TREATMENT OF A PATHOLOGY RELATED TO AN EXCESSIVE EFFECT OF TNF BY A BENZENE SULFONAMIDE COMPOUND

Abstract

A benzene sulfonamide compound of formula I or one of its addition salts with pharmaceutically acceptable acids, for use in a method of treating a pathology related to an excessive effect of TNF and for use in a method of treating the human or animal body.

Description

C1-C5 alkylsulfonyl acyl, amino nitro, C1-C6 alkylamino di(C1-C6 alkyl)amino, acylamino, - a group chosen from R2 represents - a hydrogen atom, - a C4-C7 phenyl or cycloalkyl group optionally substituted by one or more substituents, preferably 1, 2 or 3, in particular 1 or 2 substituents chosen from the radicals C1-C5 alkyl, C1-C5 alkenyl, halo, C3-C8 cycloalkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, acyl, amino, nitro, C1-C6 alkylamino, di(C1-C6 alkyl)amino, acylamino, two substituents meta to each other may form a ring said group being directly linked to nitrogen, or linked by a group -(CH2)n- where n= 1, 2 or 3, preferably 1 or 2, it being understood that R1 and R2 cannot at the same time represent hydrogen, X represents a hydrogen atom or one or more substituents, preferably 1, 2 or 3, in particular 1 or 2 substituents chosen from C1-C5 alkyl, C1-C5 alkenyl, halogeno, C3-C8 cycloalkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl radicals acyl, amino nitro, C1-C6 alkylamino 5 di(C1-C6 alkyl)amino, acylamino, as well as the following compounds for which R2 = H: the compound for which X= 2-methyl and 5- andR1 = the compound for which X= 4- the compound for which X= 4- H the compound for which X= 2-methyl and 5- as well as their addition salts with pharmaceutically acceptable acids. These compounds are known and commercially available from ChemBridge Corporation (www.chembridge.com). These compounds can be prepared according to well-known methods. Examples include Lemaire et al, Eur J Org Chem 13, 2840:2847 (2004), and Adams, R and Whitaker, L, J Am Chem Soc (1953),78:658-663 showing how different benzinic acids or active methylene derivatives, when placed in the presence of p-quinonemonobenzenesulfonimide or naphthoquinonemonobenzenesulfonimides in an acidic medium, form benzofuran or naphthofuran derivatives, respectively. The term "C1-C5 alkyl" means a straight or branched alkyl group of 1 to 5 carbon atoms inclusive, such as methyl, ethyl, propyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl, preferably methyl or ethyl, Similarly, "C2-5 alkenyl" and "C2-5 alkynyl" respectively refer to such groups having from 2 to 5 carbon atoms inclusive. Halogen means fluoro, chloro, bromo or iodo. The term "C3-C8 cycloalkyl" means a monocyclic or bicyclic carbocycle of 3 to 8 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The terms C1-C5 alkoxy, C1-C5 alkylthio and C1-C5 alkylsulfonyl denote such groups in which the C1-C5 alkyl group is as defined above. The term "acyl" means -CO-alkyl where the alkyl group is C1-C5 alkyl as defined above. "Amino" means NH2. "C1-C5 alkylamino" means -NH-alkyl and "di(C1-C5 alkyl)amino" means -N-(alkyl)2 where the alkyl group is C1-C5 alkyl as defined above. "Acylamino" means -NH-acyl where acyl has the definition above. The organic group containing from 6 to 30 carbon atoms including one or more saturated or unsaturated, fused or unfused cycles or heterocycles may comprise, as cycles or heterocycles, phenyl groups, mono- or bicyclic heterocyclic groups containing at least one N, S or O atom, such as furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrimidyl, tetrazolyl, benzofuranyl, benzothienyl, benzimidazolyl, indolyl groups. Preferred heterocycles are monocyclic aryls. Especially preferred are thienyl and piperidinyl groups. Organic groups containing from 6 to 30 carbon atoms including one or more saturated or unsaturated, fused or unfused cycles or heterocycles are preferred phenyl, benzyl, phenethyl, piperazinyl, phenylpiperazinyl, phenylamino, benzylamino, benzo(c)piperidinyl groups. Their preferred substituents are C1-C5 alkyl, C1-C5 alkenyl, halogeno and C1-C5 alkoxy groups. Examples of organic acid addition salts according to the invention are those formed with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline-acetic acids. Examples of inorganic acid addition salts according to the invention are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids. Their toxicological properties are also well known. However, the applicant has discovered with astonishment that the compounds of formula I above possess very interesting original pharmacological properties. In particular, they have remarkable anti-TNF alpha properties. These properties are illustrated further in the experimental section. They justify the use of the benzene sulfonamide compounds described above and their addition salts with pharmaceutically acceptable acids for the manufacture of a medicament intended for the treatment of a pathology linked to an excessive effect of TNF, or of an anti-TNF agent. This is why the present invention relates to the benzene sulfonamide compounds of formula I described above for their use in a method of treating a pathology linked to an excessive effect of TNF. Among the compounds described above, we particularly retain the compounds of formula I for which R2=H as well as their addition salts with pharmaceutically acceptable acids. We also retain the compounds of formula I for which R2=H and R1 represents - a benzofuran group, preferably 5-benzofuran or naphthofuran, preferably 5-naphthofuran optionally substituted by one or more substituents, preferably 1, 2 or 3, in particular 1 or 2 substituents chosen from the radicals C1-C5 alkyl, preferably methyl or ethyl, C1-C5 alkenyl, halogeno, C3-C8 cycloalkyl C1-C5 alkoxy, preferably methoxy or ethoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl acyl, amino C1-C6 alkylamino di(C1-C6 alkyl)amino, acylamino, or - a group chosen from groups a, b, c, d, e, f, g, h, i and j above, as well as their addition salts with pharmaceutically acceptable acids. Also particularly relevant are the compounds of formula I above for which R1 represents a group - CHR4 - CO- R3, in which R3 and R4 have the meaning already indicated and R2 represents an optionally substituted phenyl or C4-C7 cycloalkyl group, as well as their addition salts with pharmaceutically acceptable acids. Among the compounds of the invention, mention may be made more particularly of the products cited in the examples, in particular those whose percentage of inhibition 10pM is greater than 50%, particularly greater than 60%, very particularly greater than 70% as well as their addition salts with pharmaceutically acceptable acids. On peut citer plus particulièrement les produits suivants, ainsi que leurs sels d'addition avec les acides pharmaceutiquement acceptables : 1- le N-(3-acetyl-2-methylnaphtho[1,2-b]furan-5-yl)-4- ethoxybenzenesulfonamide 2- le N-(3-acetyl-2,6-dimethyl-1-benzofuran-5-yl)-4- methoxybenzenesulfonamide 3- le N-benzyl-4-methoxy-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2- oxoethyl}-3-methylbenzenesulfonamide 4- le methyl 1-(2-fluorophenyl)-2-methyl-5-oxo-4-[(5- {[(phenylsulfonyl)amino]methyl}-2-furyl)methylene]-4,5-dihydro-1H-pyrrole-3-carboxylate 5- le methyl 5-{[(4-methoxyphenyl)sulfonyl]amino}-2-methyl-1-benzofuran-3-carboxylate 6- le N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4- methoxybenzenesulfonamide 7- le N~2~-(3-chlorobenzyl)-N~1~-(2,4-dimethoxyphenyl)-N~2~-[(4- methylphenyl)sulfonyl]glycinamide 8- le 3-(4-fluorophenyl)-4-oxo-4H-chromen-7-yl N-[(4-methylphenyl)sulfonyl]- beta-alaninate 9- le methyl 2-methyl-5-{[(4-methylphenyl)sulfonyl]amino}-1-benzofuran-3- carboxylate 10- le 5-[4-(benzylamino)-1 -phthalazinyl]-2-methyl-N-(tetrahydro-2-furanylmethyl)benzenesulfonamide 11 - le N-(1,2-dihydro-5-acenaphthylenyl)-2,4,6-trimethylbenzenesulfonamide 12- le N~1 — (3-acetylphenyl)-N~2~-(2,5-dimethoxyphenyl)-N~2~-[(4- methylphenyl)sulfonyl]glycinamide The compounds according to the present invention find their use for example in the treatment both curative and preventive of chronic inflammatory diseases known to be linked to the overproduction of TNF alpha such as: inflammatory bowel diseases, inflammations, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, bone resorption / osteoporosis, Crohn's disease, septic shock, endotoxin shock, atherosclerosis, ischemia-reperfusion injuries, coronary artery disease, vasculitis, amydoloidis, multiple sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus, malaria, ulcerative colitis, cachexia, psoriasis, plasmacytoma, endometriosis, Behçet's disease, Wegener's granulomatosis, meningitis, AIDS, HIV infections, autoimmune diseases, immune deficiency,Common variable immunodeficiency (CVID), chronic graft / host disease, trauma and transplant rejection, respiratory distress syndrome, pulmonary fibrosis, recurrent ovarian cancer, lymphoproliferative disorder, refractory multiple myeloma, myeloproliferative disorder, diabetes, juvenile diabetes, ankylosing spondylitis, and skin disorders due to delayed hypersensitivity reactions, Alzheimer's disease, systemic lupus erythematosus, and allergic asthma. The usual dose, which varies depending on the subject being treated and the condition in question, may be, for example, 1 mg to 5000 mg, preferably 10 mg to 3000 mg, possibly from 100 mg to 3000 mg per day orally in humans of the compound of Example 1, taken daily or taken in alternating periods depending on the disease considered. The present invention also relates to the benzene sulfonamide compounds of formula I described above for their use in a method of treatment of the human or animal body, in particular human. As medicaments, the compounds corresponding to general formula I as well as their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route. These pharmaceutical compositions may be, for example, solid or liquid and may be in the pharmaceutical forms commonly used in human medicine, such as, for example, plain or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods. The active ingredient(s) may be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives. In these compositions, the active ingredient is advantageously present at physiologically effective doses; the aforementioned compositions contain in particular an effective dose of 500 mg or for example 100 mg of at least one active ingredient above. The present invention therefore also relates to the above pharmaceutical compositions, in particular the above pharmaceutical compositions for their use in a method of treating a pathology linked to an excessive effect of TNF. The present invention also relates to a process for preparing a composition described above, characterized in that one mixes, according to methods known in themselves the active ingredient(s) with acceptable excipients, in particular pharmaceutically acceptable ones. The present invention also relates to a process for preparing an anti-TNF agent, characterized in that a compound of formula I or one of its addition salts with pharmaceutically acceptable acids is used as the essential active constituent of said agent. According to another of its aspects, the invention relates to a set comprising two anticancer agents including (i) at least one benzenesulfonamide compound above and (ii) at least one agent useful for the prevention and / or treatment of cancer, said agent being different from said benzenesulfonamide compound. A method of treating diseases known to be related to the overproduction of TNF alpha, including chronic inflammatory diseases, comprises administering to a patient a physiologically effective dose of at least one of the above active ingredients. The preferential conditions for implementing the uses of the compounds of formula I described above also apply to the other objects of the invention referred to above, in particular to the above processes. The following examples illustrate this application. Figure 1 shows the inhibition curve obtained with compound 6 versus human TNF-alpha DO activity at 570 nm as a function of the log concentration of the test compound. Figure 2 shows the activity index obtained with compound 6 as a function of time in days after DSS administration in a DSS-induced mouse colitis model. Figure 3 shows the clinical arthritis scores obtained with compound 6 as a function of time in days after last collagen injection in a collagen-induced murine arthritis model. Figure 4 shows the number of surviving mice as a function of the product administered in a murine model of endotoxin shock. EXAMPLE 1 Tablets were prepared with the formula N-(3-acetyl-2-methylnaphtho[1,2-b]furan-5-yl)-4-ethoxybenzenesuifonamide..................................10 mg Excipient qs for a finished tablet at ..100 mg (details of the excipient: lactose, starch, talc, magnesium stearate) EXAMPLE 2 Scored tablets of the formula N-(3-acetyl-2,6-dimethyl-1-benzofuran-5-yl)-4-methoxybenzenesulfonamide..........................................15 mg were prepared Excipient qs for a finished tablet at ..100 mg (details of the excipient: lactose, starch, talc, magnesium stearate). EXPERIMENTATION 1 / Effects of compounds of formula I on human TNF-alpha activity The compounds were dissolved in DMSO at a concentration of 10 mM and stored at -20 °C. The compounds were tested for their potential to inhibit human TNF alpha-induced apoptosis on murine L929 cells. The cells were cultured in RPMl medium supplemented with 10% fetal bovine serum. 4 x 104 cells in 200 μl of culture medium were exposed for 24 h in 96-well plates to human TNF alpha (R & D Diagnostics) at different concentrations, and the compound at a final concentration of 100 μM and 10 μM, XTT staining agent solution was added (20 μl at 5 mg / ml) to each well for two hours to measure cell survival. Absorbance was measured using a BMG Fluostar microplate reader at 485 nm. The inhibitory activity of the products was expressed as % survival calculated from control cells without the addition of TNF. Compounds showing human TNF alpha inhibitory efficacy greater than 50% at 100 pm and 10 pM for TNF-alpha activity were also tested at the concentration of 0.01 pM to 100 pM of test compound. The inhibitory activity of the compounds is expressed as % survival at 10 pM, 100 pM and inhibitory concentration 50 (IC50). See Figure 1 for compound 6. 5 The following table summarizes the results obtained for the compounds of the benzenesulfonamide of formula I tested as described above. For the compounds below, R2 = H Compound Position of X(s) on the benzene sulfonamide ring 3 2 S 6 4 * 7 R1 = 0 / / 0 Inhibition 10 pM 1 4-O-CH3 2-CH3 ; 3-CO-CH3 ; 6-CH3 71.15 2 4-O-CH3 2-CH3 ; 3-CO-O-CH3 57.51 3 4-CH3 2-CH3 ; 3-CO-O-CH3 48.09 4 4-O-CH3 2-CH3 ; 3-CO-O-CH2-CH3 41.55 5 4-O-CH2-CH3 2-CH3 ; 3-CO-O-CH2-CH3 39.09 6 4-O-CH2-CH3 2-CH3 ; 3-CO-O-CH3 23.91 7 4-O-CH2-CH3 2-CH3; 3-CO-O-CH2-CH3; 7-Br 21.80 8 4-O-CH2-CH3 2-CH3 ; 3-CO-O-CH2-CH3; 7-CI 18.36 9 4-CH(CH3)3 2-CH3 ; 3-CO-O-CH3 17.93 10 4-CI; 3-CHg 2-CH3; 3-CO-O-CH3 16.15 11 4-CH3; 3-NO2 2-CH3; 3-CO-CH3 13.57 12 4-O-CH3 2-CH3; 3-CO-OH 13.31 13 2-CH3; 5-CH3 2-CH3 ; 3-CO-O-CH3 12.41 14 4-CI 2-CH2-O-CH3; 3-CO-O-CH3 11.26 15 4-CI; 3-NO2 2-CH3; 3-CO-O-CH3 10.6 4 3 XXi c R1 16 4-O-CH2-CH3 2-CH3; 3-CO-CH3 80.40 17 3-NO2 2-CH3; 3-CO-O-CH2-CH3 14.93 18 4-CH3 2-CH3; 3-CO-CH3 13.61 19 H 2-CH3; 3-CO-CH3 6.64 20 4-CI 2-CH3; 3-CO-CH3 5.12 21 4-O-CH3 - CH3 6- CH3 43.84 27 HH 4- ° 0 >=\ / CH- ----\\ R1= 37.26 28 11 / z — N„S__Z. A—0 H II / / 4- 0 --- ch3 R1 = 35.69 29 JZT / OO 2 2 ÇH3 ch3 R1 = 34.81 For the compounds below, R1 = a group - CHR4 - CO- R3 where R4=H; Compound Position of X(s) on the benzene sulfonamide ring 3_____2 4 H-- 5 6 R2 R3 % Inhibition 10pM 32 3-CH3 4-O-CH3 —N\ / N — 0 \ CH, 69.73 33 4-CH3 jÇy Z=\ CH, 0 \ ch3 52.4 34 4-CH3 H,C \ 0 0 \ CH, "N-£ \ X—CH} O 42.26 35 2-O-CH3 5-CH3 Cl 41.57 36 CH, \\ / / °? o — ch3 / ~—a 0 r-- '“OfO 38.8 37 3-O-CH3 4-O-CH3 V / )---CH-, 38.55 N---c / H \ __ / 38 H — \\ 36.43 o' — CH, y~\ H,C CH, 39 4-CH3 / HP / 33.91 -CH, N — 5. — CH, / HH,C 0 40 3-CH3 4-O-CH3 --N ---- 33.48 41 4-CH3 cH, _ / / \\ H \ / 32.90 CH, 42 3-O-CH3 4-O-CH3 H,C \ O ^pl. 31.84 H -N— / H \ / c>' 'ch, CH, 43 H 29.38 --c --VH, ' \---&r H \__ / 44 4-CH3 / / \\ H,C 26.77 \ o — ch3 < CH, 45 H -p h5c \ zCH^ N — N --U ï HN / --- ■' "U 25.67 46 3-O-CH3 4-O-CH3 — N —Z ​​\ H \\ / / 0 CH. HN — C --( H. \ CH. 25.60 47 4-FZZ 24.12 48 4-CH3 — N--GXHVV \ n N — S — CH, / HH,C 0 23.69 49 4-CI CH, / =A / H, — NG À—□ HV / / 0 — ch3 22.99 50 3-O-CH3 4-O-CH3 —r ~N ~ 0 —Z \__ / Q 22.60 51 3-O-CH3 4-O-CH3 0 / 0 xn,c — N—Z \ CH, H # 22.05 52 3-O-CH3 4-O-CH3 — N --ZXHV / / 0 CH. 21.46 53 4-CH3 0< H,C Vo \ / \ >= / CH3 — N --GAHVV 21.08 54 4-Br ZC 3 1 z : 1 20.80 55 3-O-CH3 4-O-CH3 H,C — N--ZAH XX / / CH, 20.75 56 H / =\ CH, —Z z / —° O —CH, !---X 0 -N \CH, \— / 0—-Z 20.42 57 4-CH3 X CH, - h / 20.00 58 H oz CH, h3c — NG \--CH, HVVH,C 19.30 59 3-O-CH3 4-O-CH3 F --N\ / N---- 18.95 60 4-CH3 —CZA CH, H, VV ci — N —C--ZAHH, XX / / 18.16 61 4-CH3 H,C \ O 0 \ CH, — N--ZAH XX / / v—y 0 \ h N —S —CH, O 17.60 62 3-O-CH3 4-O-CH3 CI OX CH, CH, -N--f) Hy / H,C 17.41 63 4-CH3 CH, û Z 17.30 64 4-F / =\ / CH' .—O / \ Il / ^-1 — N-----S - NH \\ / / J) \ JO 17.28 EXPERIMENT 2 The compounds were tested for their ability to inhibit apoptosis induced on murine L929 cells by murine TNF-alpha. The cells were cultured in RPMI supplemented with 10% fetal bovine serum. 4 x 104 cells in 200 µl of culture medium were exposed for 24 h in 96-well plates to murine TNF-alpha (R & D Diagnostics) at different concentrations, and the compound at a final concentration of 100 µM and 10 µM, XTT solution was added (20 µl at 5 mg / ml) to each well for two hours to measure cell survival. Absorbance was measured using a BMG Fluostar microplate reader at 485 nm. The inhibitory activity of the drugs was expressed as % survival calculated from control cells without the addition of TNF. The similar activities obtained with benzenesulfonamide derivatives against murine TNF-alpha were similar to those obtained against human TNF-alpha EXPERIMENTATION 3 Mouse colitis model induced by dextran sodium sulfate Benzenesulfonamide derivatives were tested in vivo in a mouse model of DSS-induced colitis. Colitis is induced by the absorption of dextran sodium sulfate (DSS) in distilled water during the first 7 days of the test (2%). The presence of colitis was measured by a disease activity index combining weight loss, rectal bleeding, diarrhea, and the presence of blood in the stool. DSS-induced colitis was also assessed by macroscopic and histological analyses of the colon. Groups of 10 C57BL mice were formed. Mice in the control group received distilled water until the end of the protocol. Mice in the DSS, DSS-DMSO and mice in the DSS-BSD mice received distilled water with 2% DSS for 7 days and then distilled water until the end of the protocol. During the test, from day 1 to 20 (group 1) or day 8 to 20 (group 2) mice were injected daily intraperitoneally (IP) with 100 μl of phosphate buffer saline (PBS) (control group and MAS group), 10% PBS-DMSO (DSS-DMSO group), or 10 μM benzenesulfonamide derivatives dissolved in 10% PBS-DMSO (DSS-BSD group). Similar activities were obtained with benzenesulfonamide derivatives on either human or murine TNF alpha (see experiments 1 and 2). At the end of treatment, mice were killed by cervical dislocation. The entire colon (including the cecum, proximal colon, and distal colon) was excised. The colon was macroscopically assessed by determining (a) the presence or absence of blood and (b) length. The presence or absence of blood (in the cecum, proximal colon, and distal colon) was indexed as 1 or 0, respectively. Colonic biopsies were histopathologically indexed by a blinded investigator (to estimate the severity of inflammation, the extent of inflammation, and damage to the digestive crypts). DSS treatment significantly reduced colon length. More importantly, benzenesulfonamide derivatives, administered concomitantly with DSS treatment (group 1), strongly inhibited DSS-induced colon shortening. In contrast, the PBS-DMSO group (vehicle control for benzenesulfonamide derivatives) had no effect on DSS-induced colon shortening. Macroscopic observation revealed the constant presence of blood in the colon of DSS mice, but rarely, if ever, in the colon of control mice. The occurrence of blood was significantly less frequent (especially in the proximal and distal colon) in the treated mice of the DSS-BSD group compared with the mice of the DSS-DMSO group. It is notable that benzenesulfonamide derivatives administered after DSS treatment was initiated (group 2) significantly reversed DSS-induced colonic shortening. More importantly, the Mean colon length of DSS-treated mice given benzenesulfonamide derivatives after initiation of DSS treatment was not significantly different from that of control mice. Consistent with these observations on colon length, bloody features were less frequent (particularly in the proximal and distal colon) in DSS-BSD-treated mice compared with DSS-treated or DSS-DMSO mice. See Figure 2 EXPERIMENTATION 4 Collagen-induced murine arthritis model The activity of benzenesulfonamide compounds was tested in vivo in a collagen-induced murine arthritis model. Collagen-induced arthritis is a well-known model of rheumatoid arthritis, which reproduces the main features of the disease in humans. The experimental disease is induced in animals by two successive injections of bovine type II collagen into the tail. Clinical signs of the disease occur a few days later, mainly marked by severe joint inflammation and joint destruction. Joint inflammation can be measured and recorded as clinical scores by those skilled in the art: a score from 0 (no clinical signs) to 4 (total inflammation) is given for each joint of each mouse. Groups of 10 mice are compared by the mean value of the scores obtained on the mice.Similarly, joint inflammation and destruction can be observed on histological sections of joints and reported as histological scores by those skilled in the art. DBA-1 mice (n = 10 per treatment group) were treated two hours before the first collagen injection or received a control made of PBS alone. Then, they received a daily injection corresponding to an amount of 0.1 mg per mouse of benzenesulfonamide compounds until the end of the trial. Clinical signs of the disease appeared concomitantly with the last collagen injection and clinical scores were progressively increased for each diseased animal until day 80 (counted from the first collagen injection) when the animals were euthanized for ethical reasons. The results show that treatment with benzenesulfonamide compounds provides statistically significant protection in the late stage of the disease, similar to that of etanercept. See Figure 3 EXPERIMENTATION 5 Mouse model of endotoxin shock. The activity of benzenesulfonamide compounds was tested in vivo in a murine model of endotoxin shock, which is a simple conventional model of systemic inflammation, by intraperitoneal (IP) administration of 1 μg lipopolysaccharide (LPS) and 20 mg D-galactosamine (GaIN). Co-administration of LPS and GaIN to mice produces a lethal endotoxin shock primarily due to overproduction of TNF-alpha. After a few hours, the mice begin to become affected and exhibit a shock syndrome. They generally die within 48 hours, and the survival of mice in each group is measured within one week of the shock. DBA-1 mice (n = 10 per treatment group) were treated two hours before injection of LPS-GaIN or with a DMSO-only control. The dose injected into each mouse corresponds to 0.1 mg of compound 6 above, benzenesulfonamide (diluted in PBS with 10% DMSO). The results show that treatment with benzenesulfonamide compounds provides significant protection against shock similar to that provided by etanercept. See Figure 4

Claims

REVENDICATION 1. Le N~2~-(3-chlorobenzyl)-N~1 ~-(2,4-dimethoxyphenyl)-N~2~-[(4- methylphenyl)sulfonyl]glycinamide, or one of its addition salts with pharmaceutically acceptable acids, for use in a method of treating a non-cancerous pathology related to an excessive effect of TNF chosen from inflammatory bowel diseases, inflammations, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, bone resorption / osteoporosis, Crohn's disease, septic shock, endotoxin shock, atherosclerosis, ischemia-reperfusion injuries, coronary artery disease, vasculitis, amydoloidis, multiple sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus, malaria, ulcerative colitis, cachexia, psoriasis, endometriosis, Behçet's disease, Wegener's granulomatosis, meningitis, AIDS, HIV infections, autoimmune diseases,immunodeficiency, common variable immunodeficiency (CVID), chronic graft / host disease, graft trauma and rejection, respiratory distress syndrome, pulmonary fibrosis, diabetes, juvenile diabetes, ankylosing spondylitis, and skin disorders due to delayed hypersensitivity reactions, Alzheimer's disease, systemic lupus erythematosus, and allergic asthma.

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