MXPA00011444A - Novel 2-alkyl substituted imidazole compounds - Google Patents

Abstract

The present invention is related to novel 2-alkyl substituted imidazole compounds of Formula (I) useful for the treatment of CSBP kinase mediated diseases.

Description

NOVEDOUS COMPOUNDS OF I IDAZQL REPLACED WITH RENT IN POSITION 2 FIELD OF THE INVENTION This invention relates to a novel group of imidazole compounds substituted in the 2-position, methods for the preparation thereof, the use thereof for treating diseases mediated by CSBP and pharmaceutical compositions that are used in such therapy.

BACKGROUND OF THE INVENTION Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (eg, protein tyrosine kinase or G protein coupled with seven transmembrane domains), protein kinases and phosphatases together with phospholipases are the essential machinery by which the signal is transmitted additionally within the cell [Marshall, JC Cell, 80, 179-278 (1995)]. Protein kinases can be classified into five classes being the two main classes, tyrosine kinases and serine / threonine kinases depending on whether the enzyme phosphorylates its substrate (s) in specific tyrosine (s) or serine? Reonin (s) residues [Hunter.

T., Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter. T .; Sfton, B. M .; vol. 200, Academic Press; San Diego, 1991]. For most biological responses, multiple intracellular kinases are involved and an individual kinase may be involved in more than one signaling event. These kinases are frequently cytosolic and can be translocated to the nucleus or ribosomes where they can affect transcription and translation events, respectively. The involvement of kinase in the control of transcription is currently much better understood than its effect on translation as illustrated by the studies on signal transduction induced by growth factor involving the MAP / ERK kinase [Marshall, CJ Cell , 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell, 80, 225 (1995); Seger, R., and Krebs, EG FASEB J., 726-735 (1995), although many signaling pathways are part of cellular homeostasis, numerous cytosines (eg IL-1 and TNF) and some other mediators of inflammation ( for example COX-2, eNOS) are produced only as a response to stress signals such as bacterial lipopolysaccharides (LPS): The first indications suggesting that the signal transduction pathway leading to protein kinases involved in biosynthesis of cytosine induced by LPS are from the Weinstein studies [Weinstein, et al., J. Immunol, 151, 3829 (1993)] but the specific protein kinases involved were not identified Working from a similar perspective, Han [Han, et al. al., Science 265, 808 (1994)] identified p38 of muhno as a kinase that is phosphorylated on tyrosine in response to LPS. The definitive proof of the involvement of p38 kinase in the signal transduction pathway stimulated by LPS leading to the initiation of proinflammatory cytosine biosynthesis was provided by the independent discovery of p38 kinase by Lee [Lee, et al., Nature, 372, 739 (1994)] as the molecular target for a novel class of anti-inflammatory agents. The discovery of p38 (referred to by Lee as CSBP 1 and 2) provided a mechanism of action of a class of anti-inflammatory compounds for which compound SK &F 86002 was the prototypical example. These compounds inhibited the synthesis of IL-1 and TNF in human monocytes at concentrations in the low range of uM [Lee, et al., Int. J. Immunopharmac. 10 (7), 835 (1988)] and showed activity in animal models which are refractory to cyclooxygenase inhibitors [Lee, et al., Annals N. Y. Acad. Sci., 696, 149 (1993)]. Currently, it has been firmly established that CSBP / p38 is one of several kinases involved in a stress / response signal transduction pathway that is parallel to and quite independent of the mitogen-activated protein kinase (MAP) analog kinase cascade (FIG. 1). Stress signals, including LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic stress, activate the kinases that are before CSBP / p38 which in turn phosphorylate CSBP / p38 in threonine 180 and tyrosine 182 giving as a result the activation of MAPKAP-2 kinase and MAPKAP-3 kinase. The MAPKAP-2 kinase and the MAPKAP-3 kinase have been identified as substrates of CSBP / p38 that are found later in the cascade which in turn phosphorylate the heat shock protein Hsp 27 (figure 2). It is not yet known if MAPKAP-2, MAPKAP-3, Mnk1 or Mnk2 are involved in cytosine biosynthesis or alternatively which inhibitors of CSBP / p38 kinase could regulate cytosine biosynthesis by blocking an unidentified substrate after CSBP / p38 [Cohen] , P. Trends Cell Biol., 353-361 (1997)]. However, what is known is that in addition to inhibiting IL-1 and TNF, the CSBP / p38 kinase inhibitors (SK &F 86002 and SB 203580) also reduce the synthesis of a wide variety of pro-inflammatory proteins including IL -6, IL-8, GM-CSF and COX-2. It has also been shown that inhibitors of CSBP / p38 kinase suppress TNF-induced expression of VCAM-1 in endothelial cells, phosphorylation and TNF-induced activation of cytosolic PLA2, and the stimulation, stimulated by IL-1, of collagenase and stromelysin. These data and additional data demonstrate that CSBP / p38 is involved not only in the synthesis of cytosines, but also in the cytosine signaling [CSBP / p38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361 (1997)] . Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. It has been shown that IL-1 mediates a variety of biological activities that are thought to be important in immunoregulation and other physiological conditions such as inflammation [see, for example, Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The multitude of known biological activities of IL-1 include the activation of helper T cells, the induction of fever, the stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, the induction of acute phase proteins and the suppression of levels plasma iron. There are many disease states in which excessive or unregulated production of IL-1 is involved in the increase and / or the cause of the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock syndrome, other conditions of acute or chronic inflammatory disease such as inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links the activity of IL-1 to diabetes and pancreatic β-cells [review of biological activities that have been attributed to IL-1 Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985 )]. Excessive or unregulated production of TNF has been implicated in mediating or increasing a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, sepsis due to gram-negative bacteria, toxic shock syndrome, respiratory distress syndrome in adults, cerebral malaria, inflammatory lung disease chronic, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft-versus-host reaction, allograft rejections, fevers and myalgias due to infection, such as influenza, cachexia secondary to infection or malignant tumor, cachexia, secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (complex related to AIDS), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis. Interleukin-8 (IL-8) is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysaccharides (LPS). IL-8 stimulates a number of in vitro functions. It has been shown to have chemoattractant properties towards neutrophils, T lymphocytes and basophils. It also induces the release of histamine from basophils from both normal and atopic individuals as well as the release of lysozomal enzyme and the respiratory burst of neutrophils. IL-8 has also been shown to increase surface expression of Mac-1 (CD11 b / CD18) in neutrophil without synthesizing new proteins, this may contribute to increased adhesion of neutrophils to vascular endothelial cells. Many diseases are characterized by a massive infiltration of neutrophils. The conditions associated with an increased production of IL-8 (which is responsible for the chemotaxis of neutrophils to the site of inflammation) could be benefited by compounds that suppress the production of IL-8.

IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte-derived cytokines are important and critical inflammation mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit to control, reduce and alleviate many of these disease states. The inhibition of signal transduction by CSBP / p38 which, in addition to IL-1, TNF and IL-8 described above, is also expected for the synthesis and / or action of several additional pro-inflammatory proteins (ie, IL) is expected. -6, GM-CSF, COX-2, collagenase and stromelysin), is a highly effective mechanism to regulate the excess and destructive activation of the immune system. This hope is supported by the potent and diverse anti-inflammatory activities described for inhibitors of the CSBP / p38 kinase [Badger, et al., J. Pharm. Exp. Thera 279 (3): 1453-1461. (nineteen ninety six); Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996)].

The need remains for the treatment, in this field, of compounds that are anti-inflammatory cytokine suppressive drugs, ie compounds that are capable of inhibiting the CSBO / p38 / RK kinase.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to the novel compounds of the formula (I) and to pharmaceutical compositions comprising a compound of the formula (I) and a pharmaceutically active diluent or carrier. This invention relates to a method of prophylaxis, or treatment of a disease mediated by the CSBP / RK / p38 kinase in a mammal in need thereof, which method comprises administering to said mammal a prophylactic or treatment effective amount of a compound of the formula (I). This invention also relates to a method for inhibiting cytokines and to the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula (I). Accordingly, the present invention provides the novel compounds of the formula (I) represented by the structure: wherein X is oxygen, carbon, sulfur or nitrogen, or the X-Ri portion is hydrogen; V is CH or N; Ri is hydrogen, C 1 alkyl, aryl, C 1 -C 6 alkyl, heterocyclic, heterocyclyl C 6 alkyl, heteroaryl or heteroaryl C 6 alkyl, in which each of these portions it can be optionally replaced. Xi is hydrogen, XRi, NHRa, optionally substituted CM alkyl, halogen, hydroxyl, optionally substituted C-M alkoxy, C1-alkylthio. optionally substituted, optionally substituted C1.4 alkylsulfinyl, CH2OR12, amino, amino substituted with C1-6 mono- or dialkyl, N (R? o) C (0) R, N (R-? o) S (0) 2Rd, or a N-heterocyclyl ring whose ring has from 5 to 7 links and optionally containing an additional heteroatom which is selected from oxygen, sulfur or R15; Rb is hydrogen, C1.6alkyl, C3.7 cycloalkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocyclyl, or heterocyclyl-C-Malkyl; Rd is C-? -6 alkyl, C3.7 cycloalkyl, aryl, arylC? 4 alkyl, heteroaryl, heteroaryl-C- alkyl, heterocyclyl or heterocyclyl-C1-4alkyl; R is independently an optionally substituted C 1-4 alkyl, and in which the two R 2 portions together can form a C 3-7 cycloalkyl or a C 5-7 cycloalkenyl whose ring may be optionally substituted; Y is C2-4 alkenyl, CM alkyl substituted with hydroxy, heterocyclyl, C (Z) OH, or N (R? _) C (Z) R3; R is C600alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6alkyl, heteroaryl or heteroarylCalkyl, in which each of these portions may be optionally substituted; Ar is an aryl or heteroaryl ring whose ring may be optionally substituted; R-io is hydrogen or C-M alkyl; R12 is hydrogen, -C (Z) R-? 3 or optionally substituted C? _t alkyl, optionally substituted aryl, optionally substituted aryl C-M alkyl or S (0) 2; Z is oxygen or sulfur; R113 is hydrogen, alkyl of CMo, cycloalkyl of C3. , heterocyclyl, heterocyclyl-CMO alkyl, aryl, aryl-alkyl of CMo, heteroaryl or heteroaryl-C1-10 alkyl, in which all these portions may be optionally substituted; Ri5 is hydrogen, cyano, C-M alkyl, C3.7 cycloalkyl or aryl; R25 is C? .10 alkyl, C3.7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-aikyl of CM0, heteroaryl or heteroarylalkyl; or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram showing cascades of protein kinase activated by mitogen and stress. Figure 2 is a schematic showing the p38 kinase pathway.

BRIEF DESCRIPTION OF THE INVENTION The novel compounds of formula (I) can also be used in association with the veterinary treatment of mammals, other than humans, that require inhibition or cytokine production. In particular, cytokine-mediated diseases for treatment, either in therapeutic or prophylactic form, in mammals include disease states such as those indicated in the present invention in the Methods of Treatment section, but in particular in viral type infections. Examples of such viruses include but are not limited to, infections with lentiviruses such as infectious anemia virus, goat arthritis virus, visna virus or maedi virus or retrovirus infections, such as, but not limited to, feline immunodeficiency virus (FlV). ), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections. In the compounds of the formula (I) in appropriate form X is oxygen, carbon, sulfur or nitrogen or the X-Ri portion is hydrogen. Preferably X is oxygen, or nitrogen, more preferred oxygen. Suitably R-es is hydrogen, C - ?. alquilo alkyl, aryl, arylCi-alkyl, heterocyclic, heterocyclylC? ?6alkyl, heteroaryl, or heteroarylC de ?6alkyl, in the which each of these portions may optionally be substituted. Preferably i is Ci-β alkyl, aryl or aryl-C-? 6 alkyl. When X is carbon, Ri can be hydrogen, giving a methyl group. When X is nitrogen, Ri can be hydrogen, giving an unsubstituted amino group. Suitably when V is CH or N, the hetero ring at position 5 is a pyridine ring or a pyrimidine ring. This ring may be further substituted with Xi in which Xi is hydrogen, XR-t, optionally substituted C?-T alkyl, halogen, hydroxyl, optionally substituted C ^ alkoxy, optionally substituted C-alkylthio, C-alkylsulfinyl. optionally substituted, CH 2 OR 2, amino, amino substituted with mono- and di-alkyl of C? _6, N (R? 0) C (O) R, N (R? o) S (0) 2Rd, or an N-heterocyclyl ring whose ring has from 5 to 7 links and optionally contains an additional heteroatom which is selected from oxygen, sulfur or NR15. Preferably Xi is hydrogen. When Xi is hydrogen, the X-Ri portion can also be hydrogen, giving a pyrimidine or unsubstituted pyridyl ring. Suitably, Rio is independently selected from hydrogen or C-M alkyl. Suitably, R12 is hydrogen, C (Z) R-? 3 or optionally substituted C1.4 alkyl, optionally substituted aryl, optionally substituted C-aryl alkyl or S (0) 2R25- Appropriately, Z is oxygen or sulfur, preferably oxygen.

Suitably, R13 is hydrogen, CM alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclylC1-10 alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl, which all these portions may optionally be substituted. Suitably, R 25 is C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C-MO alkyl, heteroaryl or heteroarylalkyl. Suitably, R b is hydrogen, C 6 alkyl, cycloalkyl C3-7, aryl, aryl-C-M alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocyclyl or heterocyclyl-C-M alkyl; in which each of these portions may be optionally substituted. Suitably, Rd is C-? 6 alkyl, C3.7 cycloalkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C-M alkyl, heterocyclyl or heterocyclyl-C-M alkyl; in which each of these portions may be optionally substituted. Suitably, R2 is independently an optionally substituted C-alkyl group, and the two R2 portions together can form a cycloalkyl ring of C3.7 or C5.7 cycloalkenyl ring whose ring may be optionally substituted. Suitably, Y is an alkenyl of C -., Alkyl of CM substituted with hydroxy, a heterocyclic ring, C (Z) OH, or N (R? _) C (Z) R3. Suitably when Y is a heterocyclic ring, the ring may be optionally substituted one or more times as defined below. Preferably, the heterocyclic ring is a pyrrolidine, piperidine, piperazine, morpholine, imidazolidine or pyrazolidine ring. Suitably, R 3 is C 1-6 alkyl, aryl, aryl-C 1 alkyl. 6, heterocyclic, heterocyclyl-C de-alkyl, heteroaryl or heteoaryl-C alquilo alkyl. 6, in which each of these portions may be optionally substituted. Suitably, Ar is an aryl or heteroaryl ring whose ring may be optionally substituted. When Ar is an aryl moiety it is preferably a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl moiety, and which is independently substituted with one to three substituents, which are halogen, S (0) mRβ, OR¡, (CR1oR2.) MNR1oR2o, NR10C (Z) R8 or NR10S (O) mRn. Suitably, R8 is hydrogen, heterocyclyl, heterocyclylalkyl or Rn. Suitably Rn is CMO alkyl, C1.10 alkyl substituted with halogen, C2-10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C5.7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl . Suitably, m is 0, or a number having the value of 1 or 2. A preferred substituent for the 4-position on the aryl rings include halogen, especially fluorine and chlorine, of which fluorine is especially preferred; and SR8 and SOR8 in which R8 is preferably a C1-2 alkyl, more preferred methyl. Preferred substituents for the 3-position on the aryl ring include: halogen, especially chloro; OR8, especially C1.4 alkoxy; Not me; NR -? _ C (Z) R8, especially NHCO (C1-10 alkyl); and NR? 0S (O) mR ??, especially NHS02 (C1.10 alkyl). The Ar portion is preferably an unsubstituted or substituted phenyl portion; when the portion Ar is substituted, it is more preferably substituted in the 4-position with fluorine and / or substituted in the 3-position with fluorine, chlorine, C-4-alkoxy, methanesulfonamido or acetamido. When Ar is a heteroaryl, which includes but is not limited to, pyrrole, quinoline, isoquininoin, pyridine, pyrimidine, oxazole, thiazole, thiazole, tnazole, imidazole or benzimidazole, or indolyl, the ring may be optionally substituted (in any ring ) independently with one or more, preferably with 1 to 4 substituents, which are halogen, S (0) mR8, OR8, (CR10R2o) mNR? oR2o, NR10C (Z) R8 or NR10S (O) mRn. Suitable pharmaceutically acceptable salts are known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of the compounds of the formula (I) can also be formed with a pharmaceutically acceptable cation, for example, if a substituent Yi in R3 comprises a carboxy group. Suitable pharmaceutically acceptable cations are known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used in the present invention, refer to: "halogen" - all halogens, ie chlorine, fluorine, bromine and iodine; "C1.10 alkyl" or "alkyl" - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like; "cycloalkyl" is used in the present invention to mean cyclic radicals, preferably 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. "Cycloalicynil" is used in the present invention to mean cyclic radicals, preferably 5 to 8 carbon atoms, which have at least one linkage including but not limited to cyclopentenyl, cyclohexenyl and the like. "aryl" - is phenyl and naphthyl; • "heteroaryl" (by itself or in any combination, such as "heteroaryloxy") - is an aromatic ring system of 5-10 links in which one or more rings contain one or more heterogeneous atoms selected from the group consisting of N , O or S, such as, but not limited to, pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole or benzimidazole; • "heterocyclic" (by itself or in any combination, such as "heterocyclylalkyl") - is a 4-10 ring system saturated or completely or partially unsaturated in which one or more rings contain one or more heteroatoms that are selected from the group consisting of N, O or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morfohna, imidazolidine, or pyrazolidin; "Aroyl" - is a C (0) Ar, in which Ar is phenyl, naphthyl or an arylalkyl derivative such as defined above, including such a group, but not limited to benzyl and phenethyl; • "alkanoyl" - is a C (0) alkyl of Cpo in which the alkyl is as defined above; • "sulfinyl" - is the S (O) oxide of the corresponding sulfide, although the term "thio" refers to sulfur; "Aralkyl" or "heteroarylalkyl" or "heterocyclylalkyl" is used in the present invention to indicate an aryl, heteroaryl or heterocyclic moiety as defined above previously connected to a C 6 alkyl group also defined above unless Indicate otherwise. As used in the present invention, "optionally substituted" unless specifically defined should mean groups such as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; alkyl of C1-10 substituted with hydroxy; Cpo alkoxy, such as methoxy or ethoxy; alkoxy C1-10 substituted with halogen; S (0) m-alkyl, wherein n is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; NR7R17, such as an amino or mono- or di-substituted C1-4 alkyl group or in which the NR7R17 portion can be closed together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing a additional heteroatom that is selected from O / N / S; C1-10 alkyl, C3-7 cycloalkyl, or a (C3-7) cycloalkyl-alkyl (C? -? _) group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropylmethyl; C-p0 alkyl substituted with halogen, such as CF2CF2H, or CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, in which these aryl portions may also be substituted one or more times with halogen; hydroxy; alkyl substituted with hydroxy; C1-10 alkoxy; SÍOJm alkyl; amino, C1-4 alkylamino mono and di substituted; alkyl of C1-4 or CF3 Appropriately, R and R17 are each independently selected from hydrogen or C1-4 alkyl or R7 and R-? 7 together with the nitrogen to which they are attached form a 5- to 7-membered heterocyclic ring ring optionally contains an additional heteroatom which is selected from oxygen, sulfur or nitrogen. It is recognized that the compounds of the present invention can exist as stereoisomers, regioisomers, or diastereomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic forms and optically active forms. All of those compounds are included within the scope of the present invention.

The compounds of formula (I) are imidazole derivatives which can be easily prepared using methods well known to those skilled in the art, and described in, for example, Comprenhensive Heterocyclic Chemistry, Katritzky and Rees Publishers, Pergamon Press. 1984, 5, 457-497, from starting materials that are either commercially available or can be prepared from such by well-known analogous methods. A key step in many such syntheses is the formation of the central imidazole nucleus, to give the compounds of the formula (I). Appropriate procedures are described among other documents in the U.S.A. Nos. 3,707,475 and 3,940,486 which are incorporated in the present invention for reference in their entirety. These patents describe the synthesis of a-diketones and α-hydroxyketones (benzoins) and their subsequent use to prepare imidazoles and N-hydroxylimidazoles. After this, additional compounds of the formula (I) can be obtained by manipulating the substituents in any of the groups R-i, R ?, R3 and R4 using conventional functional group interconversion methods.

The compounds of the general formula (V = N, X = 0, N, S) can be prepared as described in the above scheme. The condensation of the anion of 4-methyl-2- (methylthio) pyrimidine with the amine of Weinreb of an aryl acid will supply the ketone, which after oxidation with sodium nitrite allows to obtain the cexyximax. Heating this product with an alkylaldehyde and ammonium acetate in acetic acid allows access to the imidazole nucleus. The replacement of the methylthio group with nucleophiles (X = 0, N, S) can be effected by oxidizing the methylsulfinyl derivative with 3-chloroperoxybenzoic acid or oxone, followed by displacement with nucleophiles with or without the addition of bases such as sodium hydride, organolithiums or trialkylamines. In the case of the amines (X = N), the aluminum amide derivatives can be used to effect the displacements. The compounds of the general formula (V = CH, X = 0, N, S) can be prepared as in example 1, except substituting 4-methylpyridine for 4-methyl-2-chloropyridine (Gallagher et al Bioorg, Med. Chem. 5.49, 1997). The nucleophilic substitution of the resulting 2-chloropyridinylamidazole can be carried out by methods described in the patent E.U.A. No. 5,670,527. The alternative synthesis for making compounds of the formula (I) is described in USSN 08/481, 671, Adams et al .; and in PCT. US93 / 00674, currently patent E.U.A. 5,686,455 Adams et al., Whose descriptions are incorporated by reference in the present invention in its entirety.

Once the imidazole nucleus has been established, additional compounds of the formula (I) which can be prepared by applying standard techniques for functional group interconversion, for example: -C (0) NR? 3R? 4 from -C02CH3 heating with or without catalytic metal cyanide, for example NaCN, and HNRi3Ri4 in CH3OH; -OC (0) R3 from -OH with for example, CIC (0) R3 in pyridine; -NR? O-C (S) NR? 3R? from -NHR10 with an alkylisothiocyanate or thiocyanic acid; NR6C (0) OR6 from -NHR6 with the alkylchloroformate; -NR-? OC (0) NRi3R? 4 from -NHR10 by treatment with an isocyanate, for example HN = C = 0 or R? Or N = C = 0; -NR10-C (O) R8 from -NHRO-i. by treatment with Cl-C (0) R3 in pyridine; -C (= NR? _) NR13R14 from -C (NR13Ri4) SR3 with H NR3 + OAc-heating in alcohol; -C (NR? 3R-i4) SR3 from -C (S) NR? 3Ri4 with R6-l in an inert solvent, for example acetone; -C (S) NR-? 3Ri4 (in which R13 or R14 is not hydrogen) from -C (S) NH2 with HNR13R14-C (= NCN) -NR13R? 4 from -C (= NRi3Ru) -SR3 with NH2CN heating in anhydrous alcohol, alternatively from treatment with BrCN and NaOEt in EtOH; -NR10-C (= NCN) SR8 from -NHR10 by treatment with (RßS) 2C = NCN; -NR-10SO2R3 from -NHR10 by treatment with CISO2R3 by heating in pyridine; -NR10C (S) R3 from -NR? _C (0) R8 by treatment of Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1, 3,2,4-dithiadiphosphetan-2,4-disulfide ]; -NR10SO2CF3 from -NHRB with triflic anhydride and base and in which R3, R6, R10, R3 and R14 are as defined above or as described in the patent E.U.A. number 5,593,991 whose description is incorporated in the present invention for reference in its entirety. Wherein R3 is heterocyclyl, heterocyclyl-C-M alkyl. or R8. Wherein R6 is hydrogen, a pharmaceutically acceptable cation, C1.10 alkyl, C3_7 cycloalkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C-O alkanoyl. R8 is C? _10 alkyl, C1.10 alkyl substituted with halogen, C2-10 alkenyl, C3.7 cycloalkyl, C5.7 cycloalkenyl, aryl, aryl-C-MO alkyl, heteroaryl, heteroaryl-alkyl C -? - 10, (CR? OR2.) NORn, (CR10R2o) nS (0) mR? 8, (CR? 0R) nNHS (0) 2R? 8, (CR10R2o) nNR? 3Ri4; wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl may be optionally substituted. Suitably, n is an integer having a value of 1 to 10. In which R 10 and R 20 are each independently selected from hydrogen or C 1-4 alkyl. Wherein R13 and RH are each independently selected from hydrogen or optionally substituted C-M alkyl, optionally substituted aryl or optionally substituted aryl-CH alkyl, or together with the nitrogen to which they are attached form a 5- to 7-membered heterocyclic ring whose ring optionally contains an additional heteroatom which is selected from oxygen, sulfur or nitrogen. Protective groups suitable for use with the hydroxyl groups and the imidazole nitrogen are known in the art and are describe in many references, for example, Protecting Groups in Organic Synthesis, Greene TW, Wiley-lnterscience, New York, 1981. Appropriate examples of hydroxyl protecting groups include silyl ethers, such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl, connected by a variable alkyl alkyl chain, (CR-iR? on) Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.It should be noted that the compounds of the formula (I), in which is substituted with an alkylsulfinyl, arylsulfinyl, alkylsulfonyl or arylsulfonyl are prodrugs which are converted in reductive form in vivo to the corresponding alkylthio or arylthio form The pharmaceutically acid addition salts of the compounds of the formula (I) can be obtained in a known form, for example by treating the same with an appropriate amount of acid in the presence of an appropriate solvent The invention will be described below with reference to the following examples which are only illustrative and should not be considered as a limitation to the scope of the present invention.

EXAMPLES OF SYNTHESIS EXAMPLE 1 Specific examples for compounds of the general formula (V = CH, R1X = H) are prepared and shown below: 2- (1, 1-dimethyl-3-butenyl.-4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole A [2 '- (t-butyl-dimethylsilyloxy)) - 2' - (4- pyridyl)] aceto- (4-fluorophenone) (573 mg, 1.66 mmol) (prepared by the method of Gallagher et al (Bioorg, Med. Chem. 5, 49, 1997) in acetic acid (8 ml) was added 2, 2-dimethyl-4-pentenal (271 uL, 1.99 mmol), ammonium acetate (716 mg, 9.3 mmol) and copper (II) acetate (329 mg, 1.8 mmol) at RT The mixture was heated at 80 ° C for 18 hours The solution was poured onto ice, basified with ammonium hydroxide and extracted with ethyl acetate.The organic extract was washed with saturated brine, dried (MgSO 4) and concentrated in vacuo.The residue was purified by chromatography of flash (silica gel, 1-2% methanol / methylene chloride) to give the title compound (123 mg) MS (ES +) m / e 322 [M + H] +.

EXAMPLE 2 2-f2- (N-Benzoyl-N-methylaminoH1,1-dimethyl) ethyl-4- (4-fluorophenyl) -5- (4-pyridinyl.imidazole Following the procedure of example 1, except that 2,2-dimethyl-4-pentenal was replaced by 3- (N-benzoyl-N-methylamino) -2,2-dimethylpropenal, the title compound MS (ES +) m was prepared. / e 429 [M + H] +.

EXAMPLE 3 (+ -2-r3.4-d1h¡droxn-1,1-d-methylbutin-4- (4-fluorophenyl) -5- (4-pyridinimidazole To a solution of the title compound of example 1 (13.5 mg, 48 umol) in acetone: water 8: 1 (0.5 ml) was added 4-methylmorpholine N-oxide (6.7 mg, 57 umol) and one drop of tetroxide osmium (2.5% in 2-methyl-2-propanol). The solution was stirred at room temperature (RT) overnight, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 5-9% methanol / methylene chloride) to give the title compound (10 mg). MS (ES +) m / e 356 [M + H] +.

EXAMPLE 4 2-r 2 - (2-carboxy) -1,1-d-methylethyl-4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole To a solution of the title compound of example 1 (52 mg, 186 μmol) in carbon tetrachloride.acetonitrile: water 2: 2: 3 (1.3 ml) was added sodium periodate (163 mg, 762 mmol) and trichloride. of catalytic ruthenium (2 mg). The solution was stirred at RT overnight. Water (5 ml) was added and the mixture was extracted with methylene chloride. The organic extract was dried (MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 2% methanol / methylene chloride followed by 0.1% acetic acid in 2-5% methanol / methylene chloride) to give the title compound (4 mg). MS (ES +) m / e 340 [M + H] +.

Method of treatment The compounds of formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the therapeutic or prophylactic treatment of any disease state in a human, or other mammal, which is increased or caused by excessive or unregulated production of cytokine by the cells of said mammal, such as but not limited to monocytes and / or macrophages. The compounds of the formula (I) can inhibit the proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore useful in the therapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. . The inhibition of these pro-inflammatory cytokines is beneficial in controlling, reducing and alleviating many of the disease states. The compounds of formula (I) can inhibit proinflammatory inducible proteins, such as COX-2, also known by many other names such as prostaglandin endoperoxidase synthetase-2 (PGHS-2) and are therefore useful in therapy. These proinflammatory lipid mediators of the clioxygenase (CO) pathway are produced by the inducible COX-2 enzyme. Therefore, the regulation of COX-2 which is responsible for these products derived from arachidonic acid, such as prostaglandins, affecting a wide variety of cells and tissues, are important and critical inflammatory mediators of a wide variety of conditions and disease conditions. The expression of COX-1 is not affected by the compounds of the formula (I). This selective inhibition of COX-2 can alleviate or repair the ulcerogenic capacity associated with the inhibition of COX-1 thereby inhibiting the protoglandins essential for cytoprotective effects. In this way, the inhibition of these pro-inflammatory mediators is beneficial in controlling, reducing and alleviating many of these disease states. Most notably, these inflammatory mediators, in particular prostoglandins, have been implicated in pain, such as sensitization of pain receptors, or edema.

This aspect of pain management therefore includes treatment of neuromuscular pain, headache pain, pain caused by cancer, and pain caused by arthritis. The compounds of the formula (I) or a pharmaceutically acceptable salt thereof are useful in the prophylaxis or therapy in a human, or other mammal, by inhibiting the synthesis of the enzyme COX-2. Accordingly, the present invention provides a method for inhibiting the synthesis of COX-2 which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The present invention also provides a method for prophylactic treatment in a human, or other mammal, by inhibiting the synthesis of the COX-2 enzyme. Accordingly, the present invention provides a method for treating a cytosine-mediated disease which comprises administering an effective amount that interferes with cytosine of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the compounds of the formula (I) or a pharmaceutically acceptable salt thereof, are useful in the prophylaxis or therapy of any disease state in a human, or other mammal, which is increased by, or is caused by by excessive or unregulated production of IL-1, IL-6, IL-8 or TNF by the cells of such a mammal, such as, but not limited to, monocytes and / or macrophages.

Accordingly, in another aspect, the invention relates to a method for inhibiting the production of IL-1 in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. There are many disease states in which excessive or unregulated production of IL-1 is involved in the augmentation and / or cause of the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock syndrome, other conditions of acute or chronic inflammatory disease such as inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia , resorption of bone tissue, psoriatic arthritis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links the activity of IL-1 to diabetes, pancreatic β-cells and Alzheimer's disease. In a further aspect, this invention relates to a method for inhibiting the production of TNF in a mammal in need thereof comprising administering to said mammal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. same. Excessive or unregulated production of TNF has been implicated in the mediation or exacerbation of a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, sepsis by gram negative bacteria, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic inflammatory disease of the lungs , silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft-versus-host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignant tumor, cachexia secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (complex related to AIDS), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis. The compounds of the formula (I) are also useful in the treatment of viral infections, in which such viruses are sensitive to regulation by TNF or will induce TNF production in vivo. The viruses contemplated for treatment in the present invention are those that produce TNF as a result of infection, or those that are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitor compounds of the formula (I) Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and herpes virus group, such as, but not limited to, Herpes Zoster and Herpes Simplex. . Accordingly, in a further aspect, this invention relates to a method for treating a mammal, preferably a human, afflicted with a human immunodeficiency virus (HIV) comprising administering to said mammal an effective amount to inhibit TNF from a compound of the formula (I) or a pharmaceutically acceptable salt thereof. It is also recognized that both IL-6 and IL-8 are produced during rhinovirus infections (HRV) and contribute to the pathogenesis of common cold and the exacerbation of asthma associated with an HRV infection (Turner et al. (1998), Clin, Infect Dis, Vol 26, p 840, Teren et al (1997), Am J Respir Crit Care Med vol 155, p1362, Grunberg et al. (1997), Am J Respir Crit Care Med 156: 609 and Zhu et al, J Clin Invest (1996), 97: 421). It has also been demonstrated in vitro that infection of pulmonary epithelial cells with HRV results in the production of IL-6 and IL-8 (Subauste et al., J. Clin.Invest. 1995, 96: 549). Epithelial cells represent the primary site of HRV infection. Therefore another aspect of the present invention is a method of treatment for reducing the inflammation associated with an infection with rhinovirus, not necessarily a direct effect on the virus itself. The compounds of the formula (I) can also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of TNF production. Diseases mediated by TNF for treatment, either therapeutically or prophylactically, in animals include disease states such as those indicated above, but in particular viral infections. Examples of such viruses include, but are not limited to, infections with lentiviruses such as equine infectious anemia virus, caprine arthritis virus, visna virus or maedi virus, or retroviruses, such as feline immunodeficiency virus (FlV), bovine immunodeficiency virus, or immunodeficiency virus canine The compounds of the formula (I) can also be used topically in the treatment or prophylaxis of topical disease states mediated by or increased by an excessive production of cytosine, such as IL-1 or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory conditions of the skin such as sunburn; ocular inflammation conditions including conjunctivitis, pyresis, pain and other conditions associated with inflammation. The compounds of the formula (I) have also been shown to inhibit IL-8 production (interleukin-8, NAP). Accordingly, in a further aspect, this invention relates to a method for inhibiting the production of IL-8 in a mammal in need thereof comprising administering to said mammal an effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof. There are many disease states in which excessive or unregulated production of IL-8 is involved in the increase and / or the cause of the disease. These diseases are characterized by a massive infiltration of neutrophils such as psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion damage, respiratory distress syndrome in adults, thrombosis and glomerulonephritis.

All these diseases are associated with the increased production of IL-8 which is responsible for the chemotaxis of neutrop at the site of inflammation. Opposed to other inflammatory cytosines (IL-1, TNF, and IL-6), IL-8 has the exclusive property of promoting neutropchemotaxis and its activation. Therefore, inhibition of IL-8 production could lead to a direct reduction in neutropinfiltration. The compounds of the formula (I) are administered in an amount sufficient to inhibit the cytosine, in particular, the production of IL-1, IL-8 or TNF, in such a way that it is regulated towards normal levels, or in some cases at subnormal levels, so that the disease state is reduced or prevented. Abnormal levels of IL-1, IL-8 or TNF, for example, in the context of the present invention, constitute; (i) levels of IL-1, IL-8 or free TNF (not bound to cell) greater than or equal to one picogram per milliliter; (ii) any IL-1, IL-8 or cell-associated TNF; or (iii) the presence of mRNA of IL-1, IL-8 or TNF above the basal levels in cells or tissues in which IL-1, IL-8 or TNF are produced, respectively. The discovery that the compounds of the formula (I) are inhibitors of cytokines, specifically IL-1, IL-8 and TNF is based on the effects of the compounds of the formulas (I) on the production of the IL-1, IL-8 and TNF in in vitro tests which are described in the present invention. As used in the present invention, the term "inhibit the production of IL-1 (IL-8 or TNF)" refers to: a) a decrease in in vivo excessive levels of the cytokine (IL-1, IL-8 or TNF) in a human towards normal or subnormal levels by inhibiting the in vivo release of the cytokine by all cells, including but not limited to not limited to monocytes or macrophages; b) a deregulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1, IL-8 or TNF) in a human to normal or subnormal levels; c) a deregulation, by inhibiting the direct synthesis of the cytokine (IL-1, IL-8 or TNF) as a post-translational event; or d) a deregulation, at the translation level, of excessive in vivo levels of the cytokine (IL-1, IL-8 or TNF) in a human to normal or subnormal levels. As used in the present invention, the term "disease or disease state mediated by TNF" refers to any and all disease states in which TNF plays a role, either by production of TNF itself or by TNF that cause another monocyte to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for example, IL-1 is a major component, and whose production or action is increased or secreted in response to TNF, would therefore be considered as a disease state mediated by TNF. As used in the present invention, the term "cytokine" refers to any secreted polypeptide that affects the functions of the cells and is a molecule that modulates the reactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monocytes and lymphokines, regardless of which cells produce them. For example, a monoclin is generally known to be produced and secreted by a mononuclear cell, such as a macrophage and / or monocyte. However, many other cells also produce monocins, such as natural killer cells, fibroblasts, basop, neutrop, endothelial cells, brain astrocytes, bone marrow stromal cells, epithelial keratinocytes and B lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a) and factor of tumor necrosis beta (TNF-β). As used in the present invention, the term "interfering with cytokines" or "cytokine suppressant amount" refers to an effective amount of a compound of formula (I) that will cause a decrease in in vivo levels of the cytokine to normal or subnormal levels, when a patient is given for the treatment or prophylaxis of a disease state that is increased by, or caused by, excessive or unregulated cytokine production. As used in the present invention, the cytokine referred to in the phrase "inhibition of a cytokine, to be used in the treatment of a human infected with HIV" is a cytokine which isinvolved in (a) the initiation and / or maintenance of a T cell activation and / or the expression of the activated T cell-mediated HIV gene and / or replication and / or (b) any problem associated with cytokine-mediated disease such as cachexia or muscle degeneration. Because TNF-β (also known as lymphotoxin) has a close structural homology with TNF-a (also known as cachectin) and because each induces similar biological responses and binds to the same cellular receptor, both TNF-a and TNF-β are inhibited by the compounds of the present invention and are therefore collectively known herein as "TNF" unless specifically indicated otherwise. A new element of the MAP kinase family, alternatively termed CSBP, p38, or RK, has recently been identified independently by several laboratories [see Lee et al, Nature, Vol. 300 n (72), 739-746 (1994 )]. Activation of this novel protein kinase by dual phosphorylation has been observed in different cellular systems after stimulation by a broad spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or pro-inflammatory cytokines such as interleukin-1 and the tumor necrosis factor. The cytokine biosynthesis inhibitors of the present invention, compounds of the formula (I), have been determined as potent and selective inhibitors of the activity of the CSBP / p38 / RK kinase. These inhibitors are helpful in determining the involvement of signaling pathways in inflammatory responses. In particular, a definitive signal transduction pathway for the action of lipopolysaccharide in the production of cytokine in macrophages can be prescribed for the first time. In addition to the aforementioned diseases, it is also included the treatment of diseases such as embolism, neurotrauma, cardiac and renal reperfusion damage, thrombosis, glomerulonephritis, diabetes and pancreatic cells, multiple sclerosis, muscle degeneration, eczema, psoriasis, burns by the sun and conjunctivitis. Cytokine inhibitors were subsequently tested in a number of animal models for their anti-inflammatory activity. The model systems were chosen in such a way that they were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of the cytokine suppressive agents. The inhibitors showed significant activity in many such studies in vivo. Most notable are its effectiveness in the model of collagen-induced arthritis and the inhibition of TNF production in the endotoxic shock model. In this last study, the reduction in the plasma level of TNF correlated with the survival and protection of mortality related to endotoxic shock. Also of great importance is the effectiveness of the compounds to inhibit resorption of bone tissue in a long-bone organ culture system of rat fetus. Griswold et al, (1988) Arthritis Rheum. 31: 1406-1412; Badger, et al, (1989) Circ. Shock 27, 51-61, Votta et al, (1994) in vitro. Bone 15, 533-538; Lee et al, (1993). B. Ann. N.Y. Acad. Sci. 696, 149-170.

In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of the formula (I) and a pharmaceutically acceptable carrier or diluent. The compounds of the formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating them can be administered conveniently by any of the routes conventionally used for the administration of drugs., for example, orally, topically, parenterally or by inhalation. The compounds of formula (I) can be administered in conventional dosage forms prepared by combining a compound of formula (I) with standard pharmaceutical carriers in accordance with conventional procedures. The compounds of the formula (I) can also be administered in conventional dosages in combination with a second known therapeutically active compound. These methods may involve mixing, granulating and compacting and dissolving the ingredients as appropriate for the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. He Vehicle or vehicles must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not be harmful to the recipient thereof. The pharmaceutical carrier used can be, for example, either a solid or a liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrups, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include materials for delayed release known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. A wide variety of pharmaceutical forms can be used. Therefore, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or tablet form or in the form of a trosisco or solid tablet. The amount of solid carrier will vary widely but will preferably be from about 25 mg to about 1 g. When a liquid carrier is used, the preparations will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as a vial or non-aqueous liquid suspension. The compounds of the formula (I) can be administered topically, ie by non-systemic administration. This includes the application of a compound of the formula (I) externally to the epidermis or the oral cavity and the instillation of a compound as such in the ear, eye and * "- * - _ á ^ ^ _ nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating through the skin to the site of inflammation such as balms, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation. However, this may comprise as much as 10% w / w but preferably it will comprise less than 5% w / w, more preferred from 0.1% to 1% w / w of the formulation. Lotions in accordance with the present invention include those suitable for application to the skin or eye. An ocular lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or balms for applying to the skin may also include an agent for accelerating drying and cooling the skin, such as alcohol or acetone, and / or a humectant such as glycerol or an oil such as castor oil or arachis oil. The creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. These can be made by mixing the ingredient active in a finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of appropriate machinery, with an oily or non-oily base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metal soap; a mucilage; an oil of natural origin such as almond oil, corn oil, arachis oil, castor oil or olive oil; wool fat or its derivatives or a fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surfactant such as an anionic, cationic or nonionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gumscellulose derivatives or inorganic materials such as siliceous silicas, and other ingredients such as lanolin may also be included. Droplets in accordance with the present invention can comprise sterile aqueous or oily solutions or suspensions and can be prepared by dissolving the active ingredient in an appropriate aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative, and preferably includes a surfactant. The resulting solution can then be clarified by filtration, transferred to an appropriate container which is then sealed and sterilized by autoclaving or maintaining at 98-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of suitable bactericidal and fungicidal agents for inclusion in the drops are phenylmercuric nitrate or phenylmercuric acetate (0.02%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for preparing an oily solution include glycerol, dilute alcohol and propylene glycol. The compounds of the formula (I) can be administered parenterally, that is, by intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. Parenteral administration forms subcutaneously and intramuscularly are generally preferred. Appropriate dosage forms for such administration can be prepared by conventional techniques. The compounds of the formula (I) can also be administered by inhalation, ie by administration by intranasal route and by oral inhalation. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, can be prepared by conventional techniques. For all the methods of use described in the present invention for the compounds of the formula (I), the daily oral dose regimen will preferably be from about 0.01 to about 80 mg / kg of total body weight, preferably from about 0.2 to 30 mg / kg, more preferred from about 0.5 mg to 15 mg. The daily parenteral dose regimen is from about 0.1 to about 80 mg / kg of total body weight, preferably from ü | B -, «- JM- • about 0.2 to about 30 mg / kg, and more preferred from about 0.5 mg to 15 mg / kg. The daily topical dose regimen will preferably be 0.1 mg to 150 mg, administered 1 to 4, preferably 2 or 3 times per day. The daily dosage regimen by inhalation preferably will be from about 0.01 mg / kg to about 1 mg / kg per day. The person skilled in the art will also recognize that the optimum amount and the individual dose separation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and degree of the condition being treated, the form , route and site of administration, and the particular patient being treated, and such optimal parameters can be determined by conventional techniques. The person skilled in the art will also appreciate that the optimum course of treatment, ie the number of doses of a compound of the formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be established by one skilled in the art using conventional treatment course determination tests.

BIOLOGICAL EXAMPLES Production of TNFa induced by LPS in mice and rats In order to evaluate the inhibition in vivo of the production of TNFa induced by LPS in rodents, both mice and rats were injected with LPS.

Method with mice Male Balb / c mice from Charles River Laboratories laboratories (30 minutes) with compound or vehicle were pretreated. After the 30-minute pretreatment period, mice are administered LPS (lipopolysaccharide from Esherichia coli serotype 055-85, Sigma Chemical Co., St. Louis, MO) 25 ug / mouse in 25 ul of phosphate-buffered saline (pH 7.0) intraperitoneally. Two hours later the mice are sacrificed by CO2 inhalation and blood samples are collected by exsanguination in heparinized blood collection tubes and stored on ice. The blood samples are centrifuged and the plasma is collected and stored at -20 ° C until analyzed for TNFa by ELISA.

Method with rats Lewis male rats from Charles River Laboratories at various times with the compound or vehicle. After the determined pretreatment period, is administered to rats LPS (lipopolysaccharide from Esherichia coli serotype 0.55-85, Sigma Chemical Co., St Louis, MO) 3.0 mg / kg intraperitoneally. The rats are sacrificed by CO2 inhalation and heparinized whole blood is collected from each rat by cardiac perforation 90 minutes after the injection of LPS. The blood samples are centrifuged and the plasma is collected for analysis by ELISA with respect to TNFa levels.

ELISA Method TNFa levels were measured using a sandwich ELISA, as described in Olivera et al., Circ. Shock, 37, 301-306 (1992), the disclosure of which is incorporated by reference in its entirety in the present invention, using monoclonal guinea pig anti-mouse TNFa (Genzyme, Boston, MA) as the capture antibody and a polyclonal rabbit anti-murine TNFa. (Genzyme) as the second antibody. A goat anti-rabbit antibody conjugated with peroxidase (Pierce, Rockford, IL) was added for detection, followed by a substrate for peroxidase (1 mg / ml orthophenylenediamine with 1% urea peroxide). The levels of TNFa in the plasma samples from each animal were calculated from a standard curve generated with recombinant murine TNFα (Genzyme).

Cytosine Specific Protein Binding Test A competitive radio binding test was performed to provide a highly reproducible primary selection for structure-activity studies. This test provides many advantages over conventional biological tests using freshly isolated human monocytes as a source of cytosines and ELISA tests to quantify them. In addition to being a much simpler test, the binding test has been extensively validated to be correlated in fairly high form with the results of the biological test. A specific and reproducible cytosine inhibitor binding test was developed using the cytosolic fraction soluble from THP.1 cells and a radioactively labeled compound. Patent applications USSN 08/123175 Lee et al., Filed September 1993, USSN; Lee et al., PCT 94/10529 filed September 16, 1994 and Lee et al., Nature 300, n (72), 739-5 746 (December 1994) whose descriptions are incorporated in the present invention for references in in their entirety, they describe the aforementioned method of drug selection to identify compounds that interact with and bind to the cytosine-specific binding protein (hereafter CSBP). However, for the purposes of the present invention the binding protein 0 may be in isolated form in solution, or in immobilized form, or it may be genetically engineered to be expressed on the surface of recombinant host cells such as the delivery systems. of phage or as fusion proteins. Alternatively, whole cells or cytosolic fractions comprising the CSBP can be used in the selection protocol. Without taking into account the shape of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound / binding protein complex and a compound is detected that can form, increase or interfere with said complexes. 0 CSBP kinase test This test measures the 32 p CSBP-catalyzed transfer from [a "32p] ATP to the threonine residue in a peptide obtained of epidermal growth factor receptor (EGFR) (T669) with the following sequence: KRELVEPL7PSGEAPNQALLR (residues 661-681). (See Gallagher et al., "Regulation of Stress Induced Cytokine Production by Pyridinyl Imidazoles: Inhibition of CSBP Kinasa," Bioorganic &Medicinal 5 Chemistry, 1997, 5, 49-64). The reactions were carried out in a 96-well round bottom plate (from Corning) in a volume of 30 μl. the reactions contained (in final concentration): 25 mM Hepes, pH 7.5; 8 mM MgCl2; 0.17 mM ATP (the Km [ATp] of p38 (see Lee et al., Nature 300, n72 pg. 639-746 (Dec. 1994)); 2.5 uCi of [? -32P] ATP; 0.2 mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.067 mM of peptide T669; and 2-4 nM of p38 expressed in yeast, activated and purified. The reactions were initiated by adding [gamma-32P] Mg / ATP, and incubating for 25 minutes at 37 ° C. The inhibitors (dissolved in DMSO) were incubated with the mixture of reaction on ice for 30 minutes before adding 32P-ATP. The final concentration in DMSO was 0.16%. The reactions were terminated by adding 10 ul of 0.3 M phosphoric acid, and the phospho-peptide was isolated from the reactions by capturing it in p81 phosphocellulose filters. The filters were washed with 75 mM phosphoric acid and the incorporated 32P was quantified using a beta flash counter. Under these conditions, the specific activity of p38 was 400-450 pmoles / pmoles of enzyme, and the activity was linear up to 12 hours of incubation. The kinase activity values were obtained after subtracting the values generated in the absence of substrate which were 10-15% of the total values. The final representative compounds of the formula (I), examples 1 to 4 have demonstrated positive inhibitory activity with an IC50 of < 50 uM in this binding test. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated in the present invention for reference as to whether each individual publication will be specifically and individually indicated to be incorporated by reference into the present invention as indicates completely. The foregoing description fully describes the invention including the preferred embodiments thereof. Modifications and improvements of the modalities specifically described in the present invention fall within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Therefore the examples in the present invention should be considered only as illustrative and not as a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula: wherein X is oxygen, carbon, sulfur or nitrogen, or the X-R-i portion is hydrogen; V is CH or N; Ri is hydrogen, Ci-β alkyl, aryl, aryl-C- [alpha] 6 -alkyl, heterocyclic, heterocyclyl-C- [alpha] 6 -alkyl, heteroaryl or heteroaryl-C- [alpha] -6alkyl, in which each one of these portions may optionally be substituted; X-? is hydrogen, XR-i, optionally substituted C-alkyl, halogen, hydroxyl, optionally substituted C 1 -t alkoxy, optionally substituted C 1 alkylthio, optionally substituted C 1-4 alkylsulfinyl, CH 2 OR 12, amino, amino substituted with mono- or dialkyl of C-? 6, N (R-? o) C (0) Rb, N (R10) S (O) 2Rd, or an N-heterocyclyl ring whose ring has from 5 to 7 links and optionally containing additional heteroatom which is selected from oxygen, sulfur or NR15; R b is hydrogen, C 1-6 alkyl, C 3 cycloalkyl. , aryl, aryl-C- alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocyclyl, or heterocyclyl-C 1 -alkyl; Rd is C1.6 alkyl,

C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl or heterocyclylCMalkyl; 2 is independently an optionally substituted C- alkyl, and in which the two R2 portions together can form a C3.7 cycloalkyl or a C5.7 cycloalkenyl whose ring may be optionally substituted; Y is C2-4 alkenyl, C- alkyl substituted with hydroxy, heterocyclyl, C (Z) OH, or N (R-? O) C (Z) R3; R3 is C1.6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6alkyl, heteroaryl or heteroarylC1.6alkyl, in which each of these portions may be optionally substituted; Ar is an aryl or heteroaryl ring whose ring may be optionally substituted; R10 is hydrogen or C1-4 alkyl; R12 is hydrogen, -C (Z) R- | 3 or optionally substituted C-alkyl, optionally substituted aryl, aryl-C1 alkyl. optionally substituted or S (0) 2R25; Z is oxygen or sulfur; R 3 is hydrogen, C 1 alkyl. 10, C3.7 cycloalkyl, heterocyclyl, heterocyclyl-C-O alkyl, aryl, aryl-C10-alkyl, heteroaryl or heteroaryl-C- .10 alkyl, in which all these portions may be optionally substituted; R15 is hydrogen, cyano, CM alkyl, C3.7 cycloalkyl or aryl; R25 is C1.10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl C1-10, heteroaryl or heteroarylalkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, further characterized in that X is oxygen.

3. The compound according to claim 1, further characterized because X is nitrogen.

4. The compound according to claim 1, further characterized in that X is carbon.

5. The compound according to claim 1, further characterized in that X-Ri is hydrogen.

6. The compound according to claim 2, further characterized in that R-i is C-? 6 alkyl, aryl or arylalkyl of C-? 6.

7. The compound according to claim 3, further characterized in that Ri is hydrogen, Ci-β alkyl, aryl or arylalkyl of

8. The compound according to claim 4, further characterized in that Ri is hydrogen, C? .6, aryl or arylalkyl of C? _6.

9. The compound according to claim 1, further characterized in that Ar is an optionally substituted phenyl.

10. The compound according to claim 9, further characterized in that the phenyl is substituted one or more times with S (0) mR8, 0R8, or (CR10R2o) mNR? R2_.

11. The compound according to claim 1, further characterized in that V is nitrogen.

12. The compound according to claim 1, further characterized in that V is carbon. 13.- The compound in accordance with any of the claims 1 to 12, further characterized in that Y is a heterocyclic ring. 14. The compound according to any of claims 1 to 12, further characterized in that Y is C (Z) OH or N (R10) C (Z) R3. 15. The compound according to claim 1 which is: 2- (1,1-dimethyl-3-butenyl) -4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole; 2- [2- (N-benzoyl-N-methylamino) - (1,1-dimethyl) etl] -4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole; (+/-) - 2- [3,4-dihydroxy) -1, 1-dimethylbutyl] -4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole; or 2- [2- (2-carboxy) -1, 1-dimethylethyl] -4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole; or a pharmaceutically acceptable salt thereof. 16. A pharmaceutical composition comprising a compound according to any of claims 1 to 12, and a pharmaceutically acceptable carrier or diluent. 17.- A method to treat a kinase-mediated disease CSBP / RK / p38 in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound according to claim 1. 18. The method of claim 17, wherein the disease mediated by kinase CSBP / RK / p38 is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, shock endotoxic, sepsis due to gram-negative bacteria, toxic shock syndrome, Alzheimer's disease, embolism, neurotrauma, CNS damage, asthma, respiratory distress syndrome in adults, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, tissue resorption disease bone, osteoporosis, restenosis, cardiac and renal reperfusion injury, chronic renal failure, congestive heart failure, angiogenic diseases, thrombosis, glomerulonephritis, diabetes, graft-versus-host reaction, allograft rejection, inflammatory bowel disease, Chron's disease, ulcerative colitis , multiple sclerosis, muscle degeneration, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis. 19. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to manufacture a medicament for the treatment of a human mammal afflicted with a rhinovirus.