MXPA00012498A - INHIBITORS OF TRANSCRIPTION FACTOR NF-&kgr;B - Google Patents

Abstract

The present invention provides pharmaceutical compositions of salicylanilide inhibitors of transcription factor NF-&kgr;B, and methods for treating diseases in which activation of NF-&kgr;B is implicated. More specifically, the present invention provides methods of treatment of a variety of diseases associated with NF-&kgr;B activation including inflammatory disorders;particularly rheumatoid arthritis, inflammatory bowel disease, and asthma;dermatosis, including psoriasis and atopic dermatitis;autoimmune diseases;tissue and organ rejection;Alzheimer's disease;stroke;atherosclerosis;restenosis;cancer, including Hodgkin's disease;certain viral infections, including AIDS;osteoarthritis;osteoporosis;and Ataxia Telangiestasia by administering to a patient in need thereof a compound of the present invention.

Description

INHIBITORS OF THE TRANSCRIPTION FACTOR NF-? B FIELD OF THE INVENTION This invention relates generally to inhibitors of the transcription factor NF-αB using salicylanilides. Said compounds are particularly useful for treating diseases in which the activation of NF-? B is involved. More specifically, these compounds inhibit phosphorylation and subsequent degradation of L? B. Said compounds are useful in the treatment of various diseases associated with NF-KB activation, including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease and asthma; dermatoses, including psoriasis and atopic dermatitis; autoimmune diseases; rejection of organs and tissues; Alzheimer disease; apoplexy; atherosclerosis; restenosis; cancer, including Hodgkin's disease; and certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia telangiestasia.

BACKGROUND OF THE INVENTION Recent advances in scientific knowledge of mediators involved in acute and chronic inflammatory diseases and cancer, have led to new strategies in the search for effective therapeutic. Traditional methods include direct target intervention, such as the use of specific antibodies, receptor antagonists, or enzyme inhibitors. Recent advances in the elucidation of the regulatory mechanisms involved in the transcription and translation of a variety of mediators have led to an increasing interest in therapeutic procedures directed to the level of gene transcription. NF-? B belongs to a family of closely related transcription factor dimeric complexes formed from various combinations of the Rel / NF-? B polypeptide family. The family consists of five individual gene products in mammals, RelA (p65), NF-? B1 (p50 / p105), NF-? B2 (p49 / p100), c-Rel and RelB, all of which can form hetero- homo-dimers. These proteins share a "reí homology domain" of 300 highly homologous amino acids, which contains dimerization and DNA binding domains. At the C-terminus of the Rei homology domain, there is a nuclear translocation sequence important in the transport of NF-? B from the cytoplasm to the nucleus. In addition, p65 and cRel possess strong transactivation domains at their C-terminal ends. The activity of NF-? B is regulated by its interaction with a member of the inhibitor protein family L? B. This interaction effectively blocks the nuclear localization sequence in the NF-? B proteins, thus preventing the migration of the dimer to the nucleus. A wide variety of stimuli activate NF-? B, through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokines (TNFa, IL-1) and environmental stress. However, apparently common to all stimuli, is the phosphorylation and subsequent degradation of L? B. IKB is phosphorylated on two N-terminal serines by the recently identified B kinases (IKK-a and IKK-β). Site-directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-? B, since once it is phosphorylated, the protein is signaled for degradation via the ubiquitin-proteasome pathway. Free of L? B, the active NF-? B complexes are capable of translocating to the nucleus, where they selectively bind to preferred gene-specific enhancer sequences. Included in the genes regulated by NF-? B, there are a number of cytokines, cell adhesion molecules and acute phase proteins. It is well known that NF-? B plays a key role in the regulated expression of a large number of proinflammatory mediators including cytokines such as IL-6 and IL-8, cell adhesion molecules such as ICAM and VCAM, and nitric oxide synthetase inducible (NOS). These mediators are known to play a role in the recruitment of leukocytes at sites of inflammation, and in the case of ¡NOS, they can lead to organ destruction in some inflammatory and autoimmune diseases. The importance of NF-? B in inflammatory disorders is further reinforced by studies of airway inflammation including asthma, in which it has been shown that NF-? B is activated. This activation may explain the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, it is known that inhaled steroids reduce the hypersensitivity of the respiratory tract and suppress the inflammatory response in the airways of asthmatic patients. In light of recent findings regarding the inhibition of NF-? B by glucocorticoids, it can be speculated that these effects are mediated through the inhibition of NF-? B. Additional evidence of a role of NF-? B in inflammatory disorders comes from studies of the rheumatoid synovium. Although NF-? B is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-? B is present in the nuclei, and therefore is active, in cells comprising rheumatoid synovium. In addition, it has been shown that NF-? B is activated in human synovial cells in response to stimulation with FNT-a. Said distribution may be the mechanism underlying the increased production of cytokine and eicosanoids characteristic of this tissue (see Roshak, A.K., et al., J. Biol. Chem., 271, 31496-31501 (1996)). Probably, the NF-? B / Rel and L? B proteins also play a key role in the neoplastic transformation. Members of this family are associated with cell transformation in vivo and in vitro as a result of overexpression, gene amplification, gene rearrangement or translocations. In addition, the rearrangement and / or amplification of the genes coding for these proteins are observed in 20 to 25% of certain human lymphoid tumors. In addition, a role for NF-? B in the regulation of apoptosis has been reported, which reinforces the function of this transcription factor in the control of cell proliferation. Several NF-? B inhibitors are described in C. Wahl, et al. J.

Clin. Invest. 101 (5), 1163-1174 (1998), R. W. Sullivan, et al. J. Med. Chem. 41, 413-419 (1998), J. W. Pierce, et al. J. Biol. Chem. 272, 21096-21103 (1997). It is known that the marine natural product hymenialdisin inhibits NF-αB (see Roshak, A, et al., JPET, 283, 955-961 (1997), Breton, JJ and Chabot-Fletcher, MC JPET, 282, 459- 466 (1997) Salicylanilides are known compounds A general solution preparation of salicylanilides is described by MT Clark, RA Coburn, RT Evans, RJ Genco, J. Med. Chem., 1986, 29, 25-29. now discovered a novel method for inhibiting the activation of the transcription factor NF-? B using salicylanilides.

BRIEF DESCRIPTION OF THE INVENTION An objective of the present invention is to provide a method for the treatment of diseases which can be therapeutically modified by altering the activity of the transcription factor NF-? B.

Accordingly, in its first aspect, this invention provides a pharmaceutical composition comprising a compound according to formula I. In still another aspect, this invention provides a method for the treatment of diseases in which the pathology of the disease can be Therapeutically modified by inhibiting NF-? B. In a particular aspect, this invention provides methods for the treatment of various diseases associated with the activation of NF-? B, including inflammatory disorders, particularly rheumatoid arthritis, inflammatory bowel disease and asthma; dermatoses, including psoriasis and atopic dermatitis; autoimmune diseases; rejection of tissues and organs; Alzheimer disease; apoplexy; atherosclerosis; restenosis; cancer, including Hodgkin's disease; and certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia telangiestasia.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for the treatment of diseases associated with the activation of NF-? B, which comprises administering to an animal, particularly a mammal, more particularly a human in need thereof, a compound of formula I: wherein: RA replaces ring A from 0 to 3 times, and is independently selected from the group consisting of: NO2, halogen, C? alkyl. 6, trifluoromethyl, O-C de-C6 alkyl and S-C alquilo-C - alkyl; and RB replaces ring B from 0 to 3 times, and is independently selected from the group consisting of: halogen, C (O) Ci-6 alkyl, Ci-β alkyl, OC 0-6 alkyl, S-C-? -6 alkyl, CH2-aryl, and aryl; and pharmaceutically acceptable salts, hydrates and solvates thereof. The present invention further provides a preferred method for the treatment of diseases associated with the activation of NF-? B, which comprises administering to an animal, particularly a mammal, more particularly a human in need thereof, a compound of formula where RA of formula I occurs once and is R-i; and RB of formula I occurs twice and is independently R2 and R3. More specifically: R1 is selected from the group consisting of: H, NO2, CF3, F, Cl, Br and I; R2 is selected from the group consisting of: H and F; and R 3 is selected from the group consisting of: F, Cl, Br, I, phenyl, and C (O) C 1-6 alkyl, preferably C 1 -C 6 alkyl is CH 3; and pharmaceutically acceptable salts, hydrates and solvates thereof. The compounds of formula II selected from the following group are more preferred for use in the methods of the present invention: N- (4-phenyl-phenyl) -2-hydroxy-5-trifluoromethylcarboxamide; N- (2,4-difluorophenyl) -2-hydroxy-5-nitrocarboxamide; N- (2,4-difluorophenyl) -2-hydroxy-5-iodocarboxamide; and N- (4-acetylphenyl) -2-hydroxy-5-iodocarboxamide.

Definitions The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently linked compound that releases the active parent drug in accordance with formulas I and II in vivo. If a chiral center or other form of an isomeric center is present in a compound of the present invention, it is intended that all forms of said isomer or isomers, including enantiomers and diastereomers, be covered herein. The compounds of the invention containing a chiral center can be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using well known techniques and only a single enantiomer can be used. In cases where the compounds have carbon-carbon unsaturated double bonds, the cis (Z) and trans (E) isomers are within the scope of this invention. In cases where the compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated to be included within this invention, whether it exists in equilibrium or predominantly in one form. The meaning of any substituent in any occurrence in formula I, or any sub-formula thereof, is independent of its meaning, or any other meaning of the substituent, in any other occurrence, unless otherwise specified. "Ci-ß-Aquilo" as used herein, means that it includes substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, pentyl, neopentyl and hexyl and unsubstituted, and the simple aliphatic isomers thereof. Any C? -6 alkyl group can be optionally substituted independently by one or two halogens, SR ', OR \ N (R') 2, C (O) N (R ') 2, carbamyl or C1- alkyl 4, wherein R 'is C? -6 alkyl. "Halogen", as applied herein, means that it includes F, Cl, Br and I.

"Ar" or "aryl", as applied herein, means that it includes phenyl or naphthyl, optionally substituted by one or more of Ph-alkyl of Co-β; Het-C0-6 alkyl; C-i-β alkoxy; Ph-alkoxy of C0-6; Het-C06 alkoxy; OH, (CH2)? - 6 NR4R5; O (CH2)? - 6 NR4R5; C1-6 alkyl) OR ", N (R") 2, SR ", CF3, NO2, CN, C02R", CON (R "), F, Cl, Br or I, wherein R4 and R5 are H, C? -6 alkyl, Ph-C0-6 alkyl or C0-6 naphthylalkyl, and R "is phenyl, naphthyl or C? -6 alkyl.

Methods of Preparation The compounds of the present invention can be conveniently prepared by the methods described in the following Schemes 1 and 2. A general solution preparation of salicylanilides is described by M. T. Clark, R. A. Coburn, R. T. Evans, R. J. Genco; J. Med. Chem; 1986: 29; 25-29. These compounds can also be conveniently prepared by solid phase techniques, including the form of a library.

General preparation A general solution preparation is shown in schemes 1 and 2. A salicylanilide is prepared by the condensation of substituted salicylic acid with a substituted aniline in the presence of phosphorus trichloride in dry chlorobenzene (scheme 1). A salicylanilide can also be prepared by conversion of a substituted salicylic acid to its corresponding acid chloride with thionyl chloride in toluene with catalytic DMF. The resulting salicylic acid chloride and a substituted aniline are then heated in toluene to form a salicylanilide (scheme 2).

SCHEME 1 SCHEME 2 With regard to the methods of preparation of the compounds of formula I described in the above schemes 1 and 2, the person skilled in the art will appreciate that the present invention includes all the novel intermediates that are required to obtain the compounds of formula I.

The starting materials used herein are commercially available, or are prepared by routine methods well known to those skilled in the art., and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vols. I-VI (published byWiley-Intersciencie). The acid addition salts of the compounds of formula I are prepared in standard form in a suitable solvent from the original compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic acid. , succinic or methanesulfonic. Some of the compounds form internal salts or zwitterions that may be acceptable. Cationic salts are prepared by treating the original compound with an excess of an alkaline reagent such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as L +, Na +, K +, Ca ++, Mg ++ and NH + are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates and sulfonates (as mesylate), are examples of anions present in pharmaceutically acceptable salts. This invention provides a pharmaceutical composition comprising a compound according to formula I, and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of formula I can be used in the manufacture of a medicament. The pharmaceutical compositions of the compounds of formula I prepared as described above can be formulated as lyophilized solutions or powders for parenteral administration. Powders can be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable vehicle before use. The liquid formulation can be a solution regulated in its pH, isotonic or aqueous. Examples of suitable diluents are normal isotonic saline solution, standard dextrose solution at 5% in water or sodium or ammonium acetate solution regulated at its pH. Said formulation is especially suitable for parenteral administration, but can also be used for oral administration, or it can be contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds may be encapsulated, tabletted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation thereof. Solid carriers include starch, lactose, calcium sulfate dihydrate, magnesia, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid vehicles include syrup, peanut oil, olive oil, saline and water. The vehicle may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, it will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are obtained following conventional pharmacy techniques including grinding, mixing, granulation and compression, when necessary, for tablet forms; or grinding, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly orally or filled into a soft gelatin capsule. For rectal administration, the compounds of this invention can also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols, and molded in a suppository. The methods of the present invention include topical administration of the compounds of formulas I and II. By topical administration, non-systemic administration is understood, including the application of a compound of the invention externally to the epidermis, to the buccal cavity and instillation of said compound in the eye, ear and nose, wherein the compound does not significantly enter the bloodstream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. The amount of a compound of the invention (hereinafter referred to as the active ingredient) required for therapeutic or prophylactic effect after topical administration will, in fact, vary with the chosen compound, the nature and severity of the condition being treated., and the animal that is suffering from the treatment, and is finally at the discretion of the doctor. Although it is possible for an active ingredient to be administered alone as the basic chemical compound, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, 0.01 to 5.0% by weight of the formulation. The topical formulations of the present invention, for veterinary use and for human medical use, comprise an active ingredient together with one or more acceptable carriers therefor, and optionally any other therapeutic ingredient. The vehicle can be "acceptable" in the sense of being compatible with the other ingredients of the formulation, and not harmful to the recipient. Formulations suitable for topical administration They include liquid or semiliquid preparations suitable for penetration through the skin to the site where the treatment is required, such as: liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The drops according to the present invention can comprise sterile aqueous or oily solutions or suspensions, and can be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative, and preferably which includes a surfactant. The resulting solution can be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining it at 90-100 ° C for 30 minutes. Alternatively, the solution can be sterilized by filtration, and transferred to a container by aseptic technique. Examples of suitable bactericidal and fungicidal agents for inclusion in the drops are nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, dilute alcohol and propylene glycol. Lotions in accordance with the present invention include those suitable for application to the skin or eye. An ocular solution may comprise a sterile aqueous solution optionally containing a bactericide, and may be prepared by methods similar to those used for the preparation of drops. Lotions or liniments for application to the skin may also include an agent for accelerating drying and for cooling the skin, such as an alcohol or acetone, and / or a humectant such as glycerol or an oil such as castor oil or oil. araquis. The creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They can be obtained by mixing the active ingredient in pulverized or finely divided form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, gricerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, ricino or olive oil; lanolin or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or macrogols. The formulation may incorporate any suitable surfactant such as an anionic, cationic or nonionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspension agents such as natural gums, cellulose derivatives or in organic materials such as siliceous silicas, and other ingredients such as lanolin may also be included.

Utility of the present invention The compounds of formulas I and II are useful as inhibitors of NF-? B. The present invention provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds. The present invention also provides methods for the treatment of diseases associated with the activation of NF-? B, which comprise administering to an animal, particularly a mammal, more particularly a human in need thereof, a compound of formulas I or II . The present invention particularly provides methods for the treatment of inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease and asthma; dermatoses, including psoriasis and atopic dermatitis; autoimmune diseases; rejection of tissues and organs; Alzheimer disease; apoplexy; atherosclerosis; restenosis; cancer, including Hodgkin's disease; and certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia telangiestasia. For acute therapy, parenteral administration of a compound of formulas I or II is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is more effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be from about 0.01 to about 50 mg / kg; preferably, between 0.1 and 20 mg / kg, in a manner to maintain the concentration of the drug in the plasma at an effective concentration to inhibit the activation of NF-? B. The compounds are administered one to four times a day at a level to achieve a total daily dose of about 0.4 to about 80 mg / kg / day. The precise amount of a compound of the invention that is therapeutically effective, and the route by which said compound is administered in the best manner, is readily determined by one skilled in the art by comparing the level of the agent in blood with the concentration that is it requires to have a therapeutic effect. The compounds of the formulas I and II can also be administered orally to the patient, such that the concentration of the drug is sufficient to inhibit NF-αB, or to achieve any other therapeutic indication as described herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose between about 0.1 to about 50 mg / kg in a manner consistent with the condition of the patient. Preferably, the oral dose would be from about 0.5 to about 20 mg / kg. The compounds of formulas I and II can also be administered topically to the patient, in such a way that the concentration of the drug is sufficient to inhibit NF-β, or to achieve any other therapeutic indication as described herein. Typically, a pharmaceutical composition containing the compound is administered in a topical formulation between about 0.01% to about 5% w / w. Unacceptable toxicological effects are not expected when the compounds of the present invention are administered in accordance with the present invention. The ability of the compounds described herein to inhibit the activation of NF-? B is clearly demonstrated by its ability to inhibit the activity of the reporter gene driven by NF-? B (see Table 1). The utility of the present inhibitors of NF-κB in the therapy of diseases is presupposed by the importance of the activation of NF-κB in several diseases.

TABLE 1 Inhibition of reporter gene activity directed by NF-? B Compound R 'R "X IC50 No. UM H or 8.14 - 4 H Ph Inactive Ph H Inactive 8 CF3 H XXX) 3.55 NF-? B plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as IL-6 and IL-8 (Mukaida et al., 1990 Liberman and Baltimore, 1990; Matsusaka et al., 1993), cell adhesion molecules such as ICAM and VCAM (Marui et al., 1993; Kawai et al., 1995; Ledebur and Parks, 1995) and inducible nitric oxide synthetase. (NOS) (Xie et al., 1994; Adcock et al., 1994) (complete reference citations are at the end of this section). These mediators are known to play a role in the recruitment of leukocytes at sites of inflammation, and in the case of NOS, can lead to organ destruction in some inflammatory and autoimmune diseases (McCartney-Francis et al., 1993; Kleemann e. al., 1993). Importantly, the compounds described herein inhibit the synthesis of IL-8 and the production of nitric oxide, a product of the NOS activity (see Table 2).

TABLE 2 Anti-inflammatory activity of compound 3 in Table 1 Evidence of an important function of NF-? B in inflammatory disorders is obtained in studies of asthmatic patients. Bronchial biopsies taken from patients with moderate atopic asthma show significant increases in the number of cells in the submucosa staining for activated NF-? B, total NF-? B and cytokines regulated by NF-? B such as GM-CSF and FNTa, compared to biopsies from normal non-atopic controls (Wilson et al., 1998). In addition, the percentage of vessels expressing NF-? B immunoreactivity is increased as the immunoreactivity of IL-8 in the epithelium of specimens for biopsy (Wilson et al., 1998). As such, it would be predicted that the inhibition of the production of IL-8 through the inhibition of NF-? B, as has been demonstrated by these compounds, would be beneficial in the inflammation of the respiratory tract. Recent studies suggest that NF-? B may also play a critical role in the pathogenesis of inflammatory bowel disease (IBD). Activated NF-? B is observed in colonic specimens for Chron's disease biopsy and patients with ulcerative colitis (Ardite et al., 1998; Rogler et al., 1998; Schreiber et al., 1998). Activation is evident in the inflamed mucosa, but not in the non-inflamed mucosa (Ardite et al., 1998; Rogler et al., 1998), and is associated with the increased expression of the IL-8 messenger RNA in the same sites. (Ardite et al., 1998). In addition, treatment with corticosteroids strongly inhibits the intertinal activation of NF-? B and reduces colonic inflammation (Ardite et al., 1998; Schreiber et al., 1998). Again, it would be predicted that inhibition of IL-8 production through NF-βB inhibition, as demonstrated by these compounds, would be beneficial in inflammatory bowel disease. Models of gastrointestinal inflammation in animals provide additional support for NF-? B as a key regulator of colon inflammation. Increased NF-? B activity is observed in the lamina propria macrophages in 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis in mice, with p65 being an important component of the activated complexes (Neurath et al., 1996 Neurath and Pettersson, 1997). Local administration of antisense p65 suppresses signs of established colitis in treated animals without signs of toxicity (Neurath et al., 1996; Neurath and Pettersson, 1997). As such, it would be predicted that the small molecule inhibitors of NF-? B would be useful in the treatment of IBD. More evidence for a role of NF-? B in inflammatory disorders comes from studies of the rheumatoid synovium. Although NF-? B is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-? B is present in the nuclei, and is therefore active, in cells comprising human rheumatoid synovium (Handel et al. ., nineteen ninety five; Marok et al., 1996; Sioud et al., 1998) and models of disease in animals (Tsao et al., 1997). Staining is associated with type A synoviocytes and vascular endothelium (Marok et al., 1996). In addition, constitutive activation of NF-? B is observed in cultured synoviocytes (Roshak et al., 1996; Miyazawa et al., 1998) and in synovial cell cultures stimulated with IL-1β or FNTa (Roshak et al., 1996).; Fujisawa et al., 1996; Roshak et al., 1997). In this way, the activation of NF-? B can determine the production of cytokines and the infiltration of increased leukocytes characteristic of the inflamed synovium. It would be predicted that the ability of these compounds to inhibit NF-? B, and thus inhibit the production of eicosanoids by these cells, would be useful in the treatment of rheumatoid arthritis (see Table 2). Mukaida N, Mahe Y, Matsushima K (1990) Cooperative interaction of nuclear factor-? B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J Biol Chem 265: 21128-21133. Liberman TA, Baltimore D (1990) Activation of interleukin-6 gene expression through NF-? B transcription factor. Mol Cell Biol 10: 2327-2334. Matsusaka T. Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993) Transcription factors NF-IL6 and NF-? B synergistically active transcription of the nflammatory cytokines interleukin 6 and interleukin 8. Proc Natl Acad Sci USA 90: 10193-10197. Mauri N, Offerman MK, Swerlick, R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM (1993) Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vacular endothelial cells. J Clin Invest 92: 1866-1874.

Kawai M, Nishikomori R, Jung E-Y, Tai G, Yamanak C, Mayumi M, Heike T (1995) Pyrrolidine dithiocarbamate inhibits intercellular adhesion molecule-1 biosynthesis induced by cytokines in human fibroblasts. J Immunol 154: 2333-2341. Ledebur HC, Parks TP (1995) Transcriptional regulation of the intracellular adhesion molecule-1 gene by nflammatory cytokines in human endothelial cells. J Biol Chem 270: 933-943. Xie Q, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-? B / Rel ¡n induction on nitric oxide synthase. J Biol Chem 269: 4705-4708. Adcock IM, Brown CR, Kwon O, Barnes PJ (1994) Oxidative stress induces NF-? B DNA binding and inducible NOS mRNA n human epithelial cells. Biochem Biophys Res Commun 199: 1518-1524. McCartney-Francis N, Alien JB, Mizel DE, Albina JE, Xie Q, Nathan CF, Wahl SM (1993) Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 178: 749-754. Kleemann R, Rothe H, Kolb-Bachofen V, Xie Q, Nathan C, Martin S, Kolb H (1993) Transcription and translation of inducible nitric oxide synthase in the pancreas of prediabetic BB rats. FEBS Lett 328: 9-12. Wilson SJ, Wallin A, Sandstrom T, Howarth PH, Holgate ST (1998) The expression of NF-kappa-B and associated adhesion molecules in mild asthma and normal controls. J Allergy Clin Immunol 101: 616.

Ardite E, Panes J, Miranda M, Rooms A, Elizalde Jl, Sans M, Maple Y, Bordas JM, Fernández-Checa JC, Pique JM (1998) Effects of steroid treatment on activation of nuclear factor KB in patients with inflammatory bowel disease . BrJ Pharmacol 124: 431-433. Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, Bacuerle PA, Scholmerich J, Gross V (1998) Nuclear factor KB is activated in macrophage and epithelial cells of inflamed intestinal mucosa. Gastroenterol 115: 357-369. Schreiber S, Nikolaus S, Hampe J (1998) Activation of nuclear factor KB in inflammatory bowel disease. Gut 42: 477-484. Neurath MF, Pettersson S, Meyer zum Buschenfelde K-H, Strober W (1996) Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-? B abrogates established experimetal colitis in mice. Nature Med 2: 998-1004. Neurath MF, Pettersson S (1997) Predominant role of NF-? B p65 in the pathogenesis of chronic intestinal inflammation. Immunobiol 198: 91-98. Handel ML, McMorrow LB, Gravallese EM (1995) Nuclear factor-KB in rheumatoide synovium; location of p50 and p65. Arthritis Rheumatism 38: 1762-1770. Marok R, Winyard PG, Coumbe A, Kus ML, Gaffney K, Blades S, Mapp Pl, Morris CJ, Blake DR, Kaltshmidt C, Baeuerle PA (1996) Activation of the transcription factor nuclear factor-? B in human inflamed synovial tissue. Arthritis Rheumatism 39: 583-591.

Sioud M, Mellbye O, Forre O (1998) Analysis of the NF-? B p65 subunit, Fas antigen, Fas ligand and Bcl-2-related proteins in the synovium of RA and polyarticular JRA. Clin Exp-Heumatol 16: 125-134. Tsao PW, Suzuki, T, Totsuka R, Murata T, Takagi T, Ohmachi Y, Fujimura H, Takata I (1997) The effect of dexamethasone on the expression of activated NF-? B in adjuvant arthritis. Clin Immunol Immunopathol 83: 173-178. Roshak AK, Jackson JR, McGough K, Chabot-Fletcher M, Mochan E, Marshall L (1996) Manipulation of distinct NFKB proteins alters interleukin-1 ß-induced human rheumatoid synovial fibroblast prostaglandin E2 formation. J Biol Chem 271: 31496-31501. Miyazawa K, Mori A, Yamamoto K, Okudaira H (1998) Constitutive transcription of the human interleukin-6 gene by rheumatoid synoviocytes; spontaneous activation of NF-? B and CBF1. Am J Pathol 152, 793-803. Fujisawa K, Aono H, Hasunuma T, Yamamoto K, Mita S, Nishiola K (1996) Activation of transcription factor NF-? B in human synovial cells n response to tumor necrosis factor a. Arthritis Rheumatism 39: 197-203. Roshak AK, Jackson JR, Chabot-Fletcher M, Marshall L (1997) Inhibition of NFKB-mediated interleukin-1 ß-stimulated prostaglandin E2 formation by the marine natural product hymenialdisine. J Pharmacol Exp Therapeut 283: 955-961.

Biological tests The compounds of the invention can be evaluated in one of several biological tests to determine the concentration of compound that is required to have a determined pharmacological effect. The NF-? B activity tests are carried out using a cell-based luciferase reporter test as described in Breton, J.J. and Chabot-Fletcher, M.C., JPET, 282, 459-466 (1997). Briefly, histiocytic human U937 lymphoma cell lines permanently transfected with the reporter plasmids of NF-? B (see below) are cultured in the above medium with the addition of 250 μg / ml Geneticin (G418 sulfate, Life Technologies , Grand Island, NY). The luciferase reporter test is performed on transfected U937 clones. These are centrifuged twice at 300 xg for 5 minutes and resuspended in RPMI 1640 with 10% FBS at a density of 1 x 106 cells / ml. Aliquots of a mi are added to the cavities of 24 cavities plates. The compound or carrier of dimethyl sulfoxide (DMSO) (1μl) is added to the appropriate wells and the plates are incubated at 37 ° C, 5% C02 for 30 minutes. The stimulus is added (5 ng / ml of TNFa, 100 ng / ml of LPS, or 0.1 μM of PMA) and the samples are incubated for 5 hours at 37 ° C, 5% C02, transferred to polypropylene tubes. 1.9 ml and centrifuged at 200 xg for 5 minutes. The cell pellets are washed twice in 1 ml of PBS without Ca2 + and Mg2 +, and centrifuged as indicated above. The resulting cell pellets are lysed in 50 μl of 1 x lysis buffer (Promega Corporation, Madison, Wl), swirled and incubated for 15 minutes at room temperature. An aliquot of 20 μl of each lysate is transferred to a 96-well opaque white plate (Wallac Inc., Gaithersburg, MD) and tested for luciferase production in a MicroLumat LB 96 P luminometer (EG &G Berthold, Bad Wilbad, Germany). The luminometer provides 100 μl luciferase test reagent (Promega Corporation, Madison, Wl) in each well and the integrated light output is recorded for 20 seconds. The light output is measured in relative light units (RLUs). The activity of NF-? B can also be measured in an electrophoretic mobility change test (EMSA) to evaluate the presence of NF-? B protein in the nucleus. The cells of interest are cultured at a density of 1 x 106 / ml. Cells are cultured by centrifugation, washed in PBS without Ca2 + and Mg2 + and resuspended in PBS with Ca2 + and Mg2 + at 1x107 cells / ml. To examine the effect of the compound on the activation of NF-? B, the cell suspensions are treated with various concentrations of drug or vehicle (DMSO, 0.1%) for 30 minutes at 37 ° C before stimulation with TNFa (5.0 ng. / ml) for 15 more minutes. The cellular and nuclear extracts are prepared. Briefly, at the end of the incubation period the cells (1x107 cells) are washed 2x in PBS without Ca2 + and Mg2 +. The resulting cell pellets are resuspended in 20 μl of buffer A (10 mM Hepes (pH 7.9), 10 mM KCl, 1.5 mM MgCl 2, 0.5 mM dithiothreitol (DTT) and 0.1% NP-40) and incubate on ice for 10 minutes. The nuclei are formed into pellets by microcentrifugation at 3500 rpm for 10 minutes at 4 ° C. The resulting supernatant is collected as the cell extract and the nuclear pellet is resuspended in 15 μl of buffer C (20 mM Hepes (pH 7.9), 0.42 mM NaCl, 1.5 mM MgCl, 25% glycerol, 0.2 mM of EDTA, 0.5 mM of DTT, and 0.5 mM of phenylmethylsulfonyl fluoride (PMSF)). The suspensions are mixed gently for 20 minutes at 4 ° C, then microcentrifuged at 14,000 rpm for 10 minutes at 4 ° C. The supernatant is collected and diluted to 60 μl with regulator D (20 mM Hepes (pH 7.9), 50 mM KCl, 20% glycerol, 0.2 mM EDTA, 0.5 mM DTT, and 0.5 mM PMSF). All samples are stored at -80 ° C until they are analyzed. The protein concentration of the extracts is determined according to the Bradford method (Bradford, 1976) with BioRad reagents. The effect of compounds on the activation of the transcription factor is determined in an electrophoretic mobility change test (EMSA) using nuclear extracts from treated cells as described above. The oligonucleotide consensus of double stranded NF-? B (d'AGTTGAGGGGACTTTCCCAGGC-S ') are labeled with T4 polynucleotide kinase and [g-32P] ATP. The binding mixture (25 μl) contains 10 mM Hepes-NaOH (pH 7.9), 4 mM Tris-HCl (pH 7.9), 60 mM HCl, 1 mM EDTA, 1 mM dithiothreitol, 10% glycerol , 0.3 mg / ml of bovine serum albumin, and 1 μg poly (dl-dC) »poly (dl-dC). Binding mixtures (10 μg of nuclear extract protein) are incubated for 20 minutes at room temperature with 0.5 ng of 32 P-labeled oligonucleotide (50,000-100,000 cpm) in the presence or absence of unlabeled competitor after which the mixture is mixed. loading on a 4% polyacrylamide gel prepared in 1X Tris borate / EDTA and subjected to electrophoresis at 200 V for 2 h. After electrophoresis the gels are dried and exposed to a film to detect the binding reaction. The effect of compounds on the phosphorylation of LβB can be monitored in a Western blot. The cell extracts are subjected to sodium polyacrylamide-dodecyl sulfate gel electrophoresis (SDS-PAGE) on 10% gels (BioRad, Hercules, CA) and the proteins are transferred to nitrocellulose sheets (Hybon ™ -ECL, Amersham Corp. , Arlington Heights, IL). The Immunoblot assays are carried out using a polyclonal rabbit antibody directed against L? Ba or L? Bß followed by a peroxidase conjugated donkey anti-rabbit secondary antibody (Amersham Corp., Arlington Heights, IL). Immunoreactive bands are detected using the Enchanced Chemiluminescence (ECL) test system (Amersham Corp., Arlington Heights, IL). The effects on the production of eicosanoids by human synovial fibroblasts (RSF) are established using primary cultures of human RSF. These are obtained by enzymatic digestion of synovium obtained from adult patients with rheumatoid. The cells are cultured in Earl's minimal essential medium (EMEM) containing 10% fetal bovine serum (FBS), 100 units / ml penicillin and 100 μg / ml streptomycin (GIBCO, Grand Island, NY), at 37 ° C and 5% of C02. The cultures are used in lines 4 to 9 in order to obtain a more uniform population of fibroblasts I. For some studies, fibroblasts are plated at 5 x 10 4 cells / ml in 24-well plates of 16 mm in diameter (Costar, Cambridge, MA). The cells are exposed to an optimal dose of IL-1β (1 ng / ml; Rosahk I went to. 1996a) (Genzyme, Cambridge, MA) during the allotted time. The drugs in the DMSO vehicle (1%) are added to the cell cultures 15 minutes before the addition of IL-1. Prostaglandin E2 levels in cell-free medium collected at the end of the culture period are measured directly using enzyme immunoassay (ElA) kits purchased from Cayman Chemical Co. (Ann Arbor, MI). Sample dilutions or standards are elaborated with experimental means. The anti-inflammatory activity in vivo is established using the model of inflammation of ear induced by ester forbólico in mice. Phorbol acetate-myristate (PMA) (4 μg / 20 μg acetone) is applied to the inner and outer surfaces of the left ear of male Balb / c mice (6 / group) (Charles River Breeding Laboratories, Wilmington, MA). Four hours later, the compound is dissolved in 25 μl of acetone and applied to the same ear. The thickness of both ears is measured with a marking micrometer (Mitutoyo, Japan) after 20 hours and a second topical dose of compound is applied. Twenty-four hours later, the ear thickness measurements are taken and the data are expressed as the change in thickness (x 10"3 cm) between ears with treatment and without treatment.The inflamed left ears are then removed and stored at - 70 ° C until its test for myeloperoxidase activity (MPO), a measure of the infiltration of inflammatory cells Inflammatory cell infiltration is evaluated by measuring the myeloperoxidase activity present in the inflamed tissue of the ear. Partially thawed ear are shredded and then homogenized (at 10% w / v) with a Tissumizer homogenizer (Tekmar Co., Cincinnati, OH) in 50 mM phosphate pH buffer (pH 6) containing 0.5% H . Tissue homogenates are then passed through three cycles of freeze-thaw, followed by brief treatment with sound (10 sec.) MPO activity in the homogenates is determined in the manner following. The appearance of colored product from the MPO-dependent o-dianisidine reaction (0.167 mg / ml, Sigma Chemical, St. Louis, MO) and hydrogen peroxide (0.0005%), is measured spectrophotometrically at 460 nm. The MPO activity of the supernatant is quantified kinetically (change in absorbance measured over 3 minutes, sampled at intervals of 15 seconds) using a Beckman DU-7 spectrophotometer and a packet for kinetic analysis (Beckman Instruments, Inc., Sommerset, NJ ). One unit of MPO activity is defined as one that degrades a micromole of peroxide per minute at 25 ° C. The effects on inflammation mediated cartilage degradation are measured in an in vitro cartilage explants system. In this model, bovine articular cartilage explants are incubated for 4 days / 96 hours with or without rHulL-1 alpha to stimulate cartilage degradation in the presence or absence of the test compound. The supernatants are removed for nitric oxide tests. Nitric oxide was measured using the Greiss reaction and reading spectrophotometrically at 530 nm. This reaction measures the nitrite (N02) which is the stable end product of nitric oxide.

General Nuclear magnetic resonance spectra were recorded at 250, 300 or 400 MHz using, respectively, a Bruker AM 250, Bruker ARX 300 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethyl sulfoxide, and CD3OD is tetradeuteriomethanol. Chemical changes are reported in parts per million (d) downfield of the internal standard tetramethylsilane. The abbreviations for the NMR data are the following: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = wide . J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared spectra (FTIR) were recorded on a Nicolet Impact 400 D infrared spectrometer. The IR and FTIR spectra were recorded in transmission mode, and the band positions were reported in inverse wave numbers (cm "1) .The mass spectra were recorded in instruments VG 70 FE, PE Syx API lll or VG ZAB HF using fast atom bombardment (FAB) or electrospray ionization (ES) techniques, elemental analyzes were obtained using a Perkin-Elmer 240C elemental analyzer.The melting points were recorded on a Thomas-Melt melting point measuring device. Hoover, and were not corrected, all temperatures were reported in degrees Celsius, plates were used for thin layer silica gel GF Analtech and silica gel 60 F-254 E. Merck for thin layer chromatography. by gravity and flash on silica gel E. Merck Kieselgel 60 (230-400 mesh) Where indicated, some of the materials were purchased from Aldrich Chemical Co., Milwaukee, Wisconsin, TCI America, Portland, OR.

EXAMPLES In the following synthesis examples, the temperature is in degrees centigrade (° C). Unless otherwise indicated, all starting materials were obtained from commercial sources. Without further elaboration, it is believed that the person skilled in the art can use, using the above description, the present invention to its fullest extent. These examples are given to illustrate the invention, and not to limit its scope. Reference is made to the claims for what is reserved for the inventors.

EXAMPLE 1 Preparation of N- (4-acetylphenyl) -2-hydroxt-5-vodocarboxamide A solution of iodosalicylic acid (1.9 g, 7.4 mmol) and 4-aminoacetophenone (0.97 g, 7.4 mmol) in chlorobenzene (40 mL) was treated with PCI3 (0.323 mL, 3.7 mmol). The solution was heated to reflux under an argon atmosphere. After 2 hours, the solution was filtered hot and the filtrate was allowed to stand at room temperature. After 18 hours, the solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.095 g, 5% yield): 1 H NMR (400 MHz, DMSO-d 6) d 2.5-2.6 (s) , 3H), 6.8-8.2 (m, 7H), 10.1-10.2 (s, 1 H).

EXAMPLE 2 Preparation of N- (2,4-difluorophenyl) -2-hydroxy-5-nitrophenylcarboxamide A solution of 5-nitrosalicylic acid (1.4 g, 7.7 mmol) and 2,4-difluoroaniline (0.8 mL, 7.7 mmol) in chlorobenzene (40 mL) was treated with PCI3 (0.338 mL, 3.8 mmol). The solution was heated to reflux under an argon atmosphere. After 2 hours, the solution was filtered hot and the filtrate was allowed to stand at room temperature. After 18 hours, the solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.733 g, 35% yield): 1 H NMR (400 MHz, DMSO-de) d 2.5-2.6 (s) , 3H), 7.1-8.9 (m, 6H), 10.6-10.7 (s, 1 H).

EXAMPLE 3 Preparation of N- (2,4-difluorophenyl) -2-hydroxy-5-iodophenylcarboxamide a) 5-Vodosalicylic acid chloride 5-Yodosalicylic acid (20 g, 7.58 mmol) in toluene was treated with SOCI2 (1.66 mL, 22.7 mmol) and catalytic DMF at reflux for 1 hour. The reaction mixture was evaporated to dryness, and the acid chloride was used in the next step without purification. b) 2,4-D-fluoro-phenoxy-2-hydroxy-5-vodophenylcarboxamide The compound of Example 3 (a) (3.79 mmol) and 2,4-difluoroaniline (380 ul, 3.79 mmol) in toluene was heated to reflux for 24 hours. The reaction mixture was evaporated, the residue was washed with ether and the solid residue was recrystallized from MeOH to give 159 mg of N- (2,4-difluorophenyl) -2-hydroxy-5-iodophenylcarboxamide. ES MS (M + H) "m / e 373.7 The specification and the foregoing examples fully describe how to obtain and use the compounds of the present invention, however, the present invention is not limited to the particular embodiments described above, but includes all modifications thereof within the scope of the following claims The various references to journals, patents and other publications cited herein, comprise the state of the art, and are hereby incorporated by reference in their entirety.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS
1. A pharmaceutical composition comprising a compound of formula I: I wherein: RA replaces ring A from 0 to 3 times, and is independently selected from the group consisting of: N02, halogen, C-j alkyl. 6, trifluoromethyl, O-C1.6alkyl and S-C-i-βalkyl; and RB replaces ring B from 0 to 3 times, and is independently selected from the group consisting of: halogen, C (O) C?-6 alkyl, Ci-β alkyl, O-Ci-β alkyl, S -alkyl of C? -6, CH2-aryl, and aryl; and pharmaceutically acceptable salts, hydrates and solvates thereof.
2. 2. The pharmaceutical composition according to claim 1, further characterized in that: RA occurs once and is R-i; and RB occurs twice and is independently R and R3.
3. 3. - The pharmaceutical composition according to claim 1, further characterized in that it comprises a compound of formula II: wherein: Ri is selected from the group consisting of: H, N02, CF3, F, Cl, Br and I; R2 is selected from the group consisting of: H and F; and R3 is selected from the group consisting of: F, Cl, Br, I, phenyl and C (O) C-i-β alkyl; and a pharmaceutically acceptable carrier, diluent or excipient.
4. 4. The pharmaceutical composition according to claim 3, further characterized in that C (O) C 1-6 alkyl is C (0) CH 3.
5. 5. The pharmaceutical composition according to claim 3, further characterized in that said compound is selected from the group consisting of: N- (4-phenyl-phenyl) -2-hydroxy-5-trifluoromethylcarboxamide; N- (2,4-difluorophenyl) -2-hydroxy-5-nitrocarboxamide; N- (2,4-difluorophenyl) -2-hydroxy-5-iodocarboxamide; and N- (4-acetylphenyl) -2-hydroxy-5-iodocarboxamide.
6. 6. The use of a compound of formula I: wherein: RA replaces ring A from 0 to 3 times, and is independently selected from the group consisting of: NO2, halogen, C-i alkyl. 6) trifluoromethyl, O-C- [alpha] -6 alkyl and S-C- [beta] -β alkyl; and RB replaces ring B from 0 to 3 times, and is independently selected from the group consisting of: halogen, C (O) C-? 6 alkyl, C? -6 alkyl, O-C- alkyl? .6, S-C6-alkyl, CH2-aryl, and aryl; and pharmaceutically acceptable salts, hydrates and solvates thereof, in the manufacture of a medicament for inhibiting NFKB and / or for treating a disease characterized by excessive activation of NF-? B.
7. 7. The use as claimed in claim 6, wherein: RA occurs once and is R-i; and RB occurs twice and is independently R2 and R3-
8. 8. The use as claimed in claim 6, wherein said compound is a compound of formula II: wherein: Ri is selected from the group consisting of: H, NO2, CF3, F, Cl, Br and I; R2 is selected from the group consisting of: H and F; and R3 is selected from the group consisting of: F, Cl, Br, I, phenyl and C (O) C-i-β alkyl; and a pharmaceutically acceptable carrier, diluent or excipient.
9. 9. The use as claimed in claim 8, wherein C (O) C? -6 alkyl is C (0) CH3.
10. 10. The use as claimed in claim 8, wherein said compound is selected from the group consisting of: N- (4-phenyl-phenyl) -2-hydroxy-5-trifluoromethylcarboxamide; N- (2,4-difluorophenyl) -2-hydroxy-5-nitrocarboxamide; N- (2,4-difluorophenyl) -2-hydroxy-5-iodocarboxamide; and N- (4-acetylphenyl) -2-hydroxy-5-iodocarboxamide.
11. 11. The use as claimed in claims 6 to 10, wherein said disease is an inflammatory disorder.
12. 12. The use as claimed in claim 11, wherein said disease is selected from the group consisting of: rheumatoid arthritis, inflammatory bowel disease and asthma.
13. 13. The use as claimed in claims 6 to 10, wherein said disease is dermatosis.
14. 14. The use as claimed in claim 13, wherein said disease is selected from the group consisting of: psoriasis and atopic dermatitis.
15. 15. The use as claimed in claims 6 to 10, wherein said disease is selected from the group consisting of: autoimmune diseases; rejection of organs and tissues; Alzheimer disease; apoplexy; atherosclerosis, restenosis; osteoarthritis, osteoporosis; and Ataxia telangiestasia.
16. 16. The use as claimed in claims 6 to 10, wherein said disease is cancer.
17. 17. The use as claimed in claim 16, wherein said cancer is Hodgkin's disease.
18. 18. The use as claimed in claims 6 to 10, wherein said disease is AIDS.