KR20010033842A - N-oxides of heterocyclic compounds with tnf and pde-iv inhibiting activity - Google Patents

Abstract

N-oxides of formula (I) and pharmaceutically acceptable salts thereof are useful as therapeutic agents, for example as therapeutic agents for inflammatory diseases.

Wherein R ₁ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ,

R ₂ is CH ₃ or CF ₃ ,

R ₃ is fluorine, chlorine, bromine, CN or CH ₃ ,

R ₄ is hydrogen, fluorine, chlorine, bromine, CN or CH ₃ .

Description

N-OXIDES OF HETEROCYCLIC COMPOUNDS WITH TNF AND PDE-IV INHIBITING ACTIVITY

European Patent Application No. A-0498722 discloses quinoline derivatives as angiotensin A ₂ (angiotensin A ₂₎ and endothelin inhibitors (endothelin inhibitors).

The mode of action of phosphodiesterase and also tumor necrosis factor (TNF) and therapeutic utility of its inhibitors are described in WO 97/44036 and US Pat. No. 5804588, the contents of which are incorporated herein by reference. These publications describe quinoline carboxamides in particular having inhibitory activity.

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

1 is a graph showing pK data of compounds of the invention and known compounds as a comparison after oral administration of rats.

The present invention provides novel compounds for the treatment of disease states which involve therapeutic utility, in particular proteins which mediate cellular activity, eg, by inhibition of TNF and / or PDE IV. The compound according to the present invention is a compound represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

In the above formula, R ₁ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ,

R ₂ is CH ₃ or CF ₃ ,

R ₃ is fluoro, chlorine, fluorine, CN, or CH ₃ ,

R ₄ is hydrogen, fluoro, chlorine, fluorine, CN or CH ₃ .

In summary, the compounds of the present invention are N-oxides of the corresponding free bases which are specifically described in WO 97/44036. The novel compounds of the present invention have good solubility, improved metabolic stability and improved pharmacokinetics. Especially preferred are the compounds of Example 8.

The present invention also provides a method of mediating or inhibiting the enzymatic or catalytic activity of PDE IV in a mammal, and a method of inhibiting TNF production in a mammal, the method comprising Effective amount of the compound of formula I) or a pharmaceutically acceptable salt thereof.

Some of the compounds of formula (I) containing basic groups form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic acid addition salts such as sulfates, nitrates, phosphates, borates, hydrochlorides and bromates, and acetates, tartarates, maleates, citrates, succinates, benzoates, ascorbates, methanesulfones Pharmaceutically acceptable organic acid addition salts such as acid salts, α-ketoglutarate, α-glycerophosphate and glucose-1-phosphate. Pharmaceutically acceptable salts of compounds of formula (I) were prepared by conventional methods.

Compounds of the invention can be prepared by N-oxidation of the corresponding free base. The free base is known or can be prepared by the method described in WO 97/44036. For example, the compound of general formula (I) can be prepared by treating the free base with peracetic acid in acetic acid or hydrogen peroxide in acetic acid in a suitable solvent such as chloroform.

The present invention encompasses the prevention and treatment of TNF-mediated diseases or disease states, which disease conditions cause, but are not limited to, the production of TNFs themselves, or the release of TNFs leading to the release of other cytokines such as IL-1 or IL-6. By all means the disease state by the action of TNF. Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to TNF can be regarded as a disease state mediated by TNF. TNF-β (also known as lymphotoxin) has a similar structure and homology to TNF-α (also known as cachectin), each of which induces a similar physiological response and binds to the same cellular receptor Because of this, TNF-α and TNF-β are inhibited by the compounds of the present invention and therefore are collectively referred to herein as "TNF" unless stated otherwise.

PDE IV inhibitors include asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, ophthalmitis, allergic reactions of the eye, eosinophil granulomatosis, psoriasis, Behcet's disease, erythema, Anaphylactic purulent nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritis abnormalities such as rheumatoid spondylitis and osteoarthritis, sepsis shock, ulcerative colitis, Crohn's disease, perfusion damage of myocardium and brain, chronic glomerulonephritis, It is useful for the treatment of various allergic and inflammatory diseases, including endotoxin shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful for the treatment of abnormal conditions associated with cerebral metabolic inhibition such as diabetes insipidus and cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia. PDE IV inhibitors are also useful for abnormal conditions that are ameliorated by neuroprotective actions such as cardiac arrest, stroke and intermittent claudication. In addition, PDE IV inhibitors may have utility as gastroprotective agents. A particular embodiment of the treatment methods of the invention is the treatment of asthma.

Viruses contemplated for treatment herein are those that are sensitive to inhibition, such as producing TNF as a result of infection, or reducing replication, directly or indirectly, by a TNF inhibitor of Formula (I). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and herpes virus groups such as but not limited to shingles or herpes simplex. .

More particularly, the present invention relates to a method of treating a mammal suffering from human immunodeficiency virus (HIV), which method comprises an effective TNF of a compound of formula (I) or a pharmaceutically acceptable salt thereof in said mammal. Administering an inhibitory amount.

The compounds of the present invention can also be used in connection with veterinary treatment of animals other than humans in need of inhibiting TNF production. Therapeutic and prophylactically, TNF related diseases for treatment in animals include those described above, in particular disease states such as viral infections. Such viruses include, but are not limited to, feline immunodeficiency virus (FIV), or other retroviruses, such as equine infectious anemia virus, goat arthritis virus, visna virus, maddi virus and other lentiviruses. Viral infections.

The compounds of the present invention are also useful for parasitic, yeast and fungal infections, such yeasts and fungi being susceptible to upregulation by TNF or inducing TNF production in vivo. Preferred disease states of treatment are fungal meningitis.

The compound of formula (I) is preferably a pharmaceutically acceptable form. A pharmaceutically acceptable form means a pharmaceutically acceptable level of purity that excludes common pharmaceutical additives, especially diluents and carriers, and contains no toxicity-related substances at normal dosage levels. Pharmaceutically acceptable levels of purity are generally at least 50%, preferably at least 75%, more preferably at 90% and still more preferably at 95%, excluding common pharmaceutical additives. As used herein, the term “pharmaceutically acceptable” includes materials suitable for both human and veterinary use.

The compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, as required, is administered as such or preferably as a pharmaceutical composition consisting of a pharmaceutically acceptable carrier. Can be.

Accordingly, the present invention provides a pharmaceutical composition consisting of a compound of formula (I), as necessary or pharmaceutically acceptable salts thereof and / or pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable carriers.

The active compound may be formulated for administration in a suitable route, in a preferred route depending on the disease in need of treatment, preferably in a unit dosage form or in which a human patient can be administered directly to itself in a single dose. Form. Advantageously, the composition is suitably via oral, rectal, topical, parenteral administration or respiratory tract. The medicament may be designed to release the active ingredient slowly.

As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats and the like, the compounds of the present invention are effective for the treatment of humans.

The compositions of the present invention may be tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, regenerative powders, or solutions such as oral or bactericidal parenteral solutions or suspensions. . Topical formulations may also be considered as needed.

In order to achieve consistency of administration, the compositions of the present invention are preferably in the form of unit doses. Unit dosage forms for oral administration may be tablets and capsules, for example binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; Fillers such as microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; For example, tablet lubricants, such as magnesium stearate salt; For example, disintegrants, such as starch, polyvinylpyrrolidone, sodium starch glycolate, or microcrystalline cellulose; Or conventional excipients such as pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid oral compositions can be formulated by conventional methods such as blending, filling, tableting, and the like. Repeated blending operations can be used to distribute the active ingredient throughout the composition using a large amount of filler.

This is, of course, common in the art. Tablets may be coated according to methods well known in the general pharmaceutical art, in particular with enteric coatings.

Oral solutions may be, for example, emulsions, syrups or elixirs, or may be present as a dry product which is reconstituted with water or other suitable excipients prior to use. Such solutions include suspending agents (e.g., sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats), emulsifiers (e.g. lecithin, sorbate). Non-aqueous monooleate, or gum arabic), water-insoluble excipients (which may include edible oils, for example oily esters such as almond oil, fractionated coconut oil, esters of glycerin), propylene glycol, or ethyl alcohol, Preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid) and, if necessary, conventional additives such as common flavors or coloring agents.

The composition may be suitably formulated for administration to the respiratory tract as an inhalation agent or aerosol or nebulizer liquid, or as an inhalation micropowder, alone or in combination with an inert carrier such as lactose. In this case, the particles of the active compound have a diameter of less than 50 μm, for example 0.1-50 μm, preferably less than 10 μm, for example 1-10 μm, 1-5 μm or 2-5 μm. It is desirable to have. If necessary, for example, sympathetic nerve-acting amines such as isoprenin, isoetarine, salbutamol phenylephrine and ephedrine, corticosteroids such as prednisolone, adrenal stimulants such as ACTH, and other anti-asthmatic agents It may include small amounts of bronchodilators.

For parenteral administration, liquid unit dosage forms may be formulated with compounds and sterile excipients, which may be suspended or dissolved in the excipient, depending on the concentration used. In solution, the compounds may be dissolved in water for injection and filtered sterilized prior to filling and sealing in suitable vials or ampoules.

It may be advantageous to dissolve adjuvant such as local anesthetics, preservatives and buffers in excipients. To increase stability, the composition can be frozen after filling the vial and water can be removed under vacuum. Parenteral suspensions can be formulated in substantially the same manner, except that the compounds are suspended in excipients instead of solubilizing, and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide prior to suspension in sterile excipients. It is advantageous to include surfactants or wetting agents in the composition to promote uniform distribution of the compound.

The composition may contain 0.1 to 99% by weight of active substance, preferably 10 to 60% by weight, depending on the method of administration.

The compound of formula (I), if desired, a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof may also be administered as a topical formulation in admixture with conventional topical excipients.

Topical formulations can be formulated, for example, as ointments, creams or lotions, saturated dressings, gels, gel sticks, sprays and aerosols, and preservatives and softeners which aid in drug penetration in ointments and creams. It may contain a suitable conventional additives such as. The formulations may contain a cream or ointment base and conventional compatible carriers such as ethanol or oleyl alcohol for lotion.

Suitable creams, lotions, gels, sticks, ointments, sprays or aerosols that can be used for the compounds of formula (I) and, if desired, pharmaceutically acceptable salts thereof, are conventionally well known in the art. Formulations, for example, conventional formulations as described in standard textbooks such as Harry's Cosmeticology, Remington's Pharmaceutical Sciences, published by Leonard Hill Books, and British and American Pharmacopoeia.

The compound of formula (I) or, if necessary, a pharmaceutically acceptable salt thereof is about 0.5 to 20% by weight, preferably about 1 to 10% by weight, for example 2 to 5% by weight of the formulation. .

The dosage of the compound used in the treatment of the present invention will vary in a conventional manner due to the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guideline, suitable unit dosages are 0.1-1000 mg, for example 0.5-200 mg, 0.5-100 mg or 0.5-10 mg, and for example 0.5, 1, 2, 3, 4, or 5 mg, and such unit dose may be administered at least once a day, for example, twice, three, four, five or six times a day, preferably once or twice a day , The total daily dose of an adult (70 kg) is in the range of about 0.1 to 1000 mg, ie about 0.001 to 20 mg / kg / day, for example 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 ˜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 can be extended for weeks or months.

Analytical Method

Assays used to confirm the phosphodiesterase IV inhibitory activity of the compounds of formula (I) are described in Anal. Biochem. 216: 154 (1994), Adv. Of Thompson and Strada. Cycl. Nucl. Res. 8: 119 (1979) and Br. Of Gristwood and Owen. J. Pharmacol. Standard analysis method described on p. 87:91 (1986).

Compounds of formula (I) showed activity at levels consistent with what is believed to be useful for the treatment of phosphodiesterase IV associated with disease states in this assay.

The ability of compounds of formula (I) to inhibit TNF production in human peripheral blood mononuclear cells (PMBC's) was measured as follows. PMBC's were prepared from freshly collected blood or "Buffy coats" by standard methods. Cells were plated in RPMI1640 + 1% fetal calf serum with or without inhibitor. LPS (Lipopolysaccharide (endotoxin); 100 ng / ml) was added and the culture was incubated for 22 hours at 37 ° C. in an atmosphere of 95% air / 5% CO ₂ . Supernatants were tested for TNFα by ELISA (enzyme-linked immunosorbent assay) using commercially available kits.

Abbreviations

Activity in the guinea pig lung model is described in Mauser et al. Rev. Respir. Dis. 148: 1623 (1993) and Am. J. Respir. Crit. Care Med. 152: It measured using the method as described in 467 (1995).

The pharmacokinetic profile of the compounds of the invention was determined in rats with cannula in the right carotid artery for blood collection. For intravenous administration, the compound was treated with a suitable formulation, for example 10 v / v% DMSO, 50 v / v% PEG 400 in water, and administration was by cannulation of the left jugular vein. Samples were collected at 5 minutes, 0.5, 1, 2, 4, 6 and 8 hours after dosing. For oral administration, the compounds were formulated in a suitable formulation, for example 0.4 w / v% methylcellulose in water. Samples were collected at 0.5, 1, 2, 4, 6 and 8 hours after dosing. In some cases, samples were collected 12 hours after dosing. Each blood sample was centrifuged to obtain plasma, and drug concentrations were then determined using standard methods such as liquid chromatography, followed by liquid chromatography-mass spectrometry.

The results are shown in the table below, and also shown in FIG. 1. 1 is a graph of PK data after oral administration of rats, where PC (plasma concentration; ng / ml) was plotted against t (hour; hrs). In the drawings, o indicates the compound of Example 8, o indicates the free base. In the above results, the superiority of the novel compounds of the present invention was demonstrated.

Example 8 Free base Dosage (iv) (mg / kg) One One Dose (po) (mg / kg) 3 3 Cmax (po) (ng / ml) 3054 1008 AUC _0-last (po) (ng.h / ml) 30169 6860 t _1/2 (po) (h) 20 4.5

The solubility of the Example 8 compound in water at pH 7 was 0.2 mg / ml. Under the same condition, the solubility of the corresponding free base was 0.002 mg / ml. Other exemplified compounds exhibited preferred solubility.

The present invention has been described in the following examples.

Intermediate 1 2-trifluoromethylquinolin-8-ol

A solution of 8-methoxy-2-trifluoromethylquinoline (10.0 g) in 48% hydrobromic acid (40 ml) was stirred overnight under reflux. 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), 37% hydrochloric acid solution was added to the aqueous layer and acidified to pH 5.3. The mixture is then extracted with dichloromethane (2 x 100 ml), the combined organic extracts are washed with water, dried over sodium sulfate, filtered and the solvent is removed in vacuo to give the title compound (9.3 g) as a white solid. Got.

M.S. [M + H] 214

Intermediate 2 8- (Tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline

A solution of 2-trifluoromethylquinolin-8-ol (11.5 g), tert-butyldimethylsilylchloride (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 removed in vacuo to give the title compound (17.9 g) as a white solid.

M.S. [M + H] 328

The following intermediates were prepared in a similar manner.

Intermediate 3 8- (Tert-butyldimethylsilanyloxy) -2-methylquinoline

Prepared from 8-hydroxyquinaldine (10 g) to give the title compound (17 g) as an orange oil.

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

Intermediate 4 5-Bromo-8- (tert-butyldimethylsilanyloxy) -2-trifluoromethyl

Quinoline

A solution of 8- (tert-butyldimethylsilanyloxy) -2-trifluoromethylquinoline (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 and washed with 1% sodium sulfite solution (100 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield the title compound (21.4 g) as a black oil.

M.S. [M + H] 406

The following intermediates were prepared 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 title compound (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) was added 37% hydrochloric acid solution (5 ml) and water (5 ml). ). The mixture was stirred at rt for 12 h and at 45 ° C. for 2 h. 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 to pH 7.2 with 37% hydrochloric acid solution 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 yield the title compound (12 g) 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) tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 54 ml ), The solution was added dropwise and treated. The mixture was 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 removed in vacuo to give an orange oil. Recrystallization from aqueous methanol solution gave the title compound (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-trifluoromethylquinoline-8-ol (12.0 g) in dioxane (120 ml) was added 47% sodium hydroxide solution (12 ml). The mixture was heated to 78 ° C., and chlorodifluoromethane (7.4 g) was added to react for at least 3 hours to foam. After cooling, the mixture was diluted with water (80 ml) and the solvent was removed in vacuo. The resulting slurry was filtered and the filter cake was washed with dichloromethane (50 ml) followed by 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, filtered and the solvent removed in vacuo. The residue was taken up in tert-butyl methyl ether (100 ml) and the cloudy solution was filtered off and the solvent was removed in vacuo to give the title compound (11.7 g) as an off-white solid.

M.S. [M + H] 342

The following intermediates were prepared 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. This solid was purified by recrystallization with methanol to give the title compound (0.96 g) as an off-white solid.

TLC R _f 0.86 (50% ethyl acetate in hexanes)

Intermediate 10 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid

5-bromo-8-difluoromethoxy-2-trifluoromethylquinoline (6.0 g), triphenylphosphine (0.3 g), bis (triphenylphosphine) palladium in tetrahydrofuran (50 ml) -A mixture of (II) (0.15 g), 47% aqueous sodium hydroxide solution (4.5 g) and water (12 ml) was clarified using carbon monoxide at 7 bar in a Parr pressure reactor. It was heated at 100 ° C. for 24 hours. After cooling and venting, 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 x 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 with 37% hydrochloric acid solution and the resulting creamy precipitate was isolated by filtration and washed with water (20 ml). The crude title compound was purified by recrystallization with toluene to give the title compound (1.8 g) as a cream solid.

M.S. [M + H] 308

The following intermediates were prepared 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 title compound (2.88 g) as a brown solid.

TLC Rf 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 added with 4-nitrophenyl (0.25 g), 4-dimethylaminopyridine (catalyst). ) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.35 g) and the mixture was stirred at rt for 12 h. The reaction was washed with water (50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography eluting with dichloromethane to afford the title compound (0.47 g) as a cream solid.

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

The following intermediates were prepared in a similar manner.

Intermediate 13 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid

4-nitrophenyl ester

The title compound was prepared from 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (0.50 g). Purification by silica column chromatography eluting with 50% ethyl acetate in hexanes gave the title compound (0.63 g) as a yellow solid.

TLC R _f 0.73 (10% methanol in dichloromethane)

Intermediate 14 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

4-nitrophenyl ester

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

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

Intermediate 15 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid

(3-chloropyridin-4-yl) amide

Under a nitrogen atmosphere, sodium hydride (60% dispersion in oil, 42 mg) was added to a stirred solution of 4-amino-3-chloropyridine (136 mg) in N, N-dimethylformamide (2 ml). The reaction mixture was stirred for 1 hour at room temperature. 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 by silica column chromatography eluting with 50% ethyl acetate in hexanes to give the title compound (155 mg) as a white solid.

TLC R _f 0.3 (ethyl acetate in 50% hexanes)

The following intermediates were prepared in a similar manner.

Intermediate 16 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid

(3-methylpyridin-4-yl) amide

The title compound was prepared from 8-difluoromethoxy-2-methylquinoline-4-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 gave the title compound (200 mg) as a pale yellow solid.

TLC R _f 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 by silica column chromatography eluting with 15% ethyl acetate in dichloromethane gave the title compound (297 mg) as a white solid.

TLC R _f 0.26 (15% ethyl acetate in dichloromethane)

Intermediate 18 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-dichloropyridin-4-yl) amide

The title compound is prepared from 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (480 mg) and 4-amino-3,5-dichloropyridine (360 mg) did. Purification by silica column chromatography eluting with 20% ethyl acetate in hexanes gave the title compound (424 mg) as a white solid.

TLC R _f 0.42 (20% ethyl acetate in hexane)

Intermediate 19 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-difluoropyridin-4-yl) amide

The title compound was converted to 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (390 mg) and 4-amino-3,5-difluoropyridine (120 mg). From. Purification by silica column chromatography eluting with 10% ethyl acetate in dichloromethane gave the title compound (180 mg) as a white solid.

TLC R _f 0.27 (15% ethyl acetate in dichloromethane)

Intermediate 20 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-difluoropyridin-4-yl) amide

The title compound is prepared from 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid 4-nitrophenyl ester (425 mg) and 4-amino-3,5-difluoropyridine (282 mg) did. Purification by silica column chromatography eluting with 5% methanol in dichloromethane gave the title compound (162 mg) as a white solid.

TLC R _f 0.34 (5% methanol in dichloromethane)

Intermediate 21 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3-chloropyridin-4-yl) amide

Under a nitrogen atmosphere, sodium hydride (60% dispersion in oil, 52 mg) was added to a stirred solution of 4-amino-3-chloropyridine (124 mg) in N, N-dimethylformamide (5 ml). The reaction mixture was stirred at rt for 1 h. 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 x 50 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by silica column chromatography eluting with ethyl acetate gave the title compound (330 mg) as a pale pink solid.

TLC R _f 0.41 (ethyl acetate)

mp 192-194 ℃

The following intermediates were prepared in a similar manner.

Intermediate 22 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3-methylpyridin-4-yl) amide

The title compound was 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 title compound (160 mg) as a white solid.

TLC R _f 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 g) in dichloromethane (30 ml) was stirred at room temperature under a nitrogen atmosphere. Oxalyl chloride (0.28 ml) was added, followed by addition of N, N-dimethylformamide (1 drop) and continued stirring overnight. The solvent was removed in vacuo to afford 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) as off-white solid.

To a stirred solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) in dichloromethane (40 ml) under nitrogen atmosphere, triethylamine (0.68 ml) and 4-amino- 3-methylpyridine (352 mg) was added. The reaction mixture was stirred for 128 h. The solvent was removed in vacuo and the resulting residue was purified by silica column chromatography eluting with 5% methanol in dichloromethane to afford the title compound (563 mg) as a pale white solid.

TLC R _f 0.53 (10% methanol in dichloromethane)

The following intermediates were prepared in a similar manner.

Intermediate 24 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-dimethylpyridin-4-yl) amide

The title compound was prepared from 8-methoxy-2-trifluoromethylquinoline-4-carbonyl chloride (500 mg) and 4-amino-3,5-dimethylpyridine (210 mg). Treatment and purification with acetone and ether gave the title compound (82 mg) as a pale yellow solid.

TLC R _f 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) was subjected to 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-chloropyridin-4-yl) amide in chloroform (10 ml) at room temperature. (50 mg) was added to the solution. After stirring overnight, the reaction was diluted with dichloromethane (20 ml) and washed with water (20 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo to give a white solid. This was purified by column chromatography eluting with 10% methanol in ethyl acetate to give the title compound (25 mg) as a white solid.

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

mp 244 ° C (dec.)

The following examples were made in a similar 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 (3-chloropyridin-4-yl) amide (261 mg) to give the title compound (223 mg) as a cream solid. Got it.

TLC R _f 0.4 (ethyl acetate)

mp 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 the title compound (25 mg) as an off-white solid.

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

mp 261.5-262.5 ℃

Example 4 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-difluoro-1-oxypyridin-4-yl) amide

Add excess peracetic acid (4 x 0.5 ml) to 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoropyridin-4-yl) amide (120 mg) The mixture was stirred at room temperature for 2 weeks to obtain a product. This was purified by column chromatography eluting with 5-10% methanol in dichloromethane to afford the title compound (28 mg) as a yellow solid.

TLC R _f 0.09 (5% methanol in dichloromethane)

mp 268-269 ° C. (dec.)

Example 5 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-difluoro-1-oxypyridin-4-yl) amide

Excess peracetic acid (3 x 0.1 ml) in 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoropyridin-4-yl) amide (160 mg) Was added and stirred for 2 weeks at room temperature to give the product. This was purified by column chromatography eluting with 15% ethyl acetate in dichloromethane and 10% methanol in dichloromethane to afford the title compound (120 mg) as a yellow solid.

TLC R _f 0.69 (2% methanol in dichloromethane)

mp 219-220 ℃

Example 6 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3-methyl-1-oxypyridin-4-yl) amide

The title compound was stirred for 2 days in the presence of peracetic acid (2 x 0.18 ml) 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methylpyridin-4-yl) amide (316 mg). This was purified by column chromatography eluting with 10% methanol in dichloromethane to afford the title compound (267 mg) as a white solid.

TLC R _f 0.25 (10% methanol in dichloromethane)

mp 210-212 ℃

Example 7 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-dimethyl-1-oxypyridin-4-yl) amide

The title compound was stirred for 2 days in the presence of peracetic acid (2 × 0.05 ml) 8-methoxy-2-trifluoromethylquinolin-5-carboxylic acid (3,5-dimethylpyridin-4-yl) amide (56 mg). This was purified by column chromatography eluting with 1% ammonium hydroxide / 10% methanol in dichloromethane to afford the title compound (37 mg) as a white solid.

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

mp 237-239 ℃

Example 8 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-dichloro-1-oxypyridin-4-yl) amide

8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloropyridin-4-yl) amide (200 mg) was added peracetic acid (36-40% in acetic acid, 0.1 ml in chloroform) Was stirred at 50 ° C. for 5 days in the presence of). Further peracetic acid (0.1 ml) was added and the reaction heated for 2 more days. This was purified by column chromatography eluting with 10% methanol in ethyl acetate to give the title compound (123 mg) as a white solid.

TLC R _f 0.17 (10% methanol in ethyl acetate)

mp 280-281 ℃

Example 9 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid

(3,5-dichloro-1-oxypyridin-4-yl) amide

The title compound was purified by 8-difluoromethoxy-2 in a similar manner as 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide. Prepared from -trifluoromethylquinoline-5-carboxylic acid (3,5-dichloropyridin-4-yl) amide (415 mg). This was purified by column chromatography eluting with 1% ammonium hydroxide / 10% methanol in dichloromethane to afford the title compound (360 mg) as a cream solid.

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

mp 244-245 ° C

Example 10 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid

(3-methyl-1-oxypyridin-4-yl) amide

Sodium hydride (60% dispersion in oil, 0.11 g) is 3-methyl-1-oxypyridin-4-yl in N, N-dimethylformamide (10 ml) in the presence of molecular sieve, at room temperature, under nitrogen atmosphere. To a stirred solution of amine (0.2 g) was added. After stirring for 1 hour, 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid 4-nitrophenyl ester was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (2 × 50 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was washed with a little ethyl acetate and dried to give the title compound (50 mg) as a pale yellow solid.

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

mp 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) were added to a stirred suspension of 3-methyl-1-oxypyridin-4-ylamine (0.23 g) in dichloromethane (40 ml) under nitrogen atmosphere at room temperature. Added. 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 × 50 ml). The precipitate of the organic layer was filtered off and dried in vacuo at 45 ° C. to give the title compound (0.2 g) as a white solid.

TLC Rf 0.12 (ethyl acetate)

mp 249.5-250.5 ℃

Claims (10)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. Wherein R ₁ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃ , R ₂ is CH ₃ or CF ₃ , R ₃ is fluorine, chlorine, bromine, CN or CH ₃ , R ₄ is hydrogen, fluorine, chlorine, bromine, CN or CH ₃ . The compound of claim 1 wherein said compound is 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide, 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide, 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-chloro-1-oxypyridin-4-yl) amide, 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoro-1-oxypyridin-4-yl) amide, 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-difluoro-1-oxypyridin-4-yl) amide, 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide, 8-methoxy-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) amide, 8-difluoromethoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide, 8-difluoromethoxy-2-methylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide, and A compound selected from the group consisting of 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3-methyl-1-oxypyridin-4-yl) amide. The compound of claim 1, wherein the compound is 8-methoxy-2-trifluoromethylquinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridin-4-yl) amide. A compound according to any one of claims 1 to 3, which can be regulated by inhibition of phosphodiesterase IV or tumor necrosis factor, or function of phosphodiesterase IV, eosinophil accumulation Or a medicament for treating a disease state that is a pathological condition associated with the function of eosinophils. The agent according to claim 4, wherein the disease state is an inflammatory disease or an autoimmune disease. The method of claim 4, wherein the disease state is asthma, chronic bronchitis, pulmonary inflammatory disease, chronic airway disease, atopic dermatitis, allergic rhinitis, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, ulcerative colitis, Crohn A drug selected from the group consisting of diseases, atopic eczema, seizures, aggregate absorption diseases, multiple sclerosis and inflammatory bowel disease. 5. The disease according to claim 4, wherein the disease state is gallitis, allergic conjunctivitis, spring conjunctivitis, ophthalmitis, allergic reactions of the eye, eosinophil granulomatosis, gouty arthritis and other joint diseases, adult respiratory depression syndrome, diabetes insipidus, keratosis, brain aging , Multiple-infarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, intermittent claudication, rheumatoid spondylitis, osteoarthritis, sepsis, septic shock, endotoxin shock, gram negative sepsis, toxin shock syndrome, acute respiratory depression Syndrome, cerebral malaria, silicosis, pulmonary sarcoidosis, perfusion injury, graft-versus-host reaction, tagograft rejection, infectious fever or myalgia, malaria, HIV, AIDS, ARC, cachexia, keloid formation, scar tissue formation, pyresis, Systemic lupus erythematosus, type 1 diabetes mellitus, Behcet's disease, anaphylactic purpura, chronic glomerulonephritis, leukemia, delayed East dyskinesia, yeast or fungal infection, abnormalities, genetic and neural inflammation drug is selected from the group from the associated inflammation and pain that requires protection above. The agent of claim 4, wherein said disease state is asthma. The agent according to claim 5, wherein the disease state is chronically impaired airway disease or chronic bronchitis. 10. A medicament according to any one of claims 4 to 9, wherein said compound is the compound of claim 3.