3-chloropyridin-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid (261 mg) to give the product (223 mg) as a cream solid color.

TLC Rfof 0.4 (ethyl acetate).

So pl. 212-213oC.

Example 3 (3-Chloro-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
Prepared from (3-chloropyridin-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid (50 mg) to give the product (25 mg) as off-white solid.

TLC Rf0,7 (10% methanol in ethyl acetate).

So pl. 261,5-262,5oC.

Example 4 (3,5-Debtor-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
Prepared from (3,5-differencein-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid (120 mg) with stirring at room temperature for 2 weeks. During this period add excess of peracetic acid (40.5 ml). Purification of column chromatography with elution of 5-10% methanol in dichloromethane gives p the oC (decomposes).

Example 5 (3,5-Debtor-1-oxypyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Prepared from (3,5-differencein-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid (160 mg) with stirring at room temperature for 2 weeks. During this period add excess of peracetic acid (30.1 ml). Purification of column chromatography with elution with 15% ethyl acetate in dichloromethane with increasing amounts of methanol to 10% in dichloromethane gives the product (120 mg) as a yellow solid.

TLC Rf0,69 (2% methanol in dichloromethane).

So pl. 219-220oC.

Example 6 (3-Methyl-1-oxypyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Prepared from (3-methylpyridin-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid (316 mg), which is stirred in the presence of peracetic acid (2of 0.18 ml) for two days. Purification of column chromatography with elution with 10% methanol in dichloromethane gives the product (267 mg) as a white solid.

TCX Rf0,25 (10% methanol in dichloromethane).

So pl. 210-212oC.

Example 7 (3,5-Dimethyl-1-oxypyridine-4-yl)amide 8 is cosmetician-5-carboxylic acid (56 mg), which is stirred in the presence of peracetic acid (2O/05 ml) for two days. Purification of column chromatography with elution with a mixture of 1% ammonium hydroxide/10% methanol in dichloromethane gives the product (37 mg) as a white solid.

TCX Rf0,22 (1% ammonium hydroxide/10% methanol in dichloromethane).

So pl. 237-239oC.

Example 8 (3,5-Dichloro-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid
(3,5-Dichloropyridine-4-yl)amide 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (200 mg) is stirred in the presence of peracetic acid (36-40% in acetic acid, 0.1 ml) in chloroform at 50oC for 5 days. Add peracetic acid (0.1 ml) and the reaction mixture is heated for another 2 days. Purification of column chromatography with elution with 10% methanol in ethyl acetate to give the product (123 mg) as a white solid.

TCX Rf0,17 (10% methanol in ethyl acetate).

So pl. 280-281oC.

Example 9 (3,5-Dichloro-1-oxypyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid
Get from (3.5 dichloropyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid (415 mg) in the same way to obtain (3,5-dichloro-1-oxypyridine a mixture of 1% ammonium hydroxide/10% methanol in dichloromethane gives specified in the title compound in the form of a cream solid color (360 mg).

TLC Rf0,5 (1% ammonium hydroxide/10% methanol in dichloromethane).

So pl. 244-245oC.

Example 10 (3-Methyl-1-oxypyridine-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid.

Sodium hydride (60% dispersion in oil, 0.11 g) is added to a stirred solution of 3-methyl-1-oxypyridine-4-ylamine (0.2 g) in N,N-dimethylformamide (10 ml) under nitrogen atmosphere at room temperature in the presence of molecular sieves. After stirring for 1 h, add 4-nitrophenyloctyl ether 8 deformedarse-2-methylinosine-5-carboxylic acid and the reaction mixture was stirred over night. Remove the solvent in vacuo and the residue distributed between ethyl acetate (50 ml) and water (250 ml). The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is washed with a small amount of ethyl acetate and dried, obtaining the product (50 mg) as a pale yellow solid.

TLC Rfa 0.27 (1% triethylamine/20% methanol in dichloromethane).

So pl. 231,5-233,5oC.

Example 11 (3-Methyl-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid.

Add triethylamine (0,55 ml) and 4-dimethylaminopyridine (catalytic amount) to a stirred suspension of 3-methyl-1-oxido salt of 8-methoxy-2-trifloromethyl-5-carbonylchloride (0.6 g) and the reaction mixture was stirred over night. Remove the solvent in vacuo and the residue distributed between ethyl acetate (50 ml) and water (350 ml). The precipitate in the organic phase is filtered off and dried in vacuum at 45oWith receiving the product (0.2 g) as a white solid.

TLC Rf0,12 (ethyl acetate).

So pl. 249,5-250,5oC.


Claims

1. The compound of formula (i)

where R1represents CH3CH2F, CHF2or CF3;
R2represents CH3or CF3;
R3represents F, Cl, Br or CH3;
R4represents H, F, Cl, Br or CH3,
or its pharmaceutically acceptable salt.

2. Connection on p. 1, characterized in that it is chosen from:
(3-chloro-1-oxypyridine-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid,
(3-chloro-1-oxypyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid,
(3-chloro-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid,
(3,5-debtor-1-oxypyridine-4-yl)amide 8-methoxy-2-Cryptor-methylinosine-5-carboxylic acid,
(3,5-debtor-1-oxypyridine-4-yl)amide 8-deformedarse-2-triptoreline acid,
(3,5-dimethyl-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid,
(3,5-dichloro-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid,
(3,5-dichloro-1-oxypyridine-4-yl)amide 8-deformedarse-2-trifloromethyl-5-carboxylic acid,
(3-methyl-1-oxypyridine-4-yl)amide 8-deformedarse-2-methylinosine-5-carboxylic acid,
(3-methyl-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid.

3. Connection on p. 1, characterized in that it is a (3,5-dichloro-1-oxypyridine-4-yl)amide 8-methoxy-2-trifloromethyl-5-carboxylic acid.

4. The compound according to any one of paragraphs.1 to 3 as an active ingredient of a medicinal product for the treatment of eosinophilia or neutrophilia.

5. The compound according to any one of paragraphs.1 to 3 as an active ingredient of a medicinal product for the treatment of asthma.

6. The compound according to any one of paragraphs.1 to 3 as an active ingredient of a medicinal product for the treatment of chronic bronchitis, chronic lung disease and chronic obstructive Airways disease.

 

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< / BR>
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< / BR>
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< / BR>
< / BR>
< / BR>
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