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Definitions

• the present invention relates to sulfonated compounds for use in a method of treating a condition related to an excessive effect of TNF.
• TNF alpha can be beneficial and need to be enhanced, which is excessive and should be reduced.
• TNF alpha tumor necrosis factor
• septic shock can be mentioned.
• TNF alpha is also involved in Crohn's disease, heart failure and atherosclerosis. It also plays an important role in rheumatoid arthritis.
• Thalidomide decreases TNF alpha production in vitro and in vivo. But it causes, when taken by pregnant women, very many malformations. It is a teratogenic product. In addition to its teratogenic effect, thalidomide prolonged administration causes neuropathies. A steroidal anti-inflammatory drug, dexamethasone, also decreases the release of TNF.
• Anti-TNF monoclonal antibodies bind to TNF, neutralize it and block its action.
• Patients treated with infliximab for the treatment of rheumatoid arthritis, Crohn's disease and ankylosing spondylitis may be subject to immune system responses to infleximab.
• Adalimumab is a humanized anti-TNF alpha monoclonal antibody that decreases this type of reaction. Soluble TNF receptors can also bind to TNF and prevent it from acting. Etanercept is used in the treatment of rheumatoid arthritis and ankylosing spondylitis. But, like monoclonal antibodies, soluble anti-TNF receptors can be associated with adverse effects such as infections (tuberculosis, others) or the appearance of certain cancers.
• these approaches have significantly improved the treatment of chronic inflammatory diseases and show that inhibition of TNF alpha is an important means of treating these diseases.
• these products have serious drawbacks: they require the subcutaneous or intravenous injection of the product every two to four weeks and they can induce rare side effects (1%) but serious (tuberculosis, lymphomas).
• ⁇ R1 represents
• R4 represents a hydrogen atom or a C1-C5 alkyl
• R3 represents an organic group, said organic group comprising 1 1 or more than 1 1 atoms other than H and containing from 6 to 30 carbon atoms, one or more rings or heterocycles, saturated or unsaturated, fused or otherwise, optionally substituted by a or more substituents, preferably 1, 2 or 3, especially 1 or 2 substituents selected from C 1 -C 5 alkyl, C 1 -C 5 alkenyl, halo, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, C 1 alkylthio radicals -C 5, C 1 -C 5 alkylsulfonyl, acyl, hydroxy, NH 2, nitro, C 1 -C 5 alkylamino, di (C 1 -C 5 alkyl) amino, acylamino, said organic group not being bound to the carboxyl by a group -NH-CH2- or by a group -NH-CH-alk- where alk represents an alkyl radical of 1 to
• n 1 or 2 and R1 represents H, Halogen, CN, alkyl or lower alkoxy, optionally substituted with halogen,
• a benzofuran group preferably 5-benzofuran or naphthofuran, preferably 5-naphthofuran optionally substituted with one or more substituents, preferably 1, 2 or 3, in particular 1 or 2 substituents chosen from C 1 -C 5 alkyl and alkenyl radicals; C1-C5-alkyl, halo, C3-C8 cycloalkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, acyl, hydroxy, NH2, nitro, C1-C6 alkylamino, C1-C6 alkyl -C6) amino, acylamino,
• R1 and R2 can not 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 selected from C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkenyl, halogen , C 3 -C 8 cycloalkyl, C 1 -C 5 alkylthio, C 1 -C 5 alkylsulfonyl, acyl, Hydroxy, NH 2, nitro, C 1 -C 6 alkylamino, di (C 1 -C 6 alkyl) amino, acylamino, it being understood that X is not 3,4-dialkoxy or 3,4-dialkylthio,
• R1 H and X is 3-nitro, 4-chloro, R2 is not a methyl, ethyl or benzyl radical,
• R1 H
• R2 is not 3,4-dimethoxyphenethyl
• R2 is not an optionally substituted phenyl radical
• sulphonated compounds are known and commercially available, in particular from ChemBridge Corporation (www.chembridge.com). These sulfonated compounds can be prepared according to well known methods. Lemaire et al., Eur J Org Chem 13, 2840: 2847 (2004), and Adams, R and Whitaker, J. Chem Soc (1953), 78: 658-663, showing how different benzinic acids or derivatives of active methylenes in the presence of p-quinonemonobenzenesulfonimide or naphthoquinonemonobenzene sulfonimides in an acid medium, respectively form benzofuran or naphthofuran derivatives.
• WO 02/32864 A1 and WO 2010/125831 A1 also describe compounds of formula I or of a close structure.
• C1-C5 alkyl refers to a linear or branched alkyl group of 1 to 5 carbon atoms inclusive, such as methyl, ethyl, propyl, 1-propyl, 2-propyl, butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl, preferably methyl or ethyl,
• C2-C5 alkenyl and “C2-C5 alkynyl” refer to such groups having 2 to 5 carbon atoms inclusive, respectively.
• Halogeno means fluoro, chloro, bromo or iodo, preferably bromo or chloro, especially the latter.
• C3-C8 cycloalkyl refers to a monocyclic or bicyclic carbocycle of 3 to 8 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• C 1 -C 5 alkoxy, C 1 -C 5 alkylthio and C 1 -C 5 alkylsulfonyl denote such groups in which the C 1 -C 5 alkyl group is as defined above.
• acyl means -CO-alkyl wherein the alkyl group is C1-C5 alkyl as defined above.
• Amino means NH2.
• Acylamino means -NH-acyl where acyl has the above definition.
• the organic group comprising 1 1 or more than 1 1 atoms other than H and containing from 6 to 30 carbon atoms, one or more rings or heterocycles, saturated or unsaturated, fused or not, can 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.
• Preferred heterocycles are monocyclic. Particularly preferred are thienyl and piperidinyl as well as piperazinyl.
• Organic groups comprising 1 1 or more than 1 1 atoms other than H and containing from 6 to 30 carbon atoms, one or more rings or heterocycles, saturated or unsaturated, fused or not preferred are phenyl, benzyl, phenethyl, piperazinyl groups , phenylpiperazinyl, phenylamino, benzylamino, benzo (c) piperidinyl.
• Their preferred substituents are C 1 -C 5 alkyl, C 1 -C 5 alkenyl, halo and C 1 -C 5 alkoxy groups.
• organic acid addition salts are those formed with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulphonic, ethanedisulphonic, acetic, propionic, tartaric, salicylic and citric acids.
• 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.
• the Applicant has discovered with astonishment that the sulfonated compounds of formula I above have very interesting original pharmacological properties. They are particularly endowed with remarkable anti-TNF-alpha direct properties by acting on the cytokine detimerization, transforming it into an inactive dimer. As a reminder, TNF alpha is pharmacologically active in the form of a trimer. This technical effect has to the knowledge of the applicant never been described for the sulfonated compounds above.
• a non-cancerous disease related to an excessive effect of TNF alpha selected from inflammatory bowel diseases, inflammation, chronic inflammatory diseases, polyarthritis rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, bone resorption / osteoporosis, Crohn's disease, ulcerative colitis, septic shock, endotoxin shock , atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, amydoloidis, multiple sclerosis, sepsis, recurrent chronic uveitis Hepatitis C virus, malaria, ulcerative colitis, cachexia, psoriasis, endometriosis, Behçet's disease, Wegener's granulomatosis, meningitis,
• the present invention also relates to the sulfonated compounds described above for use in a method for treating a pathology related to an excessive effect of TNF-alpha, in particular by direct action by acting on the TNF-alpha.
• R1 represents a group - CHR4 - CO-R3, wherein
• R 4 represents a hydrogen atom or a C 1 -C 5 alkyl and R 3 has the meanings already indicated and in particular represents an organic group comprising 11 or more than 11 atoms other than H and containing from 6 to 20 carbon atoms; especially
• a group * w wherein m is 0, 1 or 2 and preferably 0 or 1, Z has the meanings N or CH, and Ar represents an aryl radical, preferably phenyl, the aryl radical may be substituted with a or more radicals having the meaning already indicated, but preferably the aryl radical is unsubstituted or substituted by 1 or 2 halogens or alkoxy, and
• R2 and X have the meaning already indicated, X being preferably H, halo, alkoxy or alkyl.
• R1 represents R1 represents a group - CHR4 - CO-R3, in which R3 and R4 have the meaning already indicated,
• R2 represents an optionally substituted phenyl group, said phenyl group being directly attached to the nitrogen, or connected by a - (CH 2 ) - group, and X has the meaning already indicated, preferably H, halo, alkoxy or alkyl, as well as as their addition salts with pharmaceutically acceptable acids.
• R 1 represents a group - CHR 4 --CO-R 3, wherein R 4 represents a hydrogen atom or a C 1 -C 5 alkyl and R 3 represents an organic group comprising 11 or more than 11 atoms other than H and containing from 6 to 20 carbon atoms, particularly a group
• m is 0, 1 or 2 and preferably 0 or 1
• Z has the meanings N or CH
• Ar represents an aryl radical, preferably phenyl.
• the aryl radical may be substituted by one or more radicals having the meaning already indicated, but preferably the aryl radical is unsubstituted or substituted by 1 or 2 halogens or alkoxy.
• R2 represents an optionally substituted phenyl group, said phenyl group being directly attached to the nitrogen, or connected by a - (CH 2 ) - group
• X has the meaning already indicated, preferably H, halo, alkoxy or alkyl, as well as as their addition salts with pharmaceutically acceptable acids.
• R1 represents a group - CHR4 - CO- R3 where R3 represents a
• a benzofuran group preferably 5-benzofuran or naphthofuran, preferably 5-naphthofuran optionally substituted with one or more substituents, preferably 1, 2 or 3, in particular 1 or 2 substituents chosen from C 1 -C 5 alkyl radicals, preferably methyl or ethyl, C 1 -C 5 alkenyl, halo, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, preferably methoxy or ethoxy, C 1 -C 5 alkylthio, C 1 -C 5 alkylsulfonyl, acyl, amino, C 1 -C 5 alkylamino -C6, di (C1-C6) alkylamino, acylamino, or
• a group chosen from groups a, b, c, d, e, f, g, h, i and j above, and
• X has the meaning already indicated, preferably H, halo, alkoxy or alkyl, and their addition salts with pharmaceutically acceptable acids
• R 1 represents a group - CHR 4 --CO-R 3, in which R 3 and R 4 have the meaning already indicated
• R 2 represents a phenyl or C 4 -C 7 cycloalkyl group, substituted
• X has the meaning already indicated, preferably H, halo, alkoxy or alkyl, and their addition salts with pharmaceutically acceptable acids.
• the sulfonated compounds according to the present invention have direct anti-TNF alpha properties by acting on the cytokine detimerization, transforming it into an inactive dimer.
• they can be used in conjunction with compounds having anti-TNF alpha properties of a different nature, for example compounds which inhibit the production of TNF alpha, such as compounds which are active in the production of TNF by monocytes, or inhibiting compounds. the production of pro-inflammatory cytokines including TNF.
• the subject of the present invention is also a pharmaceutical composition characterized in that it contains, as active ingredient, a direct anti-TNF alpha sulfonated compound as defined above, a compound having anti-TNF alpha properties. of different nature, as well as one or more pharmaceutically acceptable excipients.
• the sulfonated compounds according to the present invention find their use in both the curative and the preventive treatment of non-cancerous diseases known to be related to the overproduction of TNF alpha.
• the sulfonated compounds according to the present invention find their use for example in the treatment as well as preventive treatment of chronic inflammatory diseases known to be related to overproduction of TNF alpha such as: inflammatory bowel diseases, inflammations, chronic inflammatory diseases, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, bone resorption / osteoporosis, Crohn's disease, ulcerative colitis, septic shock, endotoxinic shock, atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, amydoloidis, multiple sclerosis, sepsis, chronic recurrent uveitis
• the sulfonated compounds according to the present invention find their use particularly in the treatment of the following diseases: inflammatory bowel diseases, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, refractory rheumatoid arthritis, ulcerative colitis, osteoarthritis. Crohn's disease, septic shock, multiple sclerosis, chronic recurrent uveitis, cachexia, psoriasis, autoimmune diseases, immune deficiency, ankylosing spondylitis, systemic lupus erythematosus, and allergic asthma.
• diseases inflammatory bowel diseases, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, refractory rheumatoid arthritis, ulcerative colitis, osteoarthritis. Crohn's disease, septic shock, multiple sclerosis, chronic recurrent uveitis, cachexia, psorias
• the usual dose, variable according to the subject being treated and the affection in question, may be, for example, from 10 mg to 10,000 mg, preferably from 50 mg to 5000 mg, or even from 200 mg to 3000 mg per day orally. in the man of compound of Example 1, taken daily or in alternate periods depending on the disease.
• the sulfonated compounds described above can be administered as the only active agent or in combination with other active agents, of different nature, with the same therapeutic aim or not.
• the present invention also relates to the sulfonated compounds described above for use in a method for treating the human or animal body, in particular human.
• the sulphonated compounds corresponding to the general formula I and their addition salts with pharmaceutically acceptable acids may be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.
• compositions can be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as for example single or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods.
• the active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles.
• excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles.
• the active ingredient is advantageously present at physiologically effective doses; the aforementioned compositions contain in particular a dose of 500 mg or for example 100 mg or else 10 mg effective of at least one active ingredient above, depending on the compound used.
• 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 related to an excessive effect of TNF in particular by direct action on TNF.
• the subject of the present invention is also a process for the preparation of a composition described above, characterized in that, by methods known per se, the active ingredient (s) are mixed with acceptable excipients, in particular pharmaceutically acceptable excipients.
• Another subject of the present invention is a process for the preparation of an anti-TNF agent, in particular anti-TNF-alpha direct, characterized in that a compound is used as the essential active constituent of said agent. of formula I or one of its addition salts with pharmaceutically acceptable acids.
• a method of treating diseases known to be related to overproduction of TNF alpha, including chronic inflammatory diseases comprises administering to a patient a physiologically effective dose of at least one active ingredient above.
• FIG. 1 shows the inhibition curve obtained by the compound Z1 on the apoptogenic activity of human TNF-alpha at a concentration of 0.150 ng / ml on the L929 line (OD measured at 570 nm) as a function of the log of the concentration of the compound 6.
• Figure 2 shows the activity index obtained with compound Z2 as a function of time in days after administration of DSS in a model of DSS-induced mouse colitis.
• Figure 3 shows the average length (ordinate in cm) of the mice colonists in each group after exposure to DSS.
• Compounds Z1 to Z10 are described below.
• Figure 4 shows the average clinical scores of arthritis obtained in each group with compounds Z1 to Z5 as a function of time in days (abscissa) after last collagen injection in an arthritis model. murine induced by collagen.
• the control groups Cremophor® and etanercept are also present.
• Figure 5 shows the mean clinical scores of arthritis achieved in each group with Z6 compounds at Z10 versus time in days (abscissa) after last collagen injection, in a murine collagen-induced arthritis model.
• the control groups Cremophor® and etanercept are also present.
• Figure 6 shows the number of surviving mice in a murine model endotoxin shock experiment following intraperitoneal injection of the Z1 compound with Cremophor®, PBS controls, or without product injection.
• Figure 7 shows the number of surviving mice in a mouse model of endotoxin shock as a function of the product administered orally (Z1 to Z10).
• Two control groups are present with administration of DMSO or water administration.
• Figure 8 shows the mean overall score for each group of mice (ordinate) treated with compounds Z1 through Z10 during the treatment time (abscissa) to imiquimod in a psoriasis model.
• Three groups of controls are present: treatment with petrolatum (excipient of imiquimod), treatment with imiquimod alone, treatment with imiquimod and absorption of DMSO.
• Figure 9 shows the mean sacrifice ear size for each group of mice treated with Z1 to Z10 following treatment of the ears with TPA.
• Three groups of controls are present: treatment with acetone (excipient of TPA), treatment with TPA alone, treatment with TPA with DMSO absorption.
• Figure 10 shows the evolution of the mean scores of groups of 6 mice treated with the compounds Z1 to Z5, following the induction of experimental autoimmune encephalopathy, a murine model of multiple sclerosis.
• the average paralysis score of the group of mice On the abscissa, the number of days following the first MOG injection, on the ordinate, the average paralysis score of the group of mice.
• FIG. 11 shows the evolution of mean scores of groups of 6 mice treated with compounds Z6 to Z10, following the induction of experimental autoimmune encephalopathy, a murine model of multiple sclerosis.
• the abscissa the number of days following the first MOG injection, on the ordinate, the average paralysis score of the group of mice.
• the compounds are dissolved in DMSO for use in vitro or in vivo orally and in Cremophor® for in vivo intraperitoneal use.
• Human TNF alpha using a human TNF alpha-induced apoptosis assay on murine L929 cells.
• the cells were cultured in DMEM medium supplemented with 10% fetal bovine serum. 4 ⁇ 10 4 cells in 100 ⁇ l of culture medium were exposed for 24 h in 96-well plates to human TNF alpha (R & D Diagnostics) at 0.150 ng / ml, and the test compound added to a final concentration of 100 ⁇ or 10 ⁇ .
• An MTT stain solution was added (100 ⁇ to 0.5 mg / ml) to each well for two hours to measure cell survival. Absorbance was measured using a BMG Fluostar microplate reader at 570 nm.
• the inhibitory activity of the products was expressed in% survival calculated from the control cells without the addition of TNF.
• the inhibitory activity of the compounds is expressed in% survival at 10 ⁇ and inhibitory concentration 50 (IC50).
• IC50 inhibitory concentration 50
• the compounds were tested for their ability to directly inhibit murine TNF alpha using an L929 murine cell-induced apoptosis assay for murine TNF-alpha.
• the cells were cultured in DMEM supplemented with 10% fetal bovine serum. 4 ⁇ 10 4 cells in 100 ⁇ l of culture medium were exposed for 24 h in 96-well plates to murine TNF alpha (R & D Diagnostics) at 0.3 ng / ml, and the compound tested to a final concentration of 100 ⁇ or 10 ⁇ .
• MTT solution 100 ⁇ to 0.5 mg / ml
• Absorbance was measured using a BMG Fluostar microplate reader at 570 nm.
• the inhibitory activity of the drugs was expressed in% survival calculated from the control cells without the addition of TNF.
• the benzenesulfonamide derivatives were tested in vivo in a model of DSS-induced mouse colitis.
• Colitis is induced by the absorption of sodium sulfate dextran (DSS) in distilled water during the first 7 days of the test (3%).
• the presence of colitis was measured by an index of disease activity associating weight loss, rectal bleeding, diarrhea and the presence of blood in the stool.
• DSS-induced colitis was also assessed by macroscopic and histological analyzes of the colon.
• Groups of 10 C57BL mice were formed.
• the mice in the control group received distilled water until the end of the protocol.
• the DSS group DSS-DMSO mice and the DSS-BSD group mice received distilled water with 3% DSS for 7 days and then distilled water until the end of the protocol.
• the mice received 100 ⁇ of phosphate buffer (PBS) orally (po MAS group), DMSO (DSS-DMSO-group), or 10 mg benzene-sulfonamide derivatives dissolved in DMSO (DSS-BSD group).
• PBS phosphate buffer
• DSS-DMSO-group DMSO
• benzene-sulfonamide derivatives dissolved in DMSO
• mice were killed by cervical dislocation.
• the entire colon (including the cecum, proximal colon, and distal colon) was excised.
• the colon was macroscopically evaluated by determining (a) the presence or absence of blood and (b) the length.
• the presence or absence of blood in the cecum, proximal colon and distal colon was indexed as 1 or 0, respectively.
• Colon biopsies were indexed histopathologically by an investigator (to estimate the severity of inflammation, extent of inflammation and damage to digestive crypts), blinded.
• DSS treatment significantly reduced colon length. More importantly, benzene-sulfonamide derivatives, administered concomitantly with DSS treatment (group 1), strongly inhibited DSS-induced shortening of the colon. In contrast, the DMSO group (control excipient for benzenesulfonamide derivatives) had no effect on DSS-induced shortening of the colon. 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 common (particularly in the proximal and distal colon) in DSS-BSD-treated mice compared to DSS-DMSO mice.
• the activity of the sulfonated compounds was tested in vivo in a murine model of collagen-induced arthritis.
• 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 the animal by two successive injections of bovine type II collagen in the tail.
• the clinical signs of the disease occur a few days later, mainly marked by severe joint inflammation and destruction of the joints.
• Joint inflammation can be measured and recorded as clinical scores by those skilled in the art: a score of 0 (no clinical sign) at 4 (total inflammation) is given for each joint of each mouse. Groups of 10 mice are compared by the average value of the scores obtained on the mice. Similarly, joint inflammation and destruction can be observed on histological sections of the joints and reported as histological scores by those skilled in the art.
• EXPERIMENTATION 5 Mouse model of endotoxin shock The activity of the sulfonated 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 0.2 ⁇ g lipopolysaccharide (LPS) and 20 mg of D-galactosamine (GaIN).
• IP intraperitoneal
• LPS lipopolysaccharide
• GaIN D-galactosamine
• mice Co-administration of LPS and GaIN to mice produces an endotoxic lethal shock essentially due to overproduction of TNF-alpha. After a few hours, the mice begin to be affected and present with shock syndrome. They usually die within 48 hours and the survival of the mice in each group is measured in the week following the shock.
• the dose of injected compound IP for each mouse corresponds to 1 mg of the benzenesulphonamide compounds (diluted in PBS with Cremophor® in a final volume of 50 ⁇ l).
• the dose administered orally to each mouse corresponds to 10 mg of sulfonated compounds diluted in DMSO in a final volume of 100 ⁇ l.
• the results show that treatment with sulfonated compounds after IP or oral administration provides significant protection against shock similar to that provided by etanercept.
• the activity of the benzenesulfonamide compounds was tested in vivo in a model of inflammation of the skin by applying on the back of previously shaved animals a cream containing Imiquimod 5%.
• This product causes psoriasiform lesions on the skin of animals at the site of application.
• the mice receive daily 62.5 mg of cream on the back which corresponds to 3.125 mg of imiquimod per animal for 5 days.
• Clinical scores are scored on a scale of 0 to 4 for erythema, desquamation and skin thickness in the back. The cumulative clinical scores of these three parameters allow us to determine the severity of the inflammation with a score ranging from 0 to 12. Histological sections of the skin at the level of the back are made and analyzed by those skilled in the art.
• EXPERIMENT 7 Model of inflammation of the skin by application of 12-0-tetradecanoylphorbol-1 3-acetate (TPA) on the ears of animals
• TPA is a product that causes lesions characterized by erythema and edema in the ears of animals, similar to dermatitis.
• the lesions are induced by brushing the ears of Balb / C mice with 20 ⁇ l. acetone solution containing 0.01% TPA, the other ear being brushed with 20 ⁇ . acetone solution and serves as a control.
• the mice receive TPA every 2 days for 10 days and the thickness of the ears is measured for the duration of the experiment.
• the activity of myeloperoxidase (measuring neutrophil infiltration) is determined and histological sections of the ears are made.
• the animals also receive 5 mg of benzenesulphonamide compounds per 50 ⁇ l per os. of DMSO every day for the duration of the experiment or DMSO alone.
• the thickness of the ears is determined daily. The results show that benzenesulfonamide compounds decrease the inflammatory response. They cause a decrease in the thickness of the ears of animals as well as a decrease in the activity of myeloperoxidase and cellular infiltrates in the ears of treated animals.
• EAE autoimmune encephalitis
• Clinical monitoring is carried out daily by those skilled in the art and the progress of the disease is evaluated by scores ranging from 0 (no clinical sign) to 5 where the animal is paralyzed of the four limbs and moribund. An average score per group is thus calculated every two days.

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