SK10082000A3 - N-oxides of heterocyclic compounds - 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

Technical field

The present invention relates to novel heterocyclic compounds and their formulation and their use as pharmaceutical compositions.

BACKGROUND OF THE INVENTION

EP-A-0498722 discloses quinoline derivatives as angiotensin A2 and endothelin inhibitors.

Methods of action of phosphodiesterases as well as tumor necrosis factors (TNFs) and the therapeutic use of their inhibitors are described in WO-A-9744036 and US Pat. 5804588, the contents of which are incorporated herein by reference. These publications specifically disclose quinoline carboxamides exhibiting such inhibitory activity.

SUMMARY OF THE INVENTION

The present invention encompasses novel compounds for therapeutic use, in particular for the treatment of disease states associated with proteins that mediate cellular activity, e.g. suppressing TNF and / or PDE IV activity. According to the present invention, these are compounds of formula I:

C

N

R (J (D in which

R ¹ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃

R ² is CH ₃ or CF ₃

R ³ is F, Cl, Br, CN or CH ₃ , and

R ⁴ is H, F, Cl, Br, CH or CH ₃ , or a pharmaceutically acceptable salt thereof.

Essentially, the compounds of the invention are N-oxides of the corresponding free bases, some of which are specifically described in WO-A-9744036. The novel compounds have greater solubility, increased metabolic stability and increased pharmacokinetic profile. The compound of Example 8 is preferred.

The present invention also encompasses a method for mediating or suppressing PDE IV enzymatic activity or catalytic activity in a mammal in need thereof, and for preventing TNF in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. .

Some of the compounds of formula I containing a basic group form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as sulfates, nitrates, phosphates, borates, hydrochlorides and hydrobromides, and pharmaceutically acceptable organic acid addition salts such as acetates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, methanesulfates, α-ketoglutarates, α-glycerophosphates and glucose J-phosphates. The pharmaceutically acceptable salts of formula I are prepared by conventional methods.

The compounds of the present invention can be prepared by N-oxidation of the corresponding free base. The free bases are known or can be prepared according to the procedures described in WO-A-9744036. E.g. the compound of formula I may be prepared by treating the free base with peracetic acid in acetic acid in a suitable solvent such as chloroform or hydrogen peroxide in acetic acid.

The invention encompasses the prevention and treatment of diseases or conditions caused by TNF, meaning any and all disease states in which TNF plays a role, either in the formation of TNF itself or in the development of TNF due to other released cytokines such as, but not limited to, IL -1 or IL-6. A disease state in which e.g. IL-1 is a major component and its origin or action is the cause of the disease process or is secretly responsible for TNF, thus being considered a disease state caused by TNF. Since TNF-β (known as lymphotoxin) is a close structural homolog to TNF-α (also known as cachectin), and because it has the same biological responsibility and binds the same cellular receptor, and both TNF-α and TNF-β, of the present invention are suppressed herein, and are collectively described herein as "TNF," unless otherwise indicated.

PDE IV inhibitors are useful in the treatment of a variety of allergic diseases and inflammatory conditions including asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, conjunctivitis, conjunctivitis, eye inflammation, eye allergy, eosin granuloma, psoriasis, Bechet's disease, skin thinning, anaphylactoid magenta nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthrosis conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, chronic gonorrhea, cerebrovascular colitis, rheumatic colitis shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes disturbance and conditions associated with the reduction of brain metabolism such as cerebral senility, senile dementia (Alzheimer's disease), memory deficiency associated with Parkins disease, depression and multiple infarct dementia. PED IV inhibitors are also useful for ameliorating conditions caused by neuroprotective activity such as cardiac arrest, stroke, or intermittent curvature. In addition, PED IV inhibitors may be useful as gastroprotectants. A special part of the therapeutic methods of the present invention is the treatment of asthma.

Viruses considered suitable for treatment are those that allow the development of TNF due to inflammation, or which are sensitive, directly or indirectly, to the inhibitory action of TNF inhibitors of formula I, e.g. such as increased reproduction. Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and a herpes-causing virus family such as, but not limited to, Herpes Sister Herpes simplex.

In particular, the present invention relates to methods of treating a mammal afflicted with a human immunodeficiency virus (HIV) comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof inhibiting TNF.

The compounds of the present invention may also be useful in conjunction with veterinary treatment of animals, not just humans, if necessary to reduce TNF. Therapeutically or prophylactically suitable diseases for treatment induced by TNF in animals are the same as those mentioned above, particularly 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 or other lentiviruses.

The compounds of the present invention are also useful in the treatment of infectious diseases caused by parasites, yeasts and fungi when the yeasts and fungi are susceptible to TNF re-regulation or induce TNF in vivo. Especially according to the present invention, fungal meningitis is a suitable treatment.

The compounds of formula I are useful in a pharmaceutically acceptable composition. A pharmaceutically acceptable composition means, inter alia, a pharmaceutically acceptable level of the amount at the normal doses administered, in addition to the normal pharmaceutical ingredients such as diluents and carriers, and the excreted materials are considered toxic. The pharmaceutically acceptable level is generally at least 50%, in addition to the pharmaceutical additives, preferably 75%, more preferably 90% and most preferably 95%. As used herein, the term "pharmaceutically acceptable" refers to materials suitable for both human medicine and veterinary use.

The compound of formula I or the corresponding pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof may be administered per se, or more preferably as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

The present invention provides a suitable pharmaceutical composition comprising a compound of formula I, or comprising a suitable pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

The active compound may be prescribed for administration by any suitable means required by the condition being treated, and it is desirable to adjust the composition to a single dose or to adjust its form so that the patient can administer it in a single dose. Preferably, the composition may be administered orally, rectally, topically, parenterally, or via the respiratory tract. The composition should be formulated so as to release the active ingredient slowly.

As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to treating warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc. is a composition of the present invention suitable for treating humans.

In order to maintain uniformity of dosage, the composition of the invention may be formulated as a single dose. The unit dosage form for oral administration may be a tablet or capsule and may contain conventional adjuvants such as binders, e.g. syrup, resin, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers, e.g. microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, tabletting lubricants such as e.g. magnesium stearate, disintegrating retardant such as e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting and the like. Repeated blending operations can be used to completely distribute the active ingredient throughout the formulation when large quantities of fillers are used.

Similar procedures are common in the art. The tablets may be coated by known pharmaceutical practice, in particular in the case of an intestinal coating.

Oral liquid compositions may be in the form of emulsions, syrups, or beverages, or may be presented as a dry product for reconstitution in water or other suitable carrier liquid before use. Such liquid compositions may contain conventional additives as suspending agents, e.g. sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats, emulsifying agents such as e.g. lecithin, sorbitol monooleate or resin, non-aqueous vehicles (which may contain edible oils), e.g. almond oil, fractional coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol, preservatives such as e.g. methyl or propyl phydroxybenzoate or sorbic acid and the necessary amount of conventional fragrance and coloring ingredients.

The compositions may also be suitable for administration to the respiratory tract as a snuff or aerosol or spray solution, or as a microfine snuff powder, alone or in combination with an inert carrier such as lactose. In such a case, the active compound particles have a diameter of less than 50 μπη, such as 0.1 to 50 prn, preferably less than 10 μπη, e.g. from 12 to 10 μηη, 1 to 5 μm or from 2 to 5 μιτι. If necessary, small amounts of other antiasthmatic agents and bronchodilators, e.g. sympathomimetic amines such as isoprenaline, isoetharin, salbutamol, phenylephrine and ephedrine, corticosteroids such as prednisolone, and adrenaline stimuli such as ACHT.

For parenteral administration, the liquid component of the composition administered is a sterile carrier and, depending on the concentration used, the active ingredient may be either suspended or dissolved in the liquid carrier. In preparing the solution, the compound may be dissolved in water for injection or filtered sterilized water before filling into suitable vials or ampoules and sealed.

Advantageously, a local anesthesia additive, a preservative or a buffering component may be dissolved in the liquid carrier. To ensure stability, the composition can be frozen after filling into the viol and the water removed under vacuum. Parenteral suspensions are basically prepared by the same procedure, except that the active ingredient is suspended in the carrier instead of being dissolved, but sterilization cannot be accomplished by filtration. The composition may be sterilized by exposure to ethylene oxide prior to suspension in a sterile carrier. It is preferred to add a surfactant or wetting agent to the composition to facilitate uniformity of distribution of the active compound.

The composition may contain from 0.1% to 99% by weight, more preferably from 10 to 60% by weight of the active compound, depending on the route of administration.

The compounds of formula I, or their corresponding pharmaceutically acceptable salts and / or their pharmaceutically acceptable solvate, may also be administered as skin compositions concurrently with conventional skin preparations.

The skin compositions may be prepared e.g. such as ointments, creams or detergent, impregnating pads, gels, gel sticks, sprays and aerosols, and may contain appropriate amounts of conventional additives such as preservatives, drug penetration solvents and emollients in ointments and creams. The compositions may contain compatible conventional carriers based on creams or ointments and ethanol or oleyl alcohol for wash solutions.

A suitable composition of cream, solution, gel, stick, ointment, spray or aerosol, which can be used with the compounds of formula I or their corresponding pharmaceutically acceptable salts, is conventional and well known in formulations of its kind, e.g. as described in standard text books such as Harry's Cosmeticology, Leonard Hill Books publisher, Remington's Pharmaceutical Sciences and Britisch and US Pharmacopea.

Suitably the content of the compound of formula I or a pharmaceutically acceptable salt thereof in an amount of from about 0.5% to 20% by weight, more preferably from about 1% to about 10%, e.g. 2 to 5%.

The dose of the compound used as a medicament of the invention varies in a conventional manner according to the severity of the disease, the weight of the patient and the relative effect of the compound. In general, unit doses of 0.1 to 1000 mg, such as e.g. 0.5 to 200, 0.5 to 100 or 0.5 to 120 mg, e.g. 0.5, 1, 2, 3, 4 or 5 mg, and this dose is administered more than once a day, e.g. 2, 3, 4, 5 or 6 times a day, preferably 1 or 2 times a day, so that the total daily dose for an adult of 70 kg is in the range of about 0.1 to 1000 mg, i. range from about 0.001 to 20 mg / (kg.day), such as 0.007 to 3, 0.007 to 0.14 or 0.01 to 0.5 mg / (kg.day), e.g. 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.01 to 0.5 mg / (kg.day), e.g. 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1, 0.007 to 0.14 or 0.01 to 0.5 mg / (kg.day) e.g. . 0.01, 0.02, 0.04, 0.05, 0.06, 0.08.1.0 or 0.2 mg / (kg.day), and such therapy may be extended to several weeks or months .

The assays performed to confirm the inhibitory effect of the compounds of formula I on phosphodiesterase IV activity correspond to standard assay procedures as described by Schilling et al. Anal. Biochem. 216, 154 (1994), Thompson and Strada, Adv. Cyc. Nucl. Res. 8, 119 (1979) and Gristwood and Owen, Br. J. Pharmacol. 87: 91P (1986).

The compounds of formula I are effective in an amount appropriate to the treatment of diseases associated with phosphodiesterase IV and a condition corresponding to the above assays.

The ability of the compounds of formula I to inhibit TNF production in human peripheral mononuclear blood cells (PMBC's) was determined by the following procedure. PMBC's were obtained from freshly drawn blood or "Buffy Coats" by standard procedures. Cells were split in RPM11640 + 1% cattle fetal serum in the presence and absence of inhibitor. LPS (lipopolysaccharide (endotoxin), 100 ng / ml) was added and the culture was incubated for 22 h at 37 ° C in an atmosphere of 95% air / 5% CO ₂ . The supernatant was assayed by TNFu by an ELISA (Enzyme-linked Immunosorbent Assay) using commercially available devices.

The procedure described by Mauser et al., Am. Rev. Respir. Dis. 148, 1623 (1993), and Am. J. Respir. Crit. Čare Med. 152,467 (1995).

The pharmacokinetic profile of the compounds of the present invention was determined from blood collected from the right cardiac aorta in rats. For intravenous dosing, the compound has been appropriately adjusted, e.g. 10 vol. % DMSO, 50 vol. % PEG 400 in water, and administration was via cannula into the left jugular vein. Samples were taken at 5 min, 0.5, 1, 2, 4, 6 and 8 h after delivery. For oral dosing, the compound was prepared as 0.4 w / v. % methylcellulose in water. Samples were taken at 0.5, 1, 2, 4, 6 and 8 h after delivery. In some cases, a sample was taken 12 hours after delivery. Plasma was obtained by centrifugation of each blood assay and the compound content after protein precipitation was determined by standard methods such as liquid chromatography mass spectrometry.

The results are shown in the tables below and are also presented in the accompanying drawing.

Example 8 Free base Dose (iv) (mg / kg) 1 1 Dose (po) (mg / kg) 3 3 Cmax (po) (ng / ml) 3054 1008 AUCo-ultra (po) (ng.h / ml) 30169 6860 Ti / ₂ (Mo) (h) 20 4.5

The solubility of the compound of Example 8 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 exemplary compounds have the necessary solubility.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawing is a graphical record showing the PK values obtained after oral administration of a compound of the invention, and the values of the known compound are shown for comparison. The drawing is a graphical representation of PK data after oral administration in rats; PC (plasma concentration, ng / ml) time t (time, h). Represents the compound of Example 8, and the free base. The excellent effect of the novel compound is remarkable.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the present invention.

Intermediate 1

2-trofluórmetylchinolín-8-ol

A solution of 8-methoxy-2-trifluoroquinoline (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 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. The mixture was then extracted with dichloromethane (2 x 100 mL) and the combined organic filtrates were washed with water, dried over sodium sulfate, filtered and the solvent removed in vacuo. The compound (9.3 g) was obtained 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-butylmethylsilyl chloride (8.9 g) and triethanolamine (6.5 g) in dichloromethane was stirred overnight at room temperature. The reaction mixture was washed with water (2 x 50 mL). ml), dried over sodium sulfate, filtered and the solvent removed in vacuo. The title compound (17.9 g) was obtained as a white solid.

M.S. [M + H] 328

The following intermediate was prepared by the same procedure.

Intermediate 3

8- (tert-butyldimethylsilanyloxy) -2-methylquinoline

The title compound was prepared from 8-hydroxyquininaldine (10g) and the compound (17g) was obtained as an orange oil.

TLC R ₍ 0.90 (10% methanol in ethyl acetate)

Intermediate 4

5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline

A solution of 8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylchimoline (17.5 g) in dichloromethane (100 mL) was treated with N-bromosuccinimide (10.5 g) at 15 ° C. The mixture was stirred at 20 ° C for 25 minutes, washed with 1% sodium sulfite solution (100 mL) and water (50 mL). The organic layer was separated, dried over magnesium sulfate and the solvent removed in vacuo. The compound (21.4 g) was obtained as a dark oil.

M.S. [M + H] 406

The following intermediate was prepared by the same procedure.

Intermediate 5

5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-methylquinoline

Prepared from 8- (tert-butyldimethylsilanyloxy) -2-methylquinoline (0.63 g) as a yellow oil (0.66 g).

TLC R _t 0.90 (dichloromethane)

Intermediate 6

5-bromo-2-trifluoromethylquinolin-8-ol

A solution of 5-bromo-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline (21 g) in methane (150 mL) was treated with 37% hydrochloric acid (5 mL) and water (5 mL). The mixture was stirred at room temperature for 12 h and then at 45 ° C for 2 h. The methanol was removed in vacuo and the residue was partitioned with 10% sodium hydroxide solution (100 mL) and dichloromethane (50 mL). The aqueous layer was neutralized with 37% hydrochloric acid to pH 7.2 and extracted with dichloromethane (4 x 50 mL). The combined organic filtrates were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Compound (12 g) was obtained as a cream solid.

M. S. [M +] 292

Intermediate 7

5-bromo-2-methylquinolin-8-ol

To a solution of 5-bromo-8- (tert-butyldimethylsilanyloxy) -2-methylquinoline (16.3 g) in tetrahydrofuran (500 mL) was added dropwise a solution of tetrabutylammonium fluoride (0.1 mol in tetrahydrofuran (54 mL)). Dilute with dichloromethane (750 mL) and wash with water (3 x 250 mL) for 10 minutes, dry the organic solution over magnesium sulfate, filter, and remove the solvent in vacuo to give an orange oil which recrystallized from aqueous methanol to give the title compound (7.65). (g) as a white solid.

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

Intermediate 8

5-bromo-8-difluoromethoxy-2-trifluoromethylquinoline

To a solution of 5-bromo-2-trifluoroquinolin-8-ol (12.0 g) in dioxane (120 mL) was added a solution of 47% sodium hydroxide (12 mL) with stirring. The mixture was warmed to ° C with bubbling chlorodifluoromethane (7.4 g) for 3 hours. On cooling, the mixture was diluted with water (80 mL) and the solvent was removed in vacuo. The resulting slurry was filtered and the precipitate was washed with dichloromethane (50 mL) and water (50 mL). The organic layer was evaporated and the aqueous layer was extracted with 0.5% sodium hydroxide solution (100 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in tert-butyl methyl ester (100 mL), the cloudy solution filtered and the solvent removed in vacuo. The compound (11.7 g) was obtained as a white solid.

M.S. [M + H] + 342

The following intermediate was obtained in the same manner.

Intermediate 9

5-bromo-8-difluoromethoxy-2-methylquinoline

The compound was prepared from 5-bromo-2-methylquinolin-8-ol (0.1 g) and the brown solid obtained was purified by recrystallization from methanol to a white solid (0.96 g). TLC R _t 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 were subjected to a pressure of 7 bar of carbon monoxide in a Parr pressure reactor while heating to 100 ° C for 24 hours. After cooling and aeration, the reactor mixture was partitioned in a solution composed of sodium hydroxide (1.5 g in 50 mL) and tert-butyl methyl ether (100 mL). The combined aqueous extracts were shaken with activated carbon (1.5 g) for 15 minutes and then the solution was filtered. The filtrate was acidified to pH 4 with hydrochloric acid (37%) and the resulting cream precipitate isolated by filtration and washed with water (20 mL). The crude product was purified by recrystallization from toluene to give a cream solid (1.8 g).

M.S. [M + H] 308

The following intermediate was prepared in the same manner.

Intermediate 11

8-Difluoromethoxy-2-methylquinoline-2-carboxylic acid

Prepared from 5-bromo-8-difluoromethoxy-2-methylquinoline (5.72 g) as a brown solid (2.88 g).

TLC R _t 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) was mixed with 4-nitrophenol (0.25 g), 4-dimethylaminopyridine (catalyst) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (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 removed in vacuo. The residue was purified by silica gel column chromatography with dichloromethane as eluent to give the title compound as a cream solid (0.47 g).

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

The following intermediate was prepared in the same manner.

Intermediate 13

8-Difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester.

The ester was prepared from 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (0.50 g). Purification was accomplished by column chromatography on silica gel using 50% ethyl acetate in hexane as eluent to give the resulting yellow material (0.63 g). TLC R _t 0.73 (10% methanol in dichloromethane).

Intermediate 14

8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester

The ester was prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (0.60 g) and the title compound was obtained as a yellow solid (0.75 g).

TLC R _t 0.64 (50% ethyl acetate in hexane)

Intermediate 15 8-Difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-chloropyridin-4-yl) amide

To a stirred solution of 4-amino-3-chloropyridine (136 mg) in Ν, im-dimethylformamide (2 mL) was added sodium hydride (60% dispersion in oil, 42 mg) under nitrogen. The reaction mixture was stirred at room temperature for 1 h. 8-Difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester was then added and stirring continued for 18 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent. A white solid (155 mg) was obtained.

TLC R _t 0.3 (50% ethyl acetate in hexane).

The following intermediates were prepared in the same manner.

Intermediate 16 8-Difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-methylpyridin-4-yl) amide

The amide was prepared from 8-difluoromethoxy-2-methylquinoline-4-carboxylic acid 4-nitrophenyl ester (500 mg) and 4-amino-3-methylpyridine (170 mg). Purification was by column chromatography on silica gel using 10% methanol in dichloromethane to give a pale yellow solid (200 mg).

TLC R _t 0.55 (10% methanol in ethyl acetate).

Intermediate 17 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloropyridin-4-yl) amide

The title compound was prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (466 mg) and 4-amino-3-chloropyridine (283 mg). Purification was by column chromatography on silica gel using% ethyl acetate in dichloromethane as eluent to give a white solid (297 mg).

TLC R t 0.26 (16 = ethyl acetate in dichloromethane).

Intermediate 18 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloropyridin-4-yl) amide

8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (480 mg) and 4-amino-3,5-dichloropyridine (360 mg) were used. Purification was carried out by column chromatography on silica gel using 20% ethyl acetate in hexane as eluent to give a white solid (424 mg).

TLC R _t 0.42 (20% ethyl acetate in hexane).

Intermediate 19 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoropyridin-4-yl) amide

Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid nitrophenyl ester (390 mg) and 4-amino-3,5-difluoropyridine (120 mg). Purification was accomplished by column chromatography on silica gel using 10% methyl acetate in dichloromethane as eluent to give a white solid (180 mg).

TLC R _t 0.27 (15% ethyl acetate in dichloromethane).

Intermediate 20 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoropyridin-4-yl) amide

Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (425 mg) and 4-amino-3,5-difluoropyridine (285 mg). Purification was performed by column chromatography on silica gel eluting with 5% methanol in dichloromethane. The compound was obtained as a white solid (162 mg).

TLC R _t 0.34 (5% methanol in dichloromethane).

Intermediate 21 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloropyridin-4-yl) amide

Under stirring and under a nitrogen atmosphere, sodium hydride (60% dispersion in oil, 52 mg) was added to a solution of 4-amino-3-chloropyridine (124 mg) in Ν, Ν-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 1 h. Then 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (360 mg) was added and stirring was continued for 18 h. The solvent was then removed in vacuo and the residue was partitioned in a mixture of ethyl acetate (2 x 50 mL) and water (50 mL). The organic layer was separated, filtered and the solvent removed in vacuo. Purification was performed by column chromatography on silica gel using ethyl acetate as eluent to give a light pink solid (330 mg).

TLC _Rt 0.41 (ethyl acetate).

The following intermediate was prepared in the same manner.

Intermediate 22 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methylpyridin-4-yl) amide

Prepared from 8-methoxy-2-trifluoromethylquinoline-4-carboxylic chloride (430 mg) and 4-amino-3-methylpyridine (170 mg). Purification was accomplished by column chromatography eluting with 10% methanol in ethyl acetate to give a white solid (160 mg).

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

Intermediate 23 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (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 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 a white solid.

To a stirred solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) in dichloromethane (40 mL) was added triethanolamine (0.68 mg) and 4-amino-3-methylpyridine (325 mg) under a nitrogen atmosphere. The reaction mixture was stirred for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 5% methanol in dichloromethane to give a pale white solid (563 mg).

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

The following intermediate was prepared in the same manner.

Intermediate 24 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dimethylpyridin-4-yl) amide

The compound was prepared from 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (500 mg) and 4-amino-3,5-dimethylpyridine (210 mg). Purification was accomplished by trituration in acetone and ether to give a pale yellow solid (82 mg).

TLC R _t 0.42 (10% methanol in dichloromethane with 1% ammonium hydroxide).

Example 1 8-Difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-chloro-1-oxypyriden-4-yl) amide

Peracetic acid (36 to 40% in acetic acid, 0.1 ml) was 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 mixture was diluted with dichloromethane (20 mL) and washed with water (20 mL). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a white solid. Purification was accomplished by column chromatography using 10% methanol in ethyl acetate as eluent to give a white solid (25 mg).

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

Mp 244 ° C.

The following examples were carried out in the same manner.

Example 2 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide

Prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid and (3-chloropyridin-4-yl) amide (261 mg) to give a cream solid (223 mg).

TLC R _t 0.4 (ethyl acetate).

Melting point 212-213 ° C.

Example 3 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide

Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloropyridin-4-yl) amide (50 mg) to give a white solid (25 mg). TLC R _t 0.7 (10% methanol in ethyl acetate).

Mp 261.5-262.5 ° C.

Example 4 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoro-1-oxypyridin-4-yl) amide

The compound was prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoropyridin-4-yl) amide (120 mg) with stirring at room temperature for 2 weeks. During this time, excess peracetic acid (4 x 0.5 mL) was added. Purification was accomplished by column chromatography eluting with 5-10% methanol in dichloromethane to give a yellow solid (28 mg).

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

Melting point 268-269 ° C.

Example 5 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoro-1-oxypyridin-4-yl) amide

The compound was prepared from 8-difluoromethoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-difluoropyridin-4-yl) amide (160 mg) with stirring at room temperature for 2 weeks. During this time, excess peracetic acid (3 x 0.1 mL) was added. Purification was carried out by column chromatography using 15% ethyl acetate in dichloromethane, increasing the methanol to 10% in dichloromethane to give a yellow solid (120 mg).

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

Melting point 219-220 ° C.

Example 6 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide

The compound was prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methylpyridin-4-yl) amide (316 mg) by stirring in the presence of peracetic acid (2 x 0.18 mL) for two days. Purification was performed by column chromatography using 10% methanol in dichloromethane as eluent to give a white solid (267 mg).

TLC R _t 0.25 (10% methanol in dichloromethane).

Melting point 210-212 ° C.

Example 7 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dimethyl-1-oxypyridin-4-yl) amide

The compound was prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dimethylpyridin-4-yl) amide (56 mL) by stirring in the presence of peracetic acid (2 x 0.05 mL) for two days. Purification was accomplished by column chromatography using 1% ammonium hydroxide and 10% methanol in dichloromethane to give a white solid (37 mL).

TLC R _t of 0.22 (1% ammonium hydroxide and 10% methanol in dichloromethane).

Mp 237-239 ° C.

Example 8 8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-pyridin-4-yl) -amide 8-methoxy-2-trifluoromethyl-quinoline (3,5-dichloro-1-oxypyridin-4-yl) -amide The -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. In addition, peracetic acid (0.1 mL) was added and the reaction was heated for an additional 2 days. Purification was accomplished by column chromatography using 10% methanol in ethyl acetate as eluent to give a white solid (123 mg).

TLC R _t 0.17 (10% methanol in ethyl acetate).

Melting point 280-281 ° C.

Example 9 8-Difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide

Prepared from 8-Difluoromethoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-pyridin-4-yl) -amide (415 mg) in the same manner as (3,5-dichloro-1-oxypyridin-4-yl) -amide 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid. Purification was performed by column chromatography using 1% ammonium hydroxide and 10% methanol in dichloromethane as eluent to give the title compound (360 mg) as a cream solid.

TLC R _t 0.5 (1% ammonium hydroxide and 10% methanol in dichloromethane).

Mp 244-245 ° C.

Example 10 (3-Ethyl-1-oxypyridin-4-yl) and 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid mide

While stirring, sodium hydride (60% oil dispersion, 0.11 g) was added to a solution of 3-methyl-1-oxypyridin-4-ylamine (0.2 g) in, /, Λ / dimethylformamide (10 mL) under nitrogen. at room temperature in the presence of a molecular sieve. After stirring for 1 hour, 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester was added and the reaction was stirred overnight. The solvent was removed in vacuo and the residue partitioned in ethyl acetate (50 mL) and water 2 x 50 mL. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was washed with a small amount of ethyl acetate and dried to give a light yellow solid.

TLC R _t 0.27 (1% triethylamine and 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

To a suspension of 3-methyl-1-oxypyridin-4-ylamine (0.23 mg) in dichloromethane (40 mL) was added triethylamine (0.55 mL) and 4-dimethylaminopyridine (catalysis) under stirring at room temperature under nitrogen. 8-Methoxy-2-trifluoromethylquinoline-5-carbonyl chloride hydrochloride (0.6 g) was added and the reaction 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 organic phase precipitate was filtered and dried under vacuum at 45 ° C to give a white solid.

TLC _Rt 0.12 (ethyl acetate).

Melting point 249.5-250.5 ° C.

Claims (10)

PATENT CLAIMS A compound of formula I o in which R ¹ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃ , R ² is CH 3 or CF 3 R ³ is F, Cl, Br, CN or CH 3 and R ⁴ is H, F, Cl, Br, CN or CH ₃ , or a pharmaceutically acceptable salt thereof. A compound according to claim 1, selected from 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide, (3-chloro-1-oxypyridin-4-yl) acid amide 8-difluoromethoxy-2-trifluoromethylquinoline 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide 8-methoxy-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide 8-Difluoromethoxy-2 trifluoromethylquinoline-5-carboxylic acid (3,5-difluoro-1-oxypyridin-4-yl) amide, 2-trifluoromethylquinoline-5-carboxylic acid, (3-methyl-1-oxypyridin-4-yl) amide 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid, (3,5-dimethyl-1-oxypyridin-4-yl) amide 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid, (3,5-dichloro-1-oxypyridin-4) -yl) 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid amide, (3,5-Dichloro-1-oxypyridin-4-yl) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid amide, (3-methyl-1-oxypyridine) 4-yl) 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid amide, and 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide. The compound according to claim 1, which is 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide. The use of any compound according to the preceding claims for the preparation of a medicament for the treatment of disease states that may be affected by inhibitory activity against phosphodiesterase IV or tumor necrosis factor, or a pathological condition mediated by phosphodiesterase IV, eosinophil accumulation or eosinophil action. Use according to claim 4, characterized in that the disease state is an inflammatory disease or an autoimmune disease. Use according to claim 4, characterized in that the disease state is from the group of diseases: asthma, chronic bronchitis, chronic pulmonary inflammatory disease, chronic respiratory obstructive diseases, atopic dermatitis, allergic mucosal inflammation, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, ulcerative colitis, Crohn's disease, necrosis disease, atopic eczema, atopic eczema, atopic eczema inflammatory bowel disease. Use according to claim 4, characterized in that the disease state belongs to the group: urticaria, conjunctivitis, allergic conjunctivitis, eye inflammation, eye inflammation, allergic eye reactions, eosinophilic granuloma, arthritic gout and other arthrosis, adult respiratory distress syndrome, diabetes, anorexia, keratositis, cerebral senility, multi-infarct dementia, senile memory with Parkinson's disease, depression, cardiac arrest, intermittent writhing, rheumatic spondylitis, osteoarthritis, ft sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, sclerosis, siccosis, sicosis host cleavage, tissue rejection, fever caused by infection or muscle pain, malaria, HIV, AIDS, ARC, cachexia, scarring, scar tissue formation, fever, systemic erythematous ulcer, type 1 diabetes, Bechet's disease, anaphytoid purple, anaphytoid purpura chronic glomerular nephritis, leukemia, discinesia, yeast or fungal infection, conditions requiring digestive tract protection, and neurogenic inflammatory disease associated with irritation and pain. Use according to claim 4, characterized in that the disease state is asthma. Use according to claim 5, characterized in that the disease state is chronic obstructive airway insufficiency or chronic bronchitis. Use according to any one of claims 4 to 9, characterized in that the compound is defined in claim 3. Methods for describing cyclic substituted amides. 1. The compounds will be named as a substituted amide, R ² and R ³ are prefixes. The process is suitable when R ¹ and the R ¹ CO type acetyl radical are more complex than the R ² group, or R ¹ and R ² in the amino residue. E.g. N-ethyl-N-methylamide-8-quinoline carboxylic acid, or N-ethyl-N-methyl-8-quinolinecarboxamide 2. The acyl group is indicated as the N-base substituent Suitably, R1 is less complex E.g. 3-formyldiazolimid 3. For N-monosubstituted amides of the formula R ¹ CONHR ² , the group R ¹ CPNH may be considered as a substituent in HR ² , then the name is formed by converting the amide end to amido or carboxamide to carboxamido Napr. 7-cyclohexane-3-dibenzofuran 4. N-substituted amides of the formula R @ ¹ CONR @ ² R @ ³ : the previous procedure is used, in which case less complex groups are named as an amido substituent with the NNapr locant. (7-ethylacetamido) -3-dibenzofuranic acid Processes 3 and 4 are particularly suitable if the R ¹ group in the acyl radical R'CO- is less complex than the groups R ² and R ^{3 of the} amino radical R ² -NH- or R ² R ^3a and cannot be used for derivatives cyclic bases 5. The name anilide is reserved for phenolic residues. Accordingly, only nomenclature according to Group 1 is applicable. Eng. original: 8-Methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide In Czech. according to 8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide or (3,5-dichloro-1-oxypyridin-4-yl) -8 -methoxy-2-trifluoromethylquinoline-5-carboxamide; according to 4 [(3,5-dichloro-1-oxypyridin-4-yl) amido] -8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid Names according to 2 and 3 are not eligible.