MXPA06005222A - Hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones - Google Patents

Abstract

The present invention provides a compound of the formula (I) where X1, Ar1, R1, and R2 are as defined herein, and compositions comprising the same. The present invention also provides methods for using compounds of Formula (I) in treating p38 mediated disorders in a patient.

Description

PIRIDO-7-PIRIMIDIN-7-ONAS SUBSTITUTED WITH HYDROXYALKYL c t Description of the Invention The present invention relates to pyridopyrimidines and derivatives thereof. In particular, the present invention provides the 2,6-disubstituted 7-oxo-pyrido [2,3-d] pyrimidine, a process for its preparation, pharmaceutical preparations containing them and methods for using them. 10 Mitogen-activated protein kinases (MAPs) constitute a family of serine / threonine kinases induced by proline, which activate their substrates by double phosphorylation. The kinases are activated by a variety of signals among which include nutritional stress and osmotic tension, UV light, growth factors, endotoxins and inflammatory cytokines. A group of MAP kinases is the p38 kinase group that includes several isoforms (for example, p38a, p39ß, p38? and p38d). The p38 kinases are responsible for 0 phosphorylation and activating transcription factors as well as other kinases, and are activated by physical and chemical stress, pro-inflammatory cytokines and bacterial lipopolysaccharides. More importantly, the products of p38 phosphorylation have been shown to induce REF: 172423 production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2. Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF-a is a cytokine produced mainly by monocytes and activated macrophages. Its excessive and unregulated production has been implicated in the causative role of the pathogenesis of rheumatoid arthritis. More recently, the inhibition of TNF production has been shown to have wide application in the treatment of inflammations, inflammatory bowel disease, multiple sclerosis and asthma. TNF has also been implicated in viral infections, such as HIV, influenza virus and herpes virus including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6) human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others . Similarly, IL-1 is produced by monocytes and activated macrophages, and plays a role in many pathophysiological responses including rheumatoid arthritis, fever, and reduced bone resorption. Additionally, p38 intervention has been implicated in stroke, Alzheimer's disease, osteoarthritis, lung injury, septic shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis. "Exp. Opin. Ther. Patents, 2000, 10 (1) .Inhibition of these cytokines by the inhibition of p38 kinase is beneficial for the control, reduction and mitigation of many of these disease states. pyridol2, 3-d] pyrimidin-7-ones, -7-imines and -7-thiones are described as inhibitors of cell proliferation induced by the protein tyrosine kinase, in WO 96/34867. Other 6-aryl-pyrido [2, 3-d] pyrimidines and naphthyridines are also described as inhibitors of tyrosine kinase in WO 96/15128. 6-alkyl-pyrido [2,3-d] pyrimidin-7-ones are described as inhibitors of the cyclin-dependent kinases in WO 98/33798. Certain 4-amino-pyridopyrimidines are described as inhibitors of dihydrofolate reductase in EP 0 278 686 A. In one embodiment, the present invention provides compounds of formula I wherein X1 is O, C = 0 or S (0) n, where n is 0, 1 or 2; Ar1 is aryl or heteroaryl; R1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, hydroxyalkyl or hydroxycycloalkyl; and R2 is hydroxyalkyl, oxoalkyl or hydroxycycloalkyl. Although certain substituted pyrido-7-pyrimidin-7-ones are known to be active in an enzymatic assay in vi tro versus p38 (see for example, US-2003-0171584-A1 patent which is incorporated herein by reference in its entirety), surprisingly and unexpectedly, the present inventor has discovered that the compounds of formula I have a significantly higher activity in a cysteine production of whole human blood induced by a lipopolysaccharide (LPS), which previously described compounds. The compounds of formula I are inhibitors of protein kinases, and have an activity effective against p38 in vivo. They are selective against p38 kinase relative to cyclin-dependent kinases and tyrosine kinases. Therefore, the compounds of the present invention can be used for the treatment of diseases induced by pro-inflammatory cytokines such as TNF and IL-1. Thus, another aspect of the present invention provides a method for the treatment of diseases or conditions induced by p38, in which a therapeutically effective amount of a compound of formula I is administered to a patient. Unless otherwise specified, the following terms used in the specification and claims have the meanings given below: "Alkoxyalkyl" means a group of formula Ra-0-Rb-, wherein Ra is alkyl and Rb is alkylene as defined below. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxy-propyl and 1- (2-methoxyethyl) -3. -methoxypropyl. "Alkyl" means a monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monohydric hydrocarbon radical of three to six carbon atoms, eg, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl , tere-butyl, pentyl and the like. "Alkylene" means a divalent linear saturated hydrocarbon radical, from one to six carbon atoms or a branched saturated hydrocarbon radical divalent of three to six carbon atoms, for example, methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene and the like. "Aryl" means a monovalent monocyclic aromatic monocyclic or bicyclic hydrocarbon radical, which is optionally independently substituted with one or more substituents, preferably one, two or three substituents preferably selected from the group consisting of alkyl, hydroxyl, alkoxy, haloalkyl, haloalkoxy, halo, nitro, cyano, amino, monoalkylamino, dialkylamino, methylenedioxyl, ethylenedioxyl and acyl. A particularly preferred substituent of the aryl is a halide. More specifically, the term aryl includes but is not limited to phenyl, chlorophenyl, fluorophenyl, difluorophenyl (such as 2,4- and 2,6-difluorophenyl), methoxyphenol, 1-naphthyl, 2-naphthyl and derivatives thereof. "Cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons, for example, cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl-cyclohexyl and the like. The cycloalkyl may optionally be substituted with one or more substituents, preferably one, two or three, substituents. Preferably, the substituent cycloalkyl is selected from the group consisting of alkyl, hydroxyl, alkoxy, haloalkyl, haloalkoxy, halo, amino, monoalkylamino, dialkylamino, and acyl. A particularly preferred group of cycloalkyl substituents include allyl, hydroxyl, alkoxy, haloalkyl, haloalkoxy and halo. An especially preferred group of cycloalkyl substituents include alkyl, hydroxyl, alkoxy and halo. "Cycloalkylalkyl" refers to a group of formula Rc-Rd- wherein Rc is cycloalkyl and Rd is alkylene as defined in the present disclosure. "Halo" and "halide" are used interchangeably herein, and refer to fluorine, chlorine, bromine or iodine. Preferred halides are fluorine and chlorine, with fluorine being a particularly preferred halide. "Haloalkyl" means alkyl substituted with one or more halo atoms the same or different, for example, -CH2C1, -CF3, -CH2CF3, -CH2CC13 and the like. "Heteroaryl" means a monovalent monocyclic or bicyclic radical of 5 to 12 ring carbon atoms having at least one aromatic ring having one, two or three heteroatom rings selected from N, O or S (preferably N or O), the remaining ring C atoms remaining, with the proviso that the point of attachment of the heterocyclic radical is in an aromatic ring. The heteroaryl ring is optionally independently substituted with one or more substituents, preferably one or more substituents, selected from alkyl, haloalkyl, hydroxyl, alkoxy, halo, nitro or cyano. More specifically, the term "heteroaryl" includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl. , indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo [1,2- a] pyridinyl, imidazo [2, 1-b] thiazolyl, and derivatives thereof. "Heterocyclyl" means a non-aromatic, saturated or unsaturated cyclic radical of 3 to 8 ring atoms, in which one or two ring atoms are heteroatoms selected from N, O or S (0) n (where n is an integer from 0 to 2), preferably N or O, the remaining atoms of the C ring being, wherein one or two C atoms may be optionally replaced by a carbonyl group. The heterocyclyl ring may be optionally independently substituted with one, two or three substituents selected from alkyl, haloalkyl, hydroxyalkyl, halo, nitro, cyano, cyanoalkyl, hydroxyl, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, - (X) nC (0) Re (where X is' O or NRf, n is 0 or 1, Re is hydrogen (where X is NRf), alkyl, haloalkyl, hydroxyl (whose n is 0), alkoxy, amino, monoalkylamino, dialkylamino , or optionally substituted phenyl, and Rf is H or alkyl), -alkylene-C (O) R3 (wherein R9 is alkyl, -ORh or NR ^ and Rh is hydrogen, alkyl or haloalkyl, and R1 and Rj are independently yes hydrogen or alkyl), or -S (0) nRk (where n is an integer from 0 to 2) such that when n is O, Rk is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, Rk is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. A particularly preferred group of heterocyclyl substituents include alkyl, haloalkyl, hydroxyalkyl, halo, hydroxyl, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, and ~ S (0) nRk. In particular, the term heterocyclyl includes, without being limited thereto, tetrahydrofuranyl, pyridinyl, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thio-morpholin-1-oxide, thiomorpholin-1,1-dioxide, 4- (1, l-dioxo-tetrahydro-2H-thiopyranyl), pyrrolinyl, imidazolinyl, N-methanesulfonyl-piperidin-4-yl, and the derivatives of the same, each of which may be optionally substituted. "Hydroxycycloalkyl" means an alkyl group as defined herein, substituted with one or more, preferably one, two or three hydroxyl groups, with the proviso that the same carbon atom carries no more than one hydroxyl group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl , 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxy-methylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl. "Hydroxycycloalkyl" means a cycloalkyl group as defined herein wherein one, two or three hydrogen atoms of the cycloalkyl radical have been replaced with a hydroxyl substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like. "Exit group" has the conventional meaning associated with it in synthetic organic chemistry, namely, an atom or group capable of being displaced by a nucleophile, and includes halo (such as chlorine, bromine, and iodine), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (eg, acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (eg, 2,4-dinitrophenoxy), methoxy, N, 0-dimethylhydroxylamino, and the like. "Optionally substituted phenyl" means a phenyl ring that is optionally independently substituted with one or more substituents, preferably one or two substituents selected from the group consisting of alkyl, hydroxyl, alkoxy, haloalkyl, haloalkoxy, halo, nitro, cyano, amino, methylenedioxyl, ethylenedioxyl, and acyl. "Oxoalkyl" means an alkyl group that is substituted with one or more carbonyl oxygen groups (i.e., = 0), such as a group of formula Rz-C (= 0) -Ry-, where R? it is alkylene and Rz is alkyl. Examples of oxoalkyl groups include 2-propanon-3-yl, 2-methyl-3-butanon-4-yl, and the like. "Pharmaceutically acceptable excipients" means an excipient that is useful for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not undesirable neither biologically nor otherwise, and includes an excipient that is acceptable for veterinary use as well as for human pharmaceutical use. The term "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one of said excipients. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that has the pharmacologically acceptable activity of the compound from which it originated. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, acid 2-naphthalene sulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid , lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton is present in the parent compound, or is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion; or it is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. The terms "pro-drug" "and" prodrug "are used interchangeably herein and refer to any compound that releases an active parent drug according to formula I, in vivo when said prodrug is administered to a mammalian subject. Prodrugs of a compound of formula I are prepared by modifying one or more functional groups present in the compound of formula I such that the modification (s) can be cleaved in vivo to liberate the parent compound. Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group of a compound of formula I is attached to any group that can be linked in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group respectively. Examples of prodrugs include, but are not limited to, esters (e.g., derivatives of acetates, dialkylaminoacetates, formates, phosphates, sulfates and benzoates), and carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxyl functional groups, ester groups (eg ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (for example, N-acetyl), N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketols and enol esters of ketone and aldehyde functional groups in compounds of formula I, and the like, See Bundegaard, " Design of Prodrugs "(" Design of prodrugs ") pl-92, Elsevier, New York-Oxford (1985). "Protective group" refers to a group of atoms that when they bind to a reactive group of a molecule masks, reduces or prevents said reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry ("Protective Groups in Chemistry" Organic "), (Wiley, 2nd ed.1991) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods (" Compendium of organic synthesis methods "), Vols. 1-8 (John Wiley and Sons, 1971-1996 Amino groups representative of protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Representative hydroxyl protecting groups include those in which the hydroxyl group is either seized or alkylated such as the benzyl and trityl ethers as well as the isolates of ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. The "treatment" or "treatment" of a disease includes: (1) prevention of the disease, that is, causing the clinical symptoms of the disease not to develop in a mammal that may be exposed or predisposed to the disease but still does not experience or show symptoms of the disease; (2) inhibition of the disease, i.e., interrupting or reducing the development of the disease or its clinical symptoms; or (3) mitigating the disease, that is, causing a regression of the disease or its clinical symptoms. "A therapeutically effective amount" means the amount of a compound that when administered to a mammal for the treatment of a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. The term "treatment", "contact or" reaction "when referring to a chemical reaction, means the mixture of two • or more reactive under appropriate conditions to produce the indicated and / or desired product. It must be taken into account that the reaction produced by the indicated and / or desired product may not necessarily result directly from the combination of two reactants that are added initially, that is, one or more intermediate products may be produced in the mixture that end leading to the formation of the indicated and / or desired product. The compounds of the present invention can exist in unsolvated forms - as well as in solvated forms, including hydrated forms. In general, solvated forms including hydrated forms are equivalent to unsolvated forms, and are intended to be encompassed within the scope of the present invention. In addition to the compounds described above, the compounds of the present invention include all tautomeric forms. In addition, the present invention also includes all pharmaceutically acceptable salts of those compounds together with prodrug forms of the compounds and all stereoisomers, either in a pure chiral form or a racemic mixture or other form of mixture. The compounds of formula I are also capable of forming pharmaceutically acceptable acid addition salts. All these forms are within the scope of the present invention. The pharmaceutically acceptable acid addition salts of the compounds of formula I include salts derived from inorganic acids such as hydrochloric acids, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as salts derived from organic acids such as aliphatic mono and dicarboxylic acids, substituted phenyl alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic acids and aromatics, etc. Said salts therefore include sulphates, pyrosulfates, bisulfates, sulphites, bisulphites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, caprylates, isobutyrates, oxalates, malonates. succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates and the like. Also provided are amino acid salts such as arginines and the like and gluconates, galacturonates (see, for example, Berge et al., J. of Pharmaceutical Science ("Rev. of Pharmaceutical Science") 661-19 (1977). acid addition of the basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner Free base forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for For purposes of the present invention, in one embodiment, Ar1 is aryl, A particularly preferred Ar1 is optionally substituted phenyl, In certain embodiments, Ar1 is optional phenyl. It is substituted one or more times with alkyl, halo, haloalkyl or alkoxy. A more preferred Ar1 is disubstituted phenyl such as 2-4 disubstituted phenyl. It is still more preferred that Ar1 is phenyl substituted in 2,4-dihalo. A particularly preferred Ar1 is 2,4-difluorophenyl. Still in another embodiment, X1 is 0. In another embodiment R1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or heterocyclyl. Within this group, a particularly preferred R1 includes optionally substituted tetrahydropyranyl, 1-methyl-2-methoxyethyl, optionally substituted cyclopentyl, optionally substituted cyclopropyl, isopropyl, optionally substituted cyclohexyl, 1- (2-hydroxyethyl) -3-hydroxypropyl, l- hydroxymethyl-2-hydroxypropyl, 1-hydroxymethyl-3-hydroxypropyl, 1-methylpropyl, 2-hydroxy-1-methylethyl, 1- (2-methoxyethyl) -3-methoxypropyl, N-methanesulfonyl piperidinyl, ethyl, methyl, 2-hydroxypropyl , neopentyl, 1, l-dimethyl-2-hydroxyethyl, 1- (hydroxymethyl) -propyl, 2-methylpropyl, cyclopropyl, cyclobutyl, optionally substituted, 1,2-dimethyl-2-hydroxypropyl, and 1- (hydroxymethyl) -2- hydroxyethyl. In yet another embodiment, a preferred R1 is hydroxyalkyl, 2-hydroxy-1-methylethyl being a particularly preferred R1. An especially preferred R1 includes 2-hydroxy-1-methyl-ethyl, enantiomerically enriched, ie, (R) - and (S) -2-hydroxy-1-methylethyl. In a specific embodiment, R 2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1- (2-hydroxyethyl) -3-hydroxypropyl, 6-oxopropyl.

In another embodiment, R2 is hydroxyalkyl. Within this group, a particularly preferred R2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 1- (2-hydroxyethyl) -3-hydroxypropyl. An especially preferred R2 is 2-hydroxypropyl. In another embodiment, R2 is oxoalkyl. Still, certain combinations of the preferred groups described herein form other preferred versions. For example, in a particularly preferred embodiment R 1 is (R) - or (S) -2-hydroxy-1-methylethyl, R 2 is (R) - or (S) -2-hydroxypropyl, or 2-oxopropyl, X 1 is O and Ar1 is 2,4-difluorophenyl.

In one embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl and X 1 is O. In another embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl, X 1 is O and R 1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or heterocyclyl. In still another embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl, X 1 is O and R 1 is tetrahydropyranyl, 1-methyl-2-methoxyethyl, cyclopentyl, cyclopropyl, isopropyl, cyclohexyl, 1- (2-hydroxyethyl) ) -3-hydroxypropyl, 1-hydroxy-methyl-2-hydroxypropyl, 1-hydroxymethyl-3-hydroxypropyl, 1-methylpropyl, 2-hydroxy-1-methylethyl, 1- (2-methoxyethyl) -3-methoxypropyl, N- methanesulfonyl piperidinyl, ethyl, methyl, 2-hydroxypropyl, neopentyl, 1, l-dimethyl-2-hydroxyethyl, 1- (hydroxymethyl) propyl, 2-methylpropyl, cyclopentylmethyl, cyclobutyl, 1,2-dimethyl-2-hydroxypropyl, or - (hydroxymethyl) -2-hydroxyethyl. In yet another embodiment the present invention provides a compound of formula I wherein Ar 1 is aryl, X 1 is O, R 1 is tetrahydropyranyl, 1-methyl-2-methoxyethyl, cyclopentyl, cyclopropyl, isopropyl, cyclohexyl, 1- (2-hydroxyethyl) 3-hydroxypropyl, 1-hydroxymethyl-2-hydroxypropyl, 1-hydroxymethyl-3-hydroxypropyl, 1-methylpropyl, 2-hydroxy-2-methylethyl, 1- (2-methoxyethyl) -3-methoxypropyl, N-methanesulfonylpiperidinyl, ethyl, methyl, 2-hydroxypropyl, neopentyl, 1, l-dimethyl-2-hydroxyethyl, 1- (hydroxymethyl) propyl, 2-methylpropyl, cyclopropylmethyl, cyclobutyl, 1,2-dimethyl-2-hydroxypropyl, or 1- (hydroxymethyl) ) -2-hydroxyethyl and R2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1- (2-hydroxyethyl) -3-hydroxypropyl, or 2-oxopropyl. In one embodiment, the present invention provides a compound of formula I wherein Ar1 is aryl, X1 is O, R1 is (R) -2-hydroxy-1-methylethyl or (S) -2-hydroxy-1-methylethyl and R2 is 2-oxopropyl, (R) -2-hydroxypropyl or (S) -2-hydroxypropyl. In one embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl, X 1 is O and R 1 is hydroxyalkyl. In another embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl, X 1 is O, R 1 is hydroxyalkyl and R 2 is hydroxyalkyl. In yet another embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl, X 1 is 0, R 1 is hydroxyalkyl and R 2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, or 1- (2-hydroxyethyl) -3-hydroxypropyl.

In another embodiment, the present invention provides a compound of formula I wherein Ar 1 is aryl, X 2 is O, R 1 is (R) -2-hydroxy-1-methylethyl and R 2 is (R) -2-hydroxy-propyl; R1 is (R) -2-hydroxy-1-methylethyl and R2 is (R) -2-hydroxy-propyl; R1 is (S) -2-hydroxy-1-methylethyl and R2 is (R) -2-hydroxypropyl; or R1 is (S) -2-hydroxy-1-methylethyl and R2 is (S) -2-hydroxypropyl. In one embodiment, the present invention provides a compound of formula I wherein R 1 is hydroxyalkyl. In another embodiment, the present invention provides a compound of formula I wherein R 1 is hydroxyalkyl and R 2 is hydroxyalkyl. In still another embodiment, the present invention provides a compound of formula I, wherein R 1 is hydroxyalkyl, R 2 is hydroxyalkyl and Ar 1 is aryl.

In one embodiment, the present invention provides a compound of formula I, wherein R 2 is hydroxyalkyl.

In certain embodiments, the compounds of the invention may have the formula wherein m is from 0 to 4 each R3 is alkyl, halogen, alkoxy or haloalkyl; and R1 and R2 are as already described. In specific embodiments, m is 1 and R 3 is halogen. Still in other embodiments, m is 2 and R3 is halogen. In one embodiment, the present invention provides a compound of formula II wherein R 1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or heterocyclyl. In one embodiment, the present invention provides a compound of formula II wherein Rx is tetrahydropyranyl, 1-methyl-2-methoxyethyl, cyclopentyl, cyclopropyl, isopropyl, ciciohexilo, 1- (2-hydroxyethyl) -3-hydroxypropyl, 1-hydroxy -methyl-2-hydroxypropyl, 1-hydroxymethyl-3-hydroxypropyl, 1-methylpropyl, 2-hydroxy-1-methylethyl, 1-. { 2-methoxy) -3-methoxypropyl, N-methanesulfonyl piperidinyl, ethyl, methyl, 2-hydroxypropyl, neopentyl, 1, l-dimethyl-2-hydroxyethyl, 1- (hydroxymethyl) propyl, 2-methylpropyl, cyclopropylmethyl, cyclobutyl, 1 , 2-dimethyl-2-hydroxypropyl, or 1- (hydroxymethyl) -2-hydroxyethyl. In another embodiment, the present invention provides a compound of formula II wherein R1 is tetrahydropyranyl, l-methyl-2-methoxyethyl, cyclopentyl, cyclopropyl, isopropyl, ciciohexilo, 1- (2-hydroxyethyl) -3-hydroxypropyl, 1-hydroxymethyl -2-hydroxypropyl, 1-hydroxy-methyl-3 -hydroxypropyl, 1-methylpropyl, 2-hydroxy-l-methylethyl, 1- (2-methoxyethyl) -3-methoxypropyl, N-methanesulfonyl piperidinyl, ethyl, methyl, 2 - hydroxypropyl, neopentyl, 1, l-dimethyl-2 ~ hydroxyethyl, 1- (hydroxymethyl) propyl, 2-methylpropyl, cyclopropylmethyl, cyclobutyl, 1, 2-dimethyl-2-hydroxypropyl, or 1- (hydroxymethyl-2-hydroxyethyl and R2 is 2-hydroxyethyl, 3 -hydroxypropyl, 2-hydroxypropyl, 1- (2-hydroxyethyl) -3-hydroxypropyl, 2-oxopropyl or. in one embodiment, the present invention provides a compound of formula II wherein R1 is (R) -2-hydroxy-1-methylethyl or (S) -2-hydroxy-1-methylethyl and R 2 is 2-oxopropyl, (R) -2-hydroxypropyl or (S) -2-hydroxypropyl In one embodiment, the present tion provides a compound of formula II wherein R1 and R2 are hydroxyalkyl. In one embodiment, the present invention provides a compound of formula II wherein R 1 is (R) -2-hydroxy-1-methylethyl and R 2 is (R) -2-hydroxy-propyl; R1 is (R) -2-hydroxy-1-methylethyl and R2 is (S) -2-hydroxy-propyl; R1 is (S) -2-hydroxy-1-methylethyl and R2 is (R) -2-hydroxypropyl; or R1 is (S) -2-hydroxy-1-methylethyl and R2 is (S) -2-hydroxypropyl. In another embodiment, the present invention provides a compound of formula II wherein R1 and R2 are hydroxyalkyl, n is 1, and R3 is halo. In another embodiment, the present invention provides a compound of formula II wherein R1 and R2 are hydroxyalkyl, n is 2, and R3 is halo. Table 1 shows representative compounds according to the invention. TABLE 1 . 2-Cyclopentylamino-6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 2-cyclopropylamino-6 - (2,4-difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2, -difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -2-isopropylamino-8H-pyrido [2,3-d] pyrimidin-7-one 2-cyclohexylamino-6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxyoxy-ethyl) -propyl] -2- ((S) -2-methoxy-l-methyl-ethylamino) -8H-pyrido [2,3-d] pyrimidin-7- 6- (2, 4-difluorophenoxy) -2- [3-hydroxy-1- (2-hydroxy-ethyl) propylamino] -8- ((S) -2-hydroxy-propyl) -8H-pyrido 2,3-d] pyrimidin-7-one 6- (2,4-difluoro-phenoxy) -8-- ((S) -2-hydroxy-propyl) -2- (tetra-hydro-pyran-4-ylamino ) -8H-pyrido [2,3-d] pyrimid-7-one 6- (2,4-difluoro-phenoxy) -2- ((1R, 2R) -2-hydroxy-l-hydroxymethyl-propylamino) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2,4-difluor-phenoxy) -2- ((S) -2 -hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2, 4-difluorophenoxy) -2- ((R) -3-hydroxy-l-hydroxy-methyl) -propylamino) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2, 3-d] pyrimidin-7-one 2- ((S) -sec-butylamino) -6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -8H- pyrido [2,3-d] pyrimidin-7-one 2- ((R) -sec-butylamino) -6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2,4-difluorophenoxy) -2- ((S) -2-hydroxy-1-methyl-ethylamino) -8- (( S) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2,4-difluorophenoxy) -2- ((R) -2-hydroxy-1- methyl-ethylamino) -8- ((S) -2-hydroxy-oxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2,4-difluor-phenoxy) - ((S) -hydroxy-propyl) -2- ((S) -2-methoxy-1-methyl-ethylamino) -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -2- [3-methoxy-1- (2-methoxy-ethyl) -propylamino] -8H-pyrido [2,3-d] pyrimidin-7-one 6- (2,4-difluorophenoxy) -8- ((R) -2-hydroxy-propyl) -2- (tetrahydro-pyran-4-ylamino) -8H-pyrido [2,3-d] pyrimidine- 7-one 6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxy-propyl) -2- (1-methanesulfonyl-piperidin-4-ylam ino) -8H-pyrido [2,3-d] pyrimidin-7-one 2-cyclopropylamino-6- (2,4-difluorophenoxy) -8- ((R) -2-hydroxy-propyl) -8H- pyrido [2,3-d] pyrimidin-7-one 44 6- (2,4-difluorophenoxy) -2- ((S) -2-hydroxy-1,2-dimethyl-propylamino) -8- (( R) -2-hydroxy-propyl) -8H-pyrido [2,3- d] pyrimidin-7-one 6- (2, 4-difluorophenoxy) -2- ((S) -2-hydroxy-1 -methyl-ethyl-amino) -8- (2-oxo-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one 46 6- (2,4-difluorophenoxy) -2- ((R) -2-hydroxy-1-methyl-ethylamino) -8- (2-oxo-propyl) -8H-pyrido [2, 3-d ] pyrimidin-7-one 47 6- (2,4-difluorophenoxy) -2- (2-hydro-l-hydroxymethyl-ethyl-amino) -8- ((S) -2-hydroxy) -propyl) - 8H-pyrido [2, 3-d] pyrimidin-7-one 48 6- (2,4-difluorophenoxy) -2- (R) -2-hydroxy-1-methyl-ethylamino) -8- ((R ) -2-hydroxy-propyl) -8H-pyrido [2,3- d] pyrimidin-7-one 49 6- (2,4-difluorophenoxy) -2- ((R) -2 -hydroxy-1- methyl-ethylamino) -8- (2-oxopropyl) -8H-pyrido [2,3-d] pyrimidin-7-one Although the cited forms of the invention currently constitute preferred embodiments, many others are possible. It is not intended here to mention all possible equivalent forms or ramifications of the invention. It is understood that the terms employed in the present invention are merely descriptive rather than limiting, and that various changes can be made without departing from the spirit or scope of the invention. The compounds of the present invention can be prepared by a variety of methods including the methods described in commonly assigned US-2003-0171584-Al, which has previously been incorporated herein by reference. In one aspect of the present invention, a method for the preparation of compounds of formula I is shown in reaction scheme 1 below. It should be noted that although the scheme often indicates exact structures, the methods of the present invention are broadly applied to analogous compounds of formula I, with appropriate consideration given to the protection and deprotection of the reactive functional groups by standard methods of the art. of organic chemistry. For example, hydroxyl groups, in order to prevent unwanted side reactions, sometimes need to be protected (for example, converted into ethers or esters), during chemical reactions that occur elsewhere in the molecule. The hydroxyl protecting group is then removed to provide the free hydroxyl group. Similarly, amino groups and carboxylic acid groups (eg, by derivatization) can be protected to protect against undesired side reactions. The typical protection groups and methods for attaching and fixing them are fully described in the references incorporated above by Greene and Wuts, in Protective Groups in Organic Synthesis ("Protecting groups in organic synthesis"), 31st edition, John Wiley Sons, New York, 1999, and Harrison and Harrison et al., "Compendium Synthetic Organic Methods", vol.1-8 (John Wiley and Sons, 1971-1996).

Reaction Scheme 1 Treatment of a compound of the formula I with a hydroxyalkylamine (R2-NH2) provides a compound of formula Ib. This reaction is conveniently carried out in a solvent which is inert under the conditions of the reaction, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, an optionally halogenated aromatic hydrocarbon, or an open chain ether or a cyclic ether such as tetrahydrofuran (THF), a formamide or a lower alkanol. The reaction is suitably carried out from about -20 ° C to about 120 ° C, typically at about 0 ° C. A base, such as trialkylamine, preferably triethylamine, is often added to the reaction mixture. The reduction of a compound of formula Ib provides an alcohol of formula le. This reduction is typically carried out using lithium aluminum hydride in a manner well known to those skilled in the art (for example, in a solvent which is inert under the conditions of reduction, preferably an open chain or cyclic ether especially THF, from about -20 ° C to about 70 ° C, preferably from about 0 ° C to about room temperature (TA). Oxidation of an alcohol of formula provides a carboxaldehyde of formula Id. Oxidation is typically carried out with manganese dioxide, although numerous other methods can also be used (see for example, ADVANCED ORGANIC CHEMISTRY ("Superior organic chemistry"), 4th ed., March, John Wiley & amp;; Sons, New York (1992)). Depending on the oxidizing agent used, the reaction is conveniently carried out in a solvent which is inert under the specific conditions of oxidation, preferably a halogenated aliphatic hydrocarbon, especially dichloromethane, or optionally a halogenated aromatic hydrocarbon. The oxidation is suitably carried out, from about 0 ° C to about 60 ° C. The reaction of a carboxaldehyde of formula Id with an ester Ar1-X1CH2-C02R '(wherein R' is an alkyl group, and Ar1 and X1 are as defined above) in the presence of a base, provides a compound of formula you. Any non-nucleophilic base can be used, including carbonates, such as potassium carbonate, lithium carbonate, and sodium carbonate; bicarbonates, such as potassium bicarbonate, lithium bicarbonate and sodium bicarbonate; amines such as secondary and tertiary amines; and amines bound to a resin such as 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a] pyrimidine. The reaction is conveniently carried out in a solvent which is relatively polar but inert under the conditions of the reaction, preferably a loved one such as dimethyl formamide, N-substituted pyrrolidinone, especially 1-methyl-2-pyrrolidinone, and at a about 25 ° C to about 150 ° C.

Oxidation of it with an oxidizing agent, for example, a permeate such as 3-chloroperbenzoic acid (ie MCPBA) or Oxone®, provides a sulfone (If) that can be converted to a variety of target compounds. The oxidation of it is typically carried out in a solvent that is inert under the conditions of oxidation. For example, when MCPBA is used as the oxidizing agent, the solvent is preferably a halogenated, empirical hydrocarbon, especially chloroform. When Oxone® is used as the oxidizing agent, the solvent is preferably methanol, aqueous ethanol or aqueous THF. The reaction temperature depends on the solvent used. For an organic solvent, the reaction temperature is generally from about -20 ° C to about 50 ° C, preferably from about 0 ° C to about TA. When the water is used as a solvent, the reaction temperature is generally from about 0 ° C to about 50 ° C, preferably from about 0 ° C to about TA. Alternatively, the oxidation can be carried out under catalytic conditions with reagents based on rhenium / peroxide, see (Lahti et al., Inorg Chem., 2000, 39, 2164-2167, Catal.Today, 2000, 55, 317-363, and Coperet et al., J. Org. Chem. 1998, 63, 1740-1741 The reaction of the compound If with an amine (Ra-NH2) gives the compounds of formula I. The reaction can be carried out in the presence or absence of solvent. The reaction is conveniently carried out at temperatures from about 0 ° C to about 200 ° C, more preferably from about RT up to about 150 ° C. Alternatively, in some cases rather than using sulfone If, the sulfide or the corresponding sulfoxide can react directly with an amine (R1-NH2) to provide the compounds of formula I. One skilled in the art will understand that certain modifications to the above reaction schemes are tolerable, always within the scope of the invention. present invention For example, certain steps will involve the use of protection groups for functional groups that are not compatible with the particular conditions of the reaction. Alternatively, the compounds of formula I can also be prepared by the method specified in reaction scheme 2 below, Although the reactions of reaction scheme 2 are indicated in terms of specific compounds, it will be readily apparent to those skilled in the art. the technique that the method of reaction scheme 2 can be employed with all the compounds of the invention. As shown in reaction scheme 2, treatment of a diethyl acetal with a thiourea provides a pyrimidine compound Ilb. This reaction is conveniently carried out in an alcohol solvent in the presence of a base such as sodium methoxide. Methylation of the thiol group, for example, with methyl iodide, then provides the thioether lie. The thioether may then be treated with an a-aryloxyester lid such as ethyl (2,4-difluorophenoxy) acetate to give a pyrido-pyrimidone thioether lie. This reaction can be effected, for example, by heating in the presence of sodium carbonate or another soft base in n-methyl pyrrolidinone or another polar aprotic solvent. Reaction of the thioether lie with propylene carbonate or a similar carbonate, under conditions of a polar aprotic solvent, to give a N-hydroxyalkyl pyrido-pyrimidone thioether Ilf. This reaction can be facilitated by heating in the presence of potassium carbonate. The thioether Ilf is then oxidized to provide the corresponding pyrido-pyrimidone sulfone Ilg. This oxidation can be effected using hydrogen peroxide in the presence of acetic acid in a polar solvent such as methylene dichloride. The oxidation can alternatively be carried out using Oxone® or MCPBA in the manner described above for the reaction scheme 1. The treatment of the sulfone Ilg with a hydroxyamine, wherein the hydroxyl group is suitably protected, provides a pyrido-pyrimidone compound Ilh according to the invention. This reaction can be carried out by heating as described above with reference to reaction scheme 1.

Reaction Scheme 2 Pyridopyrimidinone Ilf can also be prepared by alkylating the pyridopyrimidinone with an epoxide instead of a carbonate as indicated in reaction scheme 3 below. The reaction of reaction scheme 3 can be carried out by heating the compound under pressure in the presence of an excess of propylene oxide in N-metal pyrrolidinone or under other conditions with a polar aprotic solvent. j? c H?, -feNM? - Xie Reaction scheme 3 The compounds of formula I can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered enterally, for example, orally in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example, in the form of nasal sprays, or rectally, for example, in the form of suppositories. However, they can also be administered parenterally, for example, in the form of solutions for injection. Another aspect of the present invention provides a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient therefor. The compounds of formula I can be processed with pharmaceutically inert supports, organic or inorganic, for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, said supports for tablets, coated tablets, dragees and hard gelatine capsules. Suitable supports for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; however, depending on the nature of the active ingredient, no support is usually necessary in the case of soft gelatine capsules. Suitable supports for the production of solutions and syrups are for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable supports for suppositories are, for example, natural or hardened oils, waxes, fats, polyols, illiquids or liquids and the like. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, taps, masking agents or antioxidants. They may also contain therapeutically valuable substances other than the compounds of formula I. Medicines containing a compound of formula I with a pharmaceutically compatible carrier material are also subject of the present invention, as well as a process for the production of such medicaments, the which comprises the use of one or more of these compounds or salts, and if desired, one or more other therapeutically valuable substances in a galenic administration form together with a pharmaceutically compatible carrier. As mentioned above, the compounds of formula I can be used according to the invention as therapeutically active substances, especially as anti-inflammatory agents or for the prevention of a graft rejection after a transplant operation. The dosage can vary within wide limits, and will of course be adjusted to the individual requirements of each particular case. In general, in the case of administration for adults, a convenient daily dosage should be from about 0.1 mg / kg to 100 mg / kg, preferably about 0.5 mg / kg to about 5 mg / kg. The daily dosage should be administered as a single dose or divided into doses and, in addition, the upper limit of dosage with reference to the earliest, may be exceeded when it is considered to be indicated. Finally, the use of compounds of formula I for the production of medicines, especially in the treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, in the treatment of asthma, central nervous system or diabetic complications or for the prevention of a graft rejection after a transplant operation, is also object of the invention. The compounds of formula I are useful for, but are not limited to, the treatment of any disorder or disease state in a human, or other mammal, that is exacerbated or caused by excessive or uncontrolled production of TNF or p38 kinase by said mammal. Accordingly, the present invention provides a method for the treatment of a cytokine-induced disease, comprising the administration of an effective amount of a compound of formula I, cytokine interfering agent, or a pharmaceutically acceptable salt or a tautomer thereof. . The compounds of formula I are useful for; although they are not limited to the treatment of inflammation in a subject, and for use as antipyretics for the treatment of fever. The compounds of the invention should be useful for treating arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. These compounds would be useful for the treatment of lung disorders or inflammation of the lungs, including adult respiratory pain syndrome, pulmonary sarcoidosis, asthma, silicosis and chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral or bacterial infections, including sepsis, septic shock, gram-negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome. (AIDS), AIDS, ARC (complex related to AIDS), pneumonia and the herpes virus. The compounds are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune diseases including the reaction of the graft to the recipient, and rejections of foreign grafts, cardiovascular diseases. including atherosclerosis, thrombosis, congestive heart failure and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection. The compounds are also useful for the treatment of Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation and scar tissue formation. In addition, the compounds of the invention are useful in the treatment of gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds are also useful in the treatment of ophthalmological diseases such as retinitis, retinopathies, uveitis, ocular photophobia and acute ocular tissue injury. The compounds may also be useful in the treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, neovascularization of the retina including neovascularization after injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological but not malignant conditions such as hemangiomas, including infantile hemangiomas, angiof ibroma of the nasopharynx and avascular bone necrosis; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds can also be used for the prevention of the production of cyclooxygenase-2 and have analgesic properties. Therefore, the compounds of formula I are useful for the treatment of pain. Other uses for the compounds of formula I include the treatment of HCV, severe asthma, psoriasis, chronic obstructive pulmonary disease (COPD), and other diseases that can be treated with an anti-TNF compound. In addition to being useful for human treatment, these compounds are also useful for the veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents and the like. The most preferred animals include horses, dogs and cats. The present compounds can also be used in cotherapies, partially or completely, instead of other conventional anti-inflammatories, such as in conjunction with steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDs, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors. As used in the present description, the term "TNF-induced disorder" refers to any and all disorders and disease states in which TNF plays a role either in controlling TNF itself, or because TNF it causes the release of another monokine, such as IL-1, IL-6 or IL-8 but without being limited thereto. A disease state in which, for example, IL-1 is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disorder induced by TNF. As used in the present disclosure, the term "p38-induced disorder" refers to any and all disorders and disease states in which p38 plays a role either in controlling p38 itself or because p38 causes the release of another factor, such as IL-1, IL-6 or IL-8 but without being limited thereto. A disease state in which, for example, IL-1 is a major component, and whose production or action is exacerbated or secreted in response to p38, would therefore be considered a disorder induced by p38. Since TNF-β has an intimate structural homology with TNF-α (also known as cachectin) and since it induces similar biological responses and binds to the same cellular receptor, the synthesis of both TNF-α and TNF-β has an intimate structural homology with TNF-a, as of TNF-β are inhibited by the compounds of the present invention, for all of which in the present description both are indistinctly referred to as "TNF", unless specifically stated otherwise . EXAMPLES Further objectives, advantages and new features of this invention will be apparent to those skilled in the art after examining the following illustrative examples thereof, which are not intended to be limiting. Example 1: Preparation of 6- (2,4-difluorophenoxy) -2- ((S) - (+) -2-hydroxy-1-methyl-ethylamino) -8- ((S) -2-hydroxy -propyl) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 16) Step A: Preparation of 4- ((S) -2-hydroxy-propylamino) -2-methyl-sulfonyl-pyrimidine-5 ethyl carboxylate To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 65 g, 280 mmol) in 500 ml of THF at 0 ° C was added triethylamine (140 ml, 1000 mmol), and (S) -l-amino-2-propanol (21 g, 280 mmol). After stirring for 4 hours, water (200 ml) was added and the phases were separated. The aqueous layer was extracted with dichloromethane. The organic phase was concentrated and the residue was dissolved with dichloromethane, washed with brine and dried with magnesium sulfate. It was filtered and the filtrate was evaporated under reduced pressure to obtain 77 g of ethyl 4- (S) -2-hydroxy-propylamino) -2-methylsulfanyl-pyrimidine-5-carboxylate, as a white solid. Step B: Preparation of 4- ((S) -2-hydroxy-propylamino) -2-methylsulf indigo-pyrimidin-5-methanol Lithium aluminum hydride (5.7 g, 150 mmol) in anhydrous THF (500 ml) was stirred. at 5 ° C and treated dropwise with a solution of ethyl 4- ((S) -2-hydroxy-propylamino) -2-methylsulfanyl-pyrimidine-5-carboxylate (27 g, 100 mmol) in anhydrous THF ( 450 mi). The reaction mixture was stirred for 15 minutes and then water (18 ml) was added dropwise with care. The reaction was stirred for 30 minutes and then an aqueous solution of sodium hydroxide (15%, 8.5 ml) was added dropwise, followed by water (25.5 ml). The resulting suspension was stirred for 17 h at RT and then filtered. The filter residue was washed with isopropanol (2X, 100 ml) and the filtrate and the mixed washings were evaporated under reduced pressure to obtain 25.8 g of 4- ((S) -2-hydroxy-propylamino) -2-methylsulfonyl-pyrimidin. - 5-methanol. Step C: Preparation of 4- ((S) -2-hydroxy-propylamino) -2-methylsulfonyl-pyrimidin-5-carbaldehyde 4- ((S) -2-hydroxy-propylamino) -2-methyl- sulfur anil-pyrimidin-5-methanol (26 g, 100 mmol) and 1 liter of stirred dichloromethane and treated with manganese dioxide (102 g, 1 mol). The resulting suspension was stirred for 24 hours and then filtered through celite. The filter residue was washed with dichloromethane (100 ml) and the filtrate and the mixed washings were evaporated under reduced pressure to obtain 16.5 g of 4 - ((S) -2-hydroxypropyl-lamino) -2-methyl-sulphonyl-pyrimidine- 5 - Carbaldehyde in the form of a white solid.

Sulfones Step A: Preparation of 6- (2,4-difluoromonoxy) -8- ((S) -2-hydroxypropyl) -2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidine-7- ona A mixture of 4- ((S) -2-hydroxy-propylamino) -2-methyl-sulfanyl-pyrimidine-5-carbaldehyde (16.5 g, 73 mmol) and (2,4-difluorphenoxy) -acetic acid methyl ester (29.4 g, 145 mmol) in anhydrous dimethyl formamide (300 mL) was added potassium carbonate (30 g, 218 mmol). The reaction mixture was heated to 60 ° C and after 18 hours, the reaction mixture was cooled and the dimethylformamide was removed by vacuum distillation. The crude residue was suspended in water (300 ml) and extracted with dichloromethane, washed with brine and dried with magnesium sulfate. Filtered and concentrated in vacuo to obtain 41 g of crude material which was chromatographed on a column of silica gel eluting with 1% methanol in dichloromethane to obtain 30 g of 6- (2,4-difluorphenoxy) -8- ((S) -2-hydroxypropyl) -2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (mass spec. M + 1 = 274).

Step B: Preparation of 6- (2, 4 { Di flour phenoxy) -8- ((S) -2-hydroxypropyl) -2-methanesulfanyl-8H-pyrido [2,3-d] pyrimidine- 7 - One solution to dichloromethane (500 ml) of 6- (2,4-difluorfeni) -8 - ((S) -2-hydroxypropyl) -2-methyl-sulphonyl-8H-pyrido [2,3-d] pyrimidine- 7 -one (29.7g, 108mmol) at 5 ° C, m-chloroperbenzoic acid (55g, 240mmol) was added portionwise and stirred for 24 hours. The reaction mixture was washed with aqueous sodium sulfite, aqueous sodium bicarbonate and dried with magnesium sulfate. It was filtered and evaporated to obtain 24 g of 6- (2,4-difluoromonoxy) -8- ((S) -2-hydroxypropyl) -2-methanesulfonyl-8H-pyrido [2,3-d] pyrimidine- -one (mass spectra M + l = 412). Step C: Preparation of 6- (2, 4-difluorophenoxy) -2- ((S) -2-hydroxy-1-methyl-ethylamino) -8- ((S) -2-hydroxy-propyl) -8H ~ pyrido [2,3-d] pyrimidin-7 -one To a solution in THF (5 mL) of 6- (2,4-difluoromonoxy) -8- ((S) -2-hydroxypropyl) - 2-methanesulfonyl-8H-pyrido [2,3-d] pyrimidin-7 -one (400 mg, 1 mmol), (S) -2-amino-1-propanol (0.38 mL, 5 mmol) was added and stirred overnight at RT. It was concentrated in vacuo or chromatographed on silica gel eluting with 2% methanol in dichloromethane and converted to the hydrochloride salt to obtain 320 mg of the 6- (2,4-difluorophenoxy) -2- ((S) - (+) -2-hydroxy-l-methyl-ethylamino) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one (mass spectr. M + l = 407, Pf = 175.1-179.1 ° C). Example 2: Preparation of 6- (2, -dif luor-phenoxy) -2- (R) - (-) -2-hydroxy-1-methyl-ethylamino) -8- ((S) -2-hydroxy-propyl ) -8H-pyrido [2,3-d] pyrimidin-7-one (compound 17) To a solution in THF (5 ml) of 6- (2,4-difluorophositol) -8- ((S) - 2-hydroxypropyl) -2-methanesulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one (400 mg, 1 mmol), (R) -2-amino-1-propanol (0.38 ml, 5 mmole) and stirred overnight at RT. It was concentrated in vacuo and chromatographed on silica gel, eluting with 2% methanol in dichloromethane and converted to the hydrochloride salt to obtain 370 mg of 6- (2,4-dif luorf enoxi) -2- ((R) -2 -hydroxy-l-methyl-ethylamino) -8- ((S) -2-hydroxypropyl) -8H-pyrido [2,3-d] pyrimidin-7-one (mass spec. M + l = 407, Pf = 174.9-178.1 ° C). Example 3: Preparation of 6- (2, -dif luorf enoxi) -2- (2-hydroxy-1, 1-dimethyl-ethylamino) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [ 2, 3-d] pyrimidin-7-one (compound 36) To a solution in THF (10 ml) of 6- (2,4-difluorophenoxy) -8- ((S) -2-hydroxypropyl) -2-methanesulfonyl -8H-pyrido [2,3-d] pyrimidine-1-propanol (1.55 ml, 17.43 mols), 2-amino-1-methyl-1-propanol (1.55 ml, 17.43 mmol) was added and stirred overnight at RT, concentrated in vacuo and chromatographed on silica gel eluting with 4% methanol in dichloromethane, after conversion to the hydrochloride salt, to 291 mg of 6- (2,4-difluorophenoxy) -2 - (2-hydroxy-1,1-dimethyl-ethylamino) -8- ((S) -2-hydroxy-propyl) -8H-pyrido [2, 3-d] pyrimidin-7-one, in the form of a white solid (spectr, mass M + l = 421, P.f. = 187.4-189.9 ° C). Example 4: Preparation of 6- (2,4-difluorophenoxy) -2- ((S) - (2-hydroxy-1-methyl-ethyl) -8- ((R) -2-hydroxy-propyl) -8H-pyrido [2, 3-d] irimidin-7 -one (compound 41) Step A: Preparation of 4- ((R) -2-hydroxy-propylamino) -2-methylsulfyl-pyridine-5-carboxylate ethyl To a solution of 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester (Aldrich, 62.6 g, 269 mol) in 1 liter of THF at 0 ° C, triethylamine (135 ml, 1000 mmol) and (R) were added. ) -1-amino-propanol (30 g, 400 mmol) After stirring for 4 hours, it was evaporated under reduced pressure to obtain 66.6 g of 4- ((R) -2-hydroxy-propylamino) -2-methylsulfanyl-pyrimidine Ethyl 5-carboxylate in the form of a white solid Step B: Preparation of 4- ((R) -2-hydroxy-propylamino) -2-methylsulfonyl-pyrimidin-5-methanol Lithium hydride was stirred and aluminum (14 g, 368 mmol) in anhydrous THF (500 ml) at 5 ° C and treated dropwise with a solution of 4- ((R) -2-hydroxy-propylamino) -2 ethyl methylsulfanyl-pyrimidine-5-carboxylate (66.6 g, 246 mmol) in anhydrous THF (150 ml). The reaction mixture was stirred for 15 minutes and then water (18 ml) was added dropwise with care. The reaction was stirred for 30 minutes and then an aqueous solution of sodium hydroxide (15%, 8.5 ml) was added dropwise, followed by water (25.5 ml). The resulting suspension was stirred for 17 h at RT and then filtered. The filter residue was washed with isopropanol (2X, 100 ml) and the filtrate and the mixed washings were evaporated under reduced pressure to obtain 58.6 g of 4- (R) -2-hydroxy-propylamino) -2-methylsulfanyl-pyrimidine-5 -methanol.

Step C: Preparation of 4 - ((R) -2-hydroxy-propylamino) -2-methylsulfonyl-pyrimidine-5-carbaldehyde 4- ((R) -2-hydroxy-propylammonium) -2-methylsulfanyl- pyrimidin-5-methanol (58.6 g, 256 mmol) and 1 liter of dichloromethane, stirring, and treated with manganese dioxide (222 g, 2560 mmol). The resulting suspension was stirred for 24 hours and then filtered through celite. The filter residue was washed with dichloromethane (100 mL) and the filtrate and the mixed washings were evaporated under reduced pressure to obtain 34 g of 4- ((R) -2-hydroxy-propylamino) -2-methylsulfanyl-pyrimidine-5-carbaldehyde as a solid of color White. Sulfones Step A: Preparation of 6- (2, 4 -dif luorf enoxi) -8- ((R) -2-hydroxypropyl) -2-methylsulf indigo-8H-pyrido [2,3-d] pyrimidin- 7- ona To a mixture of 4 - ((R) -2-hydroxy-propylamino) -2-methyl-sulphonyl-pyrimidin-5-carbaldehyde (17.7 g, 78 mmol) and methyl ester of acid (2, 4-dif luorf) enoxi) acetic acid (31.6 g, 156 mmol) in anhydrous dimethyl formamide (300 ml) was added potassium carbonate (30 g, 218 mmol). The reaction mixture was heated to 60 ° C and after 18 hours, the reaction mixture was cooled and the DMF was removed by distillation. The residue was suspended in water (300 ml) and extracted with dichloromethane, washed with walnut salt and dried with magnesium sulfate.

Filtered and concentrated in vacuo to obtain 29.5 g of crude material which was chromatographed on a column of silica gel eluting with 1% methanol in dichloromethane to obtain 17.5 g of 6- (2,4-difluorphenoxy) -8- ((R ) -2-hydroxypropyl) -2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (mass spectrometer M + 1 = 274. Stage B: Preparation of 6- (2, 4- dif luorf enoxi) -8- ((R) -2-hydroxypropyl) -2-methane sulf indigo-8H-pyrido [2,3-d] pyrimidin-7 -one To a solution in dichloromethane (200 ml) of 6- (2,4-di-fluorophenoxy) -8- ((R) -2-hydroxypropyl) -2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (9.38 g, 247 mmol) at 5 ° C, m-chloroperbenzoic acid (12.5 g, 54 mmol) was added in portions and stirred for 24 hours.The reaction mixture was washed with aqueous sodium sulfite, aqueous sodium bicarbonate and dried with magnesium sulfate. filtered and evaporated to obtain 10.7 g of 6- (2, -difluorphenoxy) -8- ((R) -2-hydroxypropyl) -2-methane Sulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (spectr, mass M + l = 412). Step C: Preparation of 6- (2,4-difluorophenoxy) -2- ((S) -2-hydroxy-1-methyl-ethyl-amino) -8- ((R) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7 -one To a solution in THF (5 mL) of 6- (2,4-difluorphenoxy) -8- ((R) -2-hydroxypropyl) -2- methanesulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one 8615 mg, 1.5 mmol), (S) -2-amino-1-propanol (1.2 ml, 15 mmol) was added and stirred for the night at TA. It was concentrated in vacuo and chromatographed on silica gel eluting with 2% methanol in dichloromethane and converted to the hydrochloride salt to obtain 295 mg of 6- (2,4-difluorophenoxy) 2- ((S) -2 -hydroxy-l-methyl-ethylamino) -8- ((R) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one (mass spec. M + l = 407, Mp = 186.0-189.1 ° C). Example 5: Preparation of 6- (2,4-difluorophenoxy) -2- (R) -2-hydroxy-1-methyl-ethylamino) -8- ((R) -2-hydroxy-propyl) -8H- pyrido [2,3-d] pyrimidin-7-one (compound 48) To a solution in THF (5 ml) of 6- (2,4-difluorphenoxy) -8- ((R) -2-hydroxypropyl) -2 -methanesulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one (400 mg, 1 mmol), (R) -2-amino-1-propanol (0.38 mL, 5 mmol) was added and stirred for the night at TA. It was concentrated in vacuo and chromatographed on silica gel eluting with 2% methanol in dichloromethane and converted to the hydrochloride salt, obtaining 350 mg of 6- (2,4-difluorophenoxy) -2- (2-2- hydroxy-l-methyl-ethylamino) -8- ((R) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one (mass spec. M + lg 407, Pf = 181.5-184.4 ° C). Example 6: Preparation of 6- (2, 4-difluorphenoxy) -2- (2-hydroxy-1,1-dimethyl-ethylamino) -8- ((R) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7- ona (compound 31) A mixture of 6- (2,4-difluorphenoxy) -8- ((R) -2-hydroxypropyl) -2-methanesulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one ( 886 mg, 2.15 mmol) and -amino-2-methyl-1-propanol (5.5 g, 58 mmol) was heated at 60 ° C under nitrogen for 2 hours. It was cooled and chromatographed on silica gel eluting with 2% methanol in dichloromethane to give after conversion into the hydrochloride salt, 385 mg of 6- (2,4-difluorphenoxy) -2- (2-hydroxy-1, 1- dimethyl-ethylamino) -8- ((R) -2-hydroxy-propyl) -8H-pyrido [2,3-d] pyrimidin-7-one (mass spec. M + l = 421, Pf = 182.0-183.9 ° C). Example 7: Preparation of 6- (2,4-difluorphenoxy) -2- ((S) - (2-hydroxy-1-methyl-ethylamino) -8- (2-oxopropyl) -8H-pyrido [2,3- d] pyrimidin-7-one (compound 45) Step a: Preparation of 6- (2,4-difluorofenoxi) -2-methanesulfonyl -8- (2-oxopropyl) -8H-pyrido [2,3-d] pyrimidin-7'-one To a solution in dichloromethane (100 ml.) of oxalyl chloride (1.05 ml, 12 mmol) at -60 ° C, dimethyl sulfoxide (1.7 ml, 24 mmol) and 6- ( 2,4-difluorphenoxy) -8- (2-hydroxypropyl) -2-methanesulfonyl-8H-pyrido [2,3-d] pyrimidin-7-one (4.12 g, 10 mmol). To this mixture was added triethylamine. mi, 50 mmol) and stirred overnight. (100 ml) and extracted with dichloromethane, washed with brine and dried with magnesium sulfate. Filtered and concentrated in vacuo, chromatographed on silica gel eluting with 2% methanol in dichloromethane to obtain 1.0 g of 6- (2,4-difluorphenoxy) -2-methanesulfonyl-8- (2-oxopropyl) -8H-pyrido- [2, 3-d] pyrimidin-7-one (mass spectra M + l = 410). Step b: Preparation of 6- (2,4-difluorofoxy) -2- ((S) -2-hydroxy-1-methyl-ethylamino) -8- (2-oxopropyl) -8H-pyrido [2, 3 -d] pyrimidin-7 -one (compound 45). To a THF suspension of 6- (2,4-difluorphenoxy) -2-methanesulfonyl-8- (2-oxopropyl) -8H-pyrido [2,3-d] pyrimidin-7-one (412 mg, 1 mmol) , (S) -2-amino-1-propanol (0.39 ml, 5 mmol) was added at RT and stirred overnight. It was concentrated in vacuo and chromatographed on silica gel eluting with 2% methanol in dichloromethane, after converting to the hydrochloride salt 330 mg of 6- (2,4-difluorphenoxy) -2- ((S) -2- hydroxy-l-methyl-ethylamino) -8- (2-oxopropyl) -8H-pyrido [2,3-d] pyrimidin-7-one (spectr, mass M + 405, Pf = 207.9-214.6 ° C) . Example 8: Preparation of 6- (2,4-difluorphenoxy) -2- ((R) - (2-hydroxy-1-methyl-ethylamino) -8- (2-oxopropyl) -8H-pyrido [2,3- d] pyrimidin-7 -one (compound 49) To a suspension in THF (10 ml) of 6- (2,4-difluoro-phenoxy) -2-methanesulfonyl-8- (2-oxopropyl) -8H-pyrido [2, 3] -d] pyrimidin-7-one (417 mg, 1 mmol), (R) - (-) -2-amino-1-propanol was added (0.40 ml, 5 mmol) at RT and stirred overnight. It was concentrated in vacuo and chromatographed on silica gel, eluting with 2% methanol in dichloromethane, after converting to the hydrochloride salt 330 mg of 6- (2,4-difluorphenoxy) -2- ((R) -2- hydroxy-l-methyl-ethylamino) -8- (2-oxopropyl) -8H-pyrido [2,3-d] pyrimidin-7-one (mass spec. M + l = 405, Pf = 207.8-216.4 ° C ). Example 9: In vitro assay The inhibitory activity of p38 MAP kinase of the compounds of this invention in vitro was determined by measuring the transfer of? -phosphate from? -33P-ATP by p-38 kinase the myelin basic protein ( MBP), using a minor modification of the method described in Ahn et al *, J. Biol. Chem. 266: 4220-4227 (1991). The phosphorylated form of the recombinant p38 MAP kinase was co-expressed with SEK-1 and MEKK in E. coli (see Khokhlatchev et al., J. Biol. Chem. 272: 11057-11062 (1997)) and then purified by Chromatographic affinity using a nickel column Phosphorylated p38 MAP kinase was diluted in kinase buffer (20 mM 3- (N-morpholino) propanesulfonic acid, pH 7.2, 25 mM β-glycerol phosphate, 5 mM ethylene glycol-acid bis (beta-aminoethyl ether) -N, N, N ', N' -tetraacetic acid, 1 mM sodium ortho-vanadate, 1 mM dithiothreitol, 40 mM magnesium chloride). The test compound dissolved in DMSO or only DMSO (control) was added and the samples were incubated for 10 minutes at 30 ° C. The reaction of the kinase was initiated by the addition of a mixture of substrates containing MBP and? -33P-ATP. After incubating for an additional 20 minutes at 30 ° C, the reaction was terminated by adding 0.75% phosphoric acid, The phosphorylated MBP was then separated from the residual β-33P-ATP using a phosphocellulose membrane (Millipore, Bedford, MA) and it was quantified using a scintillation counter. { Packard, Meriden, CT). Using the above assay, it was shown that the compounds of the invention were inhibitors of p38 MAP kinase. The compounds of the invention showed p38IC50 values in the range from less than 0.001 to 0.1 μM. For example, the 6-. { 2,4-difluorophenoxy) -8- (3-hydroxy-propyl) -2- (tetrahydro-pyran-4-yl-amino) -8H-pyrido [2,3-d] pyrimidin-7-one showed a IC50 of 0.0008 μM using the previous test. Example 10: In Vitro Assay This example illustrates an in vi tro assay with whole human blood (HWB) (i.e., the production of IL-lβ induced by LPS in whole human blood by inhibiting p38 MAP kinase) the evaluation of the compounds of the present invention and the comparative results of the corresponding alkyl analogs. Treatment with LPS (lipopolysaccharides) of whole human blood induces IL-lβ (interleukin-lβ) production of which can be measured by a specific ELISA assay for IL-1β. Whole human blood was pre-incubated with the indicated concentration of a compound of the present invention in 0.5% DMSO (final concentration) for 30 minutes at 37 ° C. The samples were stimulated with 0.5 μg / ml of lipopolysaccharides (Sigma LPS) (final concentration) for 18 hours to induce the synthesis and secretion of IL-1β which was measured using an ELISA assay for IL-1β IL. Compound solutions A 6 mM stock solution was prepared in DMSO (from Sigma), dissolving the compound in DMSO in 449 μl of DMSO. From the 6 mM stock solution, six subsequent semilogarithmic dilutions in series were made in DMSO. to give the following concentrations; 1.9 mM, 600, 190, 60, 19 and 6 μM. Tubes with label 1-7. The 6 mM stock solution in tube 1. 216 μl of DMSO was introduced into each of the tubes 2-7. From tube 1, 100 μl was transferred to tube 2. Tube 2 was shaken on the Vortex and 100 μl was transferred from tube 2 to tube 3. This process was repeated up to tube 7. Using the serial dilutions of the compound in DMSO prepared above, an additional 1/20 dilution was performed (10 μl in 190 μl of RPMI 1640 medium of Gibco-BRL) obtaining a final curve of compound concentrations of 30, 10, 2.9, 1, 0.3, 0.1, 0.03 μM. LPS Solutions Reconstitution of LPS; in the 10 mg vial of LPS, 10 ml of phosphate buffered saline IX (i.e., 1XPBS of Gibco-BRL) was added, mixed well and transferred to a 50 ml tube. Another 10 ml was added to the LPS vial, followed by a rinse, and this rinse was added to the 50 ml tube and mixed well. The solution was filtered and sterilized and aliquoted in desired amounts (aliquots of 100 μl was sufficient for 4 plates). This supplied a stock of 0.5 mg / ml which was diluted 1/100 to be used in the protocol. Just before being used, the stock of LPS was diluted 1/100 (100 μl in 10 ml of RPMI). Test procedure The test was carried out in a 96-well U-shaped bottom plate (from Costar). In each trial, two controls were included, plus and minus LPS in the absence of the compound. All samples and controls were carried out in triplicate.

Human blood (from donors who had received no medication for at least 14 days, and no alcohol for 48 hours) was collected in siliconized vacutainers containing heparin (19 units / ml). An aliquot of 25 μl of 5% DMSO in RPMI 1640 was added to the control wells (plus and minus LPS controls). Aliquots of 25 μl of each concentration of the compound prepared above were added to the designated wells. 200 μl of whole human blood was added to each well and incubated at 37 ° C and 5% C02 for 30 minutes. 25 μl of diluted LPS was added to all wells except the LPS minus control wells. 25 μl of RPMI were added to the LPS control wells less. The plates were incubated at 37 ° C and 5% C02 for 18 hours. After incubation, the plates were centrifuged at 400xg to pellet the cells and collect the plasma, taking care not to spoil the pellet of the pellet. The plasma was transferred to a new 96-well polypropylene plate. An ELISA analysis was performed immediately and the residual plasma was stored at -20 ° C to repeat the assay if necessary. ELISA analysis protocol The ELISA assay for IL-lβ employed two IL-1β monoclonal antibodies: ILßl-H6 (1 mg / ml) and ILßl-H67 (271 mg / ml). Materials Human recombinant IL-1β (rhuIL-lβ, 2.5 μg / ml) was obtained from R &D Systems. Dulbecco's phosphate buffered saline (1XPBS) was obtained from Gibco-BRL. Phosphate buffered saline (10XPBS) was obtained from Gibco-BRL. The Dulbecco modification - without calcium and without magnesium, pH 7.2. Unopened bottles were stored at room temperature. ELISA incubation buffer (EIB, -0.1% BSA / PBS, 1 g of bovine serum albumin (ESA), 100 ml of 10XPBS, add deionized water to 1 liter and store at 4 ° C. Wash buffer for ELISA ( EWB): 0.05% Tween / PES, 0.5 ml Tween 20, 100 ml lOx PBS, add deionized water to 1 liter and store at 4 ° C. Blocking buffer - 3% defatted dry milk / PBS: 15 g dry milk defatted powder (Carnation), 50 ml of IOXPBS, add distilled water to 500 ml and store at 4 ° C. Streptavidin conjugated with peroxidase (Pharmingen): Dilute approximately 1: 3000 (10 μl / 30 ml) in buffer EWB: 0.1 M citrate buffer, pH 4.5: 9.6 g citric acid (Pm 192.1, from Sigma), 14.7 g trisodium citrate (Pm 294.1, from Sigma), adjust to pH 4.5 using NaOH and add distilled water to 500 ml Store at 4 ° C. OPD substrate solution: 1 mg / ml OPD / 0.03% H202 / citrate buffer, 1 tablet of o-phenylenediamine (OPD, from Zymed), 12 μl of hydrogen peroxide 30% strength, 12 ml of 0.1M citrate buffer. Preparation of standards (prepare just before placing on the plate). A stock solution of rhuIL-lß (2.5 μg / ml) was used to construct a standard curve. The concentrations for the curve are: 12500, 4167, 1389, 463, 154, 51 and 17 pg / ml. The tubes were labeled from 1 to 8. The rhuIL-lß stock solution was diluted 1/500 (3 μl of stock + 597 μl of EWB) in tube 1. 400 μl of EWB was added to tubes 2-8. From tube 1, 200 μl was transferred to tube 2 and vortexed. 200 μl were transferred from tube 2 to tube 3. The process was repeated up to tube 7. Tube 8 was left blank for the ELISA assay.

Plasma samples were diluted 1: 4 in EWB (20 μl plasma + 60 μl EWB). Preparation of antibody solutions The ILßl-H6 antibody was diluted 1/100 in 1XPBS to generate 10 μg / ml of solution. Per plate, 50 μl of antibody was diluted in 5 ml of PBS. The antibody ILßl-H67 was diluted 1/100 in EWB to generate 2 μg / ml of solution. Per plate, 3.69 μl of antibody was diluted in 5 ml of EIB. Procedure EIA 96-well plates were coated with 50 μl per well of ILβ1-H6 antibody (10 μg / ml), gently shaken to remove any air bubbles and sealed with plate sealer and incubated in a chamber humidified overnight at 4 ° C. The plates were emptied and dried with a paper towel free of fibers. The non-specific binding sites were blocked with 175 μl per well of blocking buffer for 1-2 hours at RT. The plates were washed once with EWB (i.e., emptying the plate, filling with 150 μl of EWB, emptying and drying with a paper towel without fibers). Aliquots of 25 μl of the standard, triplicated, were added to appropriate wells (each plate has its own standard curve). An aliquot of 25 μl of diluted plasma was added to the appropriate well. To all wells, 25 μl of biotinylated monoclonal antibody ILßl-H67 (2 μg / ml) was added. The plates were sealed with plate sealer and incubated for 2"hours at RT (6 overnight at 4 ° C) with gentle shaking (Belice Mini-Orbital Shaker, adjust to 3.5) .After incubation, plates were washed 3 times with EWB (as described above) A 50 μl aliquot of peroxidase-streptavidin, diluted 1: 3000 in EIB, was added to each well The plates were sealed with plate sealer, the plates were incubated plates for 1 hour at RT while stirring, and washed 3 times as described above An OPD tablet was dissolved in citrate buffer (1 tablet / 12 ml citrate buffer), and 12 μl 30% H202. %, was added to the OPD / treatment t ampon 50 μl of OPD substrate solution was added to each well, and the plates were incubated in the dark for 30 minutes at RT for color development. a double wavelength: sample filter = 450 hm / reference filter = 650 The values of the samples containing the standard were used to plot a standard curve (absorbance versus concentration) used to determine the concentration of unknown samples. Statistical method If the concentration-inhibition curve does not include points on either side of 50%, then the IC50 is recorded as >; that the highest concentration or < than the lowest concentration. On the other hand, if the number of concentrations is _ > 5 l ° s data were adjusted to the following 2-parameter model to estimate an IC50.

Mean% inhibition = Conc This model assumes that the minimum and maximum responses were 0% and 100% respectively, and estimates the IC50 and the slope parameter. If the non-linear regression fails, or if the number of concentrations tested was < 5, linear regression was used to estimate the ICS0, using the 2 points that flank 50%. If linear regression was used to estimate the IC50, it was recorded in the test notes and can also be seen with the presence (non-linear regression) or absence (linear regression) of the IC50 standard error and the slope parameter. Using the above test, it was demonstrated that the compounds of the invention inhibited the production of IL-lβ induced by LPS in undiluted whole human blood, by inhibiting the p38 MAP kinase, which induces the production of IL-1β as has been described above. The compounds of the invention showed IC 50 values for the production of IL-1β, induced by LPS in whole human blood undiluted, in the range from < 0.001 μM to 0.30 μM. For example, 6- (2,4-difluorophenoxy) -8- ((R) -2-hydroxy-propyl) -2- (tetrahydro-pyran-4-ylamino) -8H-pyrido [2, 3 d] pyrimidin-7-one showed an IC 50 of 0.001 μM. Surprisingly, the production of IL-lβ induced by LPS using compounds of the invention wherein R 2 of the formula (I) is hydroxyalkyl or alkoxyalkyl is substantially greater than the results of the corresponding compounds wherein R 2 is methyl or other alkyl. This unexpected advantage of the invention is illustrated more fully in Table 2 in which the representative compounds of the invention wherein R2 (of formula I) is hydroxyalkyl, are compared to the corresponding analogs wherein R2 is methyl). The compounds of the first column to the left of table 1 are prepared as described in the examples herein, and are also included in the. Table 1. The compounds of the second column or column from the center of Table 2 were prepared according to the procedures described in WO 02/064594. The values in the third column or column to the right correspond to the ratio: (inhibition of the IC50 of the production of IL-lβ where R2 = hydroxyalkyl) / (inhibition of the IC50 of the production of IL-lβ where R2 = methyl ) As can be seen from table 2, the compounds wherein R 2 is hydroxyalkyl, provide the inhibition of the production of IL-1β in undiluted complete human blood induced by LPS, which is of the order of 2.7 a > 100 times, that is, 270% a > 10,000% greater than the corresponding methyl analogs (R2 = methyl).

TABLE 2 The foregoing description of the invention has been made for the purpose of illustrating and describing. The foregoing description is not intended to limit the invention to the form or forms that are described therein. Although the description of the invention has included the description of one or more versions and certain variations and modifications, other variations and modifications are within the scope of the invention, for example, they may be in the skill and knowledge of those skilled in the art, after knowing the present description. It is intended to obtain rights that include up to the limit of the permitted, alternative versions including structures, functions, margins or alternative, interchangeable and / or equivalent steps, to those claimed, whether said structures, functions, margins or alternative, interchangeable steps and / or equivalents are described or not herein, and without intending to publicly designate any subject as a patentable object. All publications, patents and patent applications cited herein are incorporated by reference in their entirety, for all purposes.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (4)

R E I V I ND I C A I N N E S Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula I characterized in that X1 is O, C = 0 or S (0) n / where n is 0, 1 or 2; Ar1 is aryl or heteroaryl; R1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, hydroxyalkyl or hydroxycycloalkyl; and R2 is hydroxyalkyl, oxoalkyl or hydroxycycloalkyl.

2. The compound of formula I according to claim 1, having the formula II characterized in that m is from 0 to 4 each R3 is alkyl, halogen, alkoxy or haloalkyl; and R1 and R2 are as defined in claim 1.

3. The compound according to claim 1, characterized in that it is used as a therapeutically active substance. . A process for the preparation of a compound of formula I according to claim 1, characterized in that it comprises the reaction of a compound of formula If wherein R is alkyl of 1 to 6 carbon atoms and X1, Ar1 and R2 have the meanings defined in claim 1, with an amine of formula RX-NH2. 5. A compound of formula I according to claim 1, characterized in that it is prepared according to the method according to claim

4. 6. The use of a compound of formula I according to claim 1, for the preparation of a medication for the control or prevention of a disorder induced by p38 kinase. A composition, characterized in that it comprises a pharmaceutically acceptable excipient and a compound of formula I according to claim 1. 8. The use according to claim 6, wherein the disorder induced by p38 kinase is arthritis, Crohn's syndrome, irritable bowel syndrome, adult respiratory pain syndrome, chronic obstructive pulmonary disease, or Alzheimer's disease.