MXPA01000388A - Quinoline derivatives - Google Patents

Abstract

The invention is related to compounds of general formula (I), wherein R is methyl, ethyl, n-propyl, iso-propyl, n-butyl or allyl;R'is methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, or OCHxFy, wherein x=O - 2, y=1 - 3 with the proviso that x + y=3;R''is hydrogen, fluoro or chloro;with the proviso that R''is fluoro or chloroonly when R'is fluoro;R4 is hydrogen or pharmaceutically acceptable inorganic or organic cations;R5 is ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, trifluoromethyl, OCHxFy, or OCH2CHxFy wherein x=0 - 2, y=1 - 3 with the proviso that x + y=3;R6 is hydrogen;or R5, and R6 taken together are methylenedioxy;and any tautomer thereof. The invention also relates to pharmaceutical compositions containing a compound of general formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of the compounds of formula (I), as well as methods for the treatment of mammals suffering from diseases resulting from autoimmunity and pathological inflammation by administering of a compound having formula (I) to said mammal.

Description

QUINOLINE DERIVATIVES FIELD OF THE INVENTION The present invention relates to novel substituted quinoline-3-carboxamide derivatives, to methods for their preparation, to compositions containing them and to methods and use for the clinical treatment of diseases resulting from autoimmunity, such as multiple sclerosis, diabetes insulin-dependent mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, furthermore, diseases where pathological inflammation plays a major role, such as asthma, atherosclerosis, attack and Alzheimer's disease. More particularly, the present invention relates to novel quinoline derivatives suitable for the treatment of, for example, multiple sclerosis and its manifestations.

BACKGROUND OF THE INVENTION Autoimmune diseases, eg, multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), REF .: 126509 rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis represent attacks by the body's immune system that could be systemic in nature, or even directed at the individual's organs in the body. These seem to be diseases in which the immune system makes mistakes and, instead of regulating the protective functions, it becomes the aggressor (1).

MS is the most common neurological disease acquired from young adults in Western Europe and North America. It justifies the loss of disability and financial, both in the loss of income in medical care, than any other neurological disease of this age of the group. There are approximately 250,000 cases of MS in the United States.

Although the cause of MS is unknown, advances in imaging in the brain, immunology and molecular biology have increased the understanding of the researchers of this disease. Several therapies are currently in use to treat MS, but simple treatment has not shown dramatic efficacy in the treatment. The current treatment of MS falls into three categories: treatment of acute exacerbations, modulation of progressive disease and therapy for specific symptoms.

MS affects the central nervous system and involves a process of demyelination, i.e., the myelin layers are lost while the axons are preserved. The myelin provides the insulating material that allows the rapid conduction of the nervous impulse. Obviously, in demyelination, this property is lost. Although the pathological mechanisms responsible for MS are not understood, several lines of evidence indicate that demyelination has an immunopathological basis. The pathological lesions, the plaques, are characterized by the infiltration of immunologically active cells, such as macrophages and activated T cells (2).

In the Pat. No. 4,547,511 and in Pat. No. 4,738,971 and in EP 59,698 some derivatives of N-aryl-1,2-dihydro-4-substituted-1 -alkyl 1-2 -oxo-quinoline-3-carboxamide are claimed as enhancers of cell-mediated immunity. The target compound Roquinimex known as roquinimex (Merck Index 12th Ed., No. 8418; Linomide®, LS2616, N-pheni 1-N-met i 1- 1, 2-dihydro-4-hydroxy-l-methyl-2-oxo-quinoline- 3-carboxamide) belongs to this series of compounds. Roquinimex has been reported to have multiple immunomodulatory activities not accompanied by general immunosuppression (3-12).

In addition, in Pat. No. 5,580,882, quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of conditions associated with MS. The preferred particular compound is roquinimex. In the Pat. No. 5,594,005, the quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of type I diabetes. The preferred particular compound is roquinimex.

In WO 95/24195 the quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of inflammatory bowel disease. Particularly preferred compounds are roquinimex or a salt thereof. In WO 95/24196 the quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of psoriasis. Particularly preferred compounds are roquinimex or a salt thereof.

In clinical trials comparing roquinimex to placebo, roquinimex was reported to maintain expectations in the treatment of conditions associated with MS (13, 14). However, there are some serious problems related to roquinimex. For example, it has been found that roquinimex is teratogenic in the rat, and induces the side effects that limit dosage in man, e.g., a flu-like syndrome, which avoids the use of the full clinical potential of the compound.

Furthermore, in WO 92/18483, quinoline derivatives substituted in the 6-position with RAS (O) n-group (RA = lower alkyl or aryl, n = 0-2) are claimed, which have an immunomodulatory, anti-inflammatory and anti-inflammatory effect. anti-cancer The substitution, i.e. type and pattern, of the above compounds, specifically mentioned in the prior art, places them outside the scope of the present invention.

DESCRIPTION OF THE INVENTION A principal objective of the present invention is to provide structurally novel quinoline compounds which, by virtue of their pharmacological profile, with high potency in the experimental models and low level of side effects, are considered to be of value in the treatment of the disease that results from autoimmunity and pathological inflammation. Examples of such diseases are multiple sclerosis, insulin dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and other diseases wherein inflammation plays a major role, such as asthma, atherosclerosis, stroke and Alzheimer's disease. . More particularly, the present invention relates to novel quinoline derivatives suitable for the treatment of, for example, multiple sclerosis and its manifestations.

The term "treatment" as used herein includes prophylaxis as well as alleviating the symptoms of the disease.

It has surprisingly been found that the novel compounds of the general formula (I) where R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and allyl; R 'is selected from methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x = 0-2, y = 1-3 with the proviso that x + y = 3; R "is selected from hydrogen, fluorine and chlorine, with the proviso that R" is selected from fluorine and chlorine only when R 'is selected from fluorine and chlorine; R 4 is selected from hydrogen and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium and organic cations such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like; R5 is selected from ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, trifluoromethyl and OCHxFy and OCH2CHxFy where x = 0-2, y = 1-3 with the proviso that x + y = 3; R6 is hydrogen; R5 and R6 taken together are methylenedioxy they are unexpectedly effective and specific in the treatment of individuals suffering from autoimmune and inflammatory diseases.

The compounds of the general formula (I) could exist in different tautomeric forms and all these forms where such forms exist are included here.

In a preferred embodiment of the invention R 4 is selected from hydrogen or sodium, R5 is selected from ethyl, methoxy, chloro and trifluoromethyl, R5 and R6 taken together are methylenedioxy, R is selected from methyl and ethyl, R 'is selected from methoxy, fluorine, chlorine and trifluoromethyl, when R "is hydrogen and R" is selected from m e t a' - and para-fluorine with the proviso that R 'is ortho-fluorine.

Among the most preferred compounds of the general formula (I) according to the present invention are: N-ethyl-N- (3-fluoro-phenyl) -l, 2-dihydro-hydroxy-5-chloro-1-met i-1-oxo-quinoline-3-carboxamide, N-ethyl-N- ( 4-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro-f-enyl) -1,2-dihydro-4-hydroxy-5-chloro-1-meth i 1-2-oxo-quinolin-3-carboxamide; N-methyl-N- (2, 5-difluoro-f-enyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N- (3-methyl-phenyl) -l, 2-dihydro-4-hydroxy-5-ethyl-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2-fluoro-phenyl) -1,2-dihydro-hydroxy-5-methoxy-1-meth i 1-2 -oxo-quinoline-3-carboxamide; N-methyl-N- (2,4-difluoro-f-enyl) -l, 2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2, 5-difluoro-f-enyl) -1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro-phenyl) -l, 2-dihydro-4-hydroxy-5-methoxy-1-meth i 1-2 -oxo-quinine-3-carboxamide, N-methyl- N- (4-trifluoromethyl-f-enyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro-phenyl) -l, 2-dihydro-4-hydroxy-5,6-methylenedioxy-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-trifluoromethyl-1-methyl-2-oxo-quinoline-3-carboxamide.

Several autoimmune diseases that occur spontaneously in man have experimental models that occur spontaneously in certain strains of laboratory animals or can be induced in laboratory animals by immunization with specific antigens of the target organ.

The experimental autoimmune encephalomyelitis (EAE) as a model for autoimmune inflammatory diseases of the central nervous system (CNS) has been the most widely used model for multiple sclerosis disease in humans.

Autoimmunity for type II collagen can be induced experimentally in certain strains of mice or rats and could lead to the development of polyarthritis. Collagen-induced arthritis has several characteristics in common with the condition of rheumatoid arthritis in humans.

The hallmark of asthma in humans is an increased reactivity of the ducts to a range of chemical and physical stimuli. It is now widely accepted that products released from inflammatory cells, e.g., activated eosinophils, compromise epithelial activity and promote bronchial hyperresponsiveness. The murine model of ovalbumin (OA) -induced lung inflammation is dominated by the temporally regulated influx of lymphocytes and eosinophils in the bronchial lumen.

Roquinimex has been found to induce Beagle Pain Syndrome (BPS) (15, 16) in different breeds of beagle dogs. The disease is reflected by clinical and laboratory manifestations that justify BPS as a model for the flu-like syndrome induced by roquinimex in man.

The compounds of the general formula (I) were tested for the inhibition of acute experimental autoimmune enomyelitis (aEAE) in mice. Roquinimex was used as the treatment control and more than 50% inhibition was shown at > 5 mg / kg. The surprising and unexpected results were obtained when the appropriate substitution at position 5 of the quinoline ring was introduced. In comparison with roquinimex, the potency of the substituted 5-chloro compound was increased to 100 times. The substitution at position 6, 7 and 8 resulted in less active compounds. The effect of substitution could be understood broadly in the physicochemical fields. In general, the EAE activity as observed by the inhibition of EAE was in the following descending order according to the position of the substitution: 5 > 6 > > 7 = 8 The comparison of the effects of substitution 5 and 6 showed that there is a statistically significant difference in each normal level (p <0.001) between the two, the effect of the substitution being 5 higher. Furthermore, the appropriate aromatic substitution in the radical of quinoline and the 3-carboxamide radical of the compounds of the general formula (I) significantly reduced or even abolished the side effects, ie, the teratogenic effect and the BPS of roquinimex. In this way, the physicochemical properties of the substituent 5 on the quinoline radical and the substituent or t or, m e t a and / or, in particular, for the 3-carboxamide radical are of primary importance for an improved risk / benefit ratio compared to roquinimex. Also, the replacement of the methyl group on the carboxamide nitrogen with a higher alkyl group significantly reduced the side effects. Thus, the compounds of the formula (I) have surprisingly been found to be chemically and pharmacologically different from the drugs hitherto suggested for the treatment of MS and its manifestations.

All embodiments of the invention as described in the claims are included herein in the specification.

The following examples are intended to illustrate the invention without restricting the scope thereof.

The compounds of the general formula (I) could be prepared by methods known in the literature and the following methods: Method A: m The compounds of the general formula (I) could be prepared by known methods and, for example, as shown above, by the reaction of a quinoline carboxylic acid ester derivative with an aniline in an appropriate solvent, such as toluene, xylene and similar. The general methods for the preparation of the quinoline carboxylic acid ester derivatives of the formula (II) are described below. The N-alkylated anilines of the formula (III) are commercially available or are known from the literature, e.g., in Johnstone et al., J. Chem. Soc. 1969, 2223-2224. Compounds that fall within the scope of formula (III) could be prepared by methods, which are generally analogous to those in the literature.

* Jfe & * Method B IV ni The compounds of the formula (I) could also be prepared by the reaction of a quinoline carboxylic acid (IV) with an aniline of the formula (III). Various coupling reagents known in the art could be used, e.g., carbodiimides known from the literature in US Pat. No. 4,547,511. An appropriate coupling method utilizes thionyl chloride in the presence of triethylamine and an appropriate solvent such as dichloromethane. This method could be used in cases where the direct coupling between the ester and the aniline is not carried out, e.g .., when the aniline contains electron extraction substituents. The quinoline carboxylic acids of the formula (IV) could be obtained from the corresponding esters of the formula (II) by acid hydrolysis as described below.

Example 1 .

Ethyl 1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ester.

To a solution of 2,6-difluorobenzonitrile (42 g, 0.30 mol) in 150 ml of anhydrous sodium methanol methoxide (17.9 g, 0.33 mol) was slowly added at 30 ° C. After heating to reflux for 1 hour, it added 40% aqueous methylamine (133 ml, 1.2 mol) and the resulting solution was refluxed for 4 days.When cooling, a white solid, 2-methoxy-6- (methylamino) benzonitrile, precipitated, which was collected The precipitate was dissolved in an aqueous solution of ethylene glycol (500 ml) and potassium hydroxide (14 g) .The solution was refluxed at 150 ° C overnight, cooled to room temperature and the pH it was adjusted to 4 with concentrated hydrochloric acid. The anthranilic acid formed was collected by filtration, washed with water (50 ml) and dried in vacuo. 6-methoxy-N-methyl-antimicryonic acid (32 g, 0.18 mol) and sodium bicarbonate (38 g, 0.45 mol) were suspended in 500 ml of 1,4-dioxane. Phosgene (25 ml, 0.45 mol) was slowly added under cooling in an ice bath. The mixture was heated to 40 ° C for 1 hour, cooled to 15 ° C, and then 150 ml of water was added in. The isatoic anhydride formed was collected by filtration, after carefully drying, the 5-methoxy anhydride was added. N-methylisoate (20.7 g, 0.10 mol) was added to a solution of sodium diethylmalonate (31 g, 0.17 mol) in 250 ml of anhydrous N, N-dimethylformamide at room temperature, and the solution was heated to 100 ° C. for 3 hours, it was cooled to room temperature, 250 ml of water was added and the pH was adjusted to 4 with concentrated hydrochloric acid.The precipitate was collected by filtration and dried under vacuum to give the title compound as pure white crystals ( 22 g) 48% yield.

X NMR (CDC13) d 1.43 (t, 3H), 3.62 (s, 3H), 3.96 (s, 3H), 4.45 (q, 2H), 6.70 (d, 1H), 6.92 (d, 1H), 7.55 ( t, 1H), 13.5 (s, 1H).

Example 2 Ethyl ester of l, 2-d? Hydro-4-hydro-i-5-chloro-l-meth i 1-2 -oxo-quinoline-3-carboxylic acid.

Phosgene (51 g, 0.52 mol) dissolved in 150 ml of dioxane was added in portions to a mechanically stirred suspension of 2-amino-6-chloro-benzoic acid (30 g, 0.175 mol) and sodium bicarbonate (4 4 g, 0.52 mol) in 300 ml of dioxane. The violent reaction with evolution of gas was presented and the reaction mixture was cooled to keep the temperature below 50 ° C. The stirring was then continued at 50 ° C. for 1 hour.The reaction mixture was cooled to 15 ° C. The resulting precipitate was collected, washed with water and dried to give the isatoic anhydride The anhydride (5 g, 0.025 mol) was dissolved in 50 ml of N, N-dimethylacet amide and cooled to 0 ° C. added sodium hydride (75%) (0.94 g, 0.028 mol) and then methyl iodide (1.89 ml, 0.030 mol) at a rate to maintain the temperature below 5 ° C. The resulting mixture was stirred at room temperature during 5 hours The remaining methyl iodide was removed in vacuo, sodium hydride (0.94 g, 0.028 mol) was added along with methyl malonate (4.5 g, 0.028 mol) .The mixture was heated at 85 ° C for 5 hours. After cooling to room temperature, 50 ml of methanol and 50 ml of ÍM hydrochloric acid were added and subsequently Finally, 250 ml of water formed an emulsion that crystallized at rest in a refrigerator for 72 hours. The crystalline mass was collected by filtration, washed with water, water / methanol (1: 1) and heptane and dried to provide the title compound (6.3 g), yield 74%.

X NMR. { CDC13) d 1.46 (3H, t), 3.63 (3H, s), 4.49 (2H, q), 7.23 (1H, d), 7.27 (1H, d), 7.49 (1H, t), 15.0 (1H, Example 3 Ethyl ester of 1,2-dihydro-4-hydroxy-5-t-fluoromethyl-1-methyl-2-oxo-quinoline-3-carboxylic acid.

S e c a l e n t 2 - f l u o r o - 6 - (trifluoromethyl) benzonitrile (10 g, 0.053 mol) at 40 ° C in 200 ml of anhydrous methylamine in an autoclave for 2 days. The excess methylamine was allowed to evaporate and the resulting gray solid was dissolved in 200 ml of methylene chloride together with 4-aminopyridine (0.1 g, 0.001 mol) and triethylamine (3.3 ml, 0.026 mol). To the frozen solution was slowly added ethyl malonyl chloride (8.8 g, 0.060 mol). The solution was stirred for 4 hours and then worked up to give a yellowish syrup. The syrup was dissolved in 100 ml of ethanol, and sodium methoxide (5.4 g, 0.10 mol) was added. After 1 hour, the solvent was removed and the residue was worked up with methylene chloride and water. The quinoline derivative formed was carefully dried and suspended in 250 ml of frozen anhydrous tetrahydrofuran. Sodium hydride (4 g, 0.125 mol) was added slowly followed by methyl iodide (10 ml, 0.15 mol). The mixture was refluxed for 6 hours, quenched with water and worked up with diethyl ether. The solvents were removed and the residue (17.3 g) was dissolved in a mixture of ethanol (50 ml) and concentrated hydrochloric acid (10 ml). The solution was heated to 45 ° C overnight, cooled and the precipitate was collected to give 8 g of the title compound, yield 48%.

X NMR (CDC13) d 1.46 (3H, t), 3.68 (3H, s), 4.50 (2H, q), 7.58 (1H, m), 7.71 (2H, m), 15.0 (1H, s).

In essentially the same manner, the following compound was obtained from the corresponding starter materials: l, 2-dihydro-4-hydroxy-5-trifluoromethoxy-l-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester.

Example 4 Ethyl ester of 1,2-dihydro-4-hydroxy-1-methyl-yl-2-oxo-5,6-methylenedioxy-quinoline-3-carboxylic acid.

Di-tert-butyl dicarbonate (36 g, 0.17 mol) was added portionwise to a solution of 3,4- (methylenedioxy) -aniline (20.6 g, 0.15 mol) in anhydrous tetrahydrofuran (150 ml). The solution was refluxed for 2 hours, then concentrated in vacuo to give a black solid residue. The residue was dissolved in anhydrous tetrahydrofuran (600 ml) and cooled to -40'C. A solution of sec-but-il-lithium hexane 1.3M (265 ml) was added dropwise., 0.35 mol). After stirring the solution for 0.5 hours at -40 ° C, dry ice pellets (ca 40 g) were added.The mixture was allowed to warm to 0 ° C and water was added (ca 700 ml) .The aqueous solution was acidified with water. hydrochloric acid at pH 3 and extracted with ether The extracts were dried and concentrated to give the N-tBoc-protected 5,6-methylene oxide-oxyanic acid as a solid residue (45 g). It was added to a suspension cooled with ice of sodium hydride (80% in oil, 9.0 g, 0.30 mol) in N, N-dimethyl-ilformamide (200 ml). for 0.5 hour and methyl iodide (22 ml, 0.35 mol) was added. The mixture was stirred at room temperature overnight, quenched with water (600 ml) and extracted three times with ether. The organic layer was washed with saturated brine, dried and concentrated in vacuo to give a dark brown oil. The oil was dissolved in methanol (400 ml) and concentrated hydrochloric acid (80 ml) was added. The solution was stirred overnight at room temperature, neutralized with 5M sodium hydroxide and extracted three times with ether. The combined extracts were filtered through a column with Si02 and the eluate was concentrated in vacuo to give the methylated anthranilic ester (20 g). The ester was dissolved in dichloromethane (400 ml) and cooled in an ice bath. Ethyl malonyl chloride (21 g, 0.14 mol) was added and then, after 30 minutes, triethylamine (22 ml, 0.16 mol). After being stirred for 1 hour at room temperature, the misty mixture was washed with 0.5M hydrochloric acid and then bicarbonate. The organic phase was dried carefully and concentrated in vacuo. The residue was then dissolved in dry ethanol (200 ml) and sodium methoxide (17 g, 0.32 mol) was added. The mixture was stirred for 1 hour and water (300 ml) was added. The solution was washed with ethyl acetate and then the aqueous solution was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dried under vacuum to give the title compound as gray crystals (17 g, 41% overall yield).

X NMR (CDC13) d 1.45 (3H, t), 3.58 (3H, s), 4.48 (2H, q), 6.17 (2H, s), 6.71 (1H, d), 7.14 (1H, d).

Example 5 -Ethyl isatoic anhydride A mixture of chloral hydrate (59.3 g, 0.36 mol), water (700 ml) and sodium sulfate (85.8 g, 0.60 mol) was heated to 50 ° C. When 50 ° C. was reached, a mixture of 3-et il-ani lina (40.8 q, 0. 33 mol), water (700 ml) and concentrated hydrochloric acid (33.6 ml) and a mixture of hydroxylamine hydrochloride (74.8 q, 1.04 mol) and water (330 ml). The resulting mixture was heated at 80 ° C for 30 minutes and maintained for another 10 minutes at this temperature, before the reaction mixture was cooled in an ice bath. The resulting precipitate was filtered, washed with water and dried in vacuo over P205 to give an isoni-tosatoacetanilide (36.6 g), yield 58%. The isonitrosoacetanilide (10.0 g, 0.05 mol), was added portion by portion to a mixture of water (9 ml) and concentrated sulfuric acid (60 ml) preheated to 50'C, maintaining the temperature between 50-55'C. When the addition was complete, the mixture was heated to 80 ° C and maintained at this temperature for 10 minutes. The reaction mixture was then cooled in an ice bath and poured into 10-12 times the reaction volume of crushed ice. The mixture was then allowed to stand for about one hour. The aqueous suspension was extracted with dichloromethane, which was dried and evaporated resulting in a mixture of two analogs of 4-ethyl and 6-ethyl isatins approximately 0.68: 1 (7.6 g), yield 84%.

The mixture of the two isomers was dissolved in aqueous sodium hydroxide and the solution was filtered through celite and then acidified to pH 4. The 4-analogue that was at this pH was extracted into dichloromethane which was dried and evaporated to give pure 4-ethyl isatin (3.1 g), yield 34%.

The 4-ethyl isatin (3.1 g, 0.018 mol) was added to a mixture of concentrated sulfuric acid (45 μl) in acetic acid (14 ml). The suspension was heated to 30 ° C, 35% hydrogen peroxide (2.2 ml) was added and after the addition the temperature was raised to 65 ° C. After it was heated for 3 hours, the mixture was cooled and the precipitate was filtered, washed with water and dried to give the title compound (1.7 g), 48% yield. 1 H NMR (DMSO- g) d 1.12 (3H, t), 3.02 (2H, q), 6.98 (1H, d), 7.05 (1H, d), 7.58 (1H, t), 11.6 (1H, broad).

Example 6 1, 2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-guinoline-3-carboxylic acid.

While cooling, 10 ml of concentrated hydrochloric acid was added to 30 ml of acetic anhydride. To this solution, 1,2-dihydro-4-hydroxy-5-met-oxy-1-methyl-yl-2-oxo-quinoline-3-carboxylic acid ethyl ester (10.5 g, 38 mmol) and the mixture were added. it was heated to 80CC for 14 hours. The mixture was cooled to room temperature and the crystalline product was filtered, washed with cold methanol and dried to yield the title compound (7.2 g), 77% yield 1 H NMR (CDCl 3) d 3.73 (3 H, s), 4.02 (3 H, s), 6.82 (1 H, d), 7.02 (1 H, d), 7.62 (1 H, t).

Example 7, N-Methyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-yl-2-oxo-quinoline-3-carboxamide (not included in the claims) (Method A).

N-methylaniline (2.7 g, 0.025 mol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled to obtain a dry solution. 1,2-Dihydro-hydroxy-5-methoxy-1-meth-1-2-oxo-quinoline-3 -carboxylic acid ethyl ester (2.7 g, 0.01 mol) was added to the boiling solution. The ethanol formed during the reaction was distilled together with some toluene for about 4 hours. The mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), 83% yield. 1 H NMR (CDCl 3) d 3.49 (3 H, s), 3.50 (3 H, s), 4.03 (3 H, s), 6.66 (1H, d), 6.86 (1H, d), 7.08-7.48 (6H, m). 13C NMR (CDC13) d 29.7 (CH3), 36.8 (CH3), 56.8 (CH3), 103.3 (CH), 104.2 (C), 108.4 (CH), 110.2 (C), 126.2 (CH), 127.2 (CH) , 128.6 (CH), 131.4 (CH), 141.2 (C), 143.6 (C), 157.0 (C), 157.4 (C), 160.3 (C), 165.1 (C).

ESI MS / MS [M + H] + 339, fragment 232.

Essentially in the same manner, the following compounds were obtained from the corresponding initiator materials: N-met il-N-pheni 1-1, 2-dihydro-4-hydroxy-5-chloro-l-met il-2-oxo-quinolin-3-carboxamide, (not included in the claims) 1 H NMR (CDCl 3) d 3.38 (3 H, s), 3.52 (3 H, s), 7.08-7.34 (7 H, m), 7.43 (1 H, t). 13 C NMR (CDCl 3) d 29.9 (CH 3), 38.5 (CH 3), 104.7 (C), 112. 8 (C), 113.3 (CH), 125.5 (CH), 125.6 (CH), 126.8 (CH), 128.7 (CH), 131.8 (CH), 132.9 (C), 142.6 (C), 143. 9 (C), 158.0 (C), 166.1 (C), 169.3 (C).

ESI MS / MS [M + H] + 343, fragments 236 and 108.

N-ethyl-N- (3-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-ethyl-1-met i 1-2 -oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro-phenyl) -l, 2-dihydro-4-hydroxy-5-chloro-1-meth i 1-2 -oxo-quinoline-3-carboxamide, 1 H NMR (CDCl 3) d 3.38 (3H, s), 3.45 (3H, s), 7.12-7.28 (6H, m), 7.45 (1H, t). 13 C NMR (CDCl 3) d 30.0 (CH 3), 38.4 (CH 3), 104.5 (C), 112.6 (C), 113.4 (CH), 125.6 (CH), 127.0 (CH), 128.9 (CH), 131.9 (CH) , 132.4 (C), 132.8 (CH), 142.5 (C), 142.6 (C), 158.0 (C), 166.0 (C), 169.2 (C).

ESI MS / MS [M + H] + 377, fragments 236 and 142.

N-ethyl-N- (4-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-meth i 1-2 -oxo-quinoline-3-carboxamide, 1 H NMR (CDC13) d 1.18 (3H, t), 3.33 (3H, s), 3.74 (3H, s), 3.90 (2H, q, broad), 6.73 (2H, d), 7.05-7.15 (3H, m ), 7.22 (1H, d), 7.39 (1H, t). 13 C NMR (CDCl 3) d 12.4 (CH 3), 31.1 (CH 3), 45.6 (CH 2), 55.4 (CH 3), 109.5 (C), 111.5 (C), 114.2 (CH), 115.2 (CH), 126.2 (CH) , 127.9 (CH), 130.4 (C), 132.2 (CH), 133.1 (C), 141.7 (C), 159.2 (C), 159.3 (C), 160.1 (C), 166.7 (C).

ESI MS / MS [M + H] + 387, fragments 236 and 152.

N-methyl-N- (4-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDCl 3) d 3.37 (3 H, signal width), 3.43 (3 H, s), 3.75 (3 H, s), 6.75 (2 H, signal width), 7.14 (3 H, signal width), 7.22 (1 H , d), 7.40 (1H, t). 13 C NMR (CDCl 3) d 30.0 (CH 3), 38.5 (CH 3), 55.4 (CH 3), 105.4 (C), 112.8 (C), 113.4 (CH), 113.9 (CH), 125.5 (CH), 127.0 (CH) , 131.7 (CH), 132.7 (C), 136.8 (C), 142.6 (C), 158.1 (C), 158.3 (C), 164.9 (C), 169.1 (C).

SI MS / MS [M + H] + 373, fragments 236 and 138.

N-ethyl-N- (3-fluoro-phenyl) -1,2-dihydro-4-hydroxy'-chloro-l-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDCl 3) d 1.20 (3H , t), 3-33 (3H, s), 3.95 (2H, q), 6.84-6.98 (3H, m), 7.11-7.20 (2H, m), 7.23 (1H, d), 7.42 (1H, t ). 13 C NMR (CDCl 3) d 12.9 (CH 3), 29.9 (CH 3), 45.8 (CH 2), 104.7 (C), 112.7 (C), 113.4 (CH), 113.8 + 114.0 (CH), 113.9 + 114.1 (CH), 122.3 + 122.4 (CH), 125.6 (CH), 129.5 + 129.6 (CH), 131.9 (CH), 132.8 (CH), 142.7 (C), 143.7 + 143.8 (C), 158.0 (C), 161.4 + 163.4 ( C), 165.9 (C), 168.8 (C); some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] + 375, fragments 236 and 140.

N-methyl-N- (2-fluoro-phenyl) -l, 2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDCl 3) d 3.47 (3 H, s), 3.53 (3 H, s), 4.03 (3 H, s), 6.68 (1 H, d), 6.88-6.96 (2 H,), 7.02-7.07. { 1 H, m), 7.12-7.17 (1H, m), 7.42-7.49 (2 H, m). 13 C NMR (CDCl 3) d 30.7 (CH 3), 36.8 (CH 3), 57.1 (CH 3), 104.3 (C), 104.4 (CH), 107.2 (CH), 109.2 (C), 116.4 + 116.6 (CH), 124.3+ 124.3 (CH), 128.7 (CH), 129.9 + 130.0 (C), 129.9 + 130.0 (CH), 132.9 (CH), 141.1 (C), 157.4 (C), 157.4 (C), 156.8 + 158.8 (C) , 160.3 (C), 167.0 (C).

ESI MS / MS [M + H] + 357, fragment 232.

N-methyl-N- (3-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-meth i 1-2 -oxo-quinoline-3-carboxamide, 1 H NMR (CDC13) d 3.40 (3 H, s), 3.50 (3 H, s), 4.02 (3 H, 10 s), 6.67 (1 H, d, broad), 6.90 (1 H, d, broad), 7.1 (2 H, width), 7.28 (1H, wide), 7.38 (1H, wide), 7.43 (1H, t, wide). 13 C NMR (CDCl 3) d 29.8 (CH 3), 36.8 (CH 3), 57.0 (CH 3), 15 103.5 (CH), 104.3 (C), 108.6 (CH), 109.9 (C), 124.7 (CH), 126.5 (CH) ), 127.5 (CH), 129.7 (CH), 131.7 (CH), 133.9 (C), 141.4 (C), 144.8 (C), 157.2 (C), 157.7 (C), 160.3 (C), 165.0 (C) ).

ESI MS / MS [M + H] + 373, fragment 232 N-ethyl-N- (3-fluoro-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-meth i 1-2 -oxo-quinoline-3-carboxamide, 1 H NMR (CDCl 3) d 1.22 (3H, t), 3.50 (3H, s), 3.92 (2H, ^^^^^^ s ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ - *** - • * * - • *** - * > - signal width), 4.02 (3H, s), 6.66 (1H, d), 6.81-6.92 (2H, m), 7.08-7.19 (3H, m), 7.41 (1H, t). 13C NMR (CDC13) d 13.1 (CH3), 29.8 (CH3), 43.9 (CH2), 56.9 (CH3), 103.4 (CH), 104.3 (C), 108.6 (CH), 110.4 (C), 114.5 + 114.7 ( CH), 123.4 (CH), 129.6 + 129.7 (CH), 131.6 (CH), 141.4 (C), 143.5 (C), 157.2 (C), 157.4 (C), 160.3 (C), 161.4 + 163.3 (C) ), 164.4 (C); some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] + 371, fragment 232.

N-methyl-N- (4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carbo-amide, 1 H NMR (CDCl 3) d 3.46 (3 H, s), 3.52 (3 H, s), 4.05 (3 H, s), 6.69 (1 H, d), 6.92 (1 H, d), 7.10-7.38 (4 H, d d), 7.45 (1H, t). 13 C NMR (CDCl 3) d 29.8 (CH 3), 36.8 (CH 3), 56.8 (CH 3), 103.4 (CH), 104.2 (C), 108.6 (CH), 110.0 (C), 127.6 (CH), 128.9 (CH) , 131.6 (CH), 132.8 (C), 141.3 (C), 142.2 (C), 157.1 (C), 157.5 (C), 160.3 (C), 165.0 (C).

SI MS / MS [M + H] - 373, fragment 232 N-ethyl-N- (2-fluoro-phenyl) -l, 2-dihydro-4-hydroxy-5-trif luoromethyl-l-methyl-2 -oxo -quinol in-3-carboxamide, N-methyl-N- (4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-trif-loromethyl-l-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDC13) d 3.40 (3H, s), 3.48 (3H, s), 7.08-7.25 (4H, m), 7.48 (1H, d), 7.65 (1H, t), 7.69 (1H, t). 13C NMR (CDCI3) d 30.1 (CH3), 38.7 (CH3) r 103.8 (C), 112.7 (C), 113.4 (C), 118.7 (CH), 121.9+ 121.9+ 122.0 + 122.0 (CH), 120.3+ 122.4 + 124.6 + 126.8 (C), 127.0 (CH), 127.8 + 128.0 + 128.3 + 128.5 (C), 128.9 (CH), 131.6 (CH), 132.4 (C), 142.3 (C), 142.6 (C), 157.7 (C), 166.3 (C), 169.9 (C); some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] - 411, fragments 270 and 142 N-methyl-N- (4-methoxy-phenyl) -l, 2-dihydro-4-hydroxy-5-trif-loromethyl-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- ( 4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-trifluoromethoxy-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-methyl-phenyl) -l, 2-dihydro-4-hydroxy-5-trifluoromethoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-chloro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, (not included in the claims) 1 H NMR (CDC13) d 3.38 (3 H, s, broad), 3.52 (3 H, s), 3.96 (3 H, s), 7.14-7.23 (2 H, m), 7.23-7.30 (5 H, m). 13 C NMR (CDCl 3) d 29.7 (CH 3), 38.3 (CH 3), 57.2 (CH 3), 113.6 (CH), 113.7 (C), 116.8 (CH), 120.3 (C), 125.8 (CH), 126.9 (CH) , 128.7 (CH), 136.5 (C), 143.9 (C), 150.9 (C), 158.0 (C), 165 (C), 168.9 (C). ESI MS / MS [M + H] + 373, fragments 266 and 108.

N-methyl-N- (4-chloro-phenyl) -l, 2-dihydro-4-hydroxy-5,6-methylenedioxy-l-methyl-2-oxo-quinoline-3-carboxamide.

Ex empl o 8 N-Methyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-1-2-oxo-quinoline-3-carboxamide (Method B).

To an ice-cooled solution of 1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3'-carboxylic acid (8 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) ) and 4-1-fluorometre-1-N-methanoyl-1-ene (6.1 g, 0.035 mol) in 150 ml of methylene chloride was added dropwise over 0.5 hours a solution of thionyl chloride (3.0 ml, 0.042 mol). ) in 10 ml of methylene chloride. Stirring was continued at 4 ° C for 4 hours. The solution was diluted with 10 ml of methylene chloride, washed with cold 1 M sulfuric acid and then extracted with 1 M sodium hydroxide. The pH of the aqueous phase was adjusted to 8-8.5, clarified by filtration and then it was acidified with hydrochloric acid to pH 4. At rest a crystalline precipitate was formed which was filtered, washed with water and dried to give the title compound (8.5 g) 65% yield. 1 H NMR (CDC13) d 3.48 (3H, s), 3.54 (3H, s), 4.06 (3H, rt - &faith «- * s), 6.70 (1H, d), 6.94 (1H, d), 7.46 (1H, t), 7.50 (4H, wide signal). 13C NMR (CDC13) d 29.8 (CH3), 36.9 (CH3), 56.9 (CH3), 103.5 (CH), 104.2 (C), 108.7 (CH), 109.5 (C), 117.3 + 121.7 + 126.0 + 130.3 (C) ), 125.8 + 125.9 + 125.9 + 126.0 (CH), 126.3 (CH), 127.9 + 128.4 + 128.9 + 129.4 (C), 131.8 (CH), 141.4 (C), 146.7 (C), 157.2 (C), 158.0 (C), 160.3 (C), 165.0 (C); some peaks are multiplets due to F-bonding.

ESI MS / MS [M + H] + 407, fragment 232.

Essentially in the same manner, the following compounds were obtained from the corresponding initiator materials: N-ethyl-N- (4-trifluoromethyl-phenyl) -l, 2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDCl 3) d 1.22 (3H, t), 3.28 (3H, s), 3.99 (2H, q), 7.13 (1H, d), 7.23-7.32 (3H, m), 7.40-7.51 (3H, tm ). i f 13 C NMR (CDCl 3) d 13.0 (CH 3), 29.8 (CH 3), 45.8 (CH 2), 104.0 (C), 112.7 (C), 113.5 (CH), 120. 6 + 122.8 + 124.9 + 127.1 (C), 125.7 (CH), 125. 7 + 125.7 + 125.8 + 125.8 (CH), 126.7 (CH), 128. 3 + 128.6 + 128.8 + 129.1 (C), 132.1 (CH), 133.0 (C), 142.8 (C), 145.6 (C), 157.9 (C), 166.8 (C), 169.1 (C); some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] + 425, fragments 236 and 190.

N-ethyl-N- (4-trif luoromet-il-f-enyl) -l, 2-dihydro-4'-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDC13) d 1.22 (3H, t), 3.51 (3H, s), 3.93 (2H, q), 4.02 (3H, s), 6.67 (1H, d), 6.91 (1H, d), 7.43 ( 1H, t), 7.46-7.52 (4H, m). 13 C NMR (CDCl 3) d 13.2 (CH 3), 29.8 (CH 3), 44.1 (CH 2), 56.9 (CH 3), 103.5 (CH), 104.3 (C), 108.7 (CH), 110.0 (C), 120.7 + 122.9 + 125.0 + 127.2 (C), 125.9 + 125.9 (CH), 127.7 (CH), 128.9 + 129.2 + 129.4 + 129.7 (C), 131.8 (CH), 141.5 (C), 145.3 (C), 157.2 (C), 157.8 (C), 160.3 (C), 164.4 (C); some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] + 421, fragments 232 and 206.

N-methyl-N- (4-trifluoromethoxy-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-1-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDC13) d 3.33 (3 H, s), 3.45 (3 H, s), 6.62 (1 H, broad), 6.83 (1 H, broad), 6.98-7.17 (2 H, m, broad), 7.20 (1 H, d ), 7.37 (1H, t, wide). 13 C NMR (CDCl 3) d 29.9 (CH 3), 37.3 (CH 3), 103.3 (C), 104.7 + 104.9 + 105.1 (CH), 110.5 + 110.7 (CH), 112.7 (C), 113.3 (CH), 125.7 (CH) ), 128.1 (C), 128.6 (CH), 132.1 (CH), 133.3 (C), 142.8 (C), 157.8 (C), 156.9 + 157.0 + 158.9 + 159.0 (C), 160.6 + 160.6 (C), 167.4 (C), 170.4 (C); some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] + 379, fragments 236 and 144.

N-methyl-N- (2, 5-difluoro-f-enyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide; N-methyl-N- (2,4-difluoro-phenyl) -l, 2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, 1 H NMR (CDC13) d 3.40 (3 H, s), 3.51 (3 H, s), 4.02 (3 H, s), 6.60-6.63 (1 H, m), 6.63 (1 H, d), 6.73-6.79 (1 H, 10 m), 6.90 (1H, d), 7.38-7.46 (2H, m). 13 C NMR (CDCl 3) d 29.9 (CH 3), 36.0 (CH 3), 56.9 (CH 3), 103.5 (CH), 104.2 (C), 104.4 + 104.6 + 104.6 + 104.8 (CH), 108.6 (CH), 109.2 (C) ), 110.8 + 110.9 + 111.0 + 111.0 (CH), 15 127.3 + 127.3 + 127.4 + 127.4 (C), 130.0 + 130.1 (CH), 131.8 (CH), 141.4 (C), 157.2 (C), 157.3 + 157.4 + 159.3 + 159.4 (C), 158.5 (C), 160.3 (C), 160.7 + 160.8 + 162.6 + 162.7 (C), 165.5 (C); some peaks are multiplets due to F-coupling. 20 ESI MS / MS [M + H] + 375, fragment 232 N-methyl-N- (2,5-difluoro-phenyl) -l, 2-di-idro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, Z &r * ^ * £ ^ S »» ^ s »®-. JM ___ M »H ^ J > «* Mfe ... rf« a »» »- - -" * • '• • * * * Ji? Fcafra 1H NMR (CDCI3) d 3.48 (3H, s), 3.64 (3H, s), 4.10 ( 3H, s), 6.60-7.30 (5H, m), 7.63 (1H, t). 13 C NMR (CDCl 3) d 31.0 (CH 3), 37.2 (CH 3), 57.2 (CH 3), 104.4 (C), 105.0 (CH), 105.7 (C), 109.5 (CH), 115.2 + 115. 6 (CH), 116.8 + 116. 9 (CH), 117. 2 + 117.3 + 117.5 + 117.7 (CH), 129.8 + 130.0 + 130.0 + 130.2 (C), 133.9 (CH), 141.0 (C), 151.9 + 155.8 (C), 157.6 (C), 115.8 + 159.6 (C) 161.4 (C), 161.7 (C), 167.6 (C); main form; some peaks are multiplets due to F-coupling.

ESI MS / MS [M + H] + 375, fragment 232 N-methyl-N- (2,4-difluoro-f-enyl) -1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide.

Pharmacological methods Acute experimental autoimmune encephalomyelitis (aEAE) Female SIL / N mice, 8 weeks old, were used for the experiments. The mouse spinal cord homogenate (MSCH) of C57B1 / 6 female mice aged 8 to 12 weeks was obtained. The tissue was homogenized on ice and diluted in cold PBS. M. tuberculosis hominis H37Ra of 1 mg / ml containing incomplete Freund's adjuvant was emulsified with an equal volume of MSCH to give a final concentration of 10 mg / ml of MSCH. The inoculum volume of 0.1 ml was injected int radically at the base of the tail. The pertussis toxin was injected i.p. on day 0 and 3 after immunization. The treatment was given daily either on day 3 to 12 of postimmunization or on days 3 to 7 and 10 to 12. Control animals received saline. The animals, eight per dosage group, were recorded for clinical signs of paralytic disease on a scale of 0 to 5 as follows: 0, normal; 1, flaccid tail; 2, posterior limb paresis; 3 paralysis of the hind limb and lame front leg; 4, bilateral posterior and front limb paralysis; 5, death. Clinical records were monitored on day 7 and daily from day 9 until the end of the experiment on day 14. The effects of treatment were calculated as percent inhibition of clinical records compared to controls treated with saline.

Collagen-induced arthritis Male DBA / 1 mice between 8 to 10 weeks of age were used for the experiments. On day 0, mice were immunized int radically at the base of the tail with bovine type II collagen (100 μg / mouse) in complete Freund's adjuvant. The treatment was given daily on days 3 to 7, 10 to 14, 17 to 21, 24 to 28 and 31 to 35. Fifteen days after immunization the mice were inspected for signs of arthritis. The animals were inspected three times in a week. Every second or third day the legs of the arthritic animals were recorded on a scale of 0-4 (0 = no arthritis, 1 = arthritis in one of the interphalangeal joint, metapharyngeal or intercarpal meta), 2 = two arthritic joints, 3 = three arthritic joints, 4 = as in 3, but with more severe red color and swelling of the paw). The record for each leg was added to give a maximum achievable record of 16 for each mouse.

Inflammation of the ovalbumin-induced lung C57B1 / 6 female mice between 10 to 14 weeks of age, 10 mice / group were used for the experiments. The mice were sensitized with ovalbumin (OA) in aluminum hydroxide in a volume of 0.2 ml inoculated ip. Treatment was given on day 0 to day 16. Control mice received saline. Fourteen days after the sensitization of OA, the mice were exposed for 20 minutes to an aerosol of 1.5% w / v OA in saline produced by a nebulizer. The control mice stimulated with the vehicle were exposed to saline. Seventy-two hours after stimulation of OA / vehicle, the mice were anesthetized and bronchoalveolar lavage was performed by infiltrating 0.5 ml of phosphate buffered saline (PBS) cooled with ice in the lungs twice. Total cell counts were determined and differential counts were made based on the identification of eosinophils, alveolar monocytes / macrophages, lymphocytes and neutrophils. Eosinophil infiltration into the lung tissue was evaluated by histochemical methods in sections of the lung frozen using tet diaminobenzidine hydrochloride (DAB).

Teratogenic effects in the rat.

The compounds were administered subcutaneously to female rats during pregnancy, i.e., day 8 to 14 of pregnancy. The rats were sectioned by caesarean section and necropsied on day 20 after fertilization. The fetuses were examined for external and internal abnormalities.

Beagle pain syndrome (BPS) The compounds were administered intravenously to beagle dogs. The dosage was given for five consecutive days. Dogs were evaluated for clinical and laboratory signs of pain syndrome, e.g., fever, increased erythrocyte sedimentation rate (ESR), alkaline phosphate (AP), induction of acute phase proteins and vasculitis.

Among the preferred compounds are N-methyl-N- (4-trifluoroethyl-phenyl) -1,2-dihydro-4-hydroxy-5-raet oxy-1-methyl-2-oxo-quinoline-3-carboxamide and N-methyl-N- (2, -difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide subsequently called Compound A and B, ^ £ fe * gíi ^ ate ^ ¡j? S3 ^^^ yes ^^^ tó respectively. N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide and roquinimex are included as the reference compounds subsequently called Compound C and D , respectively.

Inh ibi ci on of aEAE fifteen twenty ^ - ^ - ^^^ - ^ * ^ ^? ^^, i Tera t osen i ci da d in l a ra ta The effective amounts of the compounds of the formula (I) are preferably administered to a patient in need of such treatment according to the usual routes of administration and are formulated into the usual pharmaceutical compositions, comprising an effective amount of the active ingredient and a Appropriate pharmaceutically acceptable vehicle. Such compositions may take a variety of forms, e.g., solutions, suspensions, emulsions, tablets, capsules, and powders prepared for oral administration, aerosols for inhalations, sterile solutions for parental administration, suppositories for rectal administration or topical formulations. i n tl; appropriate. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Design," M.B. Aulton, Churchill Livingstone, 1998.

A daily dosage suitable for use in the treatment of MS is contemplated to vary between 0.0005 mg / kg to about 10 mg / kg of body weight, in particular between 0.005 mg / kg to 1 mg / kg of body weight, depending on the specific condition to be treated, the age and weight of the specific patient and the specific response of the patient to the medication. The exact individual dosage, as well as the daily dosage, will be determined according to standard medical principles under the direction of a physician.

Various additives are contemplated to improve the stability or ease of administration of the drug. The pharmaceutical composition could also contain additional therapeutically useful substances in addition to a compound of the formula (I).

References 1 . Talal, N.; Autoimmune diseases. In: Roitt, I.M. and Delves, P.J. (Eds.) Encyclopedia of Immunology, pp. 195-198. Academic Press, 1992. 2. Prineas, J.W. : The neuropa thology of multiple sclerosis. In: Koetsier, J.C. (Ed.) Handbook of Clinical Neurology, pp. 213-257. Elsevier Science Publ., Amsterdam, 1985. 3. Tarkowski, A., Gunnarsson, K. , Nilsson. L-A., Líndholm, L. and Stalhandske, T. Sucessful treatment of autoimmunity in MRL / 1 mice LS2616, a new immunomodulator. Arthritis Rheum. 29 (11): 1405-1409, 1986. 4. Larsson, E.L., Joki, A.L. and Stalhandske, T. Mechanism of action of new immunomodulator LS2616 on T-cells responses. Int J Immunopharmacol 9 (4): 425-31, 1987.

. Wanders, A., Larsson, E., Gerdin, B. and Tufveson G. Abolition of the effect of cyclosporine on rat cardiac allograft rejection by the new immunomodulator LS-2616 (Linomide). Transplantation 7 (2): 216-217, 1989. 6. Kalland, T. Regulation of natural killers progenitors: studies with a novel immunomodulator with distinct effects at the precursor level. J. Immunol 144 (11): 4472-4476, 1990. 7. Gonzalo, J.A., González-García, A., Kalland, T., Hedlund, G., Martinez, C. and Kroemer, G. Linomide, a novel immunomodulator that prevents death in four models of septic shock. Bur J Immunol 23: 2372-2374, 1993. 8, Karussis, D.M., Lehmann, D., Slavin, S. et al. Treatment of chronic-relapsing experimental autoimmune encephalomyelitis with the syntethic immunomodulator Linomide (qninoline-3-carboxam? De). Proc Nat 1 Acad Sci U5A 90: 6400-6404, 1993. 9. Gonzalo, J.A., González-García, A., Kalland, T. et al. Linomide inhibits programmed cell death of T cells in vivo. Eur J Immunol. 24: 48-52, 1994.

. Gross, D.J., Sidi, H., Weiss, L., Kalland, T., Rosenmann, E. and Slavin, S. Prevention of diabetes mellitus in non-obese diabetic mice by Linomide, a novel and munomodulating drug. Diabetology 37: 1195-1201, 1994. 11. Karussis, D.M., Lehmann, D., Brenner, T. et al. Immunomodulat ion of experimental autoimmune myasthenia gravis with Linomide. J Neuroim unol 55 (2): 187-193, 1994. 12. Bai, X.F., Shi, F.D., Zhu, J., Xiao, B.G., Hedlund, G. and Link, H. Linomide-induced suppression of experimental autoimmune neuritis is associated with down-regulat ed macrophage functions. J Neuroimmunol 76: 177-184 1997. 13. Karussis, D.M. Meiner, Z., Lehmann, D. et al. Treatment of secondary progressive multiple sclerosis with the immunomodulator Linomide. Neurology 47: 341-346, 1996. 14. Andersen, O., Lycke, J., Tollesson, P.O. et al. Linomide reduces the rate of active lesions in relapsing-remitting to many types of sclerosis. Neurology 47: 895-900, 1996 . Kelly, D.F., Grimsell, C.S.G. and Kenyon, C.J. Polyart erit is in the dog: A case report. Vet Record 92: 363-366, 1973. 16. Harcourt, R.A. Polyarterites in a colony of beagles. Vet Record 102: S 19-522, 1978.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property. 2 & ~, ~, & * - £ $ - ** - iXr '* i i - ugly ^ ¿at¿B

Claims (43)

1. The compounds of the general formula (I) characterized because R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and allyl; R 'is selected from methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and 0CHxFy, where x = 0-2, y = 1-3 with the proviso that x + y = 3; R "is selected from hydrogen, fluorine and chlorine, with the proviso that R" is selected from fluorine and chlorine only when R 'is selected from fluorine and chlorine; R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations, R5 is selected from ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, trifluoromethyl, OCHxFy and OCH2CHxFy where x = 0-2, y = 1-3 with the proviso that x + y = 3; R6 is hydrogen; R5 and R6 taken together are methylenedioxy and any tautomer of it.

2. The compounds according to the claim 1, characterized in that the pharmaceutically acceptable inorganic cations are derived from sodium, potassium and calcium and the organic cations are derived from monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like.

3. The compounds according to claims 1 and 2, characterized in that R5 is selected from ethyl, methoxy, chloro and trifluoromethyl.

4. The compounds according to claims 1 and 2, characterized in that R5 and R6 taken together are methylenedioxy.

5. The compounds according to any of the preceding claims, characterized in that R is selected from methyl and ethyl.

6. The compounds according to any of the preceding claims characterized in that R 'is selected from methoxy, fluorine, chlorine and trifluoromethyl, when R "is hydrogen.

7. The compounds according to any of the preceding claims characterized in that R "is selected from me ta '- and para-fluorine with the proviso that R' is ortho-fluorine.

8. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N- (3-fluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo- quinoline-3-carboxamide.

9. The compound according to claims 1 and 2, characterized in that it is N-met il-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-met il- 2-oxo-quinoline-3-carboxamide.

10. The compound according to claims 1 and 2, characterized in that it is N-met il-N- (2, 5-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2 -oxo-quinoline-3-carboxamide.

11. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N- (3-methoxyphenyl) -1,2-dihydro-4-hydroxy-5-ethyl-l-methyl-2-oxo-quinolin -3-carboxamide.

12. The compound according to claims 1 and 2, characterized in that it is N-methyl-N- (2,5-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-methoxy-l-met i 1 - 2 -oxo-quinoline-3-carboxamide.

13. The compound according to claims 1 and 2, characterized in that it is N-met il-N- (-tri luoromethyl-phenyl) -1,2-dihydro-hydroxy-5-methoxy-methyl-2-oxo- quinoline-3-carboxamide.

14. The compound according to claims 1 and 2, characterized in that it is N-met il-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl -2-oxo-quinoline-3-carboxamide.

15. The compounds according to any of the preceding claims, characterized in that they are used as therapeutics.

16. The pharmaceutical compositions, characterized in that they contain as an active ingredient a compound having the general formula (I) together with a pharmaceutically carrier.

17. The pharmaceutical compositions according to claim 16, characterized in that they contain other pharmacologically active substances.

18. The pharmaceutical compositions according to claims 16 and 17, characterized in that they are used as therapeutics in a daily dosage of the active substance from 0.0005 mg / kg to about 10 mg / kg of body weight, in particular 0.005 to 1 mg / kg of body weight

19. A process for the manufacture of a compound of the general formula (I), characterized in that R, R ', R ", R4, R5 and R6 are as defined above, by (A) reacting a quinoline carboxylic acid ester derivative of the formula (II) with an aniline of the formula (III), in an appropriate solvent such as toluene, xylene or the like, or (B) reacting a quinoline carboxylic acid of the general formula (IV) with an aniline of the general formula (III), IV using an appropriate coupling reagent, preferably a carbodiimide or thionyl chloride in the presence of triethylamine and an appropriate solvent such as dichloromethane.

20. A method for treating a mammal suffering from pathological inflammation and autoimmunity, characterized in that it comprises administering to the mammal a compound having the general formula (I) wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and allyl; R 'is selected from methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x = 0-2, y = 1-3 with the proviso that x + y = 3; R "is selected from hydrogen, fluorine and chlorine, with the proviso that R" is selected from fluorine and chlorine only when R 'is selected from fluorine and chlorine; R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations, R5 is selected from ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, trifluoromethyl, OCHxFy and 0CH2CHxFy where x = 0-2, y = 1-3 with the proviso that x + y = 3; R6 is hydrogen; R5 and R6 taken together are methylenedioxy and any tautomer of it

21. The method according to claim 20, characterized in pharmaceutically acceptable inorganic cations are derived from sodium, Potassium and calcium and the organic cations are derived from monoet anolamine, diethanolamine, dimethylaminoethanol, morpholine and the like.

22. The method according to claim 20 and 21, characterized in that R5 is selected from ethyl, methoxy, chloro and trifluoromethyl.

23. The method according to claim 20 and 21, characterized in that R5 and R6 taken together are 20 methylenedioxy.

24. The method according to claim 20 and 21, characterized in that R is selected from methyl and ethyl. 25 ; ta '. - pjt i k, m.,? < -go" . -. «* ... ... ......«. - ... .. .. * -.- / -. * _. «_ ^ _ __ • ~ * M?

25. The method according to claim 20 and 21, characterized in that R 'is selected from methoxy, fluorine, chlorine and trifluoromethyl when R "is hydrogen.

26. The method according to claim 20 and 21, characterized in that R "is selected from m e t a '- and para-fluorine with the proviso that R' is ortho-fluorine.

27. The method according to claim 20 and 21, characterized in that it is N-ethyl-N- (3-fluoro-phenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2 - oxo-quinol in-3 -carboxamide.

28. The method according to claim 20 and 21, characterized in that it is N-met il-N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2 -oxo-quinoline-3-carboxamide.

29. The method according to claim 20 and 21, characterized in that it is N-met il-N- (2,5-di fluorophenyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2 - oxo-quinoline-3-carboxamide.

30. The method according to claim 20 and 21, characterized in that it is N-ethyl-N- (3-methoxy-phenyl) - t,; i ^ g. 1, 2-dihydro-4-hydroxy-5-ethyl-l-methyl-2-oxo-quinoline-3-carboxamide.

31. The method according to claim 20 and 21, characterized in that it is N-met il-N- (2, 5-difluorophenyl) -1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo -quinolin-3-carboxamide.

32. The method according to claim 20 and 21, characterized in that it is N-met il-N- (-trifluoromet il-phenyl) -l, 2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo -quinolin-3-carboxamide.

33. The compound according to claim 20 and 21, characterized in that it is N-met il-N- (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-meth i 1 -2 -oxo-quinoline-3-carboxamide.

34. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from multiple sclerosis (MS).

35. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from insulin dependent diabetes mellitus (IDDM).

36. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from systemic lupus erythematosus (SLE).

37. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from rheumatoid arthritis (RA).

38. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from inflammatory bowel disease (IBD).

39. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from psoriasis.

40. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from inflammatory respiratory disease, such as asthma.

41. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from atherosclerosis.

42. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from attack or apoplexy.

43. The method according to any of claims 20 to 33, characterized in that it treats mammals suffering from Alzheimer's disease. 5 0 5 ^^^^^