MXPA01000350A - Quinoline derivatives - Google Patents

Abstract

The invention is related to compounds of general formula (I) wherein R is Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec.-Bu or allyl;R'is hydrogen, Me, MeO, fluoro, chloro, bromo, CF3, or OCHxFy;R''is hydrogen or fluoro, with the proviso that R''is fluoro when R'is fluoro;and further when R'and R''are both hydrogen, R is not Me;R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations;R5 is selected from MeS, EtS, n-PrS, iso-PrS, MeSO, EtSO, MeSO2 and EtSO2;wherein x=0-2, y=1-3 with the proviso that x+y=3;and Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl;and any tautomer, optical isomer and racemate 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 quinoline derivatives with a thio substituent incorporated in position 5, to the 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, insulin-dependent diabetes 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, stroke and Alzheimer's disease. More particularly, the present invention relates to novel quinoline derivatives suitable for the treatment of, for example, sclerosis multiple and its manifestations.

BACKGROUND OF THE INVENTION Autoimmune diseases, e.g., multiple sclerosis (MS), diabetes mellitus dependent on REF. DO NOT. 126008 Insulin (IDDM), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis represent attacks by the body's immune system that could be of a systemic 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. Loss of disability and financial loss are justified, both in the loss of income in medical care, than any other illness in this group age. 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. He , and Á A .1. 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 WO 92/18483, quinoline derivatives substituted with a RAS (0) n group (RA = lower alkyl or aryl, n = 0-2) are claimed to have an immunomodulatory, anti-inflammatory and anti-inflammatory effect. carcinogenic. However, these substituents are only described in position 6 of the quinoline ring.

In addition, in Pat. No. 4,547,511 and Pat. No. 4,738,971 and in EP 59,698 some derivatives of N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamide are claimed as enhancers of cell-mediated immunity. The compound goal Roqumimcx 15 known as roquinimex (Merck Index 12th Ed., No. 8418) belongs to this series of compounds. Roquinimex has been reported to have multiple activities and immunodeficiencies not accompanied by general immunosuppression.

In addition, in Pat. No. 5,580,882 and Pat. No. 5,594,005, WO 95/24195 and WO 95/24196 claim quinol in-3-carboxamide derivatives which are useful in the treatment of associated conditions •? ItttMfir-te with MS, type I diabetes, inflammatory bowel disease and psoriasis, respectively. The preferred particular compound is roquinimex.

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.

In clinical trials comparing roquinimex to placebo, roquinimex was reported to maintain expectations in the treatment of conditions associated with MS (3,4). However, there are some serious drawbacks connected with some quinol derivatives in 3-carboxamide. For example, it has been found that roquinimex is an organic terat 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 compound's full clinical potential.

DESCRIPTION OF THE INVENTION A primary objective of the present invention is to provide structurally-based quinoline compounds .. s í t ** t. new ones that, 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 novel compounds of the general formula (I) , j -l .a. & * & amp; & - *. ^^^^^^^^^ w ^^ 4 ^^^^^^^^^^^^^^^^^^^ j ^^^^ fc ^^. ^ a » where R is selected from Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu and allyl; R 'is selected from hydrogen, Me, MeO, fluorine, chlorine, bromine, CF3 and OCHxFy; R "is selected from hydrogen and fluorine, with the proviso that R" is fluorine when R 'is fluorine and furthermore with the proviso that when R' and R "are both hydrogen, R is not Me; 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, > *. ^ s sfe g fa-i i. morpholine and the like R5 is selected from MeS, EtS, n-PrS, iso-PrS, MeSO, EtSO, MeS02 and EtSO; where x = 0-2, y = 1-3 with the proviso that x + y = 3, and Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; 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. Also included here are the optical isomers and racemates of the compounds of the general formula (I) wherein such forms exist.

In a preferred embodiment of the invention R4 is selected from hydrogen and sodium, Vfcal yi R5 is selected from MeS and EtS, R is selected from methyl, ethyl and propyl, R 'is selected from methoxy, fluorine, chlorine and trifluoromethyl, when R "is hydrogen and R is methyl; R "is selected from m e t a 'and para-fluoro when R' is ortho-fluorine and R is methyl, and R 'and R" are both hydrogen when R is ethyl and propyl.

Among the most preferred compounds of the formula (I) according to the present invention are: N-ethyl-N-phenyl-1,2-dihydro-hydroxy-5-t-iomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-n-propyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-t-ylmethyl-1-methyl-2-oxo-quinoline-3-carbo-amide, N-methyl-N- (4-methoxy-phenyl) -1,2-dihydro-hydroxy-5-t-ylmethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N- (2,4-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3 carboxamide, N-methyl-N- (2, 5-difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, 15 N-ethyl- N-phenyl-l, 2-dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline-3-carboxamide, N-n-propyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline-3-carboxamide, and N-methyl-N- (2,4-difluoro-phenyl) -l, 2-dihydro-4-hydroxy-5-methylsulfinyl-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 activity ** - * »S * k Jtfaá & H? U * epithelial and promote bronchial hyperresponse. 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) (5, 6) 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 encephalomyelitis (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-thiomethyl compound was increased to 100 fold. The corresponding substitution at position 6 resulted in fewer active compounds, as shown in the examples.

In addition, appropriate aromatic substitution of the 3-carboxamide radical of the compounds of the general formula (I) significantly reduced or even abolished the side effects, i.e., the teratogenic effects and the BPS of roquinimex. In this way, the physicochemical properties of the substituent 5 on the quinoline radical and the substituent or to, meta and / or, in particular, for the 3-carboxamide radical are of primary importance for an improved risk / benefit ratio compared to with 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 maniestations.

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: Mé t o do A: m The compounds of the general formula (I) could be prepared by the known methods and, for example, as shown above, by the reaction of an ester derivative of the quinoline carboxylic acid with an aniline in an appropriate solvent, such as toluene, xylene and the like. 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. The compounds that fall within the scope of formula (III) could be prepared by methods, which are generally analogous to those in the literature.

M e t o d o B rv m 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-thiomethyl-l-methyl-2-oxo-quinoline-3-carboxylic acid ester. 2.6-Difluorobenzonite ryl (13.2 g, 0.10 mol) was slowly added to a solution of sodium sulfide monohydrate (26.4 g, 0.11 mol) in 300 ml of N, N-dimethylformamide. After stirring the solution overnight, it was worked up with ether and 1M hydrochloric acid. The ether phase was treated with 1M sodium hydroxide and then the aqueous phase was acidified with hydrochloric acid followed by extraction of the ether. The ether phase was carefully dried and the solvent was removed. The residue (12.5 g) was added in portions to a solution of sodium hydride (3.8 g, 0.12 mol) in 300 ml of N, N-dimet and cold formamide, followed by the addition of methyl iodide (10 ml, 0.15 mol). The mixture was stirred for 6 hours at room temperature, poured into cold water and the precipitate Resulting, 2-fluoro-6-iomethyl-1-benzo-thiol, filtered and dried. The precipitate was heated 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 yellow solid (16 g) was dissolved in 200 ml of dichloromethane together with 4-aminopyridine (0.1 g, 0.001 mol) and triethylamine (5.6 ml, 0.045 mol). To this frozen solution was slowly added ethyl malonyl chloride (15 g, 0.10 mol). The solution was stirred for 4 hours and worked up to give a yellowish syrup. The syrup was dissolved in 100 ml of anhydrous ethanol, and sodium methoxide (7.5 g, 0.14 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 suspended in 250 ml of frozen anhydrous tetrahydrofuran and sodium hydride (5.3 g, 0.175 mol) was slowly added, followed by the addition of methyl iodide (13 ml, 0.21 mol). The mixture was heated under reflux for 6 hours, quenched with water and worked up with diethyl ether. The solvents were removed / the residue (17.3 g) was dissolved in a mixture of 100 ml of ethanol and 5 ml of concentrated hydrochloric acid. The solution was heated at 80 ° C for 4 hours, cooled and the precipitate was collected and purified by chromatography «AÉto. on silica gel to give the title compound (4 g).

X H NMR (CDCl 3) d 1.46 (3H, t), 2.48 (3H, s), 3.62 (3H, s), 4.48 (2H, q), 6.98 (1H, d), 7.05 (1H, d), 7.52 ( 1H, 5 t), 15.5 (1H, s).

Example 2 N-Et i 1-N-phenyl-1,2-dihydro-4-hydroxy-5-thiomethyl-l-0-meth yl-2-oxo-quinoline-3-carboxamide.

N-ethylanimine (3.0 g, 0.025 mol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled to obtain a solution. 1,2-Dihydro-hydroxy-5-1-yl-1-l-methyl-2-yl-quinoline-3-carboxylic acid ethyl ester (2.9 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 0 to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.1 g), 57% yield.

? H NMR (CDCl3) d 1.22 (3H, t), 2.47 (3H, s), 3.35 (3H, 5 s), 3.96 (2H, q), 7.06 (1H, d), 7.09 (1H, d), 7.14-7.26 LITMlM-rlIiílifcj &XI- »• * & ** -A ntüÁ?.») * > .... -ma A T A .Í t (5H, m), 7.45 (1H, t 13 C NMR (CDCl 3) d 13.0 (CH 3), 18.5 (CH 3), 29.7 (CH 3), 45. 4 (CH2), 105.2 (C), 112.1 (CH), 113.1 (C), 121.8 (CH), 126.7 (CH), 126.9 (CH), 128.5 (CH), 131.4 (CH), 138. 7 (C), 142.3 (C), 158.5 (C), 165.5 (C), 168.4 (C).

ESI MS / MS [M + H] + 369, fragments 248 and 122.

In essentially the same manner the following compounds of the corresponding initiator materials were obtained: N-allyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-thiomethyl-l-met i 1 -2 -oxo-quinolin-3-carboxamide, N-methyl-N-phenyl-1, 2-dihydro-4-hydroxy-5-thiomethyl-l-met il-2 -oxo-quinoline-3-carboxamide (not included in the claims), 2 H NMR (CDCl 3) d 2.45 (3 H, s), 3.38 (3 H, s), 3.48 (3 H, s), 7.04 (1 H, d), 7.06 (1 H, d), 7.11-7.25 (5 H, m), 7.43 (1H, t). 13 C NMR (CDCl 3) d 18.3 (CH 3), 29.5 (CH 3), 38.4 (CH 3), 104.6 (C), 112.0 (CH), 113.2 (C), 121.5 (CH), 125.7 (CH), 125.7 (CH) ), 126.8 (CH), 128.7 (CH), 128.7 (CH), 131.5 (CH), 139.1 (C), 142.3 (C), 144.2 (C), 158.7 (C), 166.0 (C), 169.1 (C) ).

ESI MS / MS [M + H] + 355, fragments 248 and 108.

N-n-propyl-N-phenyl-l, 2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-1-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-t-methyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N- (4-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-t-ylmethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-ethoxy-f-enyl) -l, 2-dihydro-4-hydroxy-5-t-ylmethyl-1-methyl-2-oxo-quinol-3-carboxamide, XH NMR (CDC13) d 2.43 (3H, s), 3.39 (3H, s), 3.40 (3H, s), 3.72 (3H, s), 6.72 (2H, signal width), 7.01-7.21 (4H, m ), 7.44 (1H, t). 13 C NMR (CDCl 3) d 18.6 (CH 3), 29.9 (CH 3), 38.4 (CH 3), 55.4 (CH 3), 112.3 (CH), 113.2 (C), 113.9 (CH), 123 (CH), 127.1 (CH), 131.4 (CH), 137 (C), 138 (C), 142.3 (C), 158.2 (C), 158.7 (C), 169 (C).

ESI MS / MS [M + H] + 385, fragments 248 and 138.

Example 3 N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline-3-carboxamide (not included in the claims).

N-Methyl-N-phenyl-1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide (0.14 g, 0.32 mmol) was dissolved in 5 ml of dichloromethane. The solution was cooled in an ice bath and 70% 3-chloroperoxybenzoic acid (83.3 mg, 0.34 mmol) dissolved in 2 ml of dichloromethane was slowly added. After stirring for 4 hours, the solution was triturated with 3 ml of heptane followed by recrystallization of the precipitate from ethyl acetate-pentane to give the title compound (25 mg).

XH NMR (CDC13) d 2.79 (3H, s), 3.39 (3H, s), 3.50 (3H, s), 7.15-7.29 (5H, m), 7.35 (1H, d), 7.75 (1H, t), 8.06 Íw »< n * .- (1H, d) ESI MS / MS [M + H] + 371, fragment 264 In essentially the same manner, the following compound was obtained from the corresponding starter materials: N-ethyl-N-phenyl-l, 2-dihydro-4-hydroxy-5-methylsulfinyl'l-methyl-2-oxo-quinoline-3-carboxamide, N-n-propyl-N-phenyl-l, 2-dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-methoxy-phenyl) -1,2-dihydro-4-hydroxy-5-yl-1-sulfin-1-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-chloro-phenyl) -1,2-dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline-3-carboxamide.

* «Tt * + i ^ í- & M,% * -g -« ^ ~ ^ -. y- -C A g -. »- > J * **. *. i * ** ***** «. -A? 1. ¿¿¿.

Example 4 N-methyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-hydroxy-5-thiomethyl-l-methyl-2-oxo-quinoline-3-carboxamide (Method B).

To an ice-cooled solution of 1,2-dihydro-4-hydroxy-5-thiomet il-1-met il-2-oxo-quinoline-3-carboxylic acid (8.5 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and 4-1 rif luorome ti 1 -N-me ti lani 1ane (6.1 g, 0.035 mol) in 150 ml of methylene chloride was added dropwise over 0.5 hours to a solution of sodium chloride. thionyl (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 1M sulfuric acid and extracted with 1M sodium hydroxide. The pH of the aqueous phase was adjusted to 8-8.5, clarified by filtration and then acidified with hydrochloric acid solution to pH 4. A crystalline precipitate was formed at rest which was filtered, washed with water and dried to give the title compound (8.5 g), yield 72%.

In essentially the same manner the following compounds were obtained from the corresponding initiator materials: N-ethyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-methyl-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-quinoline-3-carboxamide, N-ethyl-N- (2,4-difluoro-phenyl) -l, 2-dihydro- -hydroxy-5-t-ymethyl-1-methyl-yl-2-oxo-quinoline-3-carb oxamide, N-methyl-N- (2, -difluoro-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-l-methyl-2-oxo-quinoline-3-carboxamide, ? ti NMR (CDC13) d 2.46 (3H, s), 3.33 (3H, s), 3.37 (3H, s), 6.63 (1H, broad), 6.83 (1H, wide), 6.95-7.15 (3H, m, wide), 7.45 (1H, t). 13 C NMR (CDCl 3) d 17.7 (CH 3), 29.8 (CH 3), 37.2 (CH 3), 103.2 (C), 104.6 + 104.8 + 105.0 (CH), 110.5 (CH), 111.3 (CH), 112.7 (C), 120.1 (CH), 128.4 (C), 128.5 (CH), 131.9 (CH), 140.6 (C), 142.6 (C), 156. 9 + 157.0 + 159.0 + 159.1 (C), 158.4 (C), 160.6 + 162.6 (C), 168.0 (C), 170.4 (C); some peaks are multiple due to coupling F.

ESI MS / MS [M + H] + 391, fragment 248.

N-methyl-N- (2,5-difluoro-phenyl) -1,2-dihyd or-4-hydroxy-5-t iomet il-1-met il-2-oxo-quinoline-3-carboxamide and N-methyl-N- (4-trif luoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline-3-carboxamide and N-methyl-N- (2,4-difluoro-phenyl) -1,2-dihydro-hydroxy-5-methylsulfinyl-methyl-2-oxo-quinoline-3-carboxamide.

Pharmacological methods Encefalomiel i t i s autoimmune experimental come (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. ff ^^^^ 1 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ g ^^^^^ ^^ j ^^^ * ^^^^ * ^^^^^^^ gg ^^^ g¿ M. tuberculosis hominis H37Ra 1 mg / ml containing incomplete Freund's adjuvant was emulsified with an equal volume of MSCH for give a final concentration of 10 mg / ml of MSCH. The inoculum volume of 0.1 ml was injected int radiometrically 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, the 5 mice were immunized int radérm cament e 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 = without arthritis, 1 = arthritis in one of the inthalangeal joint, metat arsofalangiana or int ercarpiana, 2 = two arthritic joints, 3 = three arthritic joints, 4 = as in 3, but with more severe red color and swelling of the paw) . Register for each leg was added to give a maximum achievable reading of 16 for each mouse.

Inflammation of the ovalbumin-induced lung Female mice were used for the experiments C57B1 / 6 between 10 to 14 weeks of age, 10 mice / group. 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 bronchial lavage was performed infiltrating 0.5 ml of phosphate buffered saline (PBS) cooled with ice in the lungs twice. The total cell counts were determined and the differential counts were made based on the identification of eosinophils, alveolar monocytes / macrophages, lymphocytes and neutrophils. Eosinophil infiltration in the lung tissue was evaluated by histochemical methods in sections of the lung frozen using t et raclorhidrat or diaminobenz idina (DAB).

Efe c t os t ogen t ogen e s FtJ-5-a 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.

Yes n drome d or Bea gl e (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, erythrocyte sedimentation rate increased (ESR), alkaline phosphate (AP), induction of acute phase proteins and vasculitis.

Among the preferred compounds are N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-thiomethyl-l-methyl-2-oxo-20-quinoline-3-carboxamide and N-met-il-N - (2,4-difluorophenyl) -1,2-dihydro-4-hydroxy-5-thiomet il-1-met-il-2-oxo-quinoline-3-carboxamide subsequently called Compound A and B, respectively. N-et i 1-N-phenyl-1,2-dihydro-4-hydroxy-6-t-ylmethyl-l-methyl-2-oxo-quinoline-3-carboxamide and N-met i 1 -N- ( 2, -di fluoro-feni 1) - 1, 2 - dihydro-4-hydroxy-6-thiomethyl-l-methyl-2-oxo-quinoline-3-carboxamide are included as the reference compounds subsequently called Compound C and D, respectively.

Inhibition of aEAE Toraenic tera effects in the rat While in a dosage of 6 mg / kg / day of N-methyl-N-phenyl-l, 2-dihydro-4-hydroxy-5-thiomethyl-l-met i 1 -2 -oxo-quinol in 3 - Carboxamide was found to be teratogenic in the rat, Compounds A and B were found to be non-teratigenic.

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, which comprise an effective amount of the active ingredient and a suitable 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 inhalation, sterile solutions for parental administration, suppositories for rectal administration or appropriate topical formulations. 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 neuropathology of multiple sclerosis. In: Koetsier, J.C. (Ed.) Handbook of Clinical Neurology, pp. 213-257. Elsevier Science Publ., Amsterdam, 1985. 3. Karussis, D.M. Meiner, Z. Lehmann, D. et al. Treatment of multiple progressive sclerosis Jfci l i with the immunomodulator Linomide. Neurology 47: 341-346, 1996. 4. Andersen, 0., Lycke, J., Tollesson, P.O. et al. Linomide reduces the rate of active lesions in relaps ing-remi t t ing multiple sclerosis, Neurology 47: 895-900, 1996.

. Kelly, D.F., Grumsell, C.S.G. and Kenyon, C.J. Polyarteritis in the dog: A case report :. Vet Record 92: 363-366, 1973. 6. Harcourt, R.A. Polyarteri t is in a 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 is claimed as property. 4 ? J í "and & ,; ^ *. + T;»

Claims (35)

1. The compounds of the general formula (I) characterized because R is selected from Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu and allyl; R 'is selected from hydrogen, Me, MeO, fluorine, chlorine, bromine, CF3 and OCHxFy; R "is selected from hydrogen and fluorine, with the proviso that R" is fluorine when R 'is fluorine and furthermore with the proviso that when R' and R "are both hydrogen, R is not Me; R, is selected from hydrogen and cations »... > . Inorganic and organic pharmaceutically acceptable inorganic and organic compounds; R5 is selected from MeS, EtS, n-PrS, iso-PrS, MeSO, EtSO, MeS02 and EtS02; where x = 0-2, y = 1-3 with the proviso that x + y = 3, and Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; and any tautomer, optical isomer and racemate of the same.

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

3. The compounds according to claims 1 and 2, characterized in that R5 is selected from MeS and EtS.

4. The compounds according to claims 1 and 2, characterized in that R is methyl when at least one of R 'and R "is not hydrogen.

5. The compounds according to claims 1 and 2, characterized in that R is ethyl or propyl and R 'and R "are not both hydrogen.

6. The compound according to claims 1, 2, 3 and 5, characterized in that it is Nn-propyl-N-phenyl-1,2-dihydro-4-hydroxy-5-t iomethyl-1-met i 1-2 -oxo -quinolin-3 -carboxamide.

7. The compound according to claims 1, 2, 3 and 4, characterized in that it is N-met il-N- (4-trifluoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-t iomet il-1 -met i 1-2 -oxo-quinoline-3-carboxamide.

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

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

10. The compound according to claims 1, 2, 3 and 5, characterized in that it is Nn-propyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methylsulfinyl-1-met il-2 -oxo- quinoline-3-carboxamide.

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

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

13. The pharmaceutical compositions according to claim 12, characterized in that they contain other pharmacologically active substances.

14. The pharmaceutical compositions according to claims 12 and 13, 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.

15. A process for the preparation of a compound of the general formula (I), wherein R, R ', R ", R4 and R5 are as defined above, characterized by the process by (A) reacting a quinoline carboxylic acid ester derivative of the formula (II) m 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), using an appropriate coupling reagent, preferably a carbodiimide or thionyl chloride in the presence of tetylamine and an appropriate solvent such as dichloromethane.

16. 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) (D where R is selected from Me, Et, n-Pr, so-Pr, n-Bu, iso-Bu, sec-Bu and allyl; R 'is selected from hydrogen, Me, MeO, fluorine, chlorine, bromine, CF3 and OCHxFy; R "is selected from hydrogen and fluorine, with the proviso that R" is fluorine when R 'is fluorine and furthermore with the proviso that when R' and R "are both hydrogen, R is not Me; R 4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations; R5 is selected from MeS, EtS, n-PrS, iso-PrS, MeSO, EtSO, MeS02 and EtS02; where x = 0-2, y = 1-3 with the proviso that x + y = 3, and Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; t L ^ -., A-i and í. ¿PM.nníiH.ñ-: and any tautomer, optical isomer and racemate of the same.

17. The 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, dimethylaminoet anol, morpholine and the like.

18. The method according to claims 16 and 17, characterized in that R5 is selected from MeS and EtS.

19. The method according to claims 16 and 17, characterized in that R is methyl when at least one of R 'and R "is not hydrogen.

20. The method according to claims 16 and 17, characterized in that R is ethyl or propyl and R 'and R "are not both hydrogen.

21. The method according to claims 16 and 17, characterized in that it is N-n-propyl-N-phenyl-1,2-dihydro-4-hydroxy-5-t iomet il-1-met il-2-oxo-quinolin- yj $ k. . . . -tgyyj *. tLitA * ^. , *. A * AS. , .- ¿¿-...; -, -anafe -.-- .- .j: ... r, _s? _ ^^^ L _ ^^ - a - »^ * LÍ2Í-iÉ_ív ^ - ^^ - 3-carboxamide

22. The method according to claims 16 and 17, characterized in that it is N-met il-N- (- trif luoromethyl-phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-l-methyl-2-oxo -quinolin-3-carboxamide.

23. The method according to claims 16 and 17, characterized in that it is N-methyl-N- (2,4-difluoro-10 phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2 - oxo-quinoline-3-carboxamide.

24. The method according to claims 16 and 17, characterized in that it is N-methyl-N- (2, 5-di fluoro¬) Phenyl) -1,2-dihydro-4-hydroxy-5-thiomethyl-1-methyl-2-oxo-qu i non-3-carboxamide.

25. The method according to claims 16 and 17, characterized in that it is Nn-propyl-N-phenyl-l, 2- 20 dihydro-4-hydroxy-5-methylsulfinyl-l-methyl-2-oxo-quinoline- 3 - carboxamide.

26. The method according to any of claims 16 to 25, characterized in that it treats 25 to mammals suffering from multiple sclerosis (ES).

27. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from insulin dependent diabetes mellitus (IDDM).

28. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from systemic lupus erythematosus (SLE).

29. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from rheumatoid arthritis (RA).

30. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from inflammatory bowel disease (IBD).

31. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from psoriasis.

32. The method according to any of claims 16 to 25, characterized in that it treats ȣ & A ^ a &^ ^ ^ mammals suffering from inflammatory respiratory disease, such as asthma.

33. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from atherosclerosis.

34. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from attack.

35. The method according to any of claims 16 to 25, characterized in that it treats mammals suffering from Alzheimer's disease. AA ü Bí Jn ?. Í '1 i.