MXPA00000129A - 2-substituted imidazoles useful in the treatment of inflammatory diseases - Google Patents

Abstract

This invention relates to substituted imidazoles of Formula (I), pharmaceutical compositions containing them, methods of using them and intermediates useful in their manufacture. The compounds of the invention modulate the production of a number of inflammatory cytokines, and are useful in the treatment of diseases associated with the production of inflammatory cytokines.

Description

1MIDAZOLES 2 - USEFUL USEFUL IN THE TREATMENT OF INFLAMMATORY DISEASES DESCRIPTIVE MEMORY The present invention relates to a series of substituted imidazoles, pharmaceutical compositions containing them of intermediates used in their manufacture. The compounds of the invention inhibit the production of a number of inflammatory cytokines, particularly TNF-a and IL-1β. The compounds of this invention are useful in the treatment of diseases associated with the overproduction of inflammatory cytokines, such as rheumatoid arthritis, inflammatory bowel disease, septic shock, osteoporosis and osteoarthritis.

BACKGROUND OF THE INVENTION Inflammatory cytokines, IL-1β and TNF-a play an important role in a number of inflammatory diseases such as rheumatoid arthritis. C. Dinarello et al, Inflammatory cytokines: Interleukin-1 and Tumor Necrosis Factor as Effector Molecules in Autoimmune Diseases Curr. Opin. Immunol. 1991, 3, 941-48. Arthritis is an inflammatory disease that affects any joint in the human body. The symptoms of the above vary from pain and mild inflammation in affected joints, to severe and debilitating pain and inflammation. Although the disease is mainly associated with elderly adults, it is not restricted to adults. The most common arthritis therapy involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve symptoms. However, despite its widespread use, several individuals can not tolerate the doses necessary to treat the disease for a prolonged period. In addition, NSAIDs merely treat the symptoms of disease without affecting the original cause. Other drugs, such as metrotrexate, gold salts, D-penzylamine and prednisone are often used when patients do not respond to NSAIDs. These drugs also have significant toxicities and their mechanism of action remains unknown. Receptor antagonists for IL-1β and monoclonal antibodies to TNF-a have been shown to reduce the symptoms of rheumatoid arthritis in human clinical trials on a small scale. In addition to protein-based therapies, there are small molecule agents that inhibit the production of such cytokines and have demonstrated activity in animal arthritis models. J.C. Boehm et al., 1 -Substituted 4-Aryl-5-pyridinylimidazoles: A New Class of Cytokine Suppressive Drugs With Low 5-Lipoxygenase and Cyclooxygenase Inhibitory Potency, J. Med. Chem., 1996, 39, 3929-37. Of said small molecule agents, SB 203580 has been shown to be effective in reducing the production of TNF-a and IL-1 in LPS from stimulated human monocyte cell lines with IC50 values of 50 to 100 nM. J.Adams et al., Imidazole Derivatives and Their Use as Cytokine Inhibitor, International Patent Application WO 93/14081, July 23, 1993. In addition to said in vitro test, SB 203580 inhibits the production of inflammatory cytokines in rats and mice at Cl50 values of 15 to 25 mg / kg. A.M. Badger, et al, Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein / p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function, The Journal of Pharmacology and Experimental Therapeutics 1996, 279, 1453 -61. Although human data are not currently available for SB 203580, monoclonal antibodies to TNF-a have been shown to be effective in the treatment of rheumatoid arthritis. M.J. Elliot et al., Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor a, Arthritis Rheum. 1993 36, 1681-90. Due to the oral and potential activity of SB 203580 in animal models, researchers have suggested that a compound with said profile has potential as a viable treatment for rheumatoid arthritis. A.M. Badger, et al. Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein / p38 Kinase, in Animal Mode of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function, The Journal of Pharmacology and Experimental Therapeutics, 1996, 279, 1453-61. SB 203580 and other small molecule agents reduce the production of inflammatory cytokines by inhibiting the activity of a p38 serine / threonine kinase (note that other researchers refer to this enzyme as CSBP), at a Cl50 value of 200 nM . D.

Griswold et al., Parmacology of Cytokine Suppressive Anti-inflammatory Drug Binding Protein (CSPB), A Novel Stress-invented Kinase, Pharmacology Commnications, 1996, 7, 323-29. Although the precise mechanism of said kinase is unknown, it has been implicated in the production of TNF-α and the signaling responses associated with the TNF-a receptor.

SB 203580 BRIEF DESCRIPTION OF THE INVENTION The invention relates to composition of the formula wherein: Ri is phenyl, heteroaryl wherein the heteroaryl contains from 5 to 6 ring atoms, or substituted phenyl wherein the substituents are independently selected from 1 or more members of the group consisting of C 5 alkyl, halogen , nitro, trifluoromethyl and nitrile; R 2 is phenyl, heteroaryl wherein the heteroaryl contains from 5 to 6 ring atoms, substituted heteroaryl; wherein the substituents are independently selected from 1 or more members of the group consisting of C 1-5 alkyl and halogen, or substituted phenyl; wherein the substituents are independently selected from 1 or more members of the group consisting of C 1-5 alkyl, halogen, nitro, trifluoromethyl and nitrile; R3 is hydrogen, SEM, C1-5 alkoxycarbonyl, aryloxycarbonium, arylalkyloxycarbonyl of C-1.5, arylalkyl of C1.5, phthalimidoalkyl of C1.5, aminoalkyl of C1.5, diaminoalkyl of C1-5, succinimidoalkyl of C1.5, C1.5 alkylcarbonyl, arylcarbonyl, C5.5 alkylcarbonyl, C5.5alkyl, aryloxycarbonyl-C1.5alkyl, C5-5 heteroarylalkyl, wherein the heteroaryl contains from 5 to 6 ring atoms, or substituted arylalkyl of C ^ s; wherein the aryl substituents are independently selected from one or more members of the group consisting of C-1.5 alkyl, C 1-5 alkoxy, halogen, amino, C 1-5 alkylamino, and C 1 alkylamino.; R4 is (A) n- (CH2) q-X where: A is sulfur or carbonyl; n is 0 or 1; q is 0-9; X is selected from the group consisting of hydrogen, hydroxy, halogen, vinyl, ethynyl, Cs alkyl, C3.7 cycloalkyl, Cs alkoxy, phenoxy, phenyle, Crs arylalkyl, amino, C1-5 aicylamino, nitrile, phthalimido, amido, phenylcarbonyl, alkylaminocarbonyl of C-1.5, phenylaminocarbonyl, arylakylamino, carbonyl of Crs, alkylthio of C-? 5, alkylsulfonyl of C-1.5, phenylsulfonyl, substituted sulfonamido wherein the sulfonyl substituent is selected from the group consisting of C1.5 alkyl, phenyl, C-1.5 aralkyl, thienyl, furanyl and naphthyl; substituted vinyl wherein the substituents are independently selected from one or more members of the group consisting of fluoride, bromide, chloride and iodide, substituted ethynyl; wherein the substituents are independently selected from one or more members of the group consisting of fluoride, bromide, chloride and iodide, substituted C-1.5 alkyl wherein the substituents are selected from the group consisting of one or more Crs alkoxy, thialoalkyl, phthalimido and amino, substituted phenyl; wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen and d-5 alkoxy, substituted phenoxy; wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen and C 1-5 alkoxy, C 1-5 alkoxy, wherein the alkyl substituent is selected from the group It consists of phthalimido and amino. substituted C-1.5 arylalkyl wherein the alkyl substituent is C5-substituted arylalkyl hydroxyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of C-1.5 alkyl, halogen and C1.5 alkoxy substituted amido; wherein the carbonyl substituent is selected from the group consisting of C ?5 alkyl, phenyl, C 1-5 alkylaryl, thienyl, furanyl, and substituted phenylcarbonyl naphthyl wherein the phenyl substituents are independently selected from one or more members of the carbonyl group. group consisting of C-1.5 alkyl, halogen and d-5-alkylthio substituted alkoxy of d-5; wherein the alkyl substituent is selected from the group consisting of hydroxy and substituted phthalimido alkylsulfonyl of C-1.5, wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido, substituted phenylsulfonyl wherein the phenyl substituents are independently selected from or more members of the group consisting of bromide, fluoride, chloride, C1.5 alkoxy and trifluoromethyl, with the proviso that: if A is sulfur and X is different from hydrogen, C1-5 alkylaminocarbonyl, phenylaminocarbonyl, arylalkylaminocarbonyl of Crs. , C1-5 alkylsulphonyl or phenylsulfonyl, then q must be equal to or greater than 1; if A is sulfur and q is 1, then X can not be alkyl of C? .2; yes A is carbonyl and q is 0, then X can not be vinyl, ethynyl, alkylaminocarbonyl of d-5? phenylaminocarbonyl, arylalkyl-aminocarbonyl of C1.5, alkylsulfonyl of C1.5 or phenylsulfonyl; if A is carbonyl, q is 0 and X is H, then R3 is not SEM; if n is 0 and q is 0, then X can not be hydrogen; and pharmaceutically acceptable salts thereof. In addition, the present invention contemplates pharmaceutical compositions containing compounds of formula I, and methods of f cytokine-mediated disorders of treatment with compounds of formula I.

The novel compounds of this invention inhibit the in vitro activity of p38 on the nanomolar scale. In addition, the compounds inhibit the in vitro secretion of TNF-a and IL-1β on the nanomolar scale. The animal models demonstrate the inhibition of TNF-a induced by LPS as well as the inhibition of rheumatoid arthritis. With this scale of activity, the • 10 compounds of the invention are useful in the treatment of a variety of cytokine related disorders including: rheumatoid arthritis, inflammatory bowel disease, septic shock osteoporosis, osteoarthritis, neuropathic pain, HIV replication, HIV dementia, viral myocarditis, diabetes dependent on insulin, diabetes that does not depend on the insulin, periodontal disease, restenosis, alopecia areta, T cell depression in HIV or AIDS infection, psoriasis, acute pancreatitis, rejection of • Allograft, allergic inflammation in the lung, arteriosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, infarction, Crohn's disease, inflammatory bowel disease, ischemia, congestive heart failure, fibrosis pulmonary, hepatitis, gliobastoma, Guiilain-Barre syndrome, and systemic lupus erythematosus.

DETAILED DESCRIPTION OF THE INVENTION The terms used to describe the invention are used They are commonly and are known to those skilled in the art. Without However, the terms that can have other meanings are defined. The term "FCS" represents fetal goat serum, "TCA" represents trichloroacetic acid and "RPM" represents the middle of the Rosweil Park Inst. Memory (Sígma cat # R0833). "Independently" means that when there is more than one substituent, the substituents may be different. The term f "alkyl" refers to the straight, cyclic and branched chain alkyl groups , "alkoxy" refers to the O-alkyl wherein the alkyl is as defined above. The term "heteroaryl" refers to a 5- or 6-membered aromatic ring wherein at least one member is a heteroatom. Suitable heteroatoms include nitrogen, oxygen and sulfur. In the case of rings of 5 members, the heteroaryl will contain a sulfur, oxygen or nitrogen atom, in addition they can contain up to 3 additional nitrogens. f With 6-membered rings, heteroaryl can contain up to 3 nitrogens. Examples of said heteroaryls include, pyridin-2-yl, pyridin-3-ylo, pyridin-4-yl, pyrimidin-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3. -ilo, Pyridazine, triazine, thiazole, oxazole, pyrazole and the like. "SEM" refers to 2- (trimethylsilyl) ethoxymethyl) and "LDA" refers to lithium diisopropylamide. The symbol "Ph" refers to phenyl, "PHT" refers to phthalimide and "aryl" includes mono and fused aromatic rings such as phenyl and naphthyl.

As used in this invention, the term "cytokine" refers to the TNF-a and IL-1β proteins. Cytokine-related disorders are diseases of humans and other mammals where the overproduction of cytokines causes the symptoms of the disease. The overproduction of cytokines, TNF-a and IL-1β. It has been linked to a number of diseases. Such cytokine-related disorders include but are not limited to rheumatoid arthritis, inflammatory bowel disease, osteosporosis of septic shock, osteoarthritis, neuropathic pain, HIV replication, HIV dementia, viral myocarditis, insulin-dependent diabetes, diabetes not dependent on insulin, periodontal disease, restenosis, alopecia areata, reduction of the T cell in HIV infection or AIDS, psoriasis, acute pancreatitis, rejection of the graft, allergic inflammation in the lung, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, infarction, Crohn's disease, inflammatory bowel disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome, and systemic lupus erythematosus. The term "effective dose" refers to an amount of a compound of formula I that reduces the amount of TNFa and / or IL-1β that can be detected in a mammal suffering from a cytokine mediated disorder. In addition, the term "effective dose" refers to an amount of a compound of formula I that reduces the symptoms of a cytokine-related disorder. The compounds of the invention can be prepared by the following schemes, wherein some schemes produce more than one embodiment of the invention. In such cases, the selection scheme is a matter of discretion that is within the capabilities of those skilled in the art. Scheme I can be used to produce the compounds of the invention wherein A is sulfur. The starting material for said scheme is a mercaptoimidazole as exemplified by intermediate 1 a. Said intermediary can be prepared by following the known imidazole preparations. Laníos, I. et al. J. Org. Chem, 1988, 53, 4223-27; Markova, Y. et al, Zh Org. Zhim. 1965, 1, 1475. Intermediate 1 a is treated with a base such as NaH, or n-BuLi in an inert solvent such as DMF or THF at room temperature for 30 minutes to several hours. This reaction mixture is treated with an alkylating agent such as 1-bromopentane to give the desired compound 1 b. Said reaction sequence can be used to produce the compounds of the invention wherein A is sulfur, n is 1, q is 0-9 and X is hydrogen, vinyl, ethynyl, substituted ethynyl, C1.5 alkyl, C3 cycloalkyl. 7, substituted alkyl of d.5 > C 1-5 alkoxy, C 1-5 arylalkyl, C 1-5 substituted arylalkyl, nitrile or C 15 alkylamino, by modifying the alkylating agent with known compounds. For example, to produce a compound of the invention wherein A is sulfur, n is 1, q is 0 and X is arylalkyl of C 1-5, one of these can treat intermediate 1 a with benzyl chloride. To produce the compounds of the invention wherein A is sulfur, n is 1, q is 0 and X is phenylaminocarbonyl, the intermediate 1a is treated with a base such as NaH, or n-BuLi in an inert solvent such as DMF or THF at room temperature for 30 minutes to several hours. This reaction mixture is treated with an isocyanate, such as phenylisocyanate at room temperature for 1 to 24 hours. Said reaction sequence can be used to produce the compounds 1c of the invention wherein A is sulfur, n is 1, q is 0 and X is alkylaminocarbonyl of d-5 by the use of known socianates. In addition, said sequence can be used to produce compounds wherein X is phenylcarbonyl, substituted phenylcarbonyl and C- | 5 alkylcarbonyl. The replacement of the isocyanate with a substituted acyl halide derivative, such as 2-bromoacetophenone, of the compound of the invention wherein X is phenylcarbonyl. The compounds of the invention wherein A is sulfur, n is 1, q is 1 and X is nitrile, can be produced as illustrated in Scheme I. Intermediate 1a is treated with a base such as NaH, or n- BuLi in an inert solvent such as DMF or THF at room temperature for 30 minutes to several hours. Said reaction mixture is treated with an acetonitrile derivative such as iodoacetonitrile for several hours at room temperature to give the compounds of type 1d. In addition to the compounds of type 1d, this sequence can be used to produce compounds wherein A is sulfur, n is 1, q is 1 or greater and X is vinyl or ethynyl. Said compounds can be prepared by the replacement of iodoacetonitrile with allyl halides or propargyl halides respectively.

Scheme I can be used to produce compounds of the invention wherein A is sulfur, n is 1, q is greater than 1 and X is phthalimido. Intermediate 1 a is treated with a base such as NaH, or n-BuLi in an inert solvent such as DMF or THF at room temperature for 30 minutes at several hours. Said reaction mixture is treated with a haloalkylphthalimido derivative for 1 to several hours to give the compounds of type 1e to produce the compounds wherein X is amino, the compounds of type 1e are treated with hydrazine to give the compounds of type 1f.

• SCHEME 1 Other compounds of the invention can be produced by Scheme 2 using the compounds of type 1f as starting materials. Compound 1f and furoyl chloride are treated with a mild base such as sodium bicarbonate and an inert solvent, such as DMF, at room temperature for 1 to several hours to give the type 2a compounds. The compounds of the invention wherein X is substituted amidocarbonyl, can be prepared by this method. For example, to prepare a compound wherein A is sulfur, n is 1, q is 2 and X is naphth-2-ylamido, 2-naphthoyl chloride may be used in place of furoyl chloride to give the desired compound. In addition, said scheme can be used to prepare compounds wherein X is substituted sulfonamido of type 2b. The replacement of furoyl chloride by propanesulfonyl chloride gives the compounds of type 2b.

SCHEME 2 2 a To produce the compounds of the invention wherein A is carbonyl, n is 1, q is 0 and X is hydrogen, Scheme 3 can be used. The starting midazole 3a can be prepared by following the literature preparations (cf. example, Klaus Hofmann, Imidazole and Its Derivatives Part I (1953)). Said material is treated with bases such as NaH, or n-BuLi in an inert solvent such as DMF or THF at room temperature for 15 minutes to several hours. The reaction mixture is treated with a nitrogen protecting group which is stable for basic conditions, such as 2,2- (trimethylsilyl) ethoxymethyl chloride at room temperature for 1 to 24 hours to give the 1 -substituted imidazoles 3b? and 3b2. The 3b isomers? and 3b2 can be treated independently with a base, such as n-BuLi, and an inert solvent, such as THF, around -78 ° C under an inert atmosphere of about 15-30 minutes. Said mixture is treated with a formylating agent, such as DMF, at room temperature for about 1 hour to give the compounds of type 3c. Treatment of intermediate 3c with an aqueous acid such as 1 N HCl at room temperature for about 30 minutes to several hours gives 3d. Said reaction sequence can be used to produce the compounds of the invention wherein A is carbonyl, q is 0-9, and X is C1-5 alkyl, phenyl and arylalkyl of C1.5 by replacing the formylating agent with a Acylation agent. For example, to prepare a compound wherein A is carbonyl, q is 1, X is phenyl, the formylating agent is replaced with benzoyl chloride. In addition, the compounds wherein A is carbonyl, q is 0-9 and X is hydroxy, can be prepared by replacing the alkylating agent with cyclic lactones. For example, to prepare a compound wherein A is carbonyl, q is 3 and X is hydroxy, intermediate 3a is treated with a butyrolactone.

SCHEME 3 3 d To prepare the compounds of the invention wherein n is 0, the intermediates of scheme 3 can be used in scheme 4. Intermediate 3c can be treated with H2 and a hydrogenation catalyst such as Pd / C, at room temperature for 1 hour. to several hours to give alcohol 4a. Said alcohol can be activated with triphenylphosphine or carbon tetrachloride and is displaced with a nucleophilic agent such as 2-propantiol at room temperature for 15 to 48 hours to give the compounds of formula 4b. Treatment of 4b with aqueous acids such as 1 N HCl at room temperature for several hours gives the compounds of type 4c. Said scheme can be used to produce compounds wherein X is amino substituted by the modification of the nucleophilic agent. For example, if the 2-propantiol is replaced with propylamine, a compound can be prepared wherein n is 0, q is 1 and X is propylamino. In addition to nucleophilic displacement, alcohol 4a can be treated with aqueous acids such as 1 N HCl at room temperature for several hours to give the deprotected alcohol 4d. The deprotected alcohol can be used to prepare other compounds of the invention. For example, to prepare a compound wherein n is 0, q is 1 and X is alkoxy of d.5, compound 4d is treated with a base such as NaH and an alkylating agent such as propyl bromide at room temperature.

SCHEME 4 4c To prepare the compounds wherein n is 0 and X is alkylsulfonyl or C 1-5 alkyl, substituted C 5 alkylsulfonyl, scheme 5 can be used. Intermediate 4a is treated with a hydroxyl activation group , such as triphenylphosphine and carbon tetrachloride in an inert solvent, such as acetonitrile. The activated intermediate is treated with an alkylation group such as 2-mercaptopropanoi and an organic or inorganic base such as NaOH at about room temperature to reflux for several hours to give type 5a intermediates. As described above, intermediate 5a can be treated with acidic solutions to give substituted midazol-2-yl compounds of type 5b. Alternatively, intermediate 5a can be treated with oxidizing agents such as oxone in an inert solvent such as MeOH at room temperature for about 4-14 hours to give sulfones of type 5c. Finally, intermediates such as 5c can be treated with aqueous acid solutions to give substituted imidazol-2-yl compounds of type 5d.

SCHOOLS Although the preceding schemes start with a ring of unsubstituted imidazole, several of the compounds of the invention can be prepare by forming the imidazole with the desired substitution 2 • as illustrated in diagram 6. In this scheme, a diona of type 6a, such such as 1- (4-chlorophenyl) -2- (4-pyrimidinyl) -2-ethanedione, is treated with such an aldehyde as ethoxypropionaldehyde, ammonium acetate and acetic acid at about 70 ° C to reflux for several hours. The desired compound is isolated from said mixture to give a compound of type 6b. This scheme can be used to produce compounds of the invention wherein n is 9, q is 1-9 and • 10 X is H, phthalimido and C 1-5 alkoxy.

SCHEME 6 6 to 6 b 20 In order to produce compounds of the invention wherein R3 is different from hydrogen or SEM, the final products of schemes 1-6 can be treated with a base such as NaH, n-BuLi or K2CO3 in an inert solvent such as DMF or THF at room temperature for 15 minutes to several hours. The resulting anion can be treated with a suitable alkylating or acylating agent. For example, to produce compounds of the invention wherein R3 is arylcarbonyl, A is sulfur and X is pentyl, compounds of type 1 b can be treated with NaH, followed by benzoyl chloride. In order to produce the compounds of the invention wherein n is 0, q is 0 and X is halogen, scheme 7 can be used. The starting material for the scheme is 4,5-disubstituted midazole of type 7a. Substituted f-10 imidazoles can be prepared following the known procedures and substituents R and R2 of the compounds of the invention are determined by the substituents of intermediate 7a. Intermediate 7a is treated with a base, such as NaH and an inert solvent such as DMF at room temperature for about 30 minutes to 1 hour. Once the anion formation is completed, an alkylating agent such as phenethyl chloride is added and the reaction mixture is stirred at about 60-100 ° C for about 2-4 hours to give the intermediates 7b? and 7b2. Said intermediates are separated in this step to allow the formation of final products with a predominant isomer. Although the final products 20 can be separated, the separation of 7b? and 7b2 leads to higher yields of the products. Intermediate 7b2 is treated with a strong base such as LDA in an inert solvent such as THF at -78 ° C for about 30 minutes. A source of halogen atoms, such as, for example, iodide or bromide, is added to the anion formed and this mixture can be heated to room temperature for 30 minutes to 1 hour to give intermediate 7c wherein X is iodide. • SCHEME 7 7 to 10 Although the claimed compounds are useful as inhibitors of TNF-a and IL-1, some compounds are more active than others and are preferred or particularly preferred. • The preferred compound of formula I includes: • 10 fifteen 2 The "R-i" particularly preferred are phenyl or phenyl • substituted wherein the phenyl substituents are halogen and nitrile. Particularly preferred "R2" s are pyrid-4-yl, pyrimidin-4-yl and 2-butyl-4-yl. Particularly preferred "R3" s are hydrogen, SEM, alkyl of d.5, phenylalkyl of C 1-5 and phenylalkyl substituted of d-5. 15 The particularly preferred "q" s are 0-6. Particularly preferred "X" s are hydrogen, hydroxy, nitrile, C 1-5 alkyl, phthalimido, amido, substituted amido, C 1-5 alkylsulfonyl, C 1-5 hydroxyalkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, substituted amido, substituted sulfonamido, C 1-5 alkoxycarbonyloxy and C 1-5 alkyl. The compounds of formula I can be used in pharmaceutical compositions for treating patients (humans and other primates) with disorders related to the overproduction of inflammatory cytokines, particularly TNF-a. The preferred route is oral administration, however, the compounds can be administered by intravenous infusion or topical administration. Oral doses vary from around 0. 05 to 100 mg / kg daily. Some compounds of the invention can be dosed orally on the scale of about 0.05 to about 50 mg / kg. daily, while others can be dosed from 0.05 to around 20 mg / kg daily. Infusion doses can vary from around 1.0 to 1. 0 x 104 μg / kg / min of inhibitor, mixed with a pharmaceutical carrier for a period ranging from several minutes to several days. For topical administration, the compounds of formula I can be mixed with a pharmaceutical carrier f 10 at a concentration of about 0.1 to about % drug to vehicle. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and composition techniques. Oral dosage forms can be elixirs, syrups, capsules, tablets and similar. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients can be mixed as required with disintegrants, diluents, agents granulation, lubricants, binders and the like using conventional techniques for preparing dosage forms known to those skilled in the art. Parenteral dosage forms can be prepared using water or another sterile carrier.

Typically, the compounds of formula I are isolated and used as free bases, however, the compounds can be isolated and used in the same way as their pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic acid, cyclohexansulfamic and saccharic. In order to illustrate the invention, the following examples are included. Said examples do not limit the invention. These are only intended to suggest a method of practice of the invention. Those skilled in the art can find other methods of practicing the invention, which are apparent to them. However, it is considered that said methods are within the scope of the invention.

SYNTHETIC EXAMPLES EXAMPLE 1 f 10 5 (4) - (4-Fluorophenin2- (1-propylUio-4 (5) - (4-pyridin-5 (4-imidazole (Compound 1) A suspension of 4- (4-fluorophenyl) -2-mercapto-5- (4-pyridyl) -midazole (0.52 g, 1.92 mmol: Lantos et al. Journal of Organic Chemistry, 1998, 53, 4223-27), 95% NaH (48 mg, 1.92 mmol) and DMF (20 mL) was stirred under N2 for 30 minutes at room temperature. 1-F iodopropane (0.19 ml, 1.92 mmol) was added and the resulting solution was stirred at room temperature for 20 hours. The reaction mixture was poured into ice / H 2 O (100 ml) and the resulting yellow solid was filtered and washed with H 2 O.

Said solid was recrystallized from MeOH / H 2 O (20: 5) to give compound 1 as a yellow solid: mp 222-27 ° C; MS (Cl +) 314 (M +).

EXAMPLE 2 (4) - (4-Fluorophenyl) -2- (3-phthalimidoprop-1-yl) thio-4 (5) - (4-pyridyl) -imidazole (compound 2) N- (3-bromopropyl) phthalimide (1.02 g, 3.8 mmol) and 60% NaH (0.152 g) were added to a solution of 4- (4-fluorophenyl) -2-mercapto-5- (4-pyridyl) - Imidazolethione (1.03 g, 3.80 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into ice / H2O and the resulting solid was washed with water and dried to give compound 2 as a solid: mp 241-43 ° C; MS 459 (MH +).

EXAMPLE 3 2- (3-Aminoprop-1-yl) thio-5 (4) - (4-fluorophenyl) -4 (5) - (4-pyridyl) -imidazole (Compound 3): 55% hydrazine was added ( 1.1 mL) was added to a solution of compound 2 (4.40 g, 9.60 mmol) in MeOH ()) and said mixture was heated to reflux for 4 hours. The resulting mixture was concentrated in vacuo and triturated with 1 N NaOH. The solid precipitate was filtered, washed with water and dried to give compound 3 as a solid: MS 329 (MH +).

EXAMPLE 4 (4) - (4-Fluorophenip-2- (3- (thien-2-ylamido) prop-1-yl) thio-4 (5) - (4-pyridyl) -imidazole (Compound 4) • 10 Sodium bicarbonate (0.42 g) and thiophenecarbonyl chloride (0.28 ml, 2.50 mmol) were added to a solution of compound 3 (0.75 g, 2.27 mmol) in DMF (6 mL) under N2 at room temperature. 45 minutes and poured into ice / H2O.

The resulting mixture was filtered, washed with H O and dried in vacuo to give compound 4 as a solid: mp 172-75 ° C; MS 439 (MH +).

EXAMPLE 5 (4). (4-Fluorophenyl) -2- (N-methylaminocarbonyl) thio-4 (5) - (4-pyridyl) -imidazole (Compound 5) 95% sodium hydride (32 mg, 1.3 mmol) and methyl isocyanate (0.77 ml, 1.30 mmol) were successively added to a solution of 4- (4-fluorophenyl) -2-mercapto-5- (4-pyridyl) imidazole ( 350 mg, 1.30 mmol) and said mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into H2O and the solid precipitate was filtered, washed with H2O and dried in vacuo to give compound 5 as a solid: mp > 275 ° C; EM 272 (M-CONHCH3).

EXAMPLE 6 Cpd. 6a Cpd. 6b 4- (4-Fluorophenol) -5- (4-pyridyl) -1 - (2- (trimethylsilyl) ethoxymethyl) -imidazole (Compound 6a) 5- (4-Fluorophenyl) -4- (4-pyridyl) - 1- (2- (trimethylsilyl) ethoxymethyl) -imidazole 15 (Compound 6b) 60% sodium hydride (0.92 g, 23 mmol) was added to a stirred solution of 5- (4) - (4-fluorophenyl) -4 (5) - (4-pyridyl) -imidazole (5.50 g, 23 mmol) ) in DMF under N2. 2- (Trimethylsilyl) ethoxymethyl chloride (4.07 20 ml, 23 mmol) was added after 15 minutes and the resulting mixture was stirred for 3 hours, poured into H2O, dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel using ethyl acetate as an eluent. The less polar isomer was crystallized to give compound 6a: mp 111-13 ° C; MS 370 (MH +). The more polar isomer was crystallized to give compound 6b: mp 62-64 ° C; MS 370 (MH +).

EXAMPLE 7 Carboxaldehyde 5- (4-fluorophenyl) -4- (4-pyridyl) -1 - (2- (trimethylsilyl) ethoxymethyl) -2 -imidazole (Compound 7) N-Butyllithium (1.6 N, 13 mL, 21.0 mmol) was added to a stirred solution of compound 6b (7.10 g, 19.2 mmol) in THF from -77 to -78 ° C. Said mixture was stirred for 15 minutes, DMF (2 mL, 26 mmol) was added and the resulting mixture was stirred at room temperature for about 1 hour. The reaction was triturated with H2O, extracted with ethyl acetate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate / hexane as an eluent to give compound 7 as a solid: mp 42-45 ° C; MS 398 (MH +).

• EXAMPLE 8 • 10 Carboxaldehyde of 5 (4) - (4-flurophenyl) -4 (5) - (4-pyridyl) -2-midazole (Compound 8) 1 N HCl (20 mL) was added to a solution of compound 7 (1.60 g) in EtOH (20 mL). Said mixture was stirred for 30 minutes, neutralized with NaHCO3 and poured into H2O. The solid precipitate was filtered and dried to give the title compound as a solid: mp 233-43 ° C (dea); EM 268 (MH +).

EXAMPLE 9 • 10 4-hydroxy-1-r5- (4-fluorophenih-4- (4-pyridin-1 - (2- (trimethylsilyl) ethoxymethyl) imidazol-2-n-butanone (Compound 9) N-Butyllithium (1.6 N, 3.5 mL, 5.6 mmol) is added to a stirred solution of compound 6b (3.5 mL, 5.78 mmol) in THF from -77 to -78 ° C. Said mixture was stirred for 15 minutes, a-butyrolactone (2 mL, 26 mmol) was added and the resulting mixture was stirred at room temperature. The reaction was quenched with H2O, extracted with ethyl acetate and concentrated in vacuo. The residue was purified by column chromatography on silica gel 20 using methylene chloride MeOH 19: 1, as an eluent to give compound 9 as a solid: mp 109.5-110.5 ° C; MS 456 (MH +).

EXAMPLE 10 4-Hydroxy-1-f5- (4-fluorophenyl) -4- (4-pyridyl) -midazole-2-n-butanone (Compound 10) Compound 9 (8.20 g, 1.8 mmol) was heated to reflux in 1 N HCl for 1 hour. The mixture was cooled and neutralized with sodium bicarbonate. The resulting solid precipitate was filtered and washed with H2O to give compound 10 as a solid: mp 205-07 ° C.

EXAMPLE 11 - (4-Fluorophenyl) -2-hydroxymethyl-4- (4-pyridyl) -1- (2-trimethylsilyl) ethoxymethyl) imidazole (Compound 11) 10% palladium on carbon (3.0 g) was added to a solution of of compound 7 (3.93 g, 9.89 mmol) in MeOH. Said mixture was stirred under H2 (2812 kg / cm2) for 1 hour, filtered and concentrated in vacuo to give the title compound as a solid: mp 169-71 ° C, MS 400 (MH +).

EXAMPLE 12 - (4-Fluorophenyl) -2-r4-hydroxy-2-thiabut-1-yl-4- (4-pyridyl) -1 - (2- (trimethylsilyl) ethoxymethyl) imidazole (Compound 12) Triphenylphosphine (3.77 g, 14.4 mmol) and CCI (1.39 mL, 14.4 mmol) were added to a solution of compound 11 (2.87 g, 7.18 mmol) in acetonitrile (70 mL) and the resulting mixture was stirred for 4 hours. 2-mercaptoethanol (2.52 ml, 35.9 mmol) and NaOH (2.44 g, 35.9 mmol) were added to the reaction and the resulting mixture was stirred for a further 18 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 1) to give the title compound as a solid: m.p. 74-76 ° C, MS 460 (MH +).

EXAMPLE 13 - (4-Fluorophenyl) -2-r4-hydroxy-2-thiabut-1-in-4- (4-pyridyl) -imidazole (Compound 13) A mixture of compound 12 (260 mg, 0.566 mmol) and 1 N HCl (10 mL) was heated at 100 ° C for 8 hours. The resulting mixture was neutralized with sodium bicarbonate and the solid precipitate was filtered, washed with H2O and dried to give the title compound as a solid: m.p. 227-29 ° C, MS 330 (MH +).

EXAMPLE 14 5- (4-Fluorophenyl) -2-r4-hydroxy-2-sulfonyl-but-1-yn-4- (4-pyridyl) -1- (2-trimethylsilyl) ethoxymethyl) imidazole (Compound 14) A solution of oxone (2.00 g, 3.25 mmol) in H2O (100 ml) was added to a stirred solution of compound 12 (0.50 g, 1.09 mmoies) in MeOH (100 ml). Said mixture was stirred for 4 hours at room temperature, concentrated in vacuo and extracted with methylene chloride. The combined organic layer was dried and concentrated to a residue. Said residue was purified by column chromatography using methylene chloride: MeOH (19.1) as an eluent to give the title compound as a solid: m.p. 45-48 ° C; MS 492 (MH +).

EXAMPLE 15 - (4-Fluorophenyl) -2-r4-hydroxy-2-sulfonyl-but-1 -n-4- (4-pyridyl) -imidazole (Compound 15) A solution of compound 14 (343 mg, 0.698 mmol) and 1 N HCl was stirred at 90 ° C for 2 hours. The mixture was neutralized with sodium bicarbonate and the resulting solid precipitate was washed with water to give the title compound: m.p. 232-237 ° C; EM 362 (MH +).

EXAMPLE 16 4-R5- (4) - (4-Fluorophenyl) -4 (5) - (4-pyridyl) imidazol-2-yl) l-butylacetate (Compound 16a) 4-r5 (4) - (4-Fluorophenyl) -4 ( 5) - (4-pyridyl) imidazole-2-ipbutanol (compound 16b) • 5-hydroxypentanal (0.97 ml) and ammonium acetate (5.60 g, 72.7 mmol) were added to a solution of 1- (4-fluorophenyl) -2- (4-pyridyl) -1, 2-ethanedione) (2.08 g, 9.08 mmol) in acetic acid (50 ml) and the mixture was refluxed for 1 hour. The resulting mixture was cooled to about ° C and the ammonium hydroxide was added until the mixture reached a pH of 8. Said mixture was extracted with ethyl acetate and purified on silica gel using methylene chloride: methanol (9: 1) as an eluent , wherein compound 12a was isolated as the last polar product: EM 354 (MH +) and compound 12b was isolated as the most polar product: mp. 213-214.5 ° C, EM 312 (MH +).

EXAMPLE 17 4-f1-Benzyl-4- (4-fluorophenyl) -5- (4-pyridin) imidazole-2-inbutylacetate (Compound 17) Sodium hydride (112 g, 2.88 mmol) was added to a solution of compound 16a (1.00 g, 2.80 mmol) in DMF (50 mL) and the mixture was stirred for 30 minutes. Benzyl bromide (.34 mL, 2.80 mmol) was added and said mixture was stirred for 2.5 hours at room temperature and poured into water. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were concentrated in vacuo and purified by column chromatography using ethyl acetate as an eluent to give compound 17 as an oil: EM 444 (MH +).

EXAMPLE 18 4-f1-Benzyloxycarbonyl-4- (4-fluorophenyl) -5- (4-pyridine) imidazole-2-butyl acetate (compound 18) Triethylamine (0.4 mL) and benzyl chloroformate (0.20 mL, 1.40 mmol) were added to a solution of compound 16a. Said mixture was stirred for 2 hours at room temperature, concentrated in vacuo and partitioned between methylene chloride and H2O. The organic extracts were concentrated in vacuo to give compound 18 as a solid: pH 97-101 ° C; MS 488 (MH +).

EXAMPLE 19 (4) - (4-Fluorophenyl) -4 (5) - (4-pyridyl) imidazole (Compound 19) A solution of selenium dioxide (4.82 g, 43.4 mmol) in H2O (20 mL) was added to a solution of 1- (4-fluorophenyl) -4- (4-pyridyl) -2-ethanone (9.33 g, 43.4 mmol. ) in dioxane (100 mL) and the resulting mixture was heated to reflux for 2 hours. Said mixture was concentrated in vacuo, triturated with ethyl acetate and filtered. The residue was purified by column chromatography using ethyl acetate / hexane (1: 1) as an eluent to give 1- (4-fluorophenyl) -2- (4-pyridyl) -1,2-ethanedione. A mixture of ammonium acetate (25.25 g, 0.320 mmol) and hexamethylenetetraamine (9.18 g, 65.5 mmol) was added to a solution of the dione isolated and dissolved in acetic acid (150 mL). Said mixture was stirred at 80 ° C for 2 hours, poured into concentrated ammonium hydroxide (200 mL) and the resulting precipitate was filtered, washed with H2O and dried to give the title compound as a solid: pH 242- 44.3 ° C; MS 240 (MH +).

BIOLOGICAL EXAMPLES One of the biological activities of the compounds of the invention was demonstrated by in vitro and in vivo tests. As previously described, agents that inhibit the activity of the p38 enzyme, inhibit the production of the inflammatory cytokines TNF-a and IL-1. The compounds of the invention were measured for their ability to inhibit p38 activity by the following in vitro test.

EXAMPLE 20 A solution (38 μL) of purified recombinant p38 (where the amount of enzyme was determined empirically considering the linear scale of the test and the acceptable signal for noise ratio; 6xHis-p38 expressed in E. coli), basic protein substrate of myelin (also determined empirically), a regulator of pH 7.5 (Hepes: 25 mm, MgCl 2: 10 mm, MnCl 2: 10 mm) were added to 92 cavities of a 96-cavity round-bottom propylene plate. The remaining cavities were used for control ("CTRL") and background ("BKG"). The CTRL was prepared with the enzyme, the substrate pH regulator and 2% DMSO, and the BKG was prepared with substrate pH regulator and 2% DMSO. A solution (12 μL) of the compound under test in DMSO (the compounds were diluted to 125 μM in 10% DMSO / H 2 O and tested at 25 μM where the final concentration of DMSO was 2%) was added to the test cavities. The ATP / 33P-ATP solution (10 μL; containing 50 μM unlabeled ATP and 1 μCi 33 P-ATP) was added to all wells and the plates completed were mixed and incubated at 30 ° C for 30 minutes. 50% TCA / 10 mM sodium phosphate (60 μL) ice-cold was added to each well and the plates were kept on ice for 15 minutes. The content of each cavity was transferred to the cavities of a 96-well filter plate (Millipore, MultiScreen-DP) and the filter plate was placed in a vacuum manifold, fixed with a waste collection tray. The wells were washed 5 times with 10% TCA 10 mM sodium phosphate (200 μL) under vacuum. The scintillator MycroScint-20 was added, the plates were sealed using Topseal-S sheets and counted in a Packard TopCount scintillation counter using a 33P liquid program with color removal correction, where the output is in color-cpm removal corrected. The% inhibition of the test compounds was calculated by the following formula:% inhibition = [1- (sample-BKG) / (CTRL-BKG)] x 100. Such data are shown in table A. Although the compounds were initially tested at 25 μM, it is guaranteed that the compounds were tested in increments of 4 times above and below the concentration. In addition, Cl50 values were calculated for some compounds using the Deltagraph 4 parameter curve setting program.

EXAMPLE 21 In addition to the enzyme test, the compounds of the invention were tested in an in vitro total cell test using peripheral blood mononuclear cells ("PBMC") that were obtained from human blood in the following manner. The freshly obtained venous blood was anticoagulated with heparin, diluted with an equal volume of pH regulated phosphate buffered saline ("PBS") and placed in a sterile tube or other container. The aliquots (30 mL) of said mixture were transferred to centrifuge tubes that were placed with Ficoll-Hypaque (15 mL). The prepared tubes were centrifuged at 400 x g without breaking for 30 minutes at room temperature. Approximately 1/2 to 2/3 of the platelet layer above the mononuclear cell band was removed with a pipette. The majority of the mononuclear cell layer was carefully removed using a pipette and said PBMCs were diluted with PBS and rotated at 600 x g for 15 minutes. The resulting PBMCs were washed with another portion of PBS and turned at 400 x g for 10 minutes at room temperature. The recovered pellets were diluted in RPMI low endotoxin / 1% FCS medium culture and gave a cell concentration of 0.5-2.0 x 106 PMBC / mL. A small volume of the suspension was removed to be counted in a hemocytometer and the remaining preparation was centrifuged at 200 x g for 15 minutes at room temperature. The recovered pelleted PBMC was resuspended in RPMI / 1% FCS at a concentration of 1.67x106 / ml. To carry out the test, the suspension of PBMC (180 μl) was • transferred to duplicate cavities of a bottom microtiter plate plane of 96 wells and incubated for 1 hour at 37 ° C. A solution of test compound (10 μl: prepared at 20 x desired final concentration) was added to each well and the plate was incubated for 1 hour at 37 ° C. A solution (10 μl) of LPS in RPMI / 1% FCS (200 ng / ml) was added and the wells were incubated overnight at 37 ° C. The supernatant (100 μl) • 10 was removed from each well and diluted with RPMI / 1% FCS (400 μl). Samples were analyzed for TNF-a using a commercial ELISA kit (Genzyme). This data is shown in Table A. In addition to the biological data, you can list the synthetic schemes that can be used to prepare the compounds. Although imidazoids that are unsubstituted in position 1 are subjected to tautomerization, the substituents listed for Ri and R2 are interchangeable when R3 is hydrogen.

TABLE A # of CPSB TNF-a R2 4 Composite scheme R1 Rs Cl50 μm Cl50 nm 1 4-F-Ph 4-pyr H S- (CH2) 2CH3 0.68 1 2 4-F-Ph 4-pyr H S- (CH2) 3PHT 0.79-1.8 1000 1 3 4-F-Ph 4-pyr H S- (CH2) 3NH2 26% @ 20 μm 1 4 4-F-Ph 4-pyr H S (CH 2) 3NHC (0) - 1.25 10 2 2-thienyl 5 4-F-Ph 4-pyr H SC (0) NHCH 3 81% @ 20 μm 1 8 4-F-Ph 4-pyr H C (0) H 0.8 140 3 9 4-pyr 4-F-Ph SEM C (0) (CH 2) 3 OH > 10000 3 4-F-Ph 4-pyr H C (0) (CH 2) 3OH 400 3 13 4-F-Ph 4-pyr H CH2S (CH2) 2OH 50 4 4-F-Ph 4-pyr H CH2S02 (CH2) OH 40 5 16a 4-pyr 4-F-Ph H (CH2) 4OAc 1.42 6 16b 4-F-Ph 4-pyr H (CH 2) 4OH 1.59 10 6 17 4-F-Ph 4-pyr CH2PH (CH2) 4OAc 2.63 500 6 18 4-pyr 4-F-Ph C02CH2 (CH2) 4OAc 10% @ 5 μm 6 Ph 20 4-F-Ph 4-pyr HS (CH2) 2CH (OCH 2.0 1 2CH3) 2 21 4-FP 4-pyr H SH 1.9 1 22 4-F-Ph 4-pyr H SCH (CH3) 2 0.47 1 23 4-F-Ph 4-pyr H SCH2-c? Cloprop? L 0.47 1 4-F-Ph 4-pyr H S (CH2) 2PHT 52% @ 5 μm 500 1 26 4-F-Ph 4-pyr H S (CH 2) 3NHC (0) 2.18 100 2 Ph 27 4-F-P 4-pyr H S (CH 2) 4PHT 2.46 2000 1 28 4-F-Ph 4-pyr H S- (CH 2) 3NH-125 97 2 C (0) -1-naphthyl 29 4-F-Ph 4-pyr H S- (CH 2) 3NH- 91% @ 20 μm 1 12 2 C (0) -2-furanyl 30 4-F-Ph 4-pyr H S- (CH2) 3NH- 92% @ 20 μm 100 2 S (0) 2-Ph 31 4-F-Ph 4- pyr H S- (CH2) 3NH- 275 2 C (0) -2-naphthyl 32 4-FP 4-pyr HS (CH2) 3- 150 2 NHS (0) 2CH3 33 4-FP 4-pyr H CH2S (CH2 2PHT 200 4 34 4-F-Ph 4-pyr H S (CH2) 3NHC (0) 200 CH3 35 4-F-Ph 4-pyr H CH2S (C l) 2Cp3 30 4 36 4-pyr 4-F-Ph SEM CH2OH 5% @ 5 μm 37 4-F-Ph 4-pyr H SCH2CHCH2 0.75 38 4-F-Ph 4-pyr H SCH2CN 0.4 39 4-F-Ph 4-pyr H SCH2CH3 0.4 40 4-F-Ph 4-pyr HS (CH2) 3CH3 0.28-0.7 1 41 4-F-Ph 4-pyr H S (CH 2) 9CH 3 > 10,000 1 42 4-F-Ph 4-pyr CH2Ph (CH2) OAc 2% @ 5 μm 6 43 4-F-Ph 4-pyr CH2Ph (CH2) 4PHT 8% @ 5 μm 6 44 4-F-Ph 4-pyr SEM (CH2) 4OAc 74% @ 20 150 6 45 4-pyr 4-F-Ph SEM (CH2) 4OAc 8% @ 20 μm -active 6 46 4-pyr 4-F-Ph SEM (CH2) 40h 9% @ 20 μm inactive 6 47 4-pyr 4-F-Ph H (CH2) 4PHT 283 6 48 4-F-Ph 4-pyr CH2Ph (CH2) 4PHT 1750 6 49 4-F-Ph 4-pyr H CH2OH 250 4 50 4-F-Ph 4-pyr (CH2) 3PHT (CH2) 4OAc 150 6 51 4-F-Ph 4-pyr (CH2) 3PTH (CH2) 4OH 175 6 52 4-pyr 4-F-Ph (CH2) 3PHT (CH2) 4OH 200 6 53 4-F-Ph 4-pyr (CH2) 3PHT CH20 (CH2) 3PHT 175 4 54 4-pry 4-F-Ph (CH2) 3PHT CH20 (CH2) 3PHT 200 4 55 4-pyr 4-F-Ph (CH2) 3PHT CH2OH 1250 4 56 4-F-Ph 4-pyr (CH2) 3PHT CH2OH 30 4 57 4-pyr 4-F-Ph SEM CH2S02C3ri7 5000 5 58 4-F-Ph 4-pyr (CH2) 3PHT CH2OCH3 75 6 59 4-pyr 4-F-Ph H CH2S02C3ri7 55 5 60 4-pyr 4-F-Ph (CH2) 3PHT CH2OCH3 400 6 61 4-F-Ph 4-pyr (CH2) 3PHT (CH2) 2OC2H5 200 6 62 4-F-Ph 4-pyr (CH2) 3PHT CH3 362 6 63 4-pyr 4-F-Ph (CH2) 3PHT CH3 17 6 64 4-F-Ph 4-pyr (CH2) 3PHT C2H5 80.0 6 65 4-pyr 4-F-Ph (CH2) 3PHT C2H5 20.0 6 66 4-F-Ph 4-pyr (CH2) 3Ph C2H5 6 6 67 4-pry 4-F-Ph (CH2) 3Ph C2H5 300 6 68 4-F-Ph 4-pyr (CH2) 3Ph CH3 1.5 6 69 4-pyr 4-F-Ph (CH2) 3Ph CH3 100 6 70 4-pyr 4-F-Ph (CH 2) 3PHT H 500 7 71 4-F-Ph 4-pyr (CH 2) 3PHT H 39 7 72 4-pyr 4-F-Ph (CH2) 4PHT H 300 7 73 4-F-Ph 4-pyr (CH2) 4PHT H 500 7 74 4-F-Ph 4-pyr (CH2) 3Ph Br 200 7 75 4-F-Ph 4-pyr (CH2) 3Ph I 3 7 76 4-pyr 4-F-Ph (CH2) 4PHT I 800 7 77 4-F-Ph 4-pyr (CH2) 4PHT I 445 7 78 4-F-Ph 4- (2- (CH2) 3Ph CH2OH 450 4 butyl) pyr 79 4-pyr 4-F-Ph CH2COC2H5 H 600 80 4-F-Ph 4-pyr CH2COC2H5 H 200 81 4-pyr 4-F-Ph (CH2) 3-3-pry H 500 82 4-F-Ph 4-pyr (CH2) 3-3-pry H 20 83 4-pyr 4-F-Ph (CH2) 3-4-pry H 1000 84 4-F-Ph 4-pyr (CH2) 3-4-pry H 10 85 4-pyr 4-F-Ph (CH2) 2-OPh H 2000 86 4-F-Ph 4-pyr (CH2) 2-OPh H 40 EXAMPLE 22 The modulation activity of IL-1 B of the compounds of the invention was determined by the following in vitro test. The adherent cells to the plastic were prepared from PBMC. Briefly, the PBMCs were added to the cavities of a 96-well plate as before, incubated for 1 hour at 37 ° C, and the adherent cells were prepared by lightly resuspending them with a pipette, removing and discharging and gently washing the wells. times with 200 μL culture medium. The additional culture medium (180 μL) was added to the wells after the final wash. The addition of the compound, stimulation of LPS, incubation and harvest of supernatant were that for the TNF-a. The supernatant was tested for interleukin-1β using a commercial ELISA kit (Genzyme). Compounds 10, 28 and 59 inhibited the production of IL-1 B a Cl50 of 800, 86 and 350 nM, respectively.

EXAMPLE 23 The ability of the compounds of the formula I to inhibit the production of TNF-a induced by LPS was demonstrated in the following tests with rodents in vivo. Mice (female BALB / cJ, Jackson Laboratories) or rats (Lewis males, Charles River) were fasted for 30 minutes before the oral dose with 5-10 ml / kg of test compound at 5-50 mg / kg . Thirty minutes after the dose, the animals were injected intraperitoneally with LPS at 1 mg / kg and returned to their cages for 1 hour. The animals were anesthetized with CO2, exsanguinated by means of cardiac injection and all the blood was collected (0.1-0.7 ml). The blood could be coagulated and the serum transferred to a centrifuge tube. Said sample was centrifuged, the serum was collected, aliquoted and frozen at -80 ° C. Samples were tested by commercial ELISAs for TNF-α (endogenous for mouse TNF-α and biofuent for rat TNF-α). The compounds 15 and 56 • 10 inhibited the production of TNF-a in the mouse at 88% and 37% respectively at a dose of 25 mg / kg.

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula I wherein: R-i is phenyl, heteroaryl wherein the heteroaryl contains from 5 to 6 ring atoms, or substituted phenyl; wherein the substituents are independently selected from 1 or more members of the group consisting of C-1.5 alkyl, halogen, nitro, trifluoromethyl and nitrile; R2 is phenyl, heteroaryl wherein the heteroaryl contains from 5 to 6 ring atoms, substituted heteroaryl; wherein the substituents are independently selected from 1 or more group members consisting of C-1.5 alkyl and halogen, or substituted phenyl; wherein the substituents are independently selected from 1 or more members of the group consisting of C-1.5 alkyl, halogen, nitro, trifluoromethyl and nitrile; R3 is hydrogen, SEM, C1-5 alkoxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl of C1.5, arylalkyl of C1.5, phthalimidoalkyl of C-1-5, aminoalkyl of d.5, diaminoalkyl of C-1.5, succinimidoalkyl of C- 1.5, C 1-5 alkylcarbonyl, arylcarbonyl, d-5-alkyl-C 1-5 alkylcarbonyl, aryloxycarbonyl-C 1-5 alkyl, heteroarylalkyl-C 1-5, wherein the heteroaryl contains from 5 to 6 atoms of ring, or substituted arylalkyl of C-? 5; wherein the aryl substituents are selected independently from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, halogen, amino, d-s alkylamino, and Crs dialkylamino; R4 is (A) n- (CH2) q-X wherein: A is sulfur or carbonyl; n is 0 or 1; q is 0-9; X is selected from the group consisting of hydrogen, hydroxy, halogen, vinyl, ethynyl, Crs alkyl, C3.7 cycloalkyl, C1-5 alkoxy, phenoxy, phenyl, Crs arylalkyl, amino, C1-5 alkylamino, nitrile, 10 phthalimido, amido, phenylcarbonyl, alkylaminocarbonyl of C1.5, phenylaminocarbonyl, arylakylamino, carbonyl of ds, alkylthio of d.5, alkylsulfonyl of d5, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of alkyl of C1.5, phenyl, d-5 aralkyl, thienyl, furanyl and naphthyl; vinyl replaced, where the Substituents are independently selected from one or more members of the group consisting of fluoride, bromide, chloride and iodide, substituted ethynyl; wherein the substituents are independently selected from one or more members of the group consisting of fluoride, bromide, chloride and iodide, substituted C 1-5 alkyl, wherein the substituents are selected from the group Which consists of one or more of Crs alkoxy, thialoalkyl, phthalimido and amino, substituted phenyl; wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen and C 1-5 alkoxy, substituted phenoxy; wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, and d 5 alkoxy, C 1-5 alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylalkyl of C1-5, wherein the

The alkyl substituent is hydroxyl; substituted C 1-5 arylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d 5 alkyl, halogen and C 1-5 alkoxy, substituted amido; wherein the carbonyl substituent is selected from the group consisting of C 1-5 alkyl, phenyl, C 1-5 arylalkyl, thienyl, furanyl, and f-naphthyl; substituted phenylcarbonyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1.5 alkyl, halogen and d-5 alkoxy, substituted alkylthio of d. 5; wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido; C1-5 substituted alkylsulfonyl, wherein the substituent Alkyl is selected from the group consisting of hydroxy and phthalimido, substituted phenylsulfonyl, wherein the phenyl substituents are selected

A independently of one or more members of the group consisting of bromide, fluoride, chloride, d.5 alkoxy and trifluoromethyl, with the proviso that: if A is sulfur and X is different from hydrogen, Crs alkylaminocarbonyl, Phenylaminocarbonyl, arylalkylaminocarbonyl of d-s, alkylsulfonyl of d-s or phenylsulfonyl, then q must be equal to or greater than 1; if A is sulfur and q is 1, then X can not be C?; if A is carbonyl and q is 0, then X can not be vinyl, ethynyl, d5 alkylaminocarbonyl, phenylaminocarbonyl, arylalkylcarbonyl of d.5, C1.5 alkylsulfonyl or phenylsulfonyl; if A is carbonyl, q is 0 and X is H, then R3 is not SEM; if n is 0 and q is 0, then X can not be hydrogen; and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein Ri is substituted phenyl and R2 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-3-yl, furan-2-yl. , furan-3-yl, thiophen-2-yl, thiophen-3-yl, pyridazine, triazine, thiazole, oxazole, and pyrazole. 3. The compound according to claim 2, wherein R-i is 4-fluorophenyl and R2 is pyridin-4-yl.

4. The compound according to claim 3, wherein R3 is hydrogen, C-1.5 alkyl, C1.5 arylalkyl, or C1-5 substituted arylalkyl. 5. The compound according to claim 4, wherein R3 is hydrogen or phenylalkyl of C-1-

5. 6. The compound according to claim 5 wherein A is sulfur, n is 1, and q is 0-

6.

7. The compound according to claim 6, wherein X is hydrogen, hydroxy, nitrile, alkyl of C1.5, phthalimido, amido, substituted amido, alkylsulfonyl of C1.5, hydroxyalkylsulfonyl of C1.5, phenylisulfonyl, phenylsulfonyl substituted, substituted amido, substituted sulfonamido, C 1 alkoxycarbonyloxy or C 1-5 alkyl.

8. The compound according to claim 5, wherein n is 0.

9. The compound according to claim 8, wherein X is hydrogen, hydroxy, nitrile, C1-5 alkyl, phthalimido, amido, substituted amido. , C1-5 alkylsulfonyl, C1-5 hydroxyalkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, substituted amido, substituted sulfonamido, C1-5 alkoxycarbonyloxy or C1-5 alkyl.

10. A compound and pharmaceutically acceptable salts thereof selected from 5 (4) - (4-fluorophenyl) -2- (3- (thien-2-ylamido) prop-1-yl) thio-4 (5) - ( 4-pyridyl) -imidazole; 5- (4-fluorophenyl) -2- [hydroxyethylthiamethyl] -4- (4-pyridyl) -imidazole; 5- (4-fluorophenyl) -2- [hydroxyethylsulfonylmethyl] -4- (4-pyridyl) -imidazole; and 4- [5 (4) - (4-fluorophenyl) - (5) - (4-pyridyl) - midazol-2-yl] butanol

11. A compound and pharmaceutically acceptable salts thereof, selected from 5 ( 4) - (4-fluorophenyl) -2- (3- (naphth-1-ylamido) prop-1-yl) thio-4- (5) - (4-pyridyl) -imidazole (Cp # 28); 4) - (4-fluorophenyl) -2- (3- (phenylsulfonamido) prop-1-yl) thio-4 (5) - (4-pyridyl) -imidazole (Cp # 30); 2- [4- acetoxy-but-1-yl] -5- (4-fluorophenyl) -1- [3- (N-phthalimido) prop-1 -yl] -4- (4-pyridyl) -imidazole (Cp # 50); - (4-fluorophenyl) -2- [hydroxymethyl] -1 - [3- (N-phthalimido) prop-1 -yl] -4- (4-pyridyl) -imidazole (Cp # 56); 5 (4) - (4-fluorophenyl) -2- (n-propylsulfonylmethyl) -4 (5) - (4-pyridyl) -imidazole (Cp # 59) and 2-ethyl-5- (4-fluorophenyl) -1 - [3- ( N-phthalimido) prop-1-yl] -4- (4-pyridyl) -imidazole (Cp # 66)

12. The pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

13. - The pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier or diluent.

14. The pharmaceutical composition comprising a compound 5 according to claim 9 and a pharmaceutically acceptable carrier or diluent.

15. The use of a compound according to claim 1 for the manufacture of a medicament for treating a cytokine-mediated disease in a mammal, f

16. The use of a compound according to claim 10 for the manufacture of a medicament for treating a cytokine-mediated disease in a mammal.

17. Use according to claim 16, wherein said medicament is administered orally and provides 0.1-100 mg / kg of compound according to claim 10 to the mammal per day.

18. The use according to claim 17, wherein said medicament provides 0.1-50 mg / kg of compound according to claim 10 to the mammal per day.

19. The use of a compound according to claim 1 for the manufacture of a medicament for treating arthritis in a mammal.