MXPA00009954A - Quinoline derivatives - Google Patents

Abstract

The invention relates to compounds of general formula (I) wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl;R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations;R5 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF3, and OCHxFy;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 of treating mammals suffering from diseases resulting from autommunity and pathological inflammation by administrering a compound having formula (I) to said mammal.

Description

QUINOLINE DERIVATIVES FIELD OF THE INVENTION The present invention relates to new quinoline derivatives, to methods for their preparation, to compositions containing them, and to methods and to the use for the clinical treatment of diseases resulting from autoimmunity such as multiple sclerosis, diabetes mellitus dependent of insulin, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, in addition, diseases where pathological 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.

BACKGROUND OF THE INVENTION Autoimmune diseases, for example, multiple sclerosis (MS), insulin dependent diabetes mellitus (IDDM), lupus erythematosus, systemic (SLE), for example, English), rheumatoid arthritis REF: 123010 (RA), inflammatory bowel disease (IBD) and psoriasis represent attacks by the body's immune system which may be systemic in nature, or otherwise they are directed at individual organs in the body. They seem to be diseases in which the immune system is wrong and, instead of mediating the protective functions, it becomes an aggressor (1) • MS is the neurological, acquired disease, most common among young adults in Western Europe and North America. This responds for more disability and financial loss, both in lost income and in medical care, than any other neurological disease in this age group. There are approximately 250,000 cases of MS in the United States. Although the cause of MS is unknown, advances in brain imaging, immunology and molecular biology have increased the researchers' understanding of this disease. Currently, various therapies are being used to treat MS, but no single treatment has shown dramatic treatment efficacy. The current treatment of MS encompasses three categories: the treatment of acute exacerbations, the modulation of a progressive disease, and therapy for specific symptoms. The MS affects the central nervous system and involves a demyelination procedure, that is, the myelin sheaths are lost while the axons are conserved. Myelin provides the insulation material that increases the rapid conduction of nerve impulses. Obviously, in demyelination, this property is lost. Although the pathogenic mechanisms responsible for MS are not understood, several lines of evidence indicate that demyelination has an immunopathological basis. The pathological lesions, the plaques, were characterized by the infiltration of immunologically active cells such as macrophages and activated T cells (2). In U.S. Patent No. 4,547,511 and U.S. Patent No. 4,738,971 and in European Patent Application No. 59,698 some derivatives of l-alkyl-2-oxo-quinoline-3-carboxamide N-aryl-1,2-dihydro- 4-substituted are claimed as augmentors of cell-mediated immunity. The Roquinimcx compound known as roquinimex (Merck Index 12th Edition, No. 8418; Linomide®, LS2616, N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-l-methyl-2-oxo-quinoline-3-carboxamide) belongs to this series of compounds. It has been reported that Roquinimex has immunomodulatory, multiple activities not accompanied by general immunosuppression (3-12). Furthermore, in U.S. Patent No. 5,580,882, the quinoline-3-carboxamide derivatives are stated to be useful in the treatment of conditions associated with MS. The preferred compound, particular of roquinimex. In the North American patent No. 5, 594,005, the quinoline-3-carboxamide derivatives are said to be useful in the treatment of type I diabetes. The preferred compound, particular is roquinimex. In WO 95/24195 the quinoline-3-carboxamide derivatives are claimed to be useful in the treatment of IBD. Particularly preferred compounds are roquinimex or a salt thereof. 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, it was reported that roquinimex maintains a commitment in the treatment of conditions associated with MS (13, 14). However, there are some serious disadvantages connected with roquinimex. For example, it has been found to be teratogenic in the rat, and to induce the side effects that limit dosage in man, for example, a syndrome similar to influenza, which prevents the use of the full clinical potential of the compound. In addition, WO 92/18483 claims quinoline derivatives substituted in the 6-position with a RAS (0) n group (RA = lower alkyl or aryl).; n = 0 -2), which have an anti-inflammatory and anticancer immunomodulatory effect. The substitution, that is, the type and pattern, of the above-mentioned specifically mentioned compounds places them outside the scope of the present invention.

DESCRIPTION OF THE INVENTION A primary objective of the present invention is to provide structurally novel quinoline compounds which by virtue of their pharmacological profile, with high potency in experimental models and low level of side effects, are considered to be of value in the treatment of the disease resulting 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 where 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. It has now been surprisingly found that the novel compounds of the general formula (I) wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. -butyl and allyl; 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 methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chloro, bromo, CF3, and OCHxFy; where x = 0 - 2, y = 1 - 3 with the condition that x + y = 3; R6 is hydrogen; or R5 and R 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) can exist in different tautomeric forms and all these forms are included herein. In a preferred embodiment of the invention R4 is hydrogen or sodium, and R5 is ethyl, methoxy, chloro or bromo and R5 and R6 taken together are methylenedioxy, and R is ethyl or n-propyl, especially ethyl. Various autoimmune diseases in man have experimental models that occur spontaneously in certain strains of laboratory animals or can be induced in laboratory animals by immunization with the specific antigen (s) of the target organ. Experimental autoimmune encephalomyelitis (EAE) as a model for inflammatory, autoimmune diseases of the central nervous system (CNS) has been the most widely used model for human disease multiple sclerosis. The autoimmunity of type II collagen can be induced experimentally in certain strains of mice or rats and can lead to the development of polyarthritis. Collagen-induced arthritis has several characteristics in common with human rheumatoid arthritis disorder.

The hallmark of asthma in humans is an increased reactivity of the respiratory tract to a range of chemical and physical stimuli. It is now widely accepted that products released from inflammatory cells, for example, activated eosinophil cells, compromise epithelial integrity and promote bronchial hyperresponsiveness. The murine model of ovalbumin-induced lung inflammation (OA) is dominated by the temporally regulated influx of lymphocytes and eosinophilic cells into the bronchial lumen. It has been found that roquinimex induces Beagle Pain Syndrome (BPS) (15,16) in different breed of small, hound dogs. The disease is reflected by the clinical and laboratory manifestations that justify BPS as a model for the influenza-like syndrome induced by roquinimex in man. The compounds of the general formula (I) were subjected to an assay for the inhibition of EAE in mice. Roquinimex was used as the treatment control and showed a 70% inhibition at 5 mg / kg. Surprising and unexpected results were obtained when an appropriate substitution was introduced at position 5, for example 5-chlorine, of the quinoline ring. In comparison with the roquinimex, the power increased about 100 times. The substitution at position 6, 7 and 8 resulted in less active compounds. In general, the activity of the EAE as observed by the inhibition of the EAE was in the following order of descent according to the position of the substitution: 5 >; 6 > > 7 = 8. The effect of substitution 5 could be greatly understood in physiochemical fields. In addition, the replacement of the methyl group on the carboxamide nitrogen with an ethyl group or the further elongation of the alkyl group to a propyl or butyl group extinguished the teratogenic effect of roquinimex in the rat and significantly reduced the BPS. On the other hand, the change from the R group of alkyl to hydrogen decreased the solubility in water at the physiological pH by more than about 105 times. The replacement of the alkyl group also affected the pharmacokinetic properties. For example, in comparison with roquinimex the evacuation (Cl) of compound A in dogs was about 800 times greater.

Compound A Solubility and pharmacokinetic issues significantly reduce the useful order of the activity of this class (R = H) of the compounds. Therefore, it has surprisingly been found that the compounds of the formula (I) are different chemically and pharmacologically from those drugs suggested hitherto for the treatment of MS and its manifestations. The compounds of the general formula (I) are prepared by the following methods: Method A The compounds of the formula (I) can be prepared by known methods, for example, by reacting an ester derivative of the quinoline (II) carboxylic acid with an aniline (III) in a suitable solvent such as toluene, xylene and Similar. Suitable esters are methyl esters and ethyl esters.

Method B The compounds of the formula (I) can also be prepared by the reaction of a isathoic anhydride (IV) with an alkyl ester of N-alkyl-N-phenylcarbamoyl acetic acid (V) using a strong base, for example, sodium hydride in a suitable solvent such as N, N-dimethylacetamide. Suitable esters are methyl esters and ethyl esters.

Method C The compounds of the formula (I) can also be prepared by the reaction of a quinoline carboxylic acid of the formula (VI) with an aniline of the formula (III). Various coupling reagents known in the art may be used, for example known carbodiimides of U.S. Patent No. 4,547,511. A suitable coupling method utilizes thionyl chloride in the presence of triethylamine and a suitable solvent such as dichloromethane. This method can be used in cases when the direct coupling between the ester and the aniline does not work. The quinoline carboxylic acids of the formula (VI) can be obtained from the corresponding esters of the formula (II) by acidic hydrolysis as described below.

The carboxylic esters of quinoline (II) above can be prepared by the methods shown in Examples 5-8 below. The quinoline carboxylic acids (VI) can be prepared by the method shown in Example 9 below. All embodiments of the invention as described in the claims are included with the present specification. The following examples are proposed to illustrate the invention without restricting the scope thereof.

Example 1 N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide (Method A) N-ethylaniline (3.0 g, 25 mmol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled to obtain a dry solution. To this boiling solution was added 1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (2.7 g, 10 mmol). The ethanol formed during the reaction was distilled together with some toluene for about 4 hours. The reaction mixture was cooled to room temperature. The precipitated product was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), yield 80%. XH NMR (CDC13) d 1.26 (3H, t), 3.50 (3H, s), 3.97 (2H, q), 4.03 (3H, s), 6.67 (HI, d), 6.87 (HI, d), 7.12- 7.25 (3H, m), 7.36-7.44 (3H, m). 13 C NMR (CDCl 3) d 13.0 (CH 3), 29.6 (CH 3), 43.8 (CH 2), 56.8 (CH 3), 103.2 (CH), 104.2 (C), 108.3 (CH), 110.5 (C), 127.3 (2CH) , 127.4 (CH), 128.5 (2CH), 131.2 (CH), 141.1 (C), 141.9 (C), 156.9 (C), 157.1 (C), 160.2 (C), 164.4 (C). ESI MS / MS [M + H] +353, fragments 232 and 122.

Essentially in the same manner, the following compounds were obtained from the corresponding starting materials: N-ethyl-N-phenyl-1,2-dihydro-l, 5-dimethyl-4-hydroxy-2-oxo-quinoline-3-carboxamide. 1H-NMR (CDCl3) d 1.21 (3H, t), 2.83 (3H, s), 3.23 (3H, s), 3.98 (2H, q), 6.97 (HI, d), 7.02 (HI, d), 7.10- 7.25 (5H, m), 7.39 (ÍH, t), 13.08 (ÍH, s). 13 C NMR (CDC13) d 12.9 (CH3), 24.4 (CH3) 29.5 (CH3), 45.9 (CH2), 102.8 (C), 112.2 (CH), 114.3 (C), 125.5 (CH), 126.4 (2CH), 126.4 (CH), 128.4 (2CH), 131.7 (CH), 139.6 (C), 142.0 (C), 142.4 (C), 158.1 (C), 169.7 (C), 170.1 (C). ESI MS / MS [M + H] + 337, fragments 216 and 122.

N-ethyl-N-pheny1-1, 2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide. XH NMR (CDC13) d 1.20 (3H, t), 3.28 (3H, s), 3.97 (2H, q), 7.08-7.25 (7H, m), 7.39 (HH, t), 12.6 (HH, s). 13 C NMR (CDCl 3) d 12.9 (CH 3), 29.8 (CH 3), 45.7 (CH 2) 105.0 (C), 112.7 (C), 113.3 (CH), 125.4 (CH), 126.7 (2CH), 126.8 (CH) ), 128.5 (2CH), 131.6 (CH), 132.7 (C), 142.0 (C), 142.6 (C), 157.9 (C), 165.6 (C), 168.7 (C). ESI MS / MS [M + H] + 357, fragments 236 and 122.

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-fluoro-l-methyl-2-oxo-quinoline-3-carboxamide. X H NMR (CDCl 3 + TFA) d 1.28 (3 H, t), 3.66 (3 H, s), 3.93-4.05 (2 H, m), 7.11 (H, q), 7.26-7.37 (6 H, m), 7.68 (H) , q), 11.42 (ÍH, s). 13 C NMR (CDCl 3 + TFA) d 12.6 (CH 3), 31.4 (CH 3), 46.4 (CH 2), 104.4 + 104.5 (C), 108.7 (C), 110.4 + 110.5 (CH), 112.7 + 112.8 (CH), 126.8 (2CH), 129.7 (CH), 129.8 (2CH), 134.1 + 134.2 (CH), 139.9 (C), 141.0 (C), 158.0 (C), 159.3 + 161.3 (C), 161.4 (C), 166.8 ( C); (Some peaks are doublets due to coupling F).

ESI MS / MS [M + H] + 341, fragments 220 and 122.

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-trifluoromethyl-1-methyl-1-2-oxo-quinoline-3-carboxamide. XH NMR (CDC13 + TFA) d 1.21 (3H, t), 3.30 (3H, s), 3.99 (2H, q), 7.10-7.25 (5H, m), 7.42 (HH, d), 7.60 (HH, t), 7. 67 (ÍH, d), 13.05 (ÍH, s). 13 C NMR (CDC 13 + TFA) d 12.5 (CH 3), 31.1 (CH 3), 46.2 (CH2), 106.4 (C), 113.0 (C), 119.5 (CH), 120 + 122.2 + 124.4 (CF3), 123.4 (CH), 126.6 (2CH), 128.1 (CH), 128.1 + 128.3 (C), 129.1 (2CH), 132.1 (CH), 140.5 (C), 141.4 (C), 159. 3 (C), 163.7 (C), 167.8 (C). ESI MS / MS [M + H] + 391, fragments 270 and 122.

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-trifluoromethoxy-l-methyl-2-oxo-quinoline-3-carboxamide.

N-allyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide. X H NMR (CDCl 3) d 3.33 (3 H, s), 4.57 (2 H, m), 5.22 (H, d), 5.38 (H, d), 6.0 (H, m), 7.13-7.30 (7 H, m), 7.44 (ÍH, t), 12.45 (ÍH, s).

N-allyl-N-pheny1-1, 2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide.

X H NMR (CDCl 3) d 3.52 (3 H, s), 4.04 (3 H, s), 4.52 (2 H, m), 5.20 (H, d), 5.37 (H, d), 6.02 (H, m), 6.67 ( ÍH, d), 6.88 (ÍH, d), 7.10-7.23 (3H, m), 7.38-7.45 (3H, m), 9.82 (ÍH, s).

N-Phenyl-N-n-propy1-1, 2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide. X H NMR (CDCl 3) d 1.0 (3 H, t), 1.65 (2 H, m), 3.48 (3 H, s), 3.9 (2 H, t), 4.01 (3 H, s), 6.65 (H, d), 6.83 ( ÍH, d), 7.1-7.25 (3H, m), 7.3-7.45 (3H, m), 9.8 (ÍH, s).

Example 2 N-Eti1-N-pheny1-1, 2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide (Method B) -chloro iso-anhydride (5 g, 25 mmol) was dissolved in 50 ml of N, N-dimethylacetamide and cooled to 0 ° C. Sodium hydride (75%) (0.94 g, 1.1 eq.) Was added followed by methyl iodide (1.89 ml, 12. eq.) At a rate to maintain the temperature below 5 ° C. The reaction mixture was stirred at 20 ° C for 5 hours after which the remaining methyl iodide was removed under vacuum. Sodium hydride (0.94 g, 1.1 eq.) Was added together with N-ethyl-N-phenylcarbamoyl acetic acid ethyl ester (6.3 g, 1.1 eq.). The mixture was heated at 85 ° C for 5 hours. After cooling to room temperature 50 ml of methanol and 50 ml of 1M hydrochloric acid and subsequently 250 ml of water were added. An emulsion was formed which 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 give the title compound (6.12 g). The title compound was recrystallized with methanol in a purity > 95% Example 3 N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-l-methyl-2-oxo-quinoline-3-carboxamide (Method C) To an ice-cooled solution of acid 1, 2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid (9.6 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and N-ethylaniline (4.2 g, 0.035 moles) in 150 ml of dichloromethane was added dropwise over 0.5 hours a solution of thionyl chloride (3.0 ml, 0.042 moles) in 10 ml of dichloromethane. Stirring was continued at 4 ° C for 24 hours. The solvents evaporated. The residue was dissolved in ethyl acetate, filtered through celite and extracted with 2M sodium hydroxide. The aqueous phase was washed with ethyl acetate and then acidified with hydrochloric acid to pH 5. At rest a precipitated, crystalline product was formed which was filtered, washed with water and dried to give the title compound (8.5 g), 69% yield. 1H-NMR (CDC13) d 1.15-1.22 (3H, broad signal), 3.25 (3H, s), 3.95 (2H, broad s), 7.08-7.31 (7H, m), 7.43-7.50 (HH, m).

Essentially in the same manner, the following compounds were obtained from the corresponding starting materials: N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide. NMR XH (CDCl 3 + TFA) d 1.27 (3H, t), 3.57 (3H, s), 3.98 (2H, q), 6.23 (2H, s), 6.86 (HH, d), 7.19 (HH, d), 7.25-7.35 (5H, m), 10.3 (HH, broad). 13 C NMR (CDCl 3 + TFA) d 12.4 (CH 3), 30.9 (CH 3), 46.0 (CH 2), 101.6 (C), 103.7 (CH 2), 107.4 (C), 108.4 (CH), 113. 7 (CH), 126.7 (2CH), 128.8 (CH), 129.3 (2CH), 134.1 (C), 140.1 (C), 143.1 + 143.2 (2C), 157.3 (C), 160.9 (C), 166. 3 (C). ESI MS / MS [M + H] + 367, fragments 246 and 122.

N-ethyl-N-phenyl-l, 2-dihydro-4-hydroxy-5-ethyl-l-methyl-2-oxo-quinoline-3-carboxamide. NMR XH (CDCl 3) d 1.26 (3H, t), 1.31 (3H, t), 3.20-3.34 (5H, m), 4.0 (2H, q), 7.02-7.07 (2H,), 7.13-7.28 (5H, m), 7.44 (ÍH, t) 13.2 (ÍH, a broad). 13 C NMR (CDCl 3) d 13.2 (CH 3), 16.8 (CH 3), 29.8 + 30.2 (CH 3 + CH 2), 46.1 (CH 2), 103.3 (C), 112.5 (CH), 113.9 (C), 124.6 (CH), 126.7 + 126.7 (3CH), 128.6 (2CH), 132.1 (CH), 142. 3 (C), 142.6 (C), 146.2 (C), 158.3 (C), 169.3 (C), 170.4 (C). ESI MS / MS [M + H] + 351, fragments 230 and 122.

N-Phenyl-N-iso-propyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxamide. NMR * H (CDCl 3) d 1.24 (6H, d), 3.38 (3H, broad s), 5.09 (HH, broad signal), 7.08 (HH, d), 7.15 (HH, d), 7.15-7.34 (5H, m), 7.34 (ÍH, t), 11.1 (ÍH, s broad). 13 C NMR (CDC13) d 21.0 (2CH3), 29.9 (CH3), 48.2 (CH), 109. 4 (C), 112.4 (C), 113.5 (CH), 125.1 (CH), 127.9 (2CH), 127.9 (CH), 129.6 (2CH), 131.1 (CH), 131.6 (C), 137. 9 (broad C), 142.1 (C), 158.6 (C), 160.6 (C), 167.5 (C).

N-Phenyl-N- (n-propyl) -1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide.

XH NMR (CDCl3) d 0.95 (3H, t), 1.58-1.69 (2H, m), 3.29 (3H, broad s), 3.88 (2H, broad), 7.08-7.26 (7H, m), 7.41 (1H, t), 12.5 (ÍH, s broad).

Example 4 Sodium salt of N-ethyl-phenyl-1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide A 5 M sodium hydroxide solution was prepared by Diluting a 50% by weight sodium hydroxide solution (10.0 g) with sterile water to the total volume of 25 ml. The N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboximide (10.0 g) was suspended in ethanol (150 ml) and the 5 M sodium hydroxide solution previously prepared was added at pH 8-12 (5.6 ml). The reaction mixture was stirred for another 30 minutes at room temperature. The resulting precipitation was filtered and washed rapidly twice with ethanol (2 x 150 ml). The precipitated product was then dried in vacuo over P205 to give the title compound (9.5 g), yield 90%. 1N-NMR (D20). Two isomers in a 1: 4 ratio. d 0.90 (3H, t, minor form), 1.10 (3H, t, major form), 3.21 (3H, s, major form), 3.50 (3H, s, minor form), 3.50-3.70 (2H, m, form minor), 3.70-3.85 (2H, m, major form), 6.92-7.51 (8H, m, both forms).

EXAMPLE 5 1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester. Phosgene (51 g, 0.52 mol) dissolved in dioxane was added in portions (150 g. ml) was added to a mechanically stirred slurry of sodium bicarbonate (44 g, 0.52 mol) and 2-amino-6-chloro-benzoic acid (30 g, 0.175 mol) in dioxane (300 ml). A violent reaction with gas emission occurred and the reaction mixture was cooled to keep the temperature below 50 ° C. After 30 minutes, the reaction mixture was maintained at 50 ° C for 1 hour. After cooling to 15 ° C, the resulting precipitated product was collected, stirred with 50 ml of glacial acetic acid in 500 ml of water, collected again and dried to give the iso- whic anhydride (30.3 g, 0.15 mol). The anhydride was added slowly in portions to a mixture of sodium hydride (5.5 g, 0.18 mol) in 300 ml of N, N-dimethylformamide. After stirring at room temperature for 1 hour, methyl iodide (26 g) was added dropwise., 0.18 moles) and the stirring was continued for 2 * hours. The mixture was then added to 3 liters of a slurry of ice / water and the precipitated product was collected and dried to yield the N-methylated isathoic anhydride (24.9 g, 0.118 mol). The N-methylated anhydride was heated at 65 ° C with sodium methoxide (6.3 g, 0.117 moles) in 30 ml of methanol for 1 hour. The solvents evaporated. Water and dichloromethane were added and the organic layer was separated, dried and concentrated to yield an oily residue (22.7 g, 0.114 moles). The above residue was dissolved in 300 ml of dichloromethane together with 4-aminopyridine (0.2 g) and triethylamine. (7.1 ml). The solution was cooled and ethyl malonyl chloride (18.9 g, 0.125 mol) was slowly added. The mixture was stirred at room temperature for 4 hours and worked up to give a syrup. To this syrup was added 450 ml of ethanol and sodium methoxide (18.5 g, 0.342 mol) and the mixture was stirred for 3 hours. The solvents were evaporated and the residue was dissolved in 750 ml of water, washed with ethyl acetate and toluene and subsequently acidified with 5M hydrochloric acid. The resulting precipitated product was collected and dried to yield the title compound as a white powder (30 g, 0.106 mol) in a total yield of 60%. 1N-NMR (CDCl 3) d 1.46 (3H, t), 3.63 (3H, s), 4.49 (2H, q), 7.23 (HH, d), 7.27 (HH, d), 7.49 (HH, t), 15.0 ( ÍH, s). Essentially in the same manner, the following compounds were obtained from the corresponding starting materials: 1,2-dihydro-4-hydroxy-5-fluoro-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester, 1,2-dihydro-4-hydroxy-l, 5-dimethyl-2-oxo-quinoline-3-carboxylic acid ethyl ester, Example 6 Ethyl ester of 1,2-dihydro-4-hydroxy-5-trifluoromethyl-1-methyl-2-oxo-quinoline-3-carboxylic acid 2-Fluoro-6- (trifluoromethyl) benzonitrile (10 g, 53 mmol ) was heated at 40 ° C in anhydrous methylamine (200 ml) in an autoclave for 2 days. The excess methylamine was allowed to evaporate and the resulting gray solid was dissolved in dichloromethane (200 ml) together with 4-aminopyridine (0.1 g) and triethylamine (3.3 ml, 26 mmol). To this rapidly cooled solution, ethyl malonyl chloride (8.8 g, 60 mmol) was slowly added. The solution was stirred for 4 hours and then worked up to give a yellowish syrup. The syrup was dissolved in 100 ml of anhydrous ethanol and sodium methoxide (5.4 g, 0.1 mol) was added. After 1 hour, the solvent was removed and the residue was worked up with dichloromethane and water. The quinoline derivative formed was carefully dried and then suspended in anhydrous tetrahydrofuran, cooled rapidly (250 ml). Sodium hydride (4 g, 0.125 mole) and then methyl iodide (10 ml, 0.15 mole) were slowly added. The mixture was heated under reflux for 6 hours, quenched with water and prepared 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 precipitated product was collected to give 8 g of the title compound. XH NMR (CDC13) d 1.46 (3H, t), 3.68 (3H, s), 4.50 (2H, q), 7.58 (H, m), 7.71 (2H, m), 15.0 (H, s).

Example 7 1,2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester To a solution of 2,6-difluorobenzonitrile (42 g, • 0.3 moles) in 150 ml of anhydrous methanol sodium methoxide (17.9 g, 0.33 mol) was slowly added at 30 ° C. After being heated under reflux for 1 hour, 40% aqueous methylamine (133 ml, 1.2 moles) was added and the solution was heated to reflux for 4 days. Upon cooling, a white solid precipitated which was collected by filtration. The solid, 2-methoxy-6- (methylamino) benzonitrile, was dissolved in an aqueous solution of ethylene glycol (500 ml) and potassium hydroxide (14 g). The solution was heated to reflux at 150 ° C overnight, cooled to room temperature and the pH adjusted to 4 with concentrated hydrochloric acid. The precipitated product was collected by filtration, washed with water (50 ml) and dried under vacuum. The white solid, 5-methoxy-anthranilic acid, (32 g, 0.18 mol) and sodium bicarbonate (38 g, 0.45 mol) were suspended in 1,4-dioxane (500 ml) and then phosgene was added slowly (25 ml). , 0.45 moles) under cooling in a bath with ice. The mixture was heated at 40 ° C for 1 hour, cooled to 50 ° C, water (150 ml) was added and the white solid was collected by filtration. After being carefully dried, the solid (20.7, 0.1 mole) was added to a solution of sodium diethylmalonate (0.17 mole) in anhydrous N, N-dimethylformamide (250 ml) at room temperature. The solution was heated to 100 ° C for 3 hours, cooled to room temperature, water (250 ml) was added and the pH adjusted to 4 with concentrated hydrochloric acid. The precipitated product was collected by filtration and dried under vacuum to give the title compound as pure, white crystals, 22 g. NMR XH (CDC13) d 1.43 (t, 3H), 3.62 (s, 3H), 3.96 (s, 3H), 4.45 (q, 2H), 6.70 (d, ÍH), 6.92 (d, ÍH), 7.55 ( t, ÍH), 13.5 (s, ÍH).

Example 8 ethyl ester of 1,2-dihydro-4-hydroxy-l-methyl-2-oxo-5 acid, 6-methylenedioxy-guinolone-3-carboxylic acid. Dicarbonate di-tert-butyl portion (36 g, 0.17 mole) was added portionwise to a solution of 3,4- (methylenedioxy) -aniline (20.6 g, 0.15 mole) in anhydrous tetrahydrofuran (150 ml). The solution was refluxed for 2 hours, then concentrated in vacuo to give a solid, black residue. The residue was dissolved in anhydrous tetrahydrofuran (600 ml) and cooled to -40 ° C. A solution of 1.3 M sec-butyllithium hexane (265 ml, 0.35 mol) was added dropwise. After stirring the solution for 0.5 hours at -40 ° C, pellets of dry ice (approximately 40 g) were added. The mixture was allowed to warm to 0 ° C and water (approximately 700 ml) was added. The aqueous solution was acidified with hydrochloric acid to pH 3 and extracted with ether. The extracts were dried and concentrated to give protected 5-6- (methylenedioxy) anthranilic acid N-tBoc as a solid residue (45 g). This acid was added to a suspension of ice-cold sodium hydride (80% in oil, 9.0 g, 0.30 mol) in N, N-dimethylformamide (200 ml). The mixture was stirred for 0.5 hour and methyl iodide (22 ml, 0.35 mole) 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 5 M sodium hydroxide and extracted three times with ether. The combined extracts were filtered through a column with Si02 and the eluate concentrated under vacuum 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 mole) was added and then, after 30 minutes, triethylamine (22 ml, 0.16 mole). After being stirred for 1 hour at room temperature, the cloudy mixture was washed with 0.5 M 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 precipitated product was collected by filtration and dried under vacuum to give the title compound as gray crystals (17 g, 41% total yield). XH NMR (CDC13) d 1.45 (3H, t), 3.58 (3H, s), 4.48 (2H, q), 6.17 (2H, s), 6.71 (HH, d), 7.14 (HH, d).

Example 9 1,2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-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-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (10.5 g, 38 mmol) was added and the mixture was heated to a 80 ° C for 14 hours. The mixture was cooled to room temperature and the crystalline product was filtered, washed with cold methanol and dried to give the title compound (7.2 g), yield 77%. 1N-NMR (CDC13) d 3.73 (3H, s) 4.02 (3H, s), 6.82 (HH, d), 7.02 (HH, d), 7.62 (HH, t).

EXAMPLE 10 5-Ethyl isathoic 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-ethylaniline (40.8 g, 0.33 mol), water (700 ml) and concentrated hydrochloric acid (33.6 ml) and a mixture of hydroxylamine hydrochloride (74.6 g, 1.04) were added sequentially. moles) 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 precipitated product was filtered, washed with water and dried in vacuo over P205 to give an isonitrosoacetanilide (36.6 g), 58% yield. The isonitrosoacetanilide (10.0 g, 0.05 mol) was added portion by part 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 10-12 times the reaction volume of crushed ice was emptied. The mixture was then allowed to stand for about one hour. The water suspension was extracted with dichloromethane which was dried and evaporated resulting in a mixture of the two isatin analogues of 4-ethyl and 6-ethyl about 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 was in this extracted pH in dichloromethane, which was dried and evaporated give pure 4-ethyl isatin (3.1 g), yield 34%. 4-ethyl isatin (3.1 g, 0.018 mol) was added to a mixture of concentrated sulfuric acid (45 liters) in acetic acid (14 ml). The suspension was heated to 30 ° C, 35% hydrogen peroxide was added (2.2 ml) and after the addition the temperature was raised to 65 ° C. After it was heated for 3 hours, the mixture was cooled and the precipitated product was filtered, washed with water and dried to give the title compound (1.7 g), 48% yield). XH NMR (DMSO-d6) d 1.12 (3H, t), 3.02 (2H, q), 6.98 (H, d), 7.05 (H, d), 7.58 (H, t), 11.6 (H, broad) ).

Pharmacological Methods Experimental, acute autoimmune encephalomyelitis (aEAE) SJL / N female mice, 8 weeks old, were used for the experiments. The homogenate product of the mouse spinal cord (MSCH) was obtained from female C57B1 / 6 mice from 8 to 12 weeks of age. The tissue was homogenized on ice and diluted in cold PBS. The incomplete Freund reaction containing 1 mg / ml of M. tuberculosis hominis H37Ra 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 intradermally 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 days 3 to 12 after immunization or on days 3 to 7 and 10 to 12. The control animals received saline. The animals, eight per dose group, were recorded by the clinical signs of paralytic disease on a scale of 0 to 5 in the following way: 0, normal; 1, relaxed tail; 2, paresis of the hind limb; 3 paralysis of the hind limb and relaxed foreleg; 4, bilateral paralysis of the front and back limbs; 5, death. Clinical records were monitored on day 7 and daily from day 9 until the end of the experiment on day 14. Treatment effects were calculated as a percentage of 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 the mice were immunized intradermally at the base of the tail with bovine type II collagen (100 μg / mouse) in Freund's complete 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 the immunization, the mice were inspected for signs of arthritis. The animals were inspected three times a week. Every second or third day the individual legs of the arthritic animals were recorded on a scale of 0-4 (0 = no arthritis, 1 = arthritis in one of the interphalangeal, metatarsophalangeal or intercarpal joints, 2 = two arthritic joints, 3 = three arthritic joints, 4 = as in 3 but with more severe redness and swelling of the paw). The registration of each leg was added to give a maximum achievable record of 16 for each mouse.

Ovalbumin-induced lung inflammation C57B1 / 6 female mice between 10 to 14 weeks of age, 10 mice / group were used for the experiments. The mouse was sensitized with ovalbumin (OA) in aluminum hydroxide in a volume of 2.0 ml, inoculated ip. Treatment was given on day 0 to day 16. Control mice received saline. Fourteen days after sensitization with OA, the mice were exposed for 20 minutes to an aerosol of 1.5% w / v, of OA in saline produced by a nebulizer. Control mice challenged with the vehicle were exposed to saline. Seventy-two hours after the OA / vehicle test, the mice were anesthetized and bronchoalveolar lavage was performed by installing 0.5 ml of phosphate buffered saline, ice cold (PBS) in the lungs twice. The total cell counts were determined and the differential counts were made based on the identification of eosinophil cells, monocytes / alveolar macrophages, lymphocytes and neutrophils. The infiltration of eosinophilic cells into the lung tissue was evaluated by histochemical methods in frozen sections of the lung using diaminobenzidine tetrachlorohydrate (DAB).

Therapeutic effects in rata The compounds were administered subcutaneously to female rats during day 8 to 14 of pregnancy. The rats were caesarean and the necropsy was done on day 20 after fertilization. The fetuses were examined by the abnormal external and internal.

Beagle Pain Syndrome (BPS) The compounds were administered intravenously to hounds, small dogs. The dosage was given for five consecutive days. Dogs were evaluated for clinical signs and laboratory signs of pain syndrome, eg, fever, increased erythrocyte sedimentation rate (ESR), alkaline phosphate (AP), induction of acute phase proteins and vasculitis. Preferred compounds are N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1- methyl-2-oxo-quinoline-3-carboxamide and N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-l-methyl-2-oxo-quinoline-3-carboxamide plus further named Compounds B, C, D and E, respectively, Roquinimex and N-ethyl-N-phenyl-1, 2- dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide and N- methyl-N-pheny1-1, 2-dihydro-4-hydroxy-5-chloro-l-methy1-2-oxo-quinoline-3-carboxamide hereinafter, named F and G Compounds respectively, reference compounds were included: Arthritic Registry, arthritis induced by type II collagen Embryotoxicity - external malformations route s.c, b) route p.o The effective amounts of the compounds of the formula (I) are preferably administered to a patient in need of such treatment in accordance with the routes of administration and formulated in pharmaceutical compositions., usual comprising an effective amount of the active ingredient and a pharmaceutically acceptable carrier, suitable. Such compositions may take a variety of forms, for example solutions, suspensions, emulsions, tablets, capsules and powders prepared for oral administration, sterile solutions for parenteral administration, suppositories for rectal administration or topical formulations, suitable. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Design", M.B. Aulton, Churchill Livingstone, 1988. 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 being treated, the age and weight of the specific patient, and the response of the specific patient to the medication. The individual, exact dosage, as well as the daily dosage, will be determined in accordance with medical, normal principles under the direction of a doctor or physician. Various additives are contemplated to increase the stability or ease of administration of the drug. The pharmaceutical composition may also contain the therapeutically useful, additional, different substances of a compound of the formula (I) • References 1. Talal, N .: Autoinmmune diseases. In: Roitt, I.M. and Delves, P.J. (eds.) Encyclopedia of Immunology, pages 195-198. Academic Press, 1992. 2. Prineas, J.W .: The neuropathology of multiple sclerosis. In: Koetsier, J.C. (ed.) Handbook of Clinical Neurology, pages 213-257. Elsevier Science Publ., Amsterdam, 1985. 3. Tarkowski, A, Gunnarsson, K., Nilsson. L.-Á., Lindholm, L. and Stálhandske, T. Successful treatment of autoimmunity in MRL / 1 mice with LS2616, a new immunomodulator. Arthritis Rheum. 29 (11): 1405-1409, 1986. 4. Larsson, E.-L., Joki, A.-L. and Stálhandske, T. Mechanism of action of the new immunomodulator LS2616 on T-cell responses. Int J Immunopharmacol 9 (4): 425-31, 1987. 5. 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 47 (2): 216-217, 1989. 6. Kalland, T. Regulation of natural killer progenitors: studies with a novel immunomodulator with distinct effects at the precursor level. J Immunol 144 (11): 4472-4476, 1990. 7. Gonzalo, JA, Gonzalez-Garcia, A., Kalland, T., Hedlund, G., Martinez, C. and Kroemer, G. Linomide, a novel immunomodulator that prevents death in four models of septic shock. Eur J Im unol 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 (quinoline-3-carboxamide). Proc Nati Acad Sci USA 90: 6400-6404, 1993. 9. Gonzalo, J.A., Gonzalez-Garcia, A., Kalland, T. et al. Linomide inhibits programmed cell death of T cell in vivo. Eur J Immunol. 24: 48-52, 1994. 10. Gross, DJ, Sidi, H., Weiss, L., Kalland, T., Rosenmann, E. and Slavin, S. Prevention of diabetes mellitus in non-obese diabetic mice by Linomide , a novel immunomodulating drug. Diabetology 37: 1195-1201, 1994. 11. Karussis, D.M., Lehmannn, -D., Brenner, T. et al. Imniunomodulation of experimental autoimmune myasthenia gravis with Linomide. J Neuroimmunol 55 (2): 187-193, 1994. 12. Bai, XF, Shi, FD, Zhu, J., Xiao, B.G., Hedlund, G. and Link, H. Linomide-induced suppression of experimental autoimmune neuritis is associated with down-regulated macrophage functions. J; Neuroimmunol 76: 177-184 1997. '13. Karussis, D.M. Meiner, Z., Lehmann, 'D. et al. Treatment of secondary progreasive 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 multiple sclerosis. Neurology 47: I 895-900, 1996. 15. Kelly, D.F., Grimsell, C.S.G. and Enyon, C.J. i Polyarteritis in the dog: A case report. Vet Record 92: 363-366, 1973. I 16. Harcourt, R.A. Polyarterites in a1 colony of beagles. Vet Record 102: 519-522, 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 claims is claimed as property.

Claims (32)

1. New compounds of the formula (I) characterized in that R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. -butyl and allyl; R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations; R5 is selected from methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3, and OCHxFy; where x = 0 - 2, y = 1 - 3 with the condition that x + y = 3; Re is hydrogen; or R5 and R6 taken together are methylenedioxy; and any tautomer thereof.
2. 2. The compounds according to 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. 3. The compounds according to claim 1 and 2, characterized in that R 5 is methyl, ethyl, methoxy, chlorine, bromine.
4. 4. The compounds according to claim 3, characterized in that R is ethyl and n-propyl.
5. 5. The compounds according to claim 4, characterized in that R 4 is selected from hydrogen and sodium.
6. 6. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methyl-1-methyl-2-oxo-quinoline-3-carboxamide.
7. 7. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N-pheny1-1,2-dihydro-4-hydroxy-5-ethyl-l-methyl-2-oxo-quinoline-3-carboxamide.
8. 8. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-l-methyl-2-oxo-quinoline-3-carboxamide.
9. 9. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-l-methyl-2-oxo-quinoline-3-carboxamide or its sodium salt.
10. 10. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxamide.
11. 11. The compound according to claims 1 and 2, characterized in that it is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-l-methyl-2-oxo-quinolin-3- carboxamide.
12. 12. The compounds according to any of the preceding claims, characterized in that they are used as therapeutic compounds.
13. 13. The pharmaceutical compositions, characterized in that they contain as an active ingredient a compound having the general formula (I) together with a pharmaceutically acceptable carrier.
14. 14. The pharmaceutical compositions according to claim 12, characterized in that they contain other pharmacologically active substances.
15. 15. The pharmaceutical compositions according to claims 12 and 13, characterized in that they are used as therapeutic compositions 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.
16. 16. A method - for preparing a compound of the general formula (I), characterized by (a) reacting an ester derivative of the quinoline carboxylic acid of the formula (II), preferably the methyl or ethyl ester, with an aniline of the formula (III) in a suitable solvent such as toluene, xylene and the like; or (b) reacting an isathoic anhydride of the formula (IV), with an alkyl ester of N-alkyl-N-phenylcarbamoyl acetic acid of the formula (V), preferably the methyl or ethyl ester, using a strong base, for example, sodium hydride in a suitable solvent such as N, N-dimethylacetamide; or (c) reacting a quinoline carboxylic acid of the formula (IV) with an aniline of the formula (III), using a suitable coupling reagent, preferably a carbodiimide or thionyl chloride in the presence of triethylamine and a suitable solvent such as dichloromethane.
17. 17. A method for the treatment of a mammal suffering from diseases resulting from autoimmunity and pathological inflammation, characterized in that it comprises administering to the mammal a compound having the formula (I) wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. -butyl and allyl; R 4 is selected from hydrogen and pharmaceutically acceptable inorganic or organic cations; R5 is selected from methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chloro, bromo, CF3 and OCHxFy; where x = 0 - 2, y = 1 - 3 with the condition that x + y = 3; R6 is hydrogen; or R5 and Rs taken together are methylenedioxy; and any tautomer of it.
18. 18. A method according to claim 16, 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.
19. 19. The method according to claim 16 and 17, characterized in that R5 is methyl, ethyl, methoxy, chlorine and bromine.
20. 20. The method according to claim 18, characterized in that R is ethyl and n-propyl.
21. 21. The method according to claim 19, characterized in that R4 is selected from hydrogen and sodium.
22. 22. The method according to claims 16 and 17, characterized in that the compound administered is N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinolin-3. -carboxamide or its sodium salt.
23. 23. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from multiple sclerosis (MS).
24. 24. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from insulin-dependent diabetes mellitus (IDDM).
25. 25. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from systemic lupus erythematosus (SLE).
26. 26. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from rheumatoid arthritis (RA).
27. 27. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from inflammatory bowel disease (IBD).
28. 28. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from psoriasis.
29. 29. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from a respiratory, inflammatory disorder, such as asthma.
30. 30. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from atherosclerosis.
31. 31. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from apoplexy.
32. 32. The method according to any of claims 16 to 21, characterized in that it is for the treatment of mammals suffering from Alzheimer's disease.