MXPA00006346A - N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity - Google Patents

Abstract

N-oxides of formula (i) wherein R1 is CH3, CH2F, CHF2 or CF3;R2 is CH3 or CF3;R3 is F, Cl, Br, CN or CH3;and R4 is H, F, Cl, Br, CN or CH3;and pharmaceutically-acceptable salts thereof, are useful as therapeutic agents, e.g. for the treatment of inflammatory diseases.

Description

N-OXIDES OF HETEROCICLIC COMPOUNDS WITH INHIBITORY ACTIVITY OF TNF AND PDE-IV DESCRIPTION OF THE INVENTION The present invention is concerned with new heterocyclic compounds and their formulation and use as pharmaceutical compounds.

BACKGROUND OF THE INVENTION EP-A-0498722 describes quinoline derivatives as inhibitors of angiotensin A2 and endothelin. The modes of action of the phosphodiesterases and also tumor necrosis factors (TNF) and the therapeutic utilities of the inhibitors thereof, as described in WO-A-9744036 and US Pat. No. 5804588, the content of which are incorporated herein by reference. These publications specifically describe quinoline carboxamides having such inhibitory activity.

BRIEF DESCRIPTION OF THE INVENTION This invention provides new compounds having therapeutic utility, in particular for the treatment of disease states associated with protein that moderate cell activity, for example by inhibiting TNF and / or PDE-IV. According to the invention, the compounds are of formula (i) wherein: Ri is CH3, CH2F, CHF2 or CF3; R2 is CH3 or CF3; R3 is F, Cl, Br, CN or CH3; and R 4 is H, F, Cl, Br, CN or CH 3; or a pharmaceutically acceptable salt thereof. In summary, the compounds of the invention are N-oxides of the corresponding free bases that are described, some specifically in WO-A-9744036. The new compounds have superior solubility profiles, improved metabolic stability and an improved pharmacokinetic profile. The compound of Example 8 is particularly preferred. This invention provides a method for moderating inhibiting the activity of enzymatic or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to the mammal an effective amount of a composed of formula (i) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWING The attached drawing is a graph showing data of pK, next to the oral dosage in rat, of a compound of the invention and by comparison of a known compound.

DETAILED DESCRIPTION OF THE INVENTION Certain compounds of the formula (i) which contain a basic group form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the addition salts of sulfate, nitrate, phosphate, borate, hydrochloric and hydrobromic acid and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulfonate, a-ketoglutarate, a-glycocerophosphate and glucose-1-phosphate. The pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional procedures. The compounds of the invention can be prepared by N-oxidation of the corresponding free base. The free bases are known or can be prepared by the processes described 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 an appropriate solvent such as chloroform or with hydrogen peroxide in acetic acid. The invention includes the prevention and treatment of a disease moderated by TNF or disease states moderated by TNF which means any or all of the disease states in which TNF plays a role, either by the production of TNF by itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for example, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state moderated by TNF. Since TNF-ß (also known as lymphotoxin) has a tight structural homology with TNF-a (also known as cachectin) and since each induces similar biological responses and binds to the same cell receptor, TNF-α and TNF-β are inhibited by the compounds of the present invention and thus are referred to herein collectively as "TNF" unless specifically summarized otherwise herein. PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases in which it is included: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eyes , allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythomatosis, anaphylactoid purple nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease , reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and respiratory disease syndrome in adults. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus 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 dementia. multi-infarction PDE IV inhibitors are also useful in conditions enhanced by neuro-protective activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE I inhibitors could have utility as gastroprotectors. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma. The viruses contemplated for the treatment of the present are those that produce TNF as a result of infection or those that are sensitive to inhibition, such as by decreased 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, adenovirus and the group of herpes viruses such as but not limited to Herpes zoster and Herpes simplex. This invention is more specifically convenient with a method of treating a mammal, afflicted with the human immunodeficiency virus (HIV), comprising administering to said mammal an effective amount of TNF of a compound of formula (i) or a salt pharmaceutically acceptable thereof. The compounds of this invention can also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production. Diseases moderated by TNF for the treatment, therapeutically or prophylactically, in animals include disease states such as those indicated 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 equine infectious anemia virus, goat arthritis virus, visna virus, maedi virus and other lentiviruses. The compounds of this invention are also useful in the treatment of parasitic, yeast and fungal infections, wherein such yeast and fungi are sensitive to the regulation of TNF or that will produce TNF production in vivo. A preferred disease state for treatment is fungal meningitis. The compounds of formula (i) are preferably in a pharmaceutically acceptable form. "Pharmaceutically acceptable form" means, inter alia, an acceptably pharmaceutically level of purity that excludes normal pharmaceutical additives such as diluents and carriers and that does not include material considered to be toxic at normal dosage levels. A pharmaceutically acceptable purity level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably be 75%, more preferably 90% and still more preferably 95%. When used herein the term "pharmaceutically acceptable" encompasses materials suitable for human and veterinary use. A compound of formula (i) or where appropriate a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof can be administered per se, preferably as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or wherein a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvent thereof and a pharmaceutically acceptable carrier are appropriate. The active compound can be formulated for administration by any appropriate route, the preferred route depends on the disease for which treatment is required and is preferably in a unit dose form or in a form that a human patient can administer to itself a single dose. Advantageously, the composition is suitable for oral, rectal, topical, parenteral or respiratory system administration. The preparations may be designed to give slow release of the active ingredient. The parenteral term as used herein includes subcutaneous injections, intramuscular intramuscular injection, intrasternal injection or infusion techniques. In addition to the treatment of warm sangr animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are affective in the treatment of humans. The compositions of the invention may be in the form of tablets, capsules, sachets, flasks, powders granules, lozenges, suppositories, reconstitutable powders, liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also contemplated where appropriate. In order to obtain consistency of administration it is preferred that a composition of the invention be in the form of a unit dose. The dosage unit dosage forms for administration may now be tablets and capsules and may contain conventional excipients such as binding agents, for example, syrups, acacia, gelatin, sorbitol, polyvinyl pyrrolidone tragacanthone.; filled for example microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate; disintegrants, starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The solid oral compositions can be prepared by conventional mixing, filling, tabletting or the like. Repeated mixing operations can be used to distribute the active agent in all these compositions using large amounts of fillers. Such operations are of course conventional in the art. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of for example, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, # oily esters such as glycerin esters, propylene glycol, or alcohol ethyl; preservatives, for example methyl or propyl p-hydroxybenzoate or ascorbic acid; and if desired conventional flavoring or coloring agents. Compositions which may also be presented appropriately for administration of the respiratory system as a spray or an aerosol or solution for a nebulizer or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound have approximately diameters of less than 50 microns, such as 0.1 to 50 microns, preferably less than 10 microns, for example 1 to 10 microns, 1 to 5 microns or 2 to 5 microns . Where appropriate, small amounts of other anti-asthmatics and bronchodilators eg sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; Corticosteroids such as prednisolone and adrenal stimulants such as ACTH can be included. For parenteral administration, bound unit dosage forms are prepared using the compound and a sterile vehicle, and depending on the concentration used, they can be either suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved in water for injection and sterilized by filter before filling into an appropriate and sealed vial or vial. Advantageously, adjuvants such as a local anesthetic, preservative and pH regulating agents can be dissolved in the vehicle. To improve the stability, the composition can be frozen afterwards. from the filling to the bottle and the separated water under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization can not be carried out by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight of the active material, depending on the method of administration. The compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.

Topical formulations may for example be presented as ointments, creams or lotions, impregnated dressings, gels, gel sticks, sprays and aerosols and may contain appropriate conventional additives such as preservatives, solvents to aid in the penetration of the medicament and emollients in ointments and creams. . The formulations may contain compatible conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Suitable cream, lotion, gel, stick, ointment, spray or spray formulations that can be used for the compounds of the formula (i) or if a pharmaceutically acceptable salt thereof is appropriate are conventional formulations well known in the art, for example as described in standard textbooks such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences and the British US Pharmacopoeias. Suitably, the compound of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, will comprise from about 0.5 to 20% by weight of the formulation, favorably from about 1 to 10%, for example 2 to 5%. The dose of the compound used in the treatment of the invention will vary in the usual way with the seriousness of the diseases, the weight of the patient afflicted and the relative efficacy of the compound. However, as a general guide, the appropriate unit doses may be from 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, or 5 mg; and such unit doses may be administered more than once a day, for example, 2, 3, 4, 5, or 6 times a day, but preferably 1 or 2 times per day, such that the daily dose vital for an adult of 70 Kg. is in the range of approximately 0.1 to 1000 mg, this is in the range of approximately 0.001 to 20 mg / Kg. / day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 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 therapy can be extended for a number of weeks or months.

Methods of Analysis The assays used to confirm the inhibitory activity of phosphodiesterase IV by the compounds of the formula (I) are standard assay methods as described by Schilling et al, Anal. Biochem. 216: 154 (1994), Thompson and Strada, Adv. Cycl. Nucí Res. 8: 119 (1979) and Gristwood and Owen, Br. J. Pharmacol, 87: 91P (1986). The compounds of the formula (i) have exhibited activity at levels consistently with those believed to be useful in the treatment of the disease states related to phosphodiesterase IV in those analyzes. The ability of the compounds of the formula (i) to inhibit the production of TNF in mononuclear cells of the human peripheral blood (PMBC's) is measured as follows. PMBC's cells are prepared from freshly taken blood or "leukocyte layer" buffy mediant standard procedures. The cells are deposited in RPMI1640 + 1% fetal bovine serum in the presence and absence of inhibitors. LPS (lipopolysaccharide (endotoxin), 100 ng / ml) is added and the cultures are incubated for 22 hours at 37 ° C in an atmosphere of 95% air / 5% C02. The supernatants are tested for TNF-a by ELISA (enzyme-linked immunoabsorbent analysis) using commercially available equipment.

Abbreviations The activity of a guinea pig lung model is measured using the procedures described by 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 the invention is determined in rats having a cannula in the right carotid artery for blood collection. For iv dosing, the compound is prepared in an appropriate formulation, for example DMSO at 10% volume / volume, PEG 400 50% volume / volume in water and dosing is carried out by cannulation of the left jugular vein. Samples are collected at 5 minutesUnd , 0.5, 1, 2, 4, 6, and S hours after dosing. For oral dosing, the compois prepared in an appropriate formulation such as methylcellulose at 0.4% w / v in water. Samples are collected at 0.5, 1, 2, 4, 6, and 8 hours post-dosing. In some cases, samples are also collected 12 hours after dosing. The plasma is obtained by centrifugation of each blood sample and then the concentration of the drug is determined using standard methods, such as liquid chromatography-mass spectrometry after precipitation of the protein. The results are tabulated below and are also shown in the attached drawing. The drawing is a graph of the PK data following the oral dosage in the rat; PC (concentration in plasma; ng / ml) is plotted against t (time, hours). U represents the compound of Example 8 and • the free base. The superiority of the new compound is evident.

The solubility of the compound of Example 8, in water at pH 7, was 0.2 mg / ml. The solubility of the corresponding free base, under the same conditions, was 0.002 mg / ml. Other exemplified compounds exhibit desirable solubility. The following examples illustrate the invention.

Intermediate 1 2-Trifluoromethylquinolin-8-ol A solution of 8-methoxy-2-trif luoromethylquinoline (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 adjusted to 12.5 using a 46-48% sodium hydroxide solution. After extraction with dichloromethane (2 x 25 ml) the aqueous layer was acidified to pH 5.3 by the addition of 37% hydrochloric acid solution. The mixture was then extracted using dichloromethane (2 x 100 ml) and the combined 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. M.S. [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) in dichloromethane (60 ml) It 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 removed in vacuo to give the product (17.9 g) as a white solid. M.S. [M + H] 328 The following intermediary was prepared by a similar procedure Intermediate 3 8- (Tert-Butyldimethylsilanyloxy) -2-methyl-uinoline Prepared from 8-hydroxyquinoline (10 g) to give the product (17 g) as an orange oil Thin-layer chromatography Rf 0.90 (105% methanol) ethyl acetate) Intermediate 4 5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline A solution of 8- (tert-butyldimethylsilanoxy) -2-trifluoromethylquinoline (17.5) in dichloromethane (100 ml) was treated with N- Bromosuccinimide (10.5g) at 15 ° C. The mixture was stirred at 20 ° C. for 25 minutes, washed with 1% sodium sulfate solution (100 ml), and water (5 ° C.) The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo to leave the product (21.4 g) as a dark oil MS [M + H] 406 The following intermediate was prepared by a similar procedure.

Intermediate 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. Thin layer chromatography Rf 0.90 (dichloromethane) Intermediate 6 5-Bromo-2-trifluoromethylquinolin-8-ol A solution of 5-bromo-8- (tert-butyldi-ethyl-silanyloxy) -2-trifluoromethylquinoline (21 g) in methanol (150 ml) was treated with hydrochloric acid a 37% (5 ml) and water (5 ml). The mixture was stirred for 12 hours at room temperature and at 45 ° C for two hours. The methane was 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 solution at pH 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 solid. M.S. [M +] 292 Intermediate 7 5-Bromo-2-ylquinoline-8-ol A solution of 5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-methylquinoline (16.3 g) in tetrahydrofuran (500 ml) was treated dropwise with a solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 54 ml). The mixture was stirred during 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 removed in vacuo to give an orange oil. Recrystallization of the aqueous methanol gives the product (7.65 g) as a white solid. Thin layer chromatography Rf 0.58 (10% methanol in dichloromethane; Intermediate 8 5-Bromo-8-difluromethoxy-2-trifluoromethyl-quinoline To a stirred solution of 5-bromo-2-trifluoromethylquinolin-8-ol (12.0 g) in dioxane (120 ml) is added a solution of sodium hydroxide to the 47% (12 ml). The mixture was heated to 78 ° C and chlorodifluoromethane (7.4 g) was bubbled through the reaction for three hours. Upon cooling, the mixture was diluted in water (80 ml) and the solvent was removed in vacuo. The resulting suspension was filtered and the filter retort washed with dichloromethane (50 ml) then water (50 ml). The organic layer was separated and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts were washed with 0.5% sodium hydroxide solution (100 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was taken up in tert-butyl methyl ether (100 ml), the cloudy solution was filtered and the solvent removed in vacuo to give the product (11.7 g) as a decolorized white solid. MS [M + H] 342 The following intermediate was prepared by a similar procedure Intermediate 9 5-Bromo-8-difluromethoxy-2-methylquinoline Prepared from 5-bromo-2-methylquinolin-8-ol (1.0 g) to give a solid coffee. Purification by recrystallization from methanol gives the product (0.96 g) as a decolorized white solid. Thin layer chromatography Rf 0.86 (50% ethyl acetate in hexane).

Intermediate 10 8-di-luromethoxy-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) was purged with carbon monoxide gas in a Parr pressure reactor at 17 bar. This was heated to a temperature of 100 ° C for 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-butyl methyl ether (100 ml). The organic solution was extracted with sodium hydroxide solution (2 x 1.5 g in 50 ml). The combined aqueous extracts were stirred with activated charcoal (1.5 g) for 15 minutes and then filtered. The filtrate was acidified to pH4 using 37% hydrochloric acid solution and the resulting cream precipitate was isolated by filtration and washed with water (20 ml). The crude product was purified by recrystallization of toluene to give the product (1.8 g) as a cream solid. M.S. [M + H] 308 The following intermediate was prepared by a similar procedure.

Intermediate 11 8-difluoromethoxy-2-tri-uro-methyl-quinoline-5-carboxylic acid Prepared from 5-Bromo-8-difluoromethoxy-2-trifluoromethyl-quinoline (5.72 g) to give the product (2.88 g) as a brown solid. Thin layer chromatography Rf 0.60 (10% methanol in dichloromethane).

Intermediate 12 4-Nitrophenyl ester of 8-difluromethoxy-2-trifluoromethylquinoline-5-carboxylic acid A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (0.5 g) in dichloromethane (50 ml) was treated with 4-nitrophenol (0.25 g) 4-dimethylaminopyridine (catalytic) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.35 g) and the mixture was stirred at room temperature for 12 hours. The reaction was washed with water (50 ml), dried over sodium sulfate, filtered and the solvent dried in vacuo. The residue was purified by column chromatography on silica, elution with dichloromethane to give the product (0.47 g) as a cream solid. Thin layer chromatography Rf 0.75 (5% ethyl acetate in dichloromethane) The following intermediates were prepared by a similar procedure Intermediate 13 4-Nitrophenyl ester of 8-difluromethoxy-2-methylquinoline-5-carboxylic acid Prepared from 8-difluoromethoxy-2-methylquinol-5-carboxylic acid (0.50 g). Purification by column chromatography on silica, elution with 50% ethyl acetate in hexane gives the product (0.63 g) as a yellow solid. Thin layer chromatography Rf 0.73 (10% methanol in dichloromethane).

Intermediate 14 8-Nitophenyl ester of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (0.60 g) to give the title compound (0.75 g) as a yellow solid. Thin layer chromatography Rf 0.64 (50% ethyl acetate in hexane) Intermediate 8-difluromethoxy-2-methylquinoline-5-carboxylic acid 15 (3-chloropyridin-4-yl) amide To a stirred solution of 4-amino-4-chloropyridine (136 mg) in N, N-dimethylformamide (2 ml) under a nitrogen atmosphere is added sodium hydride (60% dispersion in oil, 42 mg). The reaction mixture was stirred at room temperature for one hour. Then 4-difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitropenil ester (200 mg) is added and the stirring is continued for 18 hours. The solvent was removed in vacuo and the resulting residue was purified by column chromatography on silica, elution with 50% ethyl acetate hexane to give the product (155 mg) as a white solid. Thin layer chromatography Rf 0.3 (50% ethyl acetate in hexane) The following intermediates were prepared by a similar procedure.

Intermediate 8-difluromethoxy-2-methylquinoline-5-carboxylic acid 16 (3-methylpyridin-4-yl) amide Prepared from the 4-nitrophenyl ester of the acid 8-difluoromethoxy-2-methylquinoline-4-carboxylic acid (500 mg) and 4-amino-3-methylpyridine (170 mg). Purification by column chromatography on silica, elution with 10% methanol in dichloromethane gives the product (200 mg) as a pale yellow solid. Thin layer chromatography Rf 0.55 (10% methanol in ethyl acetate).

Intermediate 8-difluromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloropyridin-4-yl) -amide. Prepared from 4-nitrophenyl ester of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (46 mg) and 4-amino-3-chloropyridine (283 mg). Purification by column chromatography on silica, elution with 15% ethyl acetate in dichloromethane gives the product (297 mg) as a white solid. Thin layer chromatography Rf 0.26 (15% ethyl acetate in dichloromethane).

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

Thin layer chromatography Rf 0.42 (20% ethyl acetate in hexane).

Intermediate 19 (8-difluoromethoxy-2-tri-mororomethylquinoline-5-carboxylic acid, 4-difluoromethoxy-3,5-di-luo-pyridin-4-ylide) Prepared from 4-difluoromethoxy-2-trifluoromethylquinoline-4-nitrophenyl ester carboxylic (390 mg) and 4-amino-3,5-difluropyridine (120 mg) Purification by column chromatography on silica, elution with 10% ethyl acetate in dichloromethane gives the product (180 mg) as a white solid Thin layer chromatography Rf 0.27 (15% ethyl acetate in dichloromethane) Intermediate 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 20 (3,5-difluoropyridin-4-yl) amide Prepared from 4-nitrophenyl ester of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (425) mg) and 4-amino-3,5-difluropyridine (282 mg). Purification by column chromatography on silica, elution with 5% methanol in dichloromethane gives the product (162 mg) as a white solid. Thin layer chromatography Rf 0.34 (5% methanol in dichloromethane).

Intermediate 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 21 (3-chloropyridin-4-yl) amide To a stirred solution of 4-amino-3-chloropyridine (124 mg) in N, N-dimethylformamide (5 ml) under a nitrogen atmosphere was added sodium hydride (60% dispersion in oil, 52 mg). The reaction mixture was stirred at room temperature for one hour. Then 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (360 mg) is added and the stirring is continued for 18 hours. The solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (2 x 250 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica, elution with ethyl acetate gives the product (330 mg) as a pale pink solid. Thin layer chromatography Rf 0.41 (ethyl acetate). Melting point 192-194 ° C. The next intermediary was prepared by a similar procedure.

Intermediate 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 22 (3-methylpyridin-4-yl) amide Prepared from 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (430 mg) and 4- amino-3 methylpyridine (170 mg). Purification by means of column chromatography, elution with 10% methanol and ethyl acetate gives the product (160 mg) as a white solid. Thin layer chromatography Rf 0.29 (10% methanol in ethyl acetate).

Intermediate 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 23 (3-methylpyridin-4-yl) amide A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carboxylic acid (0.50 mg) in dichloromethane (30 ml) was stirred at room temperature under a nitrogen atmosphere. Oxalyl chloride (0.28 mg) is added followed by N, N-dimethylformamide (one drop) and stirring is continued overnight. The solvent was removed in vacuo to give the 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) as a decolorized white solid. To a stirred solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) in dichloromethane (40 ml) under a nitrogen atmosphere is 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 purified by column chromatography on silica, elution with 5% methanol in dichloromethane to give the product (563 mg) as a pale white solid. Thin layer chromatography Rf 0.53 (10% methanol in dichloromethane) The following intermediate was prepared by a similar procedure.

Intermediate 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 24 (3,5-dimethylpyridin-4-yl) amide Prepared from 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (500 mg) and 4- amino-3,5-dimethylpyridine (210 mg) Purification by titration with acetone and ether gives the product (82 mg) as a pale yellow solid. Thin layer chromatography Rf 0.42 (10% methanol in dichloromethane with 1% ammonium hydroxide).

Example 1 (8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 3-chloro-1-oxypyridin-4-yl) amide. Peracetic acid (36-40% in acetic acid, 0.1 ml) is added to a solution of ( 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 3-chloropyridin-4-yl) amide (50 mg) in chloroform (10 ml) at room temperature. After stirring overnight the reaction was diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic phase was dried over magnesium sulfate and the solvent removed in vacuo to give a white solid. Purification by column chromatography, elution with 10% methanol in ethyl acetate gives the product (25 mg) as a white solid. Thin layer chromatography Rf 0.2 (10% methanol in ethyl acetate) Melting point 244 ° C (decomposes) The following examples were prepared by a similar procedure.

Example 2 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (2-chloro-1-oxo-pyridin-4-yl) -amide. Prepared from 8-difluoromethoxy-2-chloropyridin-4-yl) amide. -trifluoromethylquinoline-5-carboxylic acid (261 mg) to give the product (223 mg) as a cream solid. Thin layer chromatography Rf 0.4 (ethyl acetate). Melting point 212-213 ° C.

Example 3 (8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 3-chloro-1-oxo-pyridin-4-yl) -amide. Prepared from 8-methoxy-2-chloropyridin-4-yl) amide. -trifluoromethylquinoline-5-carboxylic acid (50 mg) to give the product (25 mg) as a decolorized white solid. Thin layer chromatography Rf 0.7 (10% methanol in ethyl acetate). Melting point 261.5-262.5 ° C Example 4 (3,5-Difluoro-l-oxypyridin-4-yl) acid amide 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3, 5-difluoropyridin-4-yl) amide (120 mg) with stirring at room temperature during 2 weeks. Excess peracetic acid is added (4 x 0.5 ml) during this period. Purification by column chromatography, elution with 5-10% methanol in dichloromethane gives the product (28 mg) as a yellow solid. Thin layer chromatography Rf 0.09 (5% methanol in dichloromethane). Melting point 268-269 ° C (decomposes).

Example 5 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoro-l-oxypyridin-4-yl) -amide. Prepared from (3, 5-difluoropyridin-4-yl) -amide of 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid. -difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (160 mg) with stirring at room temperature for 2 weeks. Excess peracetic acid (3 0.1 ml) is added during this period. Purification by column chromatography, elution with 15% ethyl acetate in dichloromethane increasing to 10% methanol in dichloromethane gives the product (120 mg) as a yellow solid. Thin layer chromatography Rf 0.69 (2% methanol in dichloromethane). Melting point 219-220 ° C.

Example 6: 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-Matyl-l-oxypyridin-4-yl) -amide. Prepared from 8-difluoromethoxy-2-acid (3-methylpyridin-4-yl) amide. -trifluoromethylquinoline-5-carboxylic acid (316 mg) stirred in the presence of peracetic acid (2 x 0.18 ml) for two days. Purification by column chromatography, elution with 10% methanol in dichloromethane gives the product (267 mg) as a white solid. Thin layer chromatography Rf 0.25 (10% methanol in dichloromethane) "Melting point 210-212 ° C.

Example 7 (3,5-dimethyl-l-oxypyridin-4-yl) amide of the acid 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3, 5-dimethylpyridin-4-yl) amide (56 mg) stirred in the presence of peracetic acid ( 2 x 0.05 ml) for two days. Purification by means of column chromatography, elution with 1% ammonium hydroxide / 10% methanol in dichloromethane gives the product (37 mg) as a white solid. Thin layer chromatography Rf 0.22 (1% ammonium hydroxide / 10% methanol in dichloromethane). Melting point 237-239 ° C.

Example 8 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 3,5-dichloro-l-oxypyridin-4-yl) amide 8-methoxy- (3, 5-dichloropyridin-4-yl) amide 2-trifluoromethylquinoline-5-carboxylic acid (200 mg) was stirred in the presence of peracetic acid (36-40% in acetic acid, 0.1 ml) in chloroform at 50 ° C for 5 days. Additional peracetic acid (0.1 ml) is added and the reaction is heated for an additional 2 days. Purification by column chromatography, elution with 10% methanol in ethyl acetate gives the product (123 mg) as a white solid. Thin layer chromatography Rf 0.17 (10% methanol in ethyl acetate). Melting point 280-281 ° C.

Example 9 (3,5-Dichloro-1-oxypyridin-4-yl) amide of 8-difluorome oxy-2-trifluoromethylquinoline-5-carboxylic acid Prepared from (3, 5-dichloropyridin-4-yl) -amide of the acid 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (415 mg) in a manner similar to 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-l-oxy-pyridin-4-yl) -amide. Purification by column chromatography, elution with 1% ammonium hydroxide / 10% methanol in dichloromethane gives the title compound as a cream solid (360 mg). Thin layer chromatography Rf 0.5 (1% ammonium hydroxide / 10% methanol in dichloromethane). Melting point 244-245 ° C.

EXAMPLE 10 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 10 (3-Methyl-1-oxypyridin-4-yl) -amide. Sodium hydride (60% dispersion in oil, 0.11 g) is added to a stirred solution of 3-Methyl-l-oxypyridin-4-ylamine (0.2 mg) in N, N-dimethylformamide (10 ml) under a nitrogen atmosphere at room temperature in the presence of molecular sieves. After stirring for one hour, the 4-nitrophenyl ester of 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid is added and the reaction is stirred overnight. The solvent was removed and vacuum and the residue partitioned between ethyl acetate (50 ml) water (2 x 50 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was washed with a little ethyl acetate and dried to give the product (5 mg) as a pale yellow solid. Thin layer chromatography Rf 0.27 (1% triethylamine / 20% methanol in dichloromethane). Melting point 231.5-233.5 ° C.

EXAMPLE 11 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) -amide. Triethylamine (0.55 ml) and 4-dimethylaminopyridine (catalyst) are added to a stirred suspension of 3-methyl. -l-oxypyridin-4-ylamine (0.23 mg) in dichloromethane (40 ml) under a nitrogen atmosphere at room temperature. The hydrochloride salt of 8-methoxy-2-methylquinoline-5-carbonyl chloride (0.6 g) is added and the reaction is stirred overnight. The solvent was removed and vacuum and the residue partitioned between ethyl acetate (50 ml) water (3 x 50 ml). The precipitate in the organic phase was filtered and dried under vacuum at 45 ° C to give the product (0.2 g) as a white solid. Thin layer chromatography Rf 0.12 (ethyl acetate) Melting point 249.5-250.5 ° C,

Claims (3)

1. REINVINDICATIONS 1. A compound of formula wherein R1 is CH3, CH2F, CHF2 or CF3; R2 is CH3 or CF3; R3 is F, Cl, Br, CN or CH3; and R 4 is H, F, Cl, Br, CN or CH 3; or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, characterized in that it is selected from: 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-chloro-l-oxypyridin-4-yl) amide, (3-chloro- 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid l-oxypyridin-4-yl) amide, 8-methoxy-2-trifluoromethylquinoline-5,5-difluoro-l-oxypyridin-4-yl) amide -carboxylic acid, (3, 5-difluoro-l-oxypyridin-4-yl) amide of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid, (3,5-difluoro-l-oxypyridin-4-yl) amide 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid, 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide, (3, 5-dimethyl-l- 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid oxypyridin-4-ylide, 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3, 5-dichloro-l-oxypyridin-4-yl) -amide) 8-difluoromethoxy-2-trifluoromethyl (3, 5-dichloro-l-oxypyridin-4-yl) amide Tilquinoline-5-carboxylic acid, 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide, (3-methyl-1-oxypyridin-4-yl) -amide of the acid 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid. 3. The compound according to claim 1, characterized in that it is 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-l-oxypyridin-4-yl) amide. . The compound according to any of the preceding claims, characterized in that it is used for the manufacture of a medicament in the treatment of a disease state susceptible to be modulated by the inhibition of phosphodiesterase IV, or tumor necrosis factor or that is a pathological condition associated with a phosphodiesterase IV function, eosinophil accumulation or an eosinophil function. 5. The compound according to claim 4, characterized in that the disease state is an inflammatory disease or an autoimmune disease. 6. The compound according to claim 4, characterized in that the disease state is selected from asthma, chronic bronchitis, chronic pulmonary inflammatory disease, chronic obstructive airway disease, atopic dermatitis, allergic rhinitis, psoriasis, arthritis, rheumatoid arthritis , joint inflammation, ulcerative colitis, Cronh's disease, atopic eczema, stroke, bone resolution disease, multiple sclerosis and inflammatory bowel disease. The compound according to claim 4, characterized in that the disease state is selected from urticaria, allergic conjunctivitis, vernal conjunctivitis, eye inflation, allergic responses in the eye, eosinophilic granuloma, gout arthritis and other arthritic conditions. , adult respiratory disease syndrome, diabetes insipidus, chloratesis, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, intermittent claudication, rheumatoid spondylitis, osteoarthritis, sepsis, septic shock, endotoxic shock, gami-negative sepsis, toxic shock syndrome, acute respiratory disease syndrome, cerebral malaria, silicosis, pulmonary sarcoidosis, reperfusion injury, graft against host reaction, allograft rejection, fever related to infection or myalgia, malaria, HIV, AIDS, ARC, cachexia, keloid formation, malf ormation of scar tissue, pyresis, systemic lupus erythematosus, diabetes mellitus type I, Bechet's disease, anaphylactoid purple nephritis, chronic glomerulonephritis, leukemia, tardive dyskinesia, yeast or fungal infection, conditions requiring gastroprotection and associated neurogenic inflammatory disease with irritation and pain. 8. The compound according to claim 4, characterized in that the state of the disease is asthma. 9. The compound according to claim 5, characterized in that the condition of the disease is chronic obstruction of the airways or chronic bronchitis. 10. The compound according to any of claims 4 to 9, characterized in that the compound is as defined in claim
3. 3.