MXPA00010355A - Benzamide derivatives for the treatment of diseases mediated by cytokines - Google Patents

Abstract

The invention concerns amide derivatives of Formula (I) wherein:R1 and R2 include hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino and heterocyclyl;m and p are independently 0-3;R3 is halo, cyano or C1-6alkoxy;q is 0-4;and R4 is aryl or cycloalkyl wherein R4 is optionally substituted with up to 3 substituents having any value defined for each R1 group;or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof;processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

Description

BENZAMIDE DERIVATIVES FOR THE TREATMENT OF MEASURED DISEASES BY CYTOKINES DESCRIPTION OF THE INVENTION This invention concerns certain amide derivatives 5 which are useful as inhibitors of cytokine mediated diseases. The invention also concerns the processes for the manufacture of the amide derivatives of the invention, the pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of the inhibition of cytokine-mediated disease. The amide derivatives described in the present invention are inhibitors of the production of cytokines such as Tumor Necrosis Factor (hereinafter TNF), for example TNFa, and various members of the family of interleukins (hereinafter IL), for example IL-1, IL-6 and IL-8. Accordingly, the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive production of cytokines occurs, for example, excessive production of TNFa or IL-1.

It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they give rise to a variety of physiological effects that are believed to be important in disease or medical conditions such as inflammation and immunoregulation. For example, TNFa and IL-1 have been implicated in the cell signaling cascade * < £: which is believed to contribute to the pathology of the condition states such as inflammatory and allergic diseases and to cytokine-induced toxicity. It is also known that in certain cellular systems, the production of INFa precedes 5 and a half the production of other cytokines such as IL-1. Abnormal levels of cytokines have also been implicated in, for example, the production of physiologically active eicosanoids such as prostaglandmas and leukotrienes, stimulation of enzyme release proteolytic agents such as collagenase, activation of the immune system, for example by stimulation of the helper T cells, activation of osteoclast activity leading to calcium resorption, stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and angiogenesis. Cytokines are also believed to be involved in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the joints (especially arthritis). rheumatoid, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory disease of the bladder, ulcerative colitis, Crohn's disease, and gastritis), skin diseases (especially psoriasis, eczema and dermatitis) and respiratory diseases (especially asthma, bronchitis, allergic rhinitis and syndrome í ¿ti,! U »t.¿A - - - -" "*» '**' ** »'--- --- > ^^ .. A «iau, .- .., ... .. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ of adult respiratory distress), and the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, plaque aggregation, angina, attack, reperfusion wound, vascular wound including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis ( which includes senile and post-menopausal osteoporosis), Paget's disease, bone metastasis, hypercalcemia. hyperparathyroidism, osteosclerosis, osteoporosis and periodontitis, and abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excess production of cytokines has also been implicated in the mediation of certain complications of bacterial, fungal and / or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in the mediation of certain complications of CNS surgery or wounds such as neurotrauma and attack ischemic. Excessive cytokine production has also been implicated in the mediation or exacerbation of the development of diseases that involve the resorption of cartilage or muscle, pulmonary fibrosis, cirrhosis, renal fibrosis, cachexia found in certain chronic diseases such as malignant diseases, immunodeficiency syndrome i-jaMMfc- '' .. ^^^? ^^? ^^^. ^, - ^ .. v «.", "^ - ^" l'ÉaM ^^ acquired (AIDS), invasion of tumors and metastasis of tumors and multiple sclerosis. Evidence of the central role played by TNFa in the cellular signaling cascade which gives rise to rheumatoid arthritis is provided by the efficiency in clinical studies of TNFa antibodies (The Lancet, 1994, 344, 1125 and British Journal of Rheumatology , 1995, 34, 334). Thus, cytokines such as TNFa and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Accordingly, inhibition of the production of and / or effects of these cytokines is expected to be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions. Without wishing to imply that the compounds described in the present invention possess pharmacological activity only by virtue of an effect of a simple biological process, it is believed that the compounds inhibit the effects of cytokines by virtue of the inhibition of p38 enzyme kinase. The p38 kinase, otherwise known as cytokine suppressor binding protein (hereinafter CSBP) and reactivation kinase (hereinafter RK), is a kinase member of the mitogen-activated protein (hereinafter MAP). ) of the family of enzymes which is known to be activated by physiological stress such as induced "..... < -A, ¿¿¿¿¿¿¿¿¿¿¿by radiation of ionization, cytotoxic agents, and toxins, for example endotoxins such as bacterial lipopolysaccharide, and by a variety of agents such as cytokines, for example TNFa and IL-1. It is known that p38 kinase phosphorylates certain intracellular proteins which are involved in the cascade of enzymatic steps that leads to the biosynthesis and excretion of cytokines such as TNFa and IL-1. The known inhibitors of p38 kinase have been reviewed by G. J. Hanson in Expert Opinions on Therapeutic 10 Patents, 1997, 1_, 729-733. It is known that p38 kinase exists in isoforms identified as p38a and p38β. The compounds described in the present invention are inhibitors of the production of cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1. It is known from J. Med. Chem., 1996, 3_9, 3343-3356, that certain benzamide derivatives can upregulate the expression of the low density lipoprotein (LDL) receptor in human hepatocyte cells. The disclosed compounds include certain N- (2-methoxyphenyl) - and N- (2-halogenophenyl) -benzamide derivatives. The compound N- (5-benzamido-2-chlorophenyl) benzamide is described in J. Chem. Res. Synop., 1998, 182-183, 886-896 (Chemical Abstracts volume 129, abstract 67538). In accordance with an aspect of the present invention ^^^^ ¿^ ^ ^ ^ ^ Wfl¡3S < ^ Jg? Age¿ »fc ^ S ^^« a compound of Formula I is provided wherein: R1 and R2 which may be the same or different, are selected from hydroxy, C6-6 alkoxy, mercapto, C6-6 alkylthio, amino, C6-6 alkylamino, di- (alkyl) of C? _6) amino, carboxy, C? -6 alkoxycarbonyl, carbamoyl, C? -6 alkylcarbamoyl, C? -6 di-alkylcarbamoyl, C? -6 alkylsulfinyl, C? -6 alkylsulfonyl, arylsulfinyl, arylsulfonyl, ± -ß alkylaminosulfonyl, di- (C? _6) aminosulfonyl, nitro, cyano, C? -6 cyanoalkyl, C? _6 hydroxyalkyl, C? -6 aminoalkyl, C? -6 alkanoylamino, C? _6 alkoxycarbonylamino, alkanoyl of C? _6, C? -6 alkanoyloxy,? - alkyl, C2_6 alkenyl? C2-6 alkynyl, halo, trifluoromethyl, aryl, arylalkyl C? _6, C? _6 arylalkoxy, heteroaryl, C? _6 heteroarylalkyl, heterocyclyl and C? -6 heterocyclylalkyl; m and p are independently 0-3, and when m and / or p is 2 or 3 each group R1 or R2 may be the same or different; R3 is halo, cyano or C6-alkoxy, -20 q is 0-4; Y R 4 is aryl or cycloalkyl wherein R 4 is optionally substituted with up to 3 substituents having any defined value for each R 1 group; or a pharmaceutically acceptable salt or ester thereof capable of unfolding in vivo; with the proviso that: N- [5- (3-cyclohexylpropionylamino) -2-methoxyphenyl] -4-acetoxybenzamide, N- [2-bromo-5- (3-cyclohexylpropionylamino) phenyl] -4-hydroxybenzamide, N- [ 2-chloro-5- (3-cyclohexylpropionylamino) phenyl] -4-acetoxybenzamide, N- [2-chloro-5- (3-cyclohexylpropionylamino) phenyl] -4-hydroxybenzamide, N- [2-fluoro-5- (3 -cyclohexylpropionylamino) phenyl] -4-hydroxybenzamide and N- (5-benzamido-2-chlorophenyl) benzamide are excluded. "Aryl" in such terms as "aryl", "arylalkyl of C? -6", "arylthio", "arylsulfinyl", "arylsulfonyl" and "C6-arylalkoxy" typically means phenyl or naphthyl, preferably phenyl. "Heteroaryl" in the terms "heteroaryl" and "heteroarylalkyl of C? _6" means a ring of 5-10 mono or bicyclic aromatic members with up to five heteroatoms in the ring ,, r ^ ff ^ f ^^ selected from nitrogen, oxygen and sulfur. Examples of 'heteroaryl' include thienyl, pyrrolyl, furyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl. and cinolinyl, "Heterocyclyl" in the terms "heterocyclyl" and "heterocyclylalkyl of C? -6", means a ring of 5-10 mono or bicyclic members not aromatic with up to five heteroatoms in the ring selected from nitrogen, oxygen and sulfur. Examples of 'heterocyclyl' include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl and dihydropyrimidinyl. "Cycloalkyl" means a ring of 5-10 members of mono or bicyclic non-aromatic carbon. Examples of "cycloalkyl" include cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl and bicyclo [4.4.0] decyl. Typical values for other generic groups include: for C? _6 alkoxy, for example, methoxy and ethoxy, for C? _ Alqu alkylthio, for example, methylthio and ethylthio, for C \ alkylamino, for example, methylamino and ethylamino, for di- (alkyl) of Cx-β) amino, for example, dimethylamino, for C 6 -alkoxycarbonyl, for example, methoxycarbonyl and Ethoxycarbonyl, for Ci-e alkylcarbamoyl, for example, ethylcarbamoyl, for C 1-6 di-alkylcarbamoyl, for example, dimethylcarbamoyl, for C 1-6 alkylsulfinyl, for example, methylsulfinyl, for C 1-6 alkylsulfonyl, for example, methylsulfonyl, for alkylaminosulfonyl of -e, for example , methylaminosulfonyl, for di- (Ci-β) -amino-sulfonyl, for example, dimethylaminosulfonyl, for cyanoalkyl of C? _6, for example, cyanomethyl, for hydroxyalkyl of C ± -? , for example, hydroxymethyl, for aminoalkyl of C? _6, for example, aminomethyl, for C? _6 alkanoylamino, for example, formamido and acetamido, for C? -6 alkoxycarbonylamino, for example, methoxycarbonylamino, for C-alkanoyl ? 6, for example, formyl and acetyl, for C? _6 alkanoyloxy, for example, acetoxy, for C? -6 alkyl, for example, methyl, ethyl, isopropyl and tert-butyl, for C2_6 alkenyl, for example, vinyl and allyl, for C2_6 alkynyl, for example, ethynyl and 2-propynyl, for halo, for example, fluoro, chlorine and bromine, for arylalkyl of C6-6, for example, benzyl, and for arylalkoxy of C? _6, for example, benzyloxy. Any ring in R1 or R2 or any ring in a substituent on R4 may be optionally substituted, for example by up to 3 substituents. Suitable substituents include: hydroxy, C? _6 alkoxy, mercapto, C? -6 alkylthio, amino, C? -6 alkylamino, di- (Ci-Xalkyl amino, carboxy, carbamoyl, C-alkylcarbamoyl? _6, say j ^ sii ^^^^^ ^^^^ i ^^^^^ to ^^^ ^^^^ Wj ^^^^^ i ^^ M? uA? mWWS3á »* áí? * ~~? tt * ta¿, ¿¿¿¿¿¿¿¿¿¿¿¿¿¿2 C-6 alkylcarbamoyl, Cs alkylsulfinyl, C? _6 alkylsulfonyl, arylsulfinyl, arylsulfonyl, C? _6 alkylaminosulfonyl, di- (C? ) - aminosulfonyl, nitro, cyano, cyanoalkyl of C? -6,5 hydroxyalkyl of C? -6, aminoalkyl of C? _6, alkanoylamino of C? -6, alkoxycarbonylamino of C? -6, alkanoyl of C? _6, alkanoyloxy of C? -6, C? -6 alkyl, C2_6 alkenyl, C2-6 alkynyl, halo and trifluoromethyl. In this specification the generic term "Alkyl" includes straight chain and branched chain alkyl groups. However, references to individual alkyl groups such as "propyl" are specific to the straight chain version only and references to individual branched chain alkyl groups such as "isopropyl" are specific to the branched chain version only. A similar convention applies to other generic terms. It should be understood that, with respect to certain of the compounds of Formula I defined above, If it exists in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any optically active or racemic form which possesses the property of inhibiting cytokines, in particular TNF. The synthesis of the forms optically can be carried out by standard techniques of the * aaSfttiafeáBg.fe ^? * ¡á ^ ¿&G? á £? &? Organic chemistry well known in the art, for example by synthesis of optically active starting materials or by resolution of a racemic form. Similarly, the inhibitory properties found of TNF can be evaluated using the standard laboratory techniques referred to below. Preferably R1 is hydroxy, C6-6 alkoxy, amino, C6-6 alkylamino, di- (C6-6alkyl) amino, carboxy, C6-6alkoxycarbonyl, carbamoyl, C6-6alkylcarbamoyl, cyano, C? -6 alkanoylamino, C? -6 alkanoyl, C? -6 alkanoyloxy, C? _6 alkyl, halo, trifluoromethyl or heterocyclyl. More preferably R1 is aminoalkyl of C? -6. More preferably R1 is hydroxy, C6-6 alkoxy, cyano, halo, morpholino or 4-methylpiperazin-1-yl. Preferably m is 1 or 2. Conveniently p is 1 and R 2 is C 1-6 alkoxy, carboxy, C 1 -6 alkoxycarbon, C 6 alkyl or halo. Preferably p is 0. Preferably R3 is halo. Preferably q is 0, 1 or 2. More preferably q is 0. Preferably R 4 is phenyl, cyclohexyl or cyclopentyl. More preferably R4 is phenyl. Preferred substituents on R4 are hydroxy, - ^^^ > j ^ ^ Sjj ^^ ®? ^^ á & ^^^ i¡! ^? * C6-6 alkoxy, amino, C? -6 alkylamino, di- (C? e alkyl) amino, carboxy, C6_6 alkoxycarbonyl, nitro, cyano, C6_6 alkanoylamino, C6_6 alkanoyl, C6_6 alkanoyloxy, C6_6 alkyl, halo, trifluoromethyl, phenyl, C6_6 phenylalkoxy and heterocyclyl. The most preferred substituents on R 4 are selected from hydroxy, cyano, dimethylamino, methoxy, ethoxy, fluoro, chloro and morpholino. Particular novel compounds of the invention include, for example, amide derivatives of Formula I, or pharmaceutically acceptable salts thereof, subject to the exclusions defined below, wherein: (a) R 1 is hydroxy, C 6 alkoxy , amino, C? -6 alkylamino, di- (C? _6 alkyl) amino, carboxy, C? -6 alkoxycarbonyl, nitro, cyano, C? _6 hydroxyalkyl cyanoalkyl, C? _6 aminoalkyl, C? 6, C? _6 alkanoylamino, C? -6 alkoxycarbonylamino, C? _6 alkanoyl, C? _6 alkanoyloxy, C? _6 alkyl, halo, or trifluoromethyl, and m is 1 or 2; and R2, R3, R4, p and q have any of the meanings defined below or in this section related to the particular novel compounds of the invention; (b) R is a saturated non-aromatic 5- or 6- membered heterocyclic ring with one or two heteroatoms selected from nitrogen, oxygen and sulfur, and m is 1 or 2; and R2, R3, R4, P and q have any of the meanings defined above or in this section related to the particular novel compounds of the invention; 5 (c) R1 is a saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and 4- (Ci-β) piperazinyl alkyl, and m is 1 or 2; and R2, R3, R4, p and q have any of the meanings defined above or in this section related to the particular novel compounds of the invention; (d) R2 is hydroxy, C6-6 alkoxy, amino, C6-6 alkylamino, di- (C6-6 alkyl) amino, carboxy, C6-6 alkoxycarbonyl, nitro, cyano, C-alkyl? _6, halo or trifluoromethyl, and p is 1; and R1, R3, R4, m and q have Any of the meanings defined above or in this section related to the particular novel compounds of the invention; (e) p is 0; and R1, R3, R4, m and q have any of the meanings defined above or in this section related to the particular novel compounds of the invention; (f) R3 is halo; and R1, R2, R4, m, p and q have any of the meanings defined above or in this section related to the novel compounds of the invention; (g) q is 1, 2, 3 or 4, and R 4 is cycloalkyl; and R1, R2, R3, m and p have any of the meanings defined above or in this section related to the particular novel compounds of the invention; 5 (h) q is 0, and R 4 is phenyl which is optionally substituted with up to 3 substituents selected from hydroxy, C? _6 alkoxy, amino, C? -6 alkylamino, di- (Ci-e alkyl) amino , carboxy, C? -6 alkoxycarbonyl, nitro, cyano, C? -6 alkoxycarbonylamino, C? -6 alkanoyl, C? -6 alkanoyloxy, C? -6 alkyl, halo, trifluoromethyl, phenyl, benzyl and benzyloxy; and R1, R2, R3, m and p have any of the meanings defined above or in this section related to the particular novel compounds of the invention; 15 (i) q is 0, and R4 is phenyl which is substituted with 1 or 2 substituents selected from heteroaryl, C6-heteroarylalkyl, heterocyclyl and C6-6 heterocyclylalkyl, and R1, R2, R3, and p have any of the meanings defined above or in this section related to the particular novel compounds of the invention; (j) q is 0, and R 4 is phenyl which is substituted with 1 or 2 heterocyclyl groups comprising a saturated 5- or 6- non-aromatic heterocyclic ring with 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur; and R1, R2, R3, m and p have any of the meanings defined above or in this section related to the particular novel compounds of the invention; and (k) q is 0, and R4 is phenyl which is substituted with 1 or 2 heterocyclic groups selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and 4- (Ci-e alkyl) piperazinyl; and R1, R2, R3, m and p have any of the meanings defined above or in this section related to the particular novel compounds of the invention. A preferred compound of the invention is an amide derivative of Formula I wherein R 1 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl. , cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or 4-methylpiperazin-1 -ilo; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is l, 2 6 3; and R is cyclohexyl or cyclopentyl; ¿Ü ^ g ^^^^^^^^ «^^^^^ ^ ¿^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ Or a pharmaceutically acceptable salt thereof. A further preferred compound of the invention is an amide derivative of Formula I wherein R 1 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl. , cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or 4-methylpiperazin-1 -ilo; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 0; and R 4 is phenyl which is optionally substituted with 1 or 2 substituents selected from hydroxy, methoxy, ethoxy, propoxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, nitro, cyano, acetamide, acetyl, acetoxy, methyl, ethyl, fluoro, chloro, bromine, trifluoromethyl, phenyl, benzyloxy, pyrrolidin-1-yl, morpholino, pipepdino, p-perazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. A further preferred compound of the invention is an amide derivative of Formula I wherein R 1 is hydroxy, methoxy, ethoxy, cyano, fluoro, chloro, morpholino or 4-methylpiperazin-1-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 0; and R 4 is phenyl which is substituted with 1 or 2 substituents selected from hydroxy, methoxy, dimethylamino, methoxycarbonyl, cyano, fluoro, chloro and morpholino; or a pharmaceutically acceptable salt thereof. A further preferred compound of the invention is an amide derivative of Formula I wherein R 1 is hydroxy, methoxy, ethoxy, amino, cyano, acetoxy, fluoro, chloro, morpholino or 4-methylpiperazin-1-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 0; and R 4 is phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from hydroxy, methoxy, amino, dimethylamino, methoxycarbonyl, nitro, cyano, fluoro, chloro and morpholino; or a pharmaceutically acceptable salt thereof. Particular preferred compounds of the invention include, for example: N- [2-chloro-5- (3-cyanobenzamido) phenyl] -3,4-dimethoxybenzamide N- [2-chloro-5- (3-dimethylaminobenzamido) phenyl] -3, -dimethoxybenzamide, N- [2-chloro] -5- (4-cyanobenzamido) phenyl] -3,4-dimethoxybenzamide and 5 N- [2-chloro-5- (4-cyanobenzamido) phenyl] -3- (4-methylpiperazin-1-yl) benzamide; or the pharmaceutically acceptable salts thereof. Additional particular preferred compounds of the invention include, for example: 10 N- (5-benzamido-2-chlorophenyl) -3,4-dimethoxybenzamide, N- [2-chloro-5- (3-morpholinobenzamido) phenyl] -3 4-dimethoxybenzamide, N- [5- (4-acetoxybenzamido) -2-chlorophenyl] -4-cyanobenzamide, N- (5-benzamido-2-chlorophenyl) -2-amino-4-methoxybenzamide and 15 N- [2-chloro-5- (3-morpholinobenzamido) phenyl] -4-cyanobenzamide; or the pharmaceutically acceptable salts thereof. A suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid addition salt of a compound of Formula I which is sufficiently basic, for example an acid addition salt with an inorganic or organic acid as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of Formula I which is sufficiently acidic, for example an alkaline or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 4_2, p. 309-396, edited by K. Idder, et al. (Academic Press, 1985); 10 b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5"Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8_, 1-38 15 (1992); d) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al. , Chem Pharm Bull, 32, 692 (1984). Examples of such prodrugs can be used to form esters capable of unfolding in vivo or a compound of Formula I. An ester capable of unfolding m vivo from a compound of Formula I containing a carboxy group is, for example, an ester pharmaceutically acceptable which is unfolded in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters ^ "^^^^, .." ^^ .. ^ ^ i - ^^^ .. ..... ^^ i ^ SiSfeá ^ for carboxy include alkoxymethyl esters of C? -6, for example methoxymethyl; alkanoyloxymethyl esters of C? _6, for example pivaloyloxymethyl; phthalidyl esters; C3-8 cycloalkoxycarbonyloxy esters of C? _6 alkyl, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, for example 5-methyl-l, 3-dioxolan-2-ylmethyl; and alkoxycarbonyloxyethyl esters of C? -6, for example 1-methoxycarbonyloxyethyl; and can be formed in any carboxy group in the compounds of this invention. To use a compound of Formula I or a pharmaceutically acceptable salt or ester capable of cleaving in vivo thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. In accordance with this aspect of the invention, there is provided a pharmaceutical composition which comprises an amide derivative of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, as defined above in association with a pharmaceutically acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (e.g. as tablets, dragees, hard or soft capsules), aqueous or oily suspensions, emulsions, powders or dispersible granules, syrups or elixirs), for local use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a powder) finely divided or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for dosing rectally). The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, the compositions desired for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid.; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. The tablet formulations may be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract or to improve their stability and / or appearance, in each case, using conventional coating methods and agents well known in the art. technique. The compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in the which active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in a finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum: dispersing agents or humectants such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or Rite-a condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or products of condensation of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylenesorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (such as sucrose, saccharin or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .Olose suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol The sweetening agents such as those previously provided, and the flavoring agents can be added to provide a pleasant oral preparation.

These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives. The dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as for example liquid paraffin or a mixture of any of them. Suitable emulsifying agents may be, for example, naturally occurring gums such as acacia gum or tragacanth gum, naturally occurring phosphatides such as soy, lecithin, an ester or partial esters derived from fatty acids and hexitol anhydrides (monooleate of sorbitan) and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. | ^ jgjj ^ MÉ tmZ- ^ K ^ ... ^^ Á M ^ Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain an emollient, preservative, flavoring and / or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. The local formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions. They can generally be obtained by formulating an active ingredient with a conventional locally acceptable carrier or diluent using conventional procedures well known in the art. The compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 μm or much less, the powder itself comprises the active ingredient alone or diluted with one or more carriers physiologically acceptable such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example 1 to 50 mg of the active ingredient for use with a turbo-inhaler device, such as that used for insufflation of the known sodium cromoglycate agent. The compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient as an aerosol containing finely divided solid or drops of liquid. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used and the aerosol device is conveniently arranged to dispense a measured amount of the active ingredient. For additional information on the formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a simple dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a desired formulation for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of active agent compound with an appropriate and convenient amount of excipients which may vary from about 5 to about 98% by weight of the total composition. The unit dosage forms will generally contain about 1 mg to about 500 mg of an active ingredient. For additional information on Administration Routes and Dosing Regimens the reader is referred to Chapter 25.3 in Volume 5 of the Comprehensive Medicinal Chemistry (CorHansch; Chairman of the Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic or prophylactic purposes a compound of Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine. Using a compound of Formula I for therapeutic or prophylactic purposes will be administered in such a way that a daily dose in the range, for example, 0.5 mg to 75 mg per kg of body weight is received, if required in divided doses. In general, lower doses will be administered when a parenteral route is used. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg of body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg of body weight will be used. However, oral administration is preferred, particularly in the form of a tablet. Typically, the unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. According to a further aspect of the invention there is provided an amide derivative of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, as defined above for use in a method of treating the human body or animal for therapy. According to a further aspect of the invention there is provided the use of an amide derivative of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, as defined above or any of those known compounds excluded from the definition of the compounds of the invention in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by cytokines, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. or an ester capable of unfolding in vivo thereof. In a further aspect the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, in the manufacture of a medicament for use in the treatment of diseases or conditions mediated by TNF, IL-1, IL-6 or IL-8. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of the invention. Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof. In a further aspect, the present invention provides the use of a compound of Formula I, or a salt - «? Egi§s > fc »and pharmaceutically acceptable or an ester capable of unfolding in vivo thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by TNF, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof. In a further aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of cleaving in vivo thereof, in the manufacture of a medicament for use to inhibit TNF, IL- 1, IL-6 or IL-8. In a further aspect, the present invention provides a method for inhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a salt thereof. pharmaceutically acceptable or an ester capable of unfolding in vivo thereof. In a further aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, in the manufacture of a medicament for -; to £ < «£ & *% -« - & Use to inhibit TNF. In a further aspect, the present invention provides a method of inhibiting TNF which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof. . In a further aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions. mediated by p38 kinase. In a further aspect, the present invention provides a method for treating diseases or medical conditions mediated by p38 kinase which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or an ester able to unfold in vivo of the same. In a further aspect, the present invention provides the use of a compound of Formula 1, or a pharmaceutically acceptable salt or ester capable of unfolding in vivo thereof, in the manufacture of a medicament for use in the production of an inhibitory effect. of p38 kinase. In a further aspect, the present invention .. ^^^ s¿ -.- ^ ..., -, ^;, J, -., ... ^, r ^ m S ísm »tí ím ^ i < ^^ &? ^^^ im provides a method for providing an inhibitory effect of p38 kinase which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or an ester able to unfold in vivo of the same. In a further aspect the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, asthma. , irritable bladder disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease or psoriasis. In a further aspect the present invention provides a method for treating rheumatoid arthritis, asthma, irritable bladder disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease or psoriasis which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof. The compounds of this invention can be used in combination with other drugs and therapies used in the treatment of conditions of disease that would benefit from the inhibition of cytosines, in particular TNF and IL-1. For example, the compounds of the formula I can be used in j = «feeas¡a-aS« »M- &ie combination with drugs and therapies used in the treatment of rheumatoid arthritis, asthma, irritable bladder disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease, psoriasis and other conditions of affection 5 mentioned earlier in this specification. For example, by virtue of their ability to inhibit cytosines, the compounds of Formula I are of value in the treatment of certain inflammatory and non-inflammatory diseases which are commonly treated with cyclooxygenase inhibitory non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, ketorolac, acetylsalisilic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of a compound of Formula I with an NSAID may result in a reduction in the amount of the last agent needed to produce a therapeutic effect. This reduces the possibility of an adverse side effect of the NSAID such as gastrointestinal effects. Thus, according to a further feature of the invention, a composition is provided Pharmaceutical which comprises a compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo thereof, in conjunction or mixtures with a nonsteroidal anti-inflammatory agent inhibiting cyclo-oxygenase, and a diluent or carrier pharmaceutically acceptable.

The compounds of the invention can also be used with anti-inflammatory agents such as an inhibitor of the enzyme 5-lipoxygenase (such as those described in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680). The compounds of Formula I can also be used in the treatment of conditions such as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate, steroids and penicillinamine, and under conditions such as osteoarthritis in combination with steroids. The compound of the present invention can also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, antidegradant and / or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril. The compounds of Formula I can be used in the treatment of asthma in combination with antiasthmatic agents such as bronchodilators or leukotriene antagonists. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within their range of approved dosage. Sequential use is contemplated when a combination formulation is inappropriate. Although the compounds of Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful regardless of when inhibiting the effects of cytosine is required. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. An amide derivative of Formula I, or a pharmaceutically acceptable salt or an ester capable of cleaving in vivo thereof, can be prepared by any process known to be applicable to the preparation of chemically related compounds. Suitable processes are illustrated by, for example, those used in J. Med. Chem., 1996, 39, 3343-3356. Such processes, when used to prepare a novel amide derivative of Formula I are provided as a further feature of the invention and illustrated by the following representative variants of the process in which, unless otherwise stated, R1, R2, R3, R4, m, p and q have any of the meanings defined above. The necessary initial materials can be obtained by standard procedures of organic chemistry. 25 The preparation of such initial materials is described ,, & ^ "f ^^. ^ p tÉf¡fÉÉlfii? (srt x? ^^^ 'i ^ &'? ^ - ^^^^^ a together with the following representative variants of the process and within the accompanying examples.Alternatively the necessary initial materials are obtained by procedures analogous to those illustrated 5 which are within the ordinary skill of an organic chemist (a) a compound of Formula I, or a pharmaceutically acceptable salt or ester capable of unfolding in vivo thereof you can be prepared by reacting 1 October aniline of Formula II with an acid of Formula III Formula III or an activated derivative thereof, under standard amide-forming conditions, wherein the variable groups are as defined above and wherein any functional group is protected, if necessary, and: (i) eliminate any protective groups; (ii) optionally forming a pharmaceutically acceptable salt or an ester capable of unfolding in vivo. A suitable activated derivative of an acid of Formula III is, for example, an acyl halide, for example 5 an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example, an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example a The ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentaflorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; an azide acyl, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphorylazide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodimide such as dicyclohexylcarbodiimide. The reaction is preferably carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, hydroxide potassium, sodium hydride, or potassium hydride, or an organometallic base such as a í, -5 * £ * fl fr "^^ alkyl lithium, for example n-butyllithium, or dialkylamino- lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as , for example, pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, 5 triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene. The reaction is also preferably carried out in a solvent or diluent suitable, for example tetraidrofurano, 1, 2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, N-dimethyl-pyrrolidin-2-one, dimethyl sulfoxide or acetone 10 and at a temperature in the range, for example, -78 ° to 150 ° C, conveniently at or near ambient temperature Typically a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature for example in the region -10 to 40 ° C, typically at room temperature of about 20 ° C. The protective groups can generally be chosen of any of the groups described in the literature or known to the expert chemists as appropriate for the protection of the group in question and can be introduced by conventional methods. Protective groups can be eliminated by any convenient method as described in the literature or known to the expert chemist as is suitable for removing the protective group in question, such methods being chosen to effect the removal of the protecting group with minimal perturbation of the groups in another part of the molecule. Specific examples of protecting groups are given subsequently for convenience, in which "lower", as in, for example, lower alkyl, means that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods are given for the removal of protecting groups subsequently these are similarly non-exhaustive. The use of deprotection protective groups and methods not specifically mentioned is, of course, within the scope of the invention. A carboxy protecting group can be the residue of an ester-forming aliphatic or arylaliphatic alcohol or an ester-forming silanol (the alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain C (_? Alquilo alquilo grupos grupos alkyl groups (eg, isopropyl, tert-butyl); lower alkyl, lower alkoxy groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); aliphatic lower alkyl acyloxy groups Lower, (for example acetoxymethyl, propionyloxymethyl, , <tb> aatJM1 '- <i> WM iS a? mKl? l ** ^ * butyryloxymethyl, pivaloyloxymethyl); lower alkyl lower alkoxycarbonyloxy groups (for example 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); lower alkyl aryl groups (for example benzyl, p-methoxybenzyl, 5-nitrobenzyl, γ-nitrobenzyl, benzhydryl and phthalidyl); tri (lower alkyl) silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); lower alkyl groups tri (lower alkyl); silyl (for example trimethylsilylethyl); and C2_6 alkenyl groups (e.g. allyl and vinylethyl). Particularly suitable methods for the removal of carboxyl protecting groups including, for example, acid-, base-, metal- or enzymatically-catalyzed hydrolysis. Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); groups Lower alkenyloxycarbonyl (for example allyloxycarbonyl); lower alkoxycarbonylaryl groups (for example benzoyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); lower trialkylsilyl groups (for example trimethylsilyl, tert-butyldimethylsilyl) and lower alkylaryl (for example benzyl). Examples of amino protecting groups include fornyl, aralkyl (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); lower alkoxycarbonylaryl group (for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl) alkylidene (for example methylidene), benzylidene and substituted benzylidene groups Suitable methods for the elimination of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymatically catalyzed hydrolysis for groups such as p_-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl. is referred to in Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. The reader is referred to in Protective Groups in Organic Synthesis, 2nd Edition, by Green et al. , published by John Wiley & Sons for guide g ^ ^^^^^^^^ general about protection groups. The aniline of Formula II can be prepared by reduction of the corresponding nitro compound of Formula IV.

Typical reaction conditions include the use of ammonium formate in the presence of a catalyst (for example palladium on carbon) in the presence of an organic solvent (preferably a polar protic solvent), preferably with heating, for example up to about 10 60 ° C. Any functional group is protected and checked out as necessary. The compound of Formula IV can be prepared by reaction of an acid of Formula V, or an activated derivative thereof, Formula V 15 with an aniline of Formula VI under suitable conditions to form amide bond. rmua Typical conditions include activating the carboxy group of the compound of Formula V for example by treatment with a halogenated reagent (for example oxalyl chloride) to form an acyl halide in an organic solvent at room temperature, then reacting the activated compound with the aniline of Formula VI. Any functional group is protected and checked out as necessary. (b) A compound of Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding 0 in vivo thereof, can be prepared by reacting an acid of Formula V.

Formula V or an activated derivative thereof as defined above, with an aniline of Formula VII If the standard conditions for forming an amide bond, the variable groups are as defined above and where any functional group is protected, if necessary, and: 5 (i) elimination of any group protective; (ii) optionally forming a pharmaceutically acceptable salt or an ester capable of unfolding in vivo. The aniline of Formula VII can be prepared by reduction of the corresponding nitro compound using convention procedures as defined above or as illustrated in the Examples. (c) A compound of Formula I wherein R 1 or a substituent on R 4 is an amino group, can be prepared by the reduction of a compound of Formula I wherein R 1 or a substituent on R 4 is a nitro group. Typical reaction conditions include the use of ammonium formate or hydrogen gas in the presence of a catalyst, for example a metal catalyst such as palladium on carbon. Alternatively it can be carried out a reduction of dissolution of metal, for example using iron in the presence of an acid, for example an inorganic or organic acid such as hydrochloric acid, sulfuric acid or acetic acid. The reaction is conveniently carried out in the presence of an organic solvent (preferably a polar protic solvent) and preferably with heating, for example up to about 60 ° C. Any functional group is protected and checked out as necessary. The following biological assays and Examples serve to illustrate the present invention. Biological Assays The following assays can be used to measure the inhibitory effects for p38 kinase, inhibitors for TNF and anti-arthritics of the compounds of the present invention: Enzyme assay in vitro The ability of compounds of the invention to inhibit the p38 kinase enzyme was assessed . The activity of particular test compounds against each of the p38a and p38β isoforms of the enzyme was determined. Human recombinant MKK6 was isolated (GenBank Accession Number G1209672) of clone Image 45578 (Genomics, 1996, 33, 151) and was used to produce protein in the form of a GST fused protein in a pGEX vector using procedures analogous to those described by J. Han et al, Journal of Biological Chemistry, 1996, 271, 2886-2891.

^^ »--..--- .- = -" ** "M« ^^ - '- - ja it ^^ * ^ »***, ^ *****» p38a (GenBank Accession Number G529039 ) and p38β (GenBank Accession Number G1469305) was isolated by PCR amplification of human lymphoblastoid cDNA (GenBank Accession Number GM1416) and human fetal brain cDNA [synthesized from mRNA 5 (Clontech, catalog number 6525-1) using a computer for Gibco-overwritten cDNA synthesis] respectively using oligonucleotides designed for the 5 'and 3' ends of the human p38a and p38β genes using methods analogous to those described by J.Han et. al, Biochimica et Biophysica Acta, 1995, 1265, 224-227 and Y. Jiang et al., Journal of Biological Chemistry, 1996, 271, 17920-17926. Both isoforms of the p38 protein would be expressed in E. coli in PET vectors. The human recombinant isoforms p38a and p38β were produced as 5'-labeled proteins c-myc, 6His. Both MKK6 and p38 proteins were purified using standard protocols: GST MKK6 was purified using a cepharose-glutathione column and p38 proteins were purified using nickel-chelated columns. The p38 enzymes were activated before being used by incubation with MKK6 for 3 hours at 30 ° C. The inactivated MKK6 expressed in coli retained sufficient activity to fully activate both isoforms of p38. The incubated activation comprises p38a (lOμl of lOmg / ml) or p38β (lOμl of 5mg / ml) together with MKK6 (lOμl of lmg / ml), kinase "[lOOμl; pH 7.4 comprising Tris (50mM), EGTA (0.1 mM), sodium orthovanadate (O.lmM) and ß-mercaptoethanol (0.1%)] and MgATP (30μl of 50mM Mg (0C0CH3) 2 and 0.5mM ATP). This produces enough p38 enzyme activated for 3 microtiter plates. The test compounds were solubilized in DMSO and lOμl of a sample diluted 1:10 in "Kinase Regulator" was added to a well in a Microtiter plate. To test a single dose, the compounds were tested at 10 μM. "The Kinase Assay Mixture" [30μl; comprising Myelin Basic Protein (Gibco BRL catalog No. 1322B-010; 1 ml of a 3.33 mg / ml solution in water), activated p38 enzyme (50μl) and "Kinase Regulator" (2ml)] was then added followed for "Marked ATP" [lOμl; comprising 50μM of ATP, 0.1μCi33P ATP (Amersham International catalog No. BF1000) and 50mM Mg (OCOCH3) 2]. Plates were incubated at room temperature with gentle shaking. The plates containing p38a were incubated for 90 min and the plates containing p38β were incubated for 45 min. Incubation was stopped by the addition of 50μl of 20% trichloroacetic acid (TCA). Precipitated protein was phosphorylated with p38 kinase and the test compounds were assessed for their ability to inhibit this phosphorylation. The plates were filtered using a Canberra Packard Unifilter and washed with 2% TCA, dried overnight and counted in a Top Count scintillation counter. The test compounds were initially tested at a single dose and the active compounds failed to allow the IC50 values to be determined. In vitro cell-based assays (i) PBMC 5 The ability of the compounds of this invention to inhibit the production of TNFα by using human peripheral blood mononuclear cells which synthesize and secrete TNFα when stimulated with lipopolysaccharide was evaluated. 10 Peripheral blood mononuclear cells (PBMC) were isolated from heparanised human blood (10 units / ml heparin) by centrifugation (Lymphoprep ™, Nycomed). The mononuclear cells were resuspended in a culture medium [RPMI 1640 medium (Gibco) supplemented with 50 units / ml of penicillin, 50μg / ml of streptomycin, 2mM of glutamine and 1% of human AB serum inactivated by heat (Sigma H-1513)]. The compounds were solubilized in DMSO at a concentration of 50mM, diluted 1: 100 in a culture medium and serially dilutions were made in series. culture medium containing 1% DMSO. The PBMCs (2.4xl05 cells in 160μl of culture medium) were incubated with 20μl of various concentrations of the test compound (triplicate cultures) or 20μl of culture medium containing 1% DMSO (control wells) for 30 minutes at 37 ° C. in a humidified incubator (5% C02 / 95% air); (Falcon 3072; 96 well flat bottom tissue culture plates). 20μl of lipolisácarido [LPS E. Coli 0111: B4 (Sigma L-4130), final concentration lOμg / ml] solubilized in a culture medium were added to the appropriate wells. 20μl of culture medium were added to control wells "only with medium" six controls of "Only with LPS and four" only with medium "were included in each 96-well plate, Various concentrations of a known TNFa inhibitor were included in each test, ie an inhibitor in the PDE Type IV enzyme (for example see Semmler, J. Wachtel, H and Endres, S., Int. J. Immunopharmac. (1993), 1_5 (3), 409-13) or a ProTNFa convertase inhibitor (e.g., see McGeehan, GM et al., Nature (1994) 370, 558-561) The plates were incubated for 7 hours at 37 ° C (humidified incubator) after which lOOμl of the supernatant was removed. from each well and stored at -70 ° C (96 well round bottom plates; Corning 25850). TNFa levels were determined in each sample using a human TNFα ELISA (see WO92 / 10190 and Current Protocols in Molecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley and Sons Inc.)% inhibition = (LPS alone -mediate only) - (test concentration-medium only) x 100 (single-medium LPS only) (ii) Whole Human Blood The ability of the compounds of this invention to inhibit the production of TNFa was also assessed in a toJtfJfc ^ a > .. "- *" '^ "^^^^ human whole blood assay Blood Whole human TNFa secreted when stimulated with LPS This property of blood forms the basis of an assay which is used as a secondary test for compounds which were profiled as active in the PBMC test, heparinized human blood (10 units / ml) obtained from volunteers was obtained, 160μl of whole blood was added to 96-well round bottom plates (Corning 25850). diluted in series in RPMI 1640 (Gibco) supplemented with 50 units / ml penicillin, 50 ug / ml streptomycin and 2mM of glutamine, as detailed above. 20μl of each test concentration was added to the appropriate wells (triplicate cultures). 20μl of an RPMI 1640 medium was added supplemented with antibiotics and glutamine to the control wells. The plates were incubated for 30 minutes at 37 ° C (humidified incubator), before the addition of 20 μl of LPS (final concentration of 10 μg / ml). An RPMI 1640 medium was added to the control wells. Six "only with LPS" were included and four "only with half" on each plate. A known inhibitor of synthesis / secretion of TNFa was included in each test. The plates were incubated for 6 hours at 7 ° C (humidified incubator). Plates were centrifuged (2000rpm for 10 minutes) and lOOμl of plasma was removed and stored at -. 25 -70 ° C (Corning plates 25850). TNFa levels were measured aa¿ > ** tttjH > "A '" s¿ * i **? ~ I * ~~. Z., ^. ^. «AaáSfa ^; ^^ by ELISA (see W092 / 10190 and Current Protocols in Molecular Biology. Vol 2 by Frederick M Ausbel et al., John Wiley and Sons Inc.) Paired antibodies that were used in the ELIZA were obtained from R & D Systems (anti-human TNFa coating antibody catalog number MAB610, anti-TNFa detection antibody -human biotinylated BAF210) Ex vivo / ln vivo titration The capacity of the compounds of this invention as ex vivo inhibitors of TNFα was assessed in the rat or mouse. Briefly, groups of male Wistar Alderley Park rats (AP) rats (180-210g) were dosed with compound vehicle (6 rats) or drug (10 rats) by the appropriate route, for example peroral (po), intraperitoneal (ip) or subcutaneous (s.c.). Ninety minutes later rats were sacrificed using a rising concentration of C02 and bled via the posterior vena cavae into 5 Units of sodium heparin / ml blood. The blood samples were immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4 ° C and the harvested plasmas frozen at -20 ° C for subsequent to their effect on TNFa production by LPS-stimulated human blood assay. The rat plasma samples were thawed and 175μl of each sample was added to a standard fixed on a plate round bottom 96 wells (Corning 25850). 50μl of blood heparinized human were then added to each well, mixed and the plate incubated for 30 minutes at 37 ° C (humidified incubator). LPS (25μl, final concentration of 10μg / ml) was added to the wells and incubation continued for an additional 5.5 hours. The control wells were incubated with 25μl of media alone. The plates were then centrifuged for 10 min at 2000 rpm and 200 ul of the supernatants were transferred to a 96 well plate and frozen at -20 ° C for subsequent analysis of TNF concentration by ELISA 10. Data analysis by dedicated software calculates for each compound / dose: ° TNF inhibition = mean TNFa (Controls) - Less TNFa (Treated) x 100 TNFa Media (Controls) 15 Alternatively, mice could be used instead of rats in the previous procedure. Testing as an anti-arthritic agent The activity of a compound as an anti-arthritic agent was tested as follows. Native type II collagen soluble in acid showed to be by Trentham et al. [1] arthritogenic in rats; this caused polyarthritis when administered in incomplete Freunds adjuvants. This is now known as collagen-induced arthritis (CIA) and similar conditions can be induced in mice and primates.

Recent studies have shown that monoclonal antibodies jj ^ ggggé ^^^ j ^ gg ^ ¡^^^ jggjg ^ i ^ s ^ jg ^^ g &? ^ g ^ fé ^ ZL ^. anti-TNF [2] and protein-as [3] fused IgG-TNF receptor enhance the established CIA indicating that TNF plays a major role in the pathophysiology of CIA. In addition, the remarkable reported efficiency for anti-TNF monoclonal antibodies in clinical trials of recent rheumatoid arthritis indicate that TNF plays a major role in this chronic inflammatory disease. Thus the CIA in DBA / 1 mice as described in references 2 and 3 is a tertiary model which can be used to demonstrate the anti-arthritic activity of a compound. See also reference 4. 1. Trentham, D.E. et al. , (1977) J. Exp. Med., 146, 857. 2. Williams, R. O. et al. , (1992) Proc. Nati Acad. 15 Sci., 8_9, 9784. 3. Williams, R.O. et al. , (1995) Immunology, 8, 433. 4 Badger, M. B. et al. , (1996) The Journal of Pharmacology and Experimental Therapeutics, 279, 1453-1461. Although the pharmacological properties of the compounds of Formula I vary with the structural change as expected, in general a compound of Formula I gives about 30% inhibition in the PBMC test at concentrations up to 50μM. No toxicity was observed physiologically unacceptable at the effective dose for ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The invention will now be illustrated in the following non-limiting Examples in which, unless stated otherwise: 5 (i) the operations were carried out at room temperature, i.e. in the range of 17 to 25 ° C and under an atmosphere of an inert gas such as argon unless otherwise stated; (ii) the evaporations were carried out by rotary evaporation in vacuo and the working procedures were carried out after the removal of residual solids by filtration; (iii) column chromatography (by the instantaneous method) and medium pressure liquid chromatography (MPLC) were performed on silica Merck Kieselgel (Art. 9385) or reverse phase silica Merck Lichroprep RP-18 (Art. 9303) obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) was carried out in C18 reverse phase silica, for example on a Dynamax C-18 60A preparative reverse phase column; (iv) the returns are given only for illustration and are not necessarily the maximum obtainable; (v) in general, the final products of the Formula I have satisfactory microanalyses and their structures are confirmed by nuclear magnetic resonance techniques * -te * a ^^^ ... ^^^. ~ ^^^ ¡^ &^^ m ^^^^: ^^^ Í? ^ ¿Á (NMR) and / or mass spectrum; Fast atom bombardment mass spectrum (FAB) data were obtained using a Platform spectrometer and, where appropriate, positive ion data or negative ion data were collected; the chemical change NMR values were measured on the delta scale [proton magnetic resonance spectrum was determined using a Varian Gemini 2000 spectrometer operating at a field strength of 300MHz or a Bruker AM250 250MHz spectrometer]; the following 10 abbreviations have been used: s, simple; d, double; t, triple; m, multiple; br, broad; (vi) the intermediates were generally not fully characterized and the purity was assessed by thin layer chromatography, HPLC, infrared (IR) 15 and / or NMR analysis; (vii) the melting points are not corrected and were determined using a Mettier SP62 automatic melting point apparatus on an oil bath apparatus, the melting points for the final products of Formula 20 I were determined after crystallization from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or as a mixture; and (viii) the following abbreviations were used: DMF N, N-dimethylformamide 25 HPLC high pressure liquid chromatography AÉ i ^^ ^ 2 ^^^^, ^^^^^^^^^^. ^., '^ ^ ^^^ t DMSO dimethylsulfoxide Example 1 N- [2-chloro-5- (3-dimethylaminobenzamido) phenyl] -3,4-dimethoxybenzamide. Oxalyl chloride (0.11 ml) was added to a stirred suspension of 3-dimethylaminobenzoic acid (0.18 g) in methylene chloride (10 ml) at 20 ° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours. The solvent was evaporated to give a solid. The solid was dissolved in methylene chloride (15 ml) and added dropwise over 5 minutes to a stirred mixture of N- (5-ammo-2-chlorophenyl) -3,4-dimethoxy-benzamide (0.306 g), triethylamine (0.4 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml). The resulting mixture was stirred at 20 ° C for 18 hours. The reaction mixture was washed with water and with saturated aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 99: 1 mixture of methylene chloride and methanol as eluent. Thus, the title compound (0.109 g), m.p. 98-99 ° C; NMR spectrum: (CDC13) 3.02 (s, 6H), 3.95 (s, 6H), 6.86 (m, 1H), 6.93 (d, 1H), 7.1 (d, 1H), 7.31 (t, 1H), 7.42 (m, 2H), 7.54 (d, 1H), 7.98 (m, 2H), 8.42 (s, 1H), 8.58 (d, 1H); Mass Spectrum: M + H + 454 N- (5-amino-2-chlorophenyl) -3,4-dimethoxybenzamide g &g; used as starting material was prepared as follows: 3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred suspension of 2-chloro-5-nitroaniline (1.72 g) in pyridine (10 ml) a 20 ° C. The reaction mixture was heated at 100 ° C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water (100 ml). The resulting precipitate was reheated, washed with water and dried. The solid was triturated under methylene chloride (20 ml) to give N- (2-chloro-5-nitrophenyl) -3,4-dimethoxybenzamide (1.2 g), m.p. 231-232 ° C; NMR spectrum: (DMS0d6) 3.82 (s, 6H), 7.08 (d, 1H), 7.62 (m, 1H), 7.82 (d, 1H), 8.08 (m, 1H), 8.54 (d, 1H), 10.07 (m, 1H); Mass Spectrum: M + H + 337. The material thus obtained (1.12 g) was added in portions for 10 minutes to a stirred suspension of iron powder (3.0 g) in a mixture of acetic acid (1 ml), water (10 ml) and ethanol (60 ml) which had been heated to 70-75 ° C. The resulting mixture was heated to reflux for 1 hour. The mixture was allowed to cool and solid sodium carbonate was added until the mixture was basic (pH = 8-9). The mixture was filtered and the solid material was washed with methylene chloride. The filtrate was evaporated and the residue was triturated with ethyl acetate, filtered and the filtrate was evaporated to give the required starting material, as a cream solid, ^ i ^ Éj ^ g p.f. 146-149 ° C; NMR spectrum: (CDC13) 3.70 (s, 2H), 3.88 (s, 3H), 3.91 (s, 3H), 6.31 (m, 1H), 6.74 (d, 1H), 7.06 (d, 1H) 7.37 ( m, 1H), 7.42 (d, 1H), 7.92 (d, 1H), 8.30 (s, 1H); Mass Spectrum: M + H + 307. Example 2 Using a procedure analogous to that described in Example 1, the appropriate benzoyl chloride was reacted with the appropriate aniline to give the compounds described in Table I.

TablaI fg ^ j ^ l ^^ ¡^^^ j¡ ^ ¡^^ g ^^^^^^^ 1. The procedure described by Brown et al. in J. Med. Chem., 1985, 28_, 143-146. 2. The reaction mixture was purified by HPLC using a gradient mixture incrementally from 5 to 30% methanol in methylene chloride. Example 3 N- [2-bromo-5- (3-dimethylaminobenzamido) phenyl] -3,4-dimethoxybenzamide. Oxalyl chloride (0.24 ml) was added dropwise to a stirred suspension of 3-dimethylammonobenzoic acid (0.36 g) in methylene chloride (15 ml) at 20 ° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours. The solvent was evaporated to give a yellow solid which was dissolved in methylene chloride (20 ml) and added dropwise. for 5 minutes to a stirred mixture of N- (5-amino-2-bromophenyl) -3,4-dimethoxybenzamide (0.7 g), triethylamine (0.8 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (20 ml). Which had been cooled to 5-10 ° C. The reaction mixture was stirred at room temperature for 18 hours. The The organic phase was washed with saturated sodium bicarbonate solution, dried (MgSO) and evaporated. The residual oil was purified by column chromatography on silica gel using a 49: 1 mixture of methylene chloride and methanol as eluent. The solid thus obtained was crystallized from a mixture ethyl acetate and methyl tert-butyl ether to give the ^ j ^ j ^^ | í ^^^ j ^^^ g ^^^ ¿g ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 184 ° C; NMR spectrum: CDC13) 3.02 (s, 6H), 3.97 (s, 6H), 6.84 (m, 1H), 6.95 (d, 1H), 7.08 (d, 1H), 7.30 (m, 2H), 7.51 ( m, 3H), 7.95 (m, 1H), 8.02 (s, 1H), 8".45 (s, 1H), 8.56 (d, 1H); Mass Spectrum: M + H + 498 Elemental Analysis: Found C, 55.8; H, 4.5; N, 7.9, C24H24N3BrO4H20 requires C, 55.8; H, 4.9; N, 8.0% The N- (5-amino-2-bromophenyl) -3,4-dimethoxybenzamide used as initial aniline was prepared as follow: 3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred suspension of 2-bromo-5-nitroaniline (2.17 g) at 25 ° C. The reaction mixture was heated at 100 ° C for 5 hours. After cooling, water (25 ml) and 3M hydrochloric acid (100 ml) were added The resulting solid was filtered and washed with water (50 ml) and dried The solid was triturated under diethylether to give N- (2) -bromo-5-nitrophenyl) -3,4-dimethoxybenzamide (2.01 g) as a sand-colored solid, mp 183-184 ° C; NMR spectrum: (DMS0d6) 3.92 (s, 6H), 7.08 (d, 1H ), 7.56 (d, 1H), 7.65 (m, 1H), 8.0 (s, 2H), 8.4 (s, 1H), 10.09 (s, 1H). The material so obtained (1.9 g) was added in portions for 5 minutes to a stirred suspension of iron powder (4.5 g) in a mixture of acetic acid (1.5 ml), water (15 ml) and ethanol (90 ml). ) which had been heated to 70-75 ° C. The mixture was heated to reflux for 0.75 hours.

^ J * > ^ ia? a ^ A > ^ ^ .... ». ^ j ffffil l ^^^^^^ Solid sodium carbonate was added until the mixture was basic (pH = 8-9). The hot mixture was filtered and the residue was washed with hot methanol. The filtrates were evaporated and the resulting residue was extracted with hot ethyl acetate (200 ml). The solution was filtered and the filtrate was evaporated to give N- (5-amino-2-bromophenyl) -3,4-d-methox-benzamide (1.43 g), p.t. 154-155 ° C; NMR spectrum: (CDC13) 3.88 (s, 2H), 3.94 (s, 3H), 3.96 (s, 3H), 6.38 (m, 1H), 6.93 (d, 1H), 7.25 (d, 1H) 7.46 ( m, 1H), 7.55 (d, 1H), 8.02 (d, 1H), 8.38 (s, 1H). Example 4 N- [2-chloro-5- (3-morpholinobenzamido) phenyl] -3,4-dimethoxybenzamide 3-Morpholinobenzoyl chloride (0.15 g) was added to a stirred solution of N- (5-amino-2- chlorophenyl) -3, 4-15 dimethoxybenzamide (0.17 g) in pyridine (3 ml). The reaction mixture was stirred and heated at 115 ° C for 18 hours. The mixture was allowed to cool and poured into water. The mixture was extracted with methylene chloride. The organic extract was dried (MgSO 4) and evaporated. The resulting solid became azeotroped with toluene and triturated under diethylether to give the title compound (0.1 g), m.p. 147.9-148.3 ° C; NMR spectrum: (DMSOd6) 3.19 (s, 4H), 3.78 (s, 4H), 3.85 (s, 6H), 7.07 (d, 1H), 7.17 (d, 1H), 7.38 (s, 2H), 7.43 (s, 1H), 7.5 (d, 1H), 7.58 (s, 1H), 7.63 (d, 1H), 7.7 (d, 1H), 8.07 (s, 1H), 9.88 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M + H + 496; Elemental Analysis: Found C, 62.2; H, 5.1; N, 8.2; C26H26N3o05C? 0.25H2O requires C, 62.4; H, 5.3; N, 8.4% The 3-morpholinobenzoyl chloride used as starting material was prepared as follows: A mixture of ethyl 3-bromobenzoate (1.92 ml), morpholino (1.25 ml), 2, 2'-bis (diphenylphosphino) -1, 1'-biphenyl (0.336 g), sodium tert-butoxide (1.615 g) and tris (dibenzylideneacetone) dipalladium (0) (0.33 g) and toluene (25 ml) was stirred and heated at 90 ° C for 18 hours under argon. The reaction mixture was allowed to cool to room temperature and extracted with 1M hydrochloric acid. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 47: 3 mixture of methylene chloride and methanol as eluent. Thus, N- (3-morpholinobenzoyl) morpholino was obtained (0.45 g). A mixture of the material thus obtained, 5M sodium hydroxide solution (2.5 ml) and butanol (2 ml) was stirred and heated at 115 ° C for 18 hours. The mixture was evaporated and the residue acidified by the addition of 1M hydrochloric acid solution (12.5 ml). The resulting precipitate was isolated, was washed with water and dried to give 3-morpholinobenzoic acid ^. ^ ag ^^ .. j ^ 'jMJfcAM ^ M ^^ a ^. ^ a ^. ,,,.,., ^ (0.15 g); NMR spectrum: (DMSOd6) 3.1 (t, 4H), 3.73 (t, 4H), 7.19 (d, 1H), 7.32 (d, 1H), 7.38 (t, 1H), 7.42 (s, 1H). Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoic acid (0.28 g) in 5 methylene chloride (10 ml) which contained DMF (2 drops). The reaction mixture was stirred for 18 hours at room temperature. The mixture was evaporated and azeotroped with toluene to give 3-mofolinobenzoyl chloride (0.3 g); Mass Spectrum: M + H + 222. Example 5 N- [2-Chloro-5- (4-cyanobenzamido) phenyl] -4-cyanobenzamide 4-Cyanobenzoyl chloride (0.25 g) was added to a stirred mixture of N- (3-amino-chlorophenyl) -4-cyanobenzamide (0.39 g), triethylamine (0.51 ml), 4-dimethylaminopyridine (0.01 g) and methylene chloride (25 ml). The mixture was stirred at room temperature for 18 hours. The mixture was washed with 2M hydrochloric acid solution and with water. The organic phase was dried (MgSO 4) and evaporated. The residue was purified by column chromatography on silica gel using a : 49: 1 mixture of methylene chloride and methanol as eluent. Thus, the title compound (0.11 g) was obtained; NMR spectrum: (CDC13) 5.5 (s, 2H), 6.58 (d, 1H), 6.7 (d, 1H), 7.18 (d, 1H), 7.93 (s, 8H); Mass Spectrum: M-H "399; 25 Elemental Analysis: Found: C, 65.4; H, 3.7; N, 13.1; C22H? 3N402Cl 0.25H2O, requires C, 65.2; H, 3.4; N, 13.8%. The N- (3-amino-4-chlorophenyl) -4-cyanobenzamide used as starting material was prepared as follows: 4-Cyanobenzoyl chloride (11.92 g) was added slowly to a stirred solution of 4-chloro-3-nitroaniline ( 10.4 g) in pyridine (20 ml) and the mixture was stirred and heated at 115 ° C for 18 hours. The mixture was cooled to room temperature and poured into water (150 ml) and stirred for 30 minutes. The resulting precipitate was isolated, washed with water and dried to give -4-chloro-3-nitrophenyl] -4-cyanobenzamide- (18 g), m.p. 213 ° C; NMR spectrum: (DMSOd6) 7.78 (d, 1H), 8.05 (m, 3H), 8.1 (d, 2H), 8.58 (s, 1H), 10.93 (s, 1H). A portion (3.6 g) of the material thus obtained was added to a stirred suspension of iron powder (10 g) in a mixture of ethanol (130 ml), water (30 ml) and glacial acetic acid (4 ml). The mixture was heated at 75 ° C for 1 hour and then, while hot, it was made basic by the addition of sodium carbonate. The mixture was filtered and the filtrate was evaporated. The resulting solid was stirred in water for 3 hours. The solid was isolated and dried to give the required starting material (2.7 g), m.p. 237.7 ° C; NMR spectrum: (DMS0d6) 5.44 (s, 2H), 6.98 (m, 1H), 7.21 (d, 1H), 7.42 (d, 1H), 8.07 (d, 2H), 8.14 (d, 2H), 10.36 (s, 1H).

Example 6 Using a procedure analogous to that described in Example 5, the appropriate benzoyl chloride was reacted with the appropriate aniline to give the compounds described in Table II. Table II ^^^^^^^^^^ C ^^^^ i ^^^^^^^^^ 1. The standard procedure was adapted to the following: Phosphoryl chloride (0.03 ml) was added dropwise to a stirred mixture of N- (3-ammo-4-chlorophenyl) -4-cyanobenzamide (0.08 g), acid 3, 4- diethoxybenzoic (0.062 g) and pyridine (4 ml) which had been cooled to -15 ° C. The mixture was stirred at -15 ° C for 3 hours. The mixture was left heat at room temperature 16 hours. The mixture was diluted with water and stirred overnight. The resulting precipitate was isolated, washed with diethyl ether and dried under vacuum at 55 ° C to give the tabulated compound (0.026 g). Example 7 N- [2-chloro-5- (4-cyanobenzamide) phenyl] -3-fluoro-4- (4-methylpiperazin-1-yl) benzamide Phosphoryl chloride (0.11 ml) was added dropwise to a mixture stirring of N- (3-amino-4-chlorophenyl) -4- 10 cyanobenzamide (0.2 g), 3-fluoro- (4-methylpiperazin-1-yl) benzoic acid (0.26 g) and pyridine (2 ml) which It was cooled down to -10 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture was diluted with water and stirred overnight. The bipropyrite was dried, dried, and dried at 55 ° C. Thus the title compound was obtained as a solid (0.212 g).; Mass Spectrum: (M-H) "490. 3-Fluoro-4- (4-methylpiperazin-1-yl) benzoic acid used as starting material was obtained as follows: A mixture of 3, -difluorobenzonitrile (8.65 g), N-methylpiperazine (7.2 ml), triethylamine (9.1 ml) and acetonitrile (12 ml) was stirred and heated to reflux for 2 hours. . The mixture was evaporated and the residue was purified by column chromatography using a 1: 5: 94 mixture of ataAtolt ^^ i ^ »^ * ^^^^^ * - ^ 'ff ^ áá? ? ^ ^ tMau? J? a ???, triethylamine, methanol and methylene chloride as eluent. Thus 3-fluoro-4- (4-methylpiperazin-1-yl) benzonitrile was obtained as an oil which crystallized slowly to give a white solid (12.47 g), m.p. 60-63 ° C; NMR spectrum: (CDC13) 2.37 (s, 3H), 2.61 (t, 4H), 3.24 (t, 4H), 6.89 (m, 1H), 7.27 (m, 1H), 7.35 (m, 1H). A portion of (3 g) of the material so obtained was dissolved in 6N hydrochloric acid (30 ml) and the solution was heated to reflux for 13 hours. The mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried with air to give the required starting material (1.63 g). Elemental analysis showed that the crystals contain approximately 6 equivalents of water. NMR spectrum: (DMS0d6) 2.81 (s, 3H), 3.28 (m, 8H), 7.17 (m, 1H), 7.62 (m, 1H), 7.71 (m, 1H), 10.9 (s, 1H). The N- (3-amino-4-chlorophenyl) -4-cyanobenzamide used as starting material was synthesized as follows: Triethylamine (6.7 ml) was added to a stirred mixture of 3-amino-4-chloroaniline (3.44 g), chloride of 4-cyanobenzoyl (4.0 g) and methylene chloride (50 ml) which had been cooled to 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The mixture was concentrated to approximately one third of the original volume and a solution of saturated aqueous sodium bicarbonate was added. The resulting solid was isolated, washed £ l l É É-á á á * * i i i i i i i i. ^ ... ^^ «81, ^^^^ with water and with methanol and dried under vacuum at 55 ° C to give the required initial material (5.23 g); NMR spectrum: (DMSOd6) 5.37 (s, 2H), 6.9 (m, 1H), 7.14 (d, 1H), 7.35 (d, 1H), 7.98 (d, 2H), 8.08 (d, 2HJ, 10.28 ( s, 1H) Example 8 N- [5- (3-dimethylaminobenzamido) -2-fluophenyl] -3,4-dimethoxybenzamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.12 g) in chloride was added of methylene (5 ml) a a stirred mixture of 3,4-dimethoxybenzoic acid (0.91 g), N- (3-amino-4-fluorophenyl) -3-dimethylaminobenzamide (0.14 g), DMF (2 ml) and 4-dimethylaminopyridine (0.004 g). The reaction mixture was stirred at room temperature for 18 hours. Water (20 ml) and methylene chloride (10 ml) were added. The phase The organic was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO 4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 49: 1 mixture of methylene chloride and methanol as eluent. The material thus obtained was crushed under diethyl ether. Thus, the title compound (0.084 g) was obtained as a colorless solid m.p. 187-188 ° C; NMR spectrum: (CDC13) 3.02 (s, 6H), 3.97 (s, 6H), 6.86 (m, 1H), 6.93 (d, 1H), 7.09 (d, 1H), 7.16 (t, 1H), 7.25 (m, 1H), 7.32 (t, 1H), 7.41 (m, 1H), 7.5 (d, 1H), 7.88 (m, 1H), 7.97 (s, 1H), 8.04 (s, 1H), 8.42 (m, 1H); Mass Spectrum: M + H + 438; Elemental Analysis: Found C, 65.4; H, 5.5; N, 9.5; C24H24NF04 requires C, 65.8; H, 5.4; N, 9.6%. The N- (3-amino-4-fluorophenyl) -3-dimethylaminobenz-5-amide used as the starting material was prepared as follows: Oxalyl chloride (1.2 ml) was added dropwise for 5 minutes to a stirred suspension of 3-amino acid. dimethylaminobenzoic acid (1.81 g) in methylene chloride (20 ml) at 20 ° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated and the residue was dissolved in methylene chloride (25 ml) and added for 5 minutes to a stirred mixture of 4-fluoro-3-nitroaniline (1.56 g), triethylamine (4.1 ml) and methylene chloride ( 25 ml). The solution was stirred for 18 hours. The organic layer was washed with 3M hydrochloric acid and water, dried (MgSO 4) and evaporated. The residual sodium was triturated under methyl tert-butyl ether and then under methylene chloride. Thus, N- (4-fluoro-3-nitrophenyl) -3-dimethylaminobenza ida (0.96 g), m.p. 176-177 ° C; Spectrum of NMR: (DMS0d6) 2.93 (s, 6H), 6.92 (m, 1H), 7.2 (m, 2H), 7.31 (t, 1H), 7.56 (c, 1H), 8.11 (m, 1H), 8.63 ( m, 1H), 10.58 (s, 1H). 10% Palladium in carbon (0.09 g) was added to a stirred suspension of the nitro compound thus obtained (0.910 g) in ethanol (90 ml). The mixture was hydrogenated under pressure atmospheric and at room temperature until the hydrogen intake stopped. The catalyst was removed by filtration and the filtrate was evaporated. The solid residue was purified by column chromatography on silica gel using a 49: 1 mixture of methylene chloride and methanol as eluent. Thus the required initial material (0.74 g) was obtained; NMR spectrum: (CDC13) 3.0 (s, 6H), 3.78 (s, 2H), 6.7 (m, 1H), 6.92 (m, 2H), 7.05 (d, 1H), 7.30 (m, 2H), 7.37 (m, 1H), 7.68 (s, 1H). EXAMPLE 9 N- (Benzamido-2-chlorophenyl) -2-amino-4-me oxybenzamide Iron powder (2.79 g) was added to a stirred suspension of N- (5-benzamido-2-chlorophenyl) -4-methoxy- 2- nitrobenzamide (2.13 g) in a mixture of ethanol (100 ml), water (20 ml) and acetic acid (4 ml). The mixture was stirred and heated to reflux for 6 hours. The mixture was cooled to room temperature. Water (50 ml) was added and the resulting mixture was basified by the sodium carbonate view. The mixture was filtered and the filtrate was evaporated. The residue was triturated under water. The resulting solid was isolated and dried under vacuum at 40 ° C. Thus, the title compound (0.911 g) was obtained; NMR spectrum: (DMS0d6) 3.72 (s, 3H), 6.09 (d, 1H), 6.27 (s, 1H), 6.62 (s, 2H), 7.45-7.61 (m, 4H), 7.66-7.72 (m, 2H), 7.95 (d, 2H), 8.07 (s, 1H), 9.52 (s, 1H), 10.37 (s, 1H); Mass Spectrum: M + H + 396 and 398. The N- (5-benzamido-2-chlorophenyl) -4-methoxy-2-nitrobenzamide used as starting material was prepared as follows: 5 Benzoyl chloride (5.2 ml) was added to a stirred mixture of 2,4-diaminochlorobenzene (6.42 g), triethylamine (12.5 ml) and methylene chloride (100 ml) which had been cooled to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture evaporated and The residue was triturated under a saturated aqueous sodium bicarbonate solution. The resulting solid was isolated, washed in turn with water and isohexane and dried under vacuum at 55 ° C. Thus, N- (3-amino-4-chlorophenyl) benzamide was obtained as a solid (10.38 g); NMR spectrum: (DMS0d6) 5.32 (s, 2H), 6.9 (m, 1H), 7.1 (d, 1H), 7.37 (d, 1H), 7.52 (m, 3H), 7.9 (d, 2H), 10.05 (s, 1H). Oxalyl chloride (0.781 ml) was added dropwise to a stirred mixture of 4-methoxy-2-nitrobenzoic acid (1.6 g), DMF (a few drops) and methylene chloride (30 ml). which had been cooled to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 4 hours. The mixture was evaporated. The residue was dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of N- (3-amino-4-chlorophenyl) benzamide (2.0 g), triethylamine (2.49 ml) and Methylene chloride (30 ml). The resulting mixture was stirred ^ J ^ j¡¡¿ ^^^^^^^^^^^^^^^^^^^^^ Xlsr ambient temperature for '16 hours. The precipitate was isolated, washed with IN aqueous hydrochloric acid solution with methanol and dried either under vacuum or at 40 ° C. Thus, the required initial material (2.49 g) was obtained; NMR spectrum: (DMSOd6) 3.9 (s, 3H), 7.39 (d, 1H), 7.47-7.62 (m, 5H), 7.72 (d, 1H), 7.78 (d, 1H), 7.97 (d, 2H), 8.14 (s, 1H), 10.28 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M + H + 426 and 428. EXAMPLE 10 N- (5-Benzamido-2-chlorophenyl) -3,4-dimethoxybenzamide Phosphoryl chloride (0.074 g) was added to a stirred mixture of 3,4-dimethoxybenzoic acid. (0.088 g), N- (3-ammo-4-chlorophenyl) benzamide (0.1 g) and pyridine (1 ml) which had been cooled to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture was poured into IN aqueous hydrochloric acid solution and the resulting solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried under vacuum at 55 ° C. Thus the title compound was obtained (0.088 g); NMR spectrum: (DMSOd6) 3.83 (m, 6H), 7.09 (d, 1H), 7.55 (m, 6H), 7.72 (d, 1H), 7.95 (d, 2H), 8.08 (s, 1H), 9.88 (s, 1H), 10.4 (s, 1H); Mass Spectrum: MH "4-09 Example 11 N- [2-Chloro-5- (2-nitrobenzamido) phenyl] -3,4-dimethoxybenzamide 3,4-Dimethoxybenzoyl chloride (1.55 g) was added to a mixture stirring of N- (3-amino-4-chlorophenyl) -2- nitrobenzamide (1.5 g) and pyridine (20 ml) and the mixture was stirred and heated at 80 ° C for 16 hours.The mixture was cooled to room temperature and The residue was partitioned between methylene chloride and aqueous hydrochloric acid solution IN.The organic phase was washed with a saturated aqueous sodium bicarbonate solution and evaporated, the residue was triturated under ethyl acetate. was isolated, washed with a sodium bicarbonate solution Aqueous saturated and dried under vacuum at 40 ° C. Thus, the title compound (1.63 g) was obtained; NMR spectrum: (DMS0d6) 7.08 (d, 1H), 7.52-7.57 (m, 3H), 7.62 (d, 1H), 7.74-7.8 (m, 2H), 7.86 (t, 1H), 7.87 (s, 1H), 8.13 (d, 1H); 15 Mass Spectrum: M + H + 456 and 458. The N- (3-amino-4-chlorophenyl) -2-n? Trobenzamide used as starting material was prepared as follows: 2-Nitrobenzoyl chloride was added (4.64 ml) to a stirred mixture of 3-amino-4-chloroanilma (5 g), Triethylamine (9.78 ml) and methylene chloride (300 ml) were added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was purified by column chromatography on silica to give the material ^ ^ ^ ^ ^ ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ NMR spectrum: (DMS0d6) 5.38 (s, 2H), 6.74 (d, 1H), 7.11 (d, 1H), 7.27 (s, 1H), 7.7-7.75 (m, 2H), 7.84 (t, 1H) , 8.1 (d, 1H), 10.5 (s, 1H); Mass Spectrum: M + H + 292 and 294. Example 12 N- [5- (2-Aminobenzamido) -2-chlorophenyl] -3,4-dimethoxybenzamide Using an analogous procedure to that described in Example 9, N- was reduced [2-Chloro-5- (2-nitrobenzamido) phenyl] -3,4-dimethoxybenzamide with iron powder in the presence of acetic acid to give the title compound in 43% yield; NMR spectrum: (DMS0d6) 3.82 (s, 6H), 6.32 (s, 2H), 6.58 (t, 1H), 7.74 (d, 1H), 7.08 (d, 1H), 7.19 (t, 1H), 7.47 (d, 1H), 7.52-7.64 (m, 4H), 8.04 (s, 1H), 9.88 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M + H + 426. EXAMPLE 13 N- [2-Chloro-5- (3-dimethylaminobenzamido) -4-fluorophenyl] -3,4-dimethylhexibenzamide 20 A mixture of 3, -dimethoxybenzoyl chloride (0.5 g) , N- (5-amino-4-chloro-2-fluorophenyl) -3-dimethylamino-benzamide (0.781 g) and pyridine (8 ml) was stirred at room temperature for 18 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a solution of Saturated aqueous copper sulfate. The organic phase was washed ffilftÉraa > i-, fi:, s ^, J * f M! ffli-f? ¡¥ r- - nifftrí-- --- * "-" turn with water and saturated sodium chloride solution, dried (MgS0) and it evaporated. The residue was purified by column chromatography on silica using a 99: 1 mixture of methylene chloride and methanol as eluent. Thus, the title compound was obtained as a solid (0.328 g); NMR spectrum: (CDC13) 3.02 (s, 6H), 3.98 (s, 6H), 6.96 (m, 2H), 7.06 (m, 1H), 7.06-7.47 (m, 3H), 7.47 (m, 1H) , 7.6 (m, 1H), 8.01 (s, 1H), 8.2 (s, 1H), 9.53 (m, 1H); Mass Spectrum: M + H + 472 and 474. The N- (5-amino-4-chloro-2-fluorophenyl) -3-dimethylaminobenzamide used as starting material was prepared as follows: Ophthalic anhydride (11.83 g) was added. ) to a solution of 2-chloro-4-fluoroaniline (11.08 g) in glacial acetic acid (150 ml) and the mixture was stirred and heated at 100 ° C for 2 hours. The mixture was allowed to cool to room temperature and the precipitate was isolated, washed with water and dried under vacuum. Thus N- (2-chloro-4-fluorophenyl) phthalimide was obtained which was used without further purification. A mixture of nitric acid (4.6 ml) and sulfuric acid (5 ml) was gradually added to a stirred mixture of N- (2-chloro-4-fluorophenyl) phthalimide thus obtained and sulfuric acid (30 ml) which were cooled in a water bath 25 with ice, the rate of addition was such that the temperature ? ^ A? ^ É ^^^ Mm? ^^^:? ' ^^ A, «J. ^ JS, 'i Zr-? ^^^^ 1 ^ ^^? ^. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The resulting clear solution was stirred at room temperature for 1 hour. A mixture (250 ml) of ice and water was added and the solid precipitate was isolated and dried under vacuum. Thus, N- (2-chloro-4-fluoro-5-nitrophenyl) phthalimide was obtained as a solid (17.9 g); NMR spectrum: (CDC13): 7.58 (d, 1H), 7.88 (m, 2H), 8.01 (m, 2H), 8.16 (d, 1H); Mass Spectrum: M-H "319 and 321. A mixture of ethanol (450 ml)water (65 ml) and acetic acid (6.5 ml) was stirred and heated to 50 ° C. Iron powder (9 g) was added followed by portionwise addition over 10 minutes of N- (2-chloro-4-fluoro-5-nitrophenyl) phthalimide (8.98 g). The resulting mixture was stirred and heated to reflux for 2 hours. The mixture was cooled to room temperature and basified with the addition of solid sodium carbonate, the mixture was filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Thus, N- (5-ammo-2-chloro-4-fluorophenyl) phthalimide was obtained as a solid (6.3 g); NMR spectrum: (CDC13) 3.87 (s, 2H), 6.74 (d, 1H), 7.2 (d, 1H), 7.81 (m, 2H), 7.96 (m, 2H); Mass Spectrum: M-H "289 and 291.

Pyridine (2.0 ml) was added to a mixture of N- (5-amino-2-chloro-4-fluorophenyl) phthatalamide (2.9 g), 3-dimethylaminobenzoyl chloride hydrochloride (3.06 g) and methylene chloride (20 g). ml) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride a (200 ml) and washed in turn with a solution of saturated aqueous copper sulfate and water. The organic solution was dried. (MgSO4) and evaporated. The residue was triturated under ethyl acetate. The solid thus obtained was isolated and washed Y? COT ace ke kechlor-2-fluoro-5-phthalimidophenyl) -3-dimethylaminobenzamide as a solid (2.46 g); NMR spectrum: (DMS0d6) 2.94 (s, 6H), 6.94 (m, 1H), 7.28 (m, 3H), 7.8-7.92 (m, 2H), 7.94 (m, 2H), 8.02 (m, 2H); Mass Spectrum: M + H + 438 and 440. 15 A mixture of the material thus obtained, ethanolamine (0.68 ml) and methylene chloride (40 ml) was stirred at room temperature for 4 hours. The mixture was diluted with methylene chloride (200 ml) and the resulting solution was washed with water and with an aqueous sodium chloride solution.

Saturated, dried over sodium sulfate and evaporated. Thus, N- (5-amino-4-chloro-2-fluorophenyl) -3-dimethylaminobenzamide was obtained as a solid (1.26 g); NMR spectrum: (CDC13) 3.02 (s, 6H), 3.94 (s, 2H), 4.0 (broad s, 2H), 6.88 (s, 1H), 7.04 (m, 1H), 7.07 (s, 1H), 7.25 (m, 1H), 7.32 (t, 1H), 7.98 (s broad, 1H), 8.08 (d, 1H); Mass Spectrum: M + H + 308 and p.sub.i.sup.-p.sub.i.sup.-310. EXAMPLE 14 N- [5- (4-acetoxybenzamido) -2-chlorophenyl] -4-cyanobenzamide. Oxalyl chloride (0.35 ml) was added to a stirred suspension of 4-acetoxybenzoic acid (0.57 g) in methylene chloride (15 ml) which had been cooled to 0 ° C. DMF (2 drops) was added and the mixture was stirred at room temperature for 4 hours. The mixture was evaporated to give 4-acetoxybenzoyl chloride which was used without purification additional. A mixture of the acid chloride thus obtained N- (3-amino-4-chlorophenyl) -4-cyanobenzamide, (0.813 g) and pyridine (15 ml) was stirred and heated at 100 ° C for 16 hours. The mixture was cooled to room temperature and poured into a 2N aqueous hydrochloric acid solution (175 ml). He The precipitate was isolated, washed with water and dried. The material thus obtained was purified by column chromatography on silica using a 7: 3 mixture of isohexane and ethyl acetate as eluent. Thus, the title compound (0.74 g) was obtained; 20 p.f. 195-196 ° C NMR spectrum: (DMSOd6) 2.3 (s, 3H), 7.28 (d, 2H), 7.51 (d, 1H), 7.73 (m, 1H), 7.81 (m, 4H), 8.12 (m , 3H), 10.08 (s, 1H), 10.64 (s, 1H); Mass Spectrum: M + H + 434.

Example 15 N- [2-Chloro-5- (3-morpholinobenzamido) phenyl] -4-cyanobenzamide Using an analogous procedure to that described in Example 14, 3-morpholinobenzoyl chloride was reacted with N- (3-amino- 4-chlorophenyl) -4-cyanobenzamide to give the title compound in 42% yield; NMR spectrum: (DMS0d6) 3.13 (t, 4H), 3.73 (t, 4H), 7.17 (s, 1H), 7.43 (m, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.06 (m, 3H), 8.1 (m, 3H), 8.17 (m, 1H); 10 Mass Spectrum: M + H + 461. Example 16 Pharmaceutical Compositions The following illustrates the representative pharmaceutical dosage form of the invention as defined herein (the active ingredient being called "compound X"), for therapeutic or prophylactic use in humans: (a) Tablet I mg / tablet Compound X 100 Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% w / v paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg / tablet 25 Compound X 50 Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% w / v paste) 2.25 5 Magnesium stearate 3.0 (c) Tablet III mg / tablet Compound X 1.0 Lactose Ph. Eur 93.25 Croscarmellose sodium 4.0 10 Corn starch paste (5% w / v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg / capsule Compound X 10 Lactose Ph. Eur 488.5 15 Magnesium 1.5 (e) Injection I (50 mg / ml) Compound X 5.0% w / v 1M sodium hydroxide solution 15.0% v / v 0.1M hydrochloric acid (to adjust pH to 7.6) 20 Polyethylene glycol 400 4.5% p / v Water for injection up to 100% (f) Injection II (10 mg / ml) Compound X 1.0% w / v Sodium phosphate BP 3.6% w / v 25 0.1M Sodium hydroxide solution 15.0% v / v - ^^ Ji ***** - - - ^ 4 & * »A ** > . * * - * + .. - * a. * ... ^ .. ^ .... ^ A ^^^. a .A ^^.? ^^ '^. ^ a ^.

Water for 100% injection (g) Injection III (1 mg / ml, regulated at pH6) Compound X 0.1% w / v X, Sodium phosphate BP? * F. '' 2.26% w / v Citric acid 0.38% w / v Polyethyleneglycol 400 3.5% w / v Water by injection at 100% (h) Aerosol I mg / ml Compound X 10.0 Sorbitan triolate 13.5 Trichlorofluoromethane 9 10.0 Dichlorodifluoromethane 490.0 (i) Aerosol II mg / ml Compound X 0.2 Sorbitan Triolate 0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j) Aerosol III mg / ml Compound X 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg / ml .i ^^. ^; ^^ ¿^^; ^ a. ^^. "_ ^ É ^ a ^^ ^^ ii fefe ^^^^^^^^ to ^^^^^^^^^ Compound X 2.5 Soy lecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (1) Ointment ml Compound X 40 mg Ethanol 300 Water .mu.l 300 .mu.l l-Dodecilazac? cloheptan-2-one 50 .mu.l Propylene glycol to 1 ml Note the above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a) - (c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h) - (k) can be used in conjunction with standard metered dose aerosol dispensers. Agents sorbitan trioleate suspension and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Claims (10)

CLAIMS 1. A compound of Formula I 5 characterized in that R1 and R2 which may be the same or different, are selected from hydroxy, C6-6 alkoxy, mercapto, C6-6 alkyl, amino, C6-6 alkylamino, di- (C1-6 alkyl) ß) amino, carboxy, alkoxycarbonyl of C? -6,
1. Carbamoyl, C? -6 alkylcarbamoyl, C? _6-alkylcarbamoyl, C? -6 alkylsulfinyl, C? _6 alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkylaminosulfonyl, di- (C? _6) aminosulfonyl, nitro, cyano, cyanoalkyl of C? _6, hydroxyalkyl of C? _6, aminoalkyl of C? _6,
2. C? -6 alkanoylamino, C? _6 alkoxycarbonylamino, C? -6 alkanoyl, C? -6 alkanoyloxy, C? _6 alkyl, C_6 alkenyl, C2_6 alkynyl, halo, trifluoromethyl, aryl, arylalkyl, C? -6, C? -6 arylalkoxy, heteroaryl, C? -6 heteroarylalkyl, heterocyclyl and C? -6 heterocyclylalkyl, - 20 m and p are independently 0-3, and when m and / or p úñßjtotmtrt * r ~ * > ~~ * '* *** - ** ^ ***' »* ^ '' ~ ^ - ^^ iiiri r, < fa ^ Mhaa > . is 2 or 3 each group R1 or R2 may be the same or different; R3 is halo, cyano or Ci-β alkoxy; q is 0-4; and R 4 is aryl or cycloalkyl wherein R 4 is optionally substituted with up to 3 substituents having any defined value for each R 1 group; or a pharmaceutically acceptable salt or ester thereof capable of unfolding in vivo; with the proviso that: 10 N- [5- (3-cyclohexylpropionylamino) -2-methoxyphenyl] -4- acetoxybenzamide, N- [2-bromo-5- (3-cyclohexylpropionylamino) phenyl] -4-hydroxybenzamide, N- [2-chloro-5- (3-cyclohexylpropionylamino) phenyl] -4- 15-acetoxybenzamide, N- [2-chloro-5- (3-cyclohexylpropionylamino) phenyl] -4-hydroxybenzamide, N- [2-fluoro-5- (3-cyclohexylpropionylamino) phenyl] -4- hydroxybenzamide and 20 N- (5-benzamido-2-chlorophenyl) benzamide are excluded. 2. The amide derivative of Formula I according to claim 1, characterized in that R1 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, 'nrtft it ** * **** - * ** ^ IIIIIIIi liiiiiiittiriiM .i' ^^^^^^^^^^^^^ methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, cyano, acetamido, acetyl, acetoxy , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or 4-methyl-piperazin-1-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is l, 2 or 3; and R 4 is cyclohexyl or cyclopentyl; or a pharmaceutically acceptable salt thereof. 3. The amide derivative of Formula I according to claim 1, characterized in that R1 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, ter -butoxycarbonyl, cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or 4- methylpiperazin-1-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; 25 q is 0; Y
3. R 4 is phenyl which is optionally substituted with 1 or 2 substituents selected from hydroxy, methoxy, ethoxy, propoxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, nitro, cyano, acetamide, acetyl, acetoxy, methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, phenyl, benzyloxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt thereof. 4. The amide derivative of the Formula I according to claim 1, characterized in that R1 is hydroxy, methoxy, ethoxy, cyano, fluoro, chloro, morpholino or 4-methylpiperazin-1-yl; m is 1 or 2; 15 p is 0; R3 is fluoro, chloro or bromo; q is 0; and R 4 is phenyl which is substituted with 1 or 2 substituents selected from hydroxy, methoxy, dimethylamino, methoxycarbonyl, cyano, fluoro, chloro, and morpholino; or a pharmaceutically acceptable salt thereof. 5. The amide derivative of Formula I according to claim 1, characterized in that R1 is hydroxy, methoxy, ethoxy, amino, cyano, acetoxy, fluoro, chloro, morpholino or 4-methylpiperazin-1-yl;
4. ** MiMh ^ -A > , ai ^ aa ^ m is 1 or 2; weight; R3 is fluoro, chloro or bromo; q is 0; and R 4 is phenyl which is substituted or unsubstituted with 1 or 2 substituents selected from hydroxy, methoxy, amino, dimethylamino, methoxycarbonyl, nitro, cyano, fluoro, chloro and morpholino; or a pharmaceutically acceptable salt thereof. 6. The compound of formula I according to claim 1, characterized in that it is selected from: N- [2-chloro-5- (3-cyanobenzamido) phenyl] -3,4-dimethoxybenzamide N- [2-chloro] -5- (3-dimethylaminobenzamido) phenyl] -3, -dimethoxybenzamide, 15 N- [2-chloro-5- (4-cyanobenzamido) phenyl] -3,4-dimethoxybenzamide and N- [2-chloro-5- ( 4-cyanobenzamido) phenyl] -3- (4-methylpiperazin-1-yl) benzamide; or the pharmaceutically acceptable salts thereof. 7. The compound of Formula I according to claim 1, characterized in that it is selected from: N- (5-benzamido-2-chlorophenyl) -3,4-dimethoxybenzamide, N- [2-chloro-5- ( 3-morpholinobenzamido) phenyl] -3,4-dimethoxybenzamide, N- [5- (4-acetoxybenzamido) -2-chlorophenyl] -4-cyanobenzamide, 25 N- (5-benzamido-2-chlorophenyl) -2-amino- 4-methoxybenzamide and s? iÁ¡-giíít¡¡ ^ 2 ^^^ | y ^ N- [2-chloro-5- (3-morpholinobenzamido) phenyl] -4-cyanobenzamide; or the pharmaceutically acceptable salts thereof. 8. The process for the preparation of an amide derivative of the Formula I, or a pharmaceutically acceptable salt or an ester capable of unfolding in vivo according to claim 1, characterized in that it comprises: (a) the reaction of a compound of the Formula II with an acid of Formula III Formula III or an activated derivative thereof, under standard conditions that form the amide bond, wherein variable groups are as defined in claim 1 and wherein any functional group is protected if necessary, and : (i) eliminate any protective group; (ii) optionally forming a pharmaceutically acceptable salt or an ester capable of unfolding in vivo;
5. B) the reaction of an acid of the Formula V
6. Formula V or an activated derivative thereof, with an aniline of the
7. Formula VII under standard conditions that form amide bond, wherein the variable groups are as defined in claim 1 and wherein any functional group is protected if necessary and: (i) remove any protecting group; (ii) optionally forming a pharmaceutically acceptable salt or an ester capable of unfolding in vivo; or (c) for the preparation of a compound of the
8. Formula I according to claim 1 wherein R 1 or a substituent on R 4 is an amino group, the reduction of a compound of Formula I wherein R 1 or a substituent on R 4 is a nitro group. 9. The pharmaceutical composition characterized in that it comprises an amide derivative of Formula I, or a salt
9. ^? ^^^^^^^ ¡¡^^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The pharmaceutically acceptable ester or ester capable of unfolding in vivo thereof according to claim 1, in association with a pharmaceutically acceptable diluent or carrier.
10. 10. The use of an amide derivative of the Formula I or a pharmaceutically acceptable salt or an ester capable of unfolding n vivo thereof according to claim 1, in the manufacture of a medicament in the treatment of medical conditions mediated by cytokines. . ^. ^^ »^ - ^. Rfa ^^^. ^. ^ .. ^^.,"., "." «BÍÉB ^ aá ^ üps. ^. A ^ .g aa ^