RU2205830C2 - Heterocyclic compound n-oxides showing inhibitory activity on tnf and pde-iv - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, medicine. SUBSTANCE: invention relates to heterocyclic compounds N-oxides of the formula (I)

where R₁ represents CH₃, CH₂F, CHF₂, CF₃; R₂ represents CH₃, CF₃; R₃ represents F, Cl, Br, CH₃; R₄ represents H, F, Cl, Br, CH₃. Invention can be used as a therapeutic agent for treatment of patients with asthma, eosinophilia, neutrophilia, chronic bronchitis, pulmonary chronic disease and chronic obstructive disease of respiratory ways. EFFECT: valuable medicinal properties of compounds. 6 cl, 1 dwg, 2 tbl

Description

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

BACKGROUND OF THE INVENTION
European Patent Application EP-A-0498722 describes quinoline derivatives as inhibitors of angiotensin A ₂ and endothelin.

 Models of the action of phosphodiesterases (PDEs) as well as tumor necrosis factors (TNFs) and the therapeutic usefulness of their inhibitors are described in WO-A-9744036 and US Pat. These publications disclose in detail quinoline carboxamides having such inhibitory activity.

где R₁ представляет собой СН₃, CH₂F, CHF₂ или СF₃;
R₂ представляет собой СН₃ или СF₃;
R₃ представляет собой F, Cl, Br, CN или СН₃; и
R₄ представляет собой Н, F, Cl, Br, CN или СН₃;
или их фармацевтически приемлемыми солями.Summary of invention
The present invention provides novel compounds therapeutically useful, in particular for the treatment of disease 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 R ₁ represents CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;
R ₂ represents CH ₃ or CF ₃ ;
R ₃ represents F, Cl, Br, CN or CH ₃ ; and
R ₄ represents H, F, Cl, Br, CN or CH ₃ ;
or their pharmaceutically acceptable salts.

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

 The present invention also provides a method for mediating or inhibiting the enzymatic activity, catalytic activity of PDE IV in a mammal in need, and inhibiting TNF production in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof.

Brief Description of the Drawing
The attached drawing is a graph that shows pK data after oral administration to rats of a specific dose of a compound of this invention and a known compound (for comparison).

Description of the invention
Certain compounds of formula (i) that contain a basic group form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulfate, α-ketoglutarate, α-glycerophosphate and glucose-1-phosphate. Pharmaceutically acceptable salts of the compounds of formula (i) are prepared using well-known procedures.

 The compounds of this invention can be obtained by N-oxidation of the corresponding free bases. Such free bases are known, or can easily be obtained by the method disclosed in WO-A-9744036. For example, a compound of formula (i) can be prepared by treating the free base with peracetic acid in acetic acid in a suitable solvent, such as chloroform, or with hydrogen peroxide in acetic acid.

 This invention includes the prevention and treatment of TNF-mediated diseases or disease states, which means any and all disease states in which TNF is involved, either by producing TNF itself or when TNF causes the release of another cytokine, such as interleukin-1 (IL -1) or interleukin-6 (IL-6), but not limited to. Therefore, a disease state mediated by TNF is considered a disease state in which, for example, IL-1 is a major component, and its production or action is enhanced or carried out in response to TNF. Since TNF-β (also known as lymphotoxin) is a close structural homolog of TNF-α (also known as cachectin), and each of them elicits similar biological reactions and binds to the same cellular receptor, both TNF-β β and TNF-α are inhibited by the compounds of the present invention, and therefore have the generic term “TNF” here, unless specifically indicated otherwise.

 PDE IV inhibitors are useful in the treatment of many allergic and inflammatory diseases, including asthma, chronic bronchitis, atopic dermatitis, endogenous eczema, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eye inflammation, allergic eye reactions, eosinophilic granuloma, psoriasis Bechet's disease), erythematosis, allergic hemorrhagic nephritis (anaphylactoid purpura nephritis), joint inflammation, arthritis, rheumatoid arthritis, and other arthritic conditions such as rheumatoid spondylitis and ost oartrit, septic shock, ulcerative colitis, Crohn's (Crohne's disease) disease, lesions due to cerebral infarction and reperfusion (reperfusion injury of the myocardium and brain), chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome in adults. In addition, PDE IV inhibitors are useful in treating diabetes insipidus and conditions associated with cerebral metabolic inhibition such as cerebral aging, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia (multi-infarct dementia) . PDE IV inhibitors are also useful in conditions in which neuroprotective agents are indicated, such as cardiac arrest, seizure, and intermittent claudication. In addition, PDE IV inhibitors may be useful as gastroprotective agents. A particular embodiment of the therapeutic methods of the present invention is the treatment of asthma.

 The viruses proposed for treatment by this method are those viruses that produce TNF as a result of infection, or viruses that are susceptible to inhibition (such as decreased replication, direct or indirect) by TNF inhibitors of formula (i). Such viruses include (but are not limited to) HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and herpes viruses such as (but not limited to) Herpes zoster and Herpes simplex.

 In more detail, this invention relates to a method of treating a mammal infected with a human immunodeficiency virus (HIV), which comprises administering to such a mammal an effective TNF-inhibiting amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof.

 The compounds of this invention can also be used in the complex veterinary treatment of non-human animals in need of inhibition of TNF production. TNF mediated diseases to be treated, therapeutic or prophylactic include disease states such as those listed above, but especially viral infections. Examples of such viruses include (but are not limited to) feline immunodeficiency virus (FIV) or other retroviral infections such as equine anemia virus, goat arthritis virus, visna virus, maedi virus, and other lentiviruses.

 The compounds of the present invention are also useful in the treatment of parasitic, yeast and fungal infections where the yeast and fungi are sensitive to upregulation by TNF or induce TNF production in vivo. Fungal meningitis is the preferred disease state for such treatment.

 Preferably, the compounds of formula (i) are in pharmaceutically acceptable form. By pharmaceutically acceptable form is meant, inter alia, a pharmaceutically acceptable level of purity, excluding conventional pharmaceutical additives, such as diluents and carriers, and not including any materials that are considered toxic at the usual dosage. A pharmaceutically acceptable level of purity is usually at least 50%, excluding conventional pharmaceutical additives, preferably 75%, more preferably 90% and even more preferably 95%. As used herein, the phrase “pharmaceutically acceptable” includes substances suitable for human and veterinary use.

 A compound of formula (i) or, if appropriate, a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof may be administered per se or, preferably, in the form of a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

 Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or, where appropriate, a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier.

 The active compound can be prepared for administration in any convenient way, the preferred method of administration depends on the diseases requiring treatment, and the preferred drug is a unit dosage form or a form that a person can take in a single dose. Mostly the composition is suitable for oral, rectal, local, parenteral administration or administration through the respiratory tract. The preparations may be intended for slow release of the active ingredient.

 The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrathoracic injections or infusions. In addition to treating warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the present invention are effective for treating humans.

 The compositions of this invention may take the form of tablets, capsules, sachets, ampoules, powders, granules, lozenges, suppositories, powders to obtain the desired composition or liquid preparations, such as solutions or suspensions for oral administration or sterile solutions or suspensions for parenteral administration. When convenient, topical preparations are also considered acceptable.

 To ensure uniformity (constancy) of administration, it is preferred that the composition of the present invention is a unit dose. Unit dosage forms for oral administration may be tablets and capsules and may contain conventional excipients, such as binding agents, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example, microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

 Solid compositions for oral administration may be prepared by conventional methods of mixing, filling, tabletting or the like. Repeated mixing steps can be used to distribute the active ingredient in the compositions using large amounts of excipients.

 Such techniques, of course, are well known to specialists. The tablets can be coated in accordance with methods well known in ordinary pharmaceutical practice, in particular enteric coating.

 Liquid preparations for oral administration can be, for example, in the form of emulsions, syrups or elixirs, or they can be a dry product to obtain, before use, the desired composition with water or another suitable solvent. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, edible hydrogenated fats; emulsifiers, for example, lecithin, sorbitan monooleate or gum arabic; non-aqueous solvents (which may include edible oils), for example, almond oil, coconut oil, butyric acid esters such as glycerol, propylene glycol or ethyl alcohol esters; preservatives, for example methyl or propyl para-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

 The compositions may also be suitable for administration to the respiratory tract in the form of a powder for inhalation through the nose, or an aerosol, or a solution for an inhaler, or a microdispersed powder for insufflation, alone or in combination with an inert carrier, such as lactose. In this case, it is convenient that the particles of the active compound have a diameter of less than 50 microns, for example, from 0.1 to 50 microns, preferably less than 10 microns, for example, from 1 to 10 microns, from 1 to 5 microns, or from 2 to 5 microns. In suitable cases, small amounts of other anti-asthma or bronchodilators may be included, for example, sympathomimetic amines such as isoprenaline, isoetarin, salbutamol, phenylephrine and ephedrine; corticosteroids, such as prednisone, and adrenal stimulants, such as ACTH.

 For parenteral administration, liquid unit dosage forms are prepared using the compound of the invention and a sterile vehicle, and depending on the concentration obtained, the compound may be suspended or dissolved in the vehicle. In preparing solutions, this compound can be dissolved in water for injection and sterilized by filtration before filling in suitable vials or ampoules and sealing.

 It is useful to dissolve adjuvants in the vehicle, such as local anesthetics, preservatives and buffering agents. To increase stability after filling the vials, the composition can be frozen and water removed in vacuo. Suspensions for parenteral use are prepared in essentially the same manner, except that the compound is suspended in the vehicle rather than dissolved and filtration cannot be used for sterilization. The compound can be sterilized by exposing it to ethylene oxide before suspension in a sterile vehicle. It is useful to include a surfactant or wetting agent in the composition to facilitate uniform distribution of the compound.

 These compositions may contain from 0.1 to 99 wt.%, Preferably from 10 to 60 wt.% Of the active compound, depending on the route of administration.

 The compound of formula (i) or a suitable pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof can also be used as a topical preparation in combination with conventional excipients for topical preparations.

 Topical preparations can be, for example, ointments, creams or lotions, dressings with impregnation, gels, gel sticks, sprays and sprays and contain the usual useful additives, such as preservatives, solvents, penetrating drugs, and emollients in ointments and creams. These preparations may contain conventional compatible carriers, such as creams and ointment bases and ethanol or oleyl alcohol for lotions.

 Suitable creams, lotions, gels, pencils, ointments, sprays or aerosols that can be used for compounds of formula (i) or, where appropriate, their pharmaceutically acceptable salts, are conventional formulations well known to those skilled in the art, for example, as described in standard works such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences and British and US Pharmacopoeias.

 Conveniently, the compound of formula (i) or, if appropriate, a pharmaceutically acceptable salt thereof contains from about 0.5 to 20% by weight of the preparation, preferably from about 1 to 10% by weight, for example, from 2 to 5%.

 The dose used in the treatment of the compounds of this invention usually depends on the severity of the disease, the weight of the patient and the relative effectiveness of the compounds. However, as a rule, a suitable single 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 doses 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 approximately from 0.1 to 1000 mg, that is, from about 0.001 to 20 mg / kg / day, namely, from 0.007 to 3, from 0.007 to 1.4, from 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 a number of weeks or months.

Research Methods
The studies used to confirm the inhibitory activity of the compounds of formula (i) against phosphodiesterase IV are standard research methods described by 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 studies, the compounds of formula (i) demonstrate activity at a level corresponding to what is considered a beneficial effect in the treatment of disease states associated with phosphodiesterase IV.

The ability of compounds of formula (i) to inhibit TNF production in mononuclear cells of human peripheral blood (PBMC's) is measured as follows. PBMC's are obtained from freshly collected blood or "Buffy coats" (white blood cells) using standard techniques. Cells are seeded in RPMI1640 + 1% fetal calf serum in the presence or absence of inhibitors. LPS (lipopolysaccharide (endotoxin); 100 ng / ml) was added and cultures were incubated for 22 hours at 37 ^° C in an atmosphere of 95% air / 5% CO ₂ . Supernatants are tested for TNFα through an ELISA assay (enzyme-linked immunosorbent assay) using commercially available kits.

Definitions
Activity is determined on a model of light guinea pigs using the techniques described in Mauser et al., Am. Rev. Respir. Dis. 148: 1623 (1993) and Am. J. Respir. Crit. Care Med. 152: 467 (1995).

 The pharmacokinetic profile of the compounds of this invention is determined in rats that have a cannula for collecting blood in the right carotid artery. The intravenous compound is prepared in a suitable composition, for example, in 10% (v / v) dimethyl sulfoxide, 50% (v / v) PEG 400 (polyethylene glycol 400) in water, and dosing is carried out by means of a catheter inserted into the left cervical vein. Samples were taken 5 minutes, 0.5, 1, 2, 4, 6, and 8 hours after dosing. A compound for oral administration is prepared in the form of a suitable composition, for example, in 0.4% (w / v) methyl cellulose in water. Blood samples are taken at 0.5, 1, 2, 4, 6, and 8 hours after dosing. In some cases, samples are taken 12 hours after dosing. By centrifuging each blood sample, plasma is obtained and then the concentration of the drug is determined using standard methods, such as liquid chromatography - mass spectrometry followed by precipitation of the protein.

 The results are presented below in table. 1 and are also shown in the attached drawing. The drawing is a graph of pK data after oral administration of a dose of a compound to rats; dependence of PC (plasma concentration; ng / ml) on time t (time; hours). ■ Represents the compound of Example 8, and • Free base. The obvious advantage of the new mix.

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

 In the table below. 2 shows test data both in vitro and in vivo.

 In vitro data were obtained using purified PDE4 enzyme isolated from U937 human cells. The test was carried out in accordance with the method described above.

 In vivo data were obtained on a light guinea pig model using the method described above and represent% inhibition of eosinophilia. This model corresponds to asthma.

 In addition, the compound of Example 8 was also evaluated in a rat neutrophilia model that corresponds to COPD, a chronic obstructive pulmonary disease. The suppression of neutrophil influx by the compound of Example 8 in this model was 62% when administered orally at a dose of 3 mg / kg. The rat model is described in detail in Pulmonary Pharmacology & Therapeuticals (2001) 14, 157-164, Spond et al.

 The compounds of the invention appear to exhibit low toxicity since no significant toxicity was found in any of the tests.

 The following Examples illustrate the invention.

 Intermediate 1 - 2-Trifluoromethylquinolin-8-ol.

 A solution of 8-methoxy-2-trifluoromethylquinoline (10.0 g) in 48% hydrobromic acid (40 ml) was stirred at reflux overnight. The reaction mixture was poured into water (200 ml) and the pH was adjusted to 12.5 using a 46-48% sodium hydroxide solution. After extraction with dichloromethane (2 • 25 ml), the aqueous layer is acidified to pH 5.3 by adding a 37% hydrochloric acid solution. The mixture was then extracted with dichloromethane (2 x 100 ml) and the combined organic extracts were washed with water, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the product (9.3 g) as a white solid.

Mass spectrum [M + H] 214
Intermediate 2-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline
A solution of 2-trifluoromethylquinolin-8-ol (11.5 g), tert-butyldimethylsilyl chloride (8.9 g) and triethylamine (6.5 g) in dichloromethane (60 ml) was stirred overnight at room temperature. The reaction mixture was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the product (17.9 g) as a white solid.

 Mass spectrum [M + H] 328.

 The following intermediate product is obtained in a similar manner.

Intermediate 3-8- (tert-butyldimethylsilanyloxy) -2-methylquinoline
Prepared from 8-hydroxyquinoline (10 g) to give the product (17 g) as an orange oil.

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

Intermediate 4-5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline
A solution of 8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline (17.5 g) in dichloromethane (100 ml) is treated with N-bromosuccinimide (10.5 g) at 15 ^° C. The mixture is stirred at 20 ^{° C.} for 25 minutes, washed with 1% sodium sulfate solution (100 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give the product (21.4 g) as a dark oil.

 Mass spectrum [M + H] 406.

 The following intermediate product is obtained in a similar manner.

Intermediate 5 - 5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-methylquinoline
Prepared from 8- (tert-butyldimethylsilanyloxy) -2-methylquinoline (0.63 g) to give the product (0.66 g) as a yellow oil.

TLC R _f 0.90 (dichloromethane).

 Intermediate 6 - 5-Bromo-2-trifluoromethylquinolin-8-ol.

A solution of 5-bromo-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline (21 g) in methanol (150 ml) is treated with a 37% solution of hydrochloric acid (5 ml) and water (5 ml). The mixture was stirred at room temperature for 12 hours and at 45 ^{° C.} for 2 hours. Methanol was removed in vacuo and the residue was partitioned between 10% sodium hydroxide solution (100 ml) and dichloromethane (50 ml). The aqueous layer was neutralized with a 37% hydrochloric acid solution to a pH of 7.2 and extracted with dichloromethane (4 x 50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the product (12 g) as a cream-colored solid.

 Mass spectrum [M] 292.

Intermediate 7 - 5-Bromo-2-methylquinolin-8-ol
A solution of 5-bromo-8- (tert-butyldimethylsilanyloxy) -2-methylquinoline (16.3 g) in tetrahydrofuran (500 ml) was dropwise treated with a solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 54 ml). The mixture is stirred for 10 minutes, diluted with dichloromethane (750 ml) and washed with water (3 x 250 ml). The organic solution was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give an orange oil. Recrystallization from aqueous methanol afforded the product (7.65 g) as a white solid.

TLC R _f 0.58 (10% methanol in dichloromethane).

Intermediate 8 - 5-Bromo-8-difluoromethoxy-2-trifluoromethylquinoline
To a stirred solution of 5-bromo-2-trifluoromethylquinolin-8-ol (12.0 g) in dioxane (120 ml) was added a 47% sodium hydroxide solution (12 ml). The mixture was heated to 78 ^{° C.} and chlorodifluoromethane (7.4 g) was passed through it for 3 hours. After cooling, the mixture was diluted with water (80 ml) and the solvent was removed in vacuo. The resulting suspension was filtered and the filter residue was washed with dichloromethane (50 ml) and then with water (50 ml). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 ml). The combined organic extracts were washed with 0.5% sodium hydroxide solution (100 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The residue was taken up in tert-butyl methyl ether (100 ml), the turbid solution was filtered and the solvent was removed in vacuo to give the product (11.7 g) as an off-white solid.

 Mass spectrum [M + H] 342.

 The following intermediate product is obtained in a similar manner.

Intermediate 9 - 5-Bromo-8-difluoromethoxy-2-methylquinoline
Prepared from 5-bromo-2-methylquinolin-8-ol (1.0 g) to give a brown solid. Purification by recrystallization from methanol gives the product (0.96 g) as an off-white solid.

TLC R _f 0.86 (50% ethyl acetate in hexane).

Intermediate 10 - 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid
A mixture of 5-bromo-8-difluoromethoxy-2-trifluoromethylquinoline (6.0 g), triphenylphosphine (0.3 g), bis (triphenylphosphine) palladium (II) chloride (0.15 g), 47% sodium hydroxide solution (4 5 g) and water (12 ml) in tetrahydrofuran (50 ml) were purged with gaseous carbon monoxide in a Parr pressure reactor at a pressure of 7 bar. The mixture was heated to 100 ^{° C.} for 24 hours. After cooling and ventilation, the reaction mixture was partitioned between sodium hydroxide solution (1.5 g in 50 ml) and tert-butyl methyl ether (100 ml). The organic solution was extracted with sodium hydroxide solution (2 • 1.5 g in 50 ml). The combined aqueous extracts were stirred with activated carbon (1.5 g) for 15 minutes and then filtered. The filtrate was acidified to pH 4 using a 37% hydrochloric acid solution, and the resulting cream-colored precipitate was separated by filtration and washed with water (20 ml). The crude product is purified by recrystallization from toluene to give the product (1.8 g) as a cream-colored solid.

 Mass spectrum [M + H] 308.

 The following intermediate product is obtained in a similar manner.

Intermediate 11 - 8-Difluoromethoxy-2-methylquinoline-5-carboxylic acid
Prepared from 5-bromo-8-difluoromethoxy-2-methylquinoline (5.72 g) to give the product (2.88 g) as a brown solid.

TLC R _f 0.60 (10% methanol in dichloromethane).

Intermediate 12 - 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester
A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-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 was stirred at room temperature for 12 hours. The reaction mixture was washed with water (50 ml), dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by silica column chromatography eluting with dichloromethane to give the product (0.47 g) as a cream-colored solid.

TLC R _f 0.75 (5% ethyl acetate in dichloromethane).

 The following intermediates are prepared in a similar manner.

Intermediate 13 - 4-Nitrophenyl ester of 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid
Prepared from 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (0.50 g). Purification by column chromatography on silica, eluting with 50% ethyl acetate in hexane, gives the product (0.63 g) as a yellow solid.

TLC R _f 0.73 (10% methanol in dichloromethane).

 Intermediate 14 is 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester.

 Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (0.60 g) to obtain the title compound (0.75 g) as a yellow solid.

TLC R _f 0.64 (50% ethyl acetate in hexane).

 Intermediate 15 - (3-Chloropyridin-4-yl) 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid amide.

 To a stirred solution of 4-amino-3-chloropyridine (136 mg) in N, N-dimethylformamide (2 ml) under nitrogen atmosphere was added sodium hydride (60% dispersion in oil, 42 mg). The reaction mixture was stirred at room temperature for 1 hour. Then 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester (200 mg) was added and stirring was continued for 18 hours. The solvent was removed in vacuo and the resulting residue was purified. column chromatography on silica, eluting with 50% ethyl acetate in hexane, to give the product (155 mg) as a white solid.

TCX R _f 0.3 (50% ethyl acetate in hexane).

 The following intermediates are prepared in a similar manner.

Intermediate 16 - (3-Methylpyridin-4-yl) 8-difluoromethoxy-2-methylquinolin-5-carboxylic acid amide
Prepared from 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester (500 mg) and 4-amino-3-methylpyridine (170 mg). Purification by silica column chromatography, eluting with 10% methanol in dichloromethane, gives the product (200 mg) as a pale yellow solid.

TCX R _f 0.55 (10% methanol in ethyl acetate).

Intermediate 17 - (3-Chloropyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (466 mg) and 4-amino-3-chloropyridine (283 mg). Purification by silica column chromatography, eluting with 15% ethyl acetate in dichloromethane, gives the product (297 mg) as a white solid.

TCX R _f 0.26 (15% ethyl acetate in dichloromethane).

Intermediate 18 - (3,5-Dichloropyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (480 mg) and 4-amino-3,5-dichloropyridine (360 mg). Purification by column chromatography on silica, eluting with 20% ethyl acetate in hexane, afforded the product (424 mg) as a white solid.

TCX R _f 0.42 (20% ethyl acetate in hexane).

Intermediate 19 - (3,5-Difluoropyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (390 mg) and 4-amino-3,5-difluoropyridine (120 mg). Purification by silica column chromatography, eluting with 10% ethyl acetate in dichloromethane, gives the product (180 mg) as a white solid.

TCX R _f 0.27 (15% ethyl acetate in dichloromethane).

Intermediate 20 - (3,5-Difluoropyridin-4-yl) 8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid amide
Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (425 mg) and 4-amino-3,5-difluoropyridine (282 mg). Purification by silica column chromatography, eluting with 5% methanol in dichloromethane, gives the product (162 mg) as a white solid.

TCX R _f 0.34 (5% methanol in dichloromethane).

Intermediate 21 - (3-Chloropyridin-4-yl) amide 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid
To a stirred solution of 4-amino-3-chloropyridine (124 mg) in N, N-dimethylformamide (5 ml) under nitrogen atmosphere was added sodium hydride (60% dispersion in oil, 52 mg). The reaction mixture was stirred at room temperature for 1 hour. Then 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (360 mg) was added and stirring was continued for 18 hours. The solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (2 × 50 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. Purification by silica column chromatography eluting with ethyl acetate gave the product (330 mg) as a pale pink solid.

TLC R _f 0.41 (ethyl acetate).

Mp 192-194 ^o C.

 The following intermediate product is obtained in a similar manner.

Intermediate 22 - 3- (Methylpyridin-4-yl) amide 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid
Prepared from 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (430 mg) and 4-amino-3-methylpyridine (170 mg). Purification by column chromatography eluting with 10% methanol in ethyl acetate gave the product (160 mg) as a white solid.

TLC R _f 0.29 (10% methanol in ethyl acetate).

Intermediate 23 - (3-Methylpyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) was stirred at room temperature under a nitrogen atmosphere. Oxalyl chloride (0.28 ml) was added, followed by N, N-dimethylformamide (1 drop) and stirring was continued overnight. The solvent was removed in vacuo to give 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) as an off-white solid.

 To a stirred solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) in dichloromethane (40 ml) under nitrogen atmosphere are added triethylamine (0.68 ml) and 4-amino-3-methylpyridine (352 mg). The reaction mixture was stirred for 18 hours. The solvent was removed in vacuo and the resulting residue was purified by column chromatography on silica eluting with 5% methanol in dichloromethane to give the product (563 mg) as an off-white solid.

TLC R _f 0.53 (10% methanol in dichloromethane).

 The following intermediate product is obtained in a similar manner.

Intermediate 24 - (3,5-Dimethylpyridin-4-yl) 8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid amide
Prepared from 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (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 R _f 0.42 (10% methanol in dichloromethane with 1% ammonium hydroxide).

Example 1 (3-Chloro-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-methylquinolin-5-carboxylic acid
Peracetic acid (36-40% in acetic acid, 0.1 ml) is added to a solution of (3-chloropyridin-4-yl) 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid amide (50 mg) in chloroform (10 ml ) at room temperature. After stirring overnight, the reaction mixture was diluted with dichloromethane (20 ml) and washed with water (10 ml). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a white solid. Purification by column chromatography, eluting with 10% methanol in ethyl acetate, gives the product (25 mg) as a white solid.

TLC R _f 0.2 (10% methanol in ethyl acetate).

 The compounds of the following Examples were prepared in a similar manner.

Example 2 (3-Chloro-1-hydroxypyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinolin-5-carboxylic acid amide
Prepared from (3-chloropyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide (261 mg) to give the product (223 mg) as a cream-colored solid.

TLC R _f 0.4 (ethyl acetate).

T. pl. 212-213 ^o C.

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

TLC R _f 0.7 (10% methanol in ethyl acetate).

T. pl. 261.5-262.5 ^o C.

Example 4 (3,5-Difluoro-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid
Prepared from (3,5-difluoropyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (120 mg) with stirring at room temperature for 2 weeks. Over this period, an excess of peracetic acid (4 x 0.5 ml) is added. Purification by column chromatography, eluting with 5-10% methanol in dichloromethane, gives the product (28 mg) as a yellow solid.

TLC R _f 0.09 (5% methanol in dichloromethane).

Mp 268-269 ^o C (decomposes).

Example 5 (3,5-Difluoro-1-hydroxypyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
Prepared from (3,5-difluoropyridin-4-yl) amide of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (160 mg) with stirring at room temperature for 2 weeks. Over this period, an excess of peracetic acid (3 x 0.1 ml) is added. Purification by column chromatography, eluting with 15% ethyl acetate in dichloromethane with an increase in methanol to 10% in dichloromethane, gives the product (120 mg) as a yellow solid.

TLC R _f 0.69 (2% methanol in dichloromethane).

Mp 219-220 ^o C.

Example 6 (3-Methyl-1-hydroxypyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
Prepared from (3-methylpyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide (316 mg), which was stirred in the presence of peracetic acid (2 x 0.18 ml) for two days. Purification by column chromatography eluting with 10% methanol in dichloromethane afforded the product (267 mg) as a white solid.

TCX R _f 0.25 (10% methanol in dichloromethane).

Mp 210-212 ^o C.

Example 7 (3,5-Dimethyl-1-hydroxypyridin-4-yl) 8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid amide
Prepared from (3,5-dimethylpyridin-4-yl) amide 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (56 mg), which was stirred in the presence of peracetic acid (2 • O / 05 ml) for two days. Purification by column chromatography, eluting with 1% ammonium hydroxide / 10% methanol in dichloromethane, afforded the product (37 mg) as a white solid.

TCX R _f 0.22 (1% ammonium hydroxide / 10% methanol in dichloromethane).

Mp 237-239 ^o C.

Example 8 (3,5-Dichloro-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid
8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloropyridin-4-yl) amide (200 mg) is stirred in the presence of peracetic acid (36-40% in acetic acid, 0.1 ml) in chloroform at 50 ^o C for 5 days. More peracetic acid (0.1 ml) was added and the reaction mixture was heated for another 2 days. Purification by column chromatography eluting with 10% methanol in ethyl acetate gave the product (123 mg) as a white solid.

TCX R _f 0.17 (10% methanol in ethyl acetate).

Mp 280-281 ^o C.

Example 9 (3,5-Dichloro-1-hydroxypyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide
Obtained from (3,5-dichloropyridin-4-yl) amide of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (415 mg) in the same manner to obtain (3,5-dichloro-1-hydroxypyridin-4-yl) amide 8 -methoxy-2-trifluoromethylquinoline-5-carboxylic acid. Purification by column chromatography eluting with 1% ammonium hydroxide / 10% methanol in dichloromethane afforded the title compound as a cream-colored solid (360 mg).

TLC R _f 0.5 (1% ammonium hydroxide / 10% methanol in dichloromethane).

Mp 244-245 ^o C.

 Example 10 (3-Methyl-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid.

 Sodium hydride (60% dispersion in oil, 0.11 g) is added to a stirred solution of 3-methyl-1-hydroxypyridin-4-ylamine (0.2 g) in N, N-dimethylformamide (10 ml) under nitrogen at room temperature temperature in the presence of molecular sieves. After stirring for 1 h, 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester was added and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (2 x 50 ml). The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue was washed with a small amount of ethyl acetate and dried, yielding the product (50 mg) as a pale yellow solid.

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

Mp 231.5-233.5 ^o C.

 Example 11 (3-Methyl-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid.

Triethylamine (0.55 ml) and 4-dimethylaminopyridine (catalytic amount) are added to a stirred suspension of 3-methyl-1-hydroxypyridin-4-ylamine (0.23 g) in dichloromethane (40 ml) under a nitrogen atmosphere at room temperature. The 8-methoxy-2-trifluoromethylquinoline-5-carbonyl chloride hydrochloride salt (0.6 g) was added and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (3 x 50 ml). The precipitate in the organic phase is filtered off and dried in vacuo at 45 ^{° C.} to give the product (0.2 g) as a white solid.

TLC R _f 0.12 (ethyl acetate).

Mp 249.5-250.5 ^o C.

Claims (6)

1. The compound of formula (i)

where R ₁ represents CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;
R ₂ represents CH ₃ or CF ₃ ;
R ₃ represents F, Cl, Br or CH ₃ ;
R ₄ represents H, F, Cl, Br or CH ₃ ,
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that it is selected from:
(3-chloro-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid,
(3-Chloro-1-hydroxypyridin-4-yl) -amide 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid,
(3-chloro-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid,
(3,5-difluoro-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoro-methylquinolin-5-carboxylic acid,
(3,5-difluoro-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid,
(3-methyl-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid,
(3,5-Dimethyl-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid,
(3,5-Dichloro-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid,
(3,5-Dichloro-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid,
(3-methyl-1-hydroxypyridin-4-yl) amide of 8-difluoromethoxy-2-methylquinolin-5-carboxylic acid,
8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid (3-methyl-1-hydroxypyridin-4-yl) amide.  3. The compound according to claim 1, characterized in that it is (3,5-dichloro-1-hydroxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid.  4. The compound according to any one of claims 1 to 3, as an active ingredient in a medicament for the treatment of eosinophilia or neutrophilia.  5. The compound according to any one of claims 1 to 3, as an active ingredient in a medicament for treating asthma.  6. The compound according to any one of claims 1 to 3, as an active ingredient in a medicament for the treatment of chronic bronchitis, chronic lung disease and chronic obstructive airway disease.

Images