MXPA04005168A - Compounds for treatment of inflammation, diabetes and related disorders. - Google Patents

Abstract

Novel acyl urea, thiourea, carbamate, thiocarbamate and related compounds are provided which are effective in inhibiting the cytokine-mediated inflammatory response in cultured cells, in ameliorating bone destruction, in an animal model of arthritis and in lowering blood glucose levels in animal models of Type II diabetes mellitus. The compounds are disclosed as useful for a variety of treatments including the treatment of diabetes mellitus, insulin resistance, inflammation, inflammatory diseases, immunological diseases and cancer.

Description

COMPOUNDS FOR THE TREATMENT OF INFLAMMATION, DIABETES AND RELATED DISORDERS FIELD OF THE INVENTION The invention is directed to compounds, for example, heterocyclic derivatives of acyl urea, thiourea, carbamate and thiocarbamate compounds, which provide a variety of useful pharmacological effects. The compounds are useful, for example, for reducing glucose levels in hyperglycemic disorders, such as diabetes mellitus, and for treating related disorders, such as obesity and hyperlipidemia. In addition, these compounds are useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, and for the treatment of inflammation, immunological and inflammatory diseases, particularly those mediated by pro-inflammatory cytokines (such as TNF-alpha, IL-1 beta and IL-6), phosphodiestearase type 3 and type 4 (PDE3 and PDE4, respectively), mitogen-activated protein kinase p44 / 42 (MAP), cyclooxygenase-2 (COX-2) and / or inducible nitric oxide synthase (iNOS).

BACKGROUND OF THE INVENTION The causes of diabetes mellitus are not yet known, although the main factors appear to be genetic and environmental. Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is an autoimmune disease in which the responsible antigen has not yet been identified. Since their pancreatic cells that produce insulin are destroyed. Type 1 diabetics need to take insulin parenterally to survive. On the other hand, type 2 diabetes, also called non-insulin-dependent diabetes mellitus (NIDDM), the most common form, is a metabolic disorder that results from the body's inability to make a sufficient amount of insulin or to properly use insulin. insulin that is produced. Deterioration of insulin secretion and insulin resistance are considered major defects; nevertheless, the precise genetic factors involved in the mechanism remain unknown. Unlike insulin administered parenterally and as shown in Table I, there are generally four main classes of hypoglycemic agents commonly used in the treatment of diabetes mellitus: TABLE 1 Class Drugs Mechanisms of Limitations Approved Action Sulphonylurea four (Ia stimulates hypoglycemia, Generation) and pancreas can increase two (2a. Release more risk Generation) cardiovascular insulin; contraindicated in renal and hepatic dysfunction; hipe insulinemia Biguanidine metformin reduces lactic acidosis; production of glucose effects by the collaterals in the liver; improves GI tract sensitivity to insulin Acarbose inhibitors reduces the effects of alpha-uptake of collaterals on glucose glucosidase by the GI tract; bowel requires frequent postprandial dosing Thiazolidinedione roglitazone stimulates Edema; (withdrawal) receptor PPAR- contraindicated in rosiglitazone nuclear range. heart failure; pioglitazone reduces the principle of resistance to prolonged action; insulin weight gain; frequent liver function test As shown in the table above, each of the common agents available for use in the treatment of diabetes mellitus has several disadvantages. Accordingly, there is a need for the identification and development of new agents, particularly water-soluble agents, which can be administered orally, for use in the treatment of diabetes mellitus and other hyperglycemic disorders. In addition, while the thiazolidinedione class has gained more widespread use in recent years as insulin sensitizers to combat "insulin resistance," a condition in which the patient becomes less responsible for the effects of insulin, there is a need for frequent liver tests using these compounds. In fact, thiazolidinediones are not effective for a significant portion of the patient population. In addition, the first drug in this class to be approved by the FDA, troglitazone, was withdrawn from the market due to liver toxicity problems. Thus, there is a continuing need for more broadly effective, non-toxic insulin sensitizers. As indicated above, the invention is also directed towards the treatment of immunological diseases or inflammation, in particular, diseases such as those mediated by cytokines, COX-2 and iNOS. The main elements of the immune system are macrophages or antigen presenting cells, T cells or B cells. Macrophages are important mediators of inflammation and also provide the "help" necessary for the stimulation and proliferation of T cells. For example, Macrophages make the cytokines IL-1, IL-12 and TNF-alpha, all of which are potent pro-inflammatory molecules. The production of cytokines can lead to the secretion of other cytokines, altered cell function, cell division or proliferation. In addition, the activation of macrophages results in the induction of enzymes, such as COX-2 and iNOS, and in the production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma. It is believed that phosphotyrosine kinases and other cellular kinases are involved in the activation process. Since macrophages are information elements for the development of an immune response, agents that modify their function, specifically their cytokine secretion profile, are likely to determine the direction and potency of the immune response. Inflammation is the body's normal response to damage or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathological inflammatory processes can lead to morbidity or mortality. The tumor necrosis factor (TNF-alpha) by cytokine plays a central role in the inflammatory response and has been selected as a point of intervention in inflammatory diseases. TNF-alpha is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-alpha participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J. Clin. Invest., 83: 444-55, 1989). At higher concentrations, TNF-alpha can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur. J. Immunol., 21: 2575-79, 1991).; Brennan et al., Lancet, 2: 244-7, 1989). TNF-alpha also stimulates the synthesis of proteins in the water phase. In rheumatoid arthritis, a progressive and chronic inflammatory disease that affects approximately 1% of the adult population of the United States. TNF-alpha mediates the cytokine cascade that leads to binding damage and destruction (Arend et al., Arthritis Rheum, 38: 151-60, 1995). TNF-alpha inhibitors, including soluble TNF receptors (etanercept) (Goldenberg, Clin. Ther., 21: 75-87, 1999) and anti-TNF-alpha (infliximab) antibody (Luong et al., Ann Pharmacother, 34: 743-60, 2000), the contents of which are incorporated herein by reference, have recently been approved by the US Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis. Elevated levels of TNF-alpha have been implicated in many other disorders and disease conditions, including cachexia (Fong et al., Am J Physiol, 256: R659-65, 1989), septic shock syndrome (Tracey et al., Proc. Soc Exp Biol Med, 200: 233-9, 1992), osteoarthritis (Venn et al., Arthritis Rheum, 36: 819-26, 1993), inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (Murch et al., Gut. , 32: 913-7, 1991), Behcet's disease (Akoglu et al., J. Rheumatol, 17: 1107-8, 1990), Kawasaki disease (Matsubara et al., Clin. Immunol. Immunopathol, 56: 29-36). , 1990), cerebral malaria (Grau et al., N. Engl J Med, 320: 1586-91, 1989), adult respiratory fatigue syndrome (Millar et al., Lancet 2: 712-4, 1989), asbestosis and silicon (Bissonnette et al., Inflammation, 13: 329-39, 1989), pulmonary sarcoidosis (Baughman et al., J Lab Clin Med, 115 : 36-42, 1990), asthma (Shan et al., Clin Exp Allergy, 25: 1038-44, 1995), AIDS (Dezube et al., J Acquir Immune Defic Syndr, 5: 1099-104, 1992), meningitis ( Waage et al., Lancet, 1: 355-7, 1987), psoriasis (Oh et al., J Am Acad Dermatol, 42: 829-30, 2000), spondyloarthritides such as ankylosing spondylitis (Braun et al., Curr Opin Rheumatol 13: 245-9, 2001 / March-Ortega et al., Arthritis Rheum 44: 2112-7, 2001), host versus graft reaction (Nestlé et al., J Exp Med, 175: 405-13, 1992), multiple sclerosis (Sharief et al., N Engl J Med, 325: 467-72, 1991), generalized lupus erythematosus (Maury et al., Int J Tissue React, 11: 189-93, 1989), diabetes (Hotamisligil et al., Science, 259: 87 91, 1993) and arteriosclerosis (Bruunsgaard et al., Clin Exp Immunol, 121: 255-60, 2000), the contents of each of which are incorporated herein by reference. It can be seen from the references cited above that TNF-alpha inhibitors are potentially useful in the treatment of a wide variety of diseases. Interleukin-6 (IL-6) is another pro-inflammatory cytokine that exhibits pleiotropy and redundancy of action. IL-6 participates in the immune response, inflammation and hematopoiesis. It is a potent inducer of the acute phase hepatic response and is a powerful stimulator of the adrenal-pituitary-hypothalamic axis that is under negative control by means of glucocorticoids. IL-6 promotes the secretion of growth hormone but inhibits the release of the thyroid stimulating hormone. Elevated levels of IL-6 have been seen in many inflammatory diseases, and inhibition of the cytokine subfamily IL-6 has been suggested as a strategy to improve therapy for rheumatoid arthritis (Carrol et al., Inflamm Res, 47: 1 -7, 1998). In addition, 11-6 has been implicated in the progress of arteriosclerosis and the pathogenesis of coronary heart disease (Yudkin et al., Atherosclerosis, 148: 209-14, 1999). Overproduction of IL-6 has also been seen in the steroid withdrawal syndrome, conditions related to dysregulated vasopressin secretion, and osteoporosis associated with increased bone resorption, such as in cases of hyperparathyroidism and sex-steroid deficiency (Papanicolaou and collaborators, Ann Intem Med, 128: 127-37, 1998). Since excessive production of IL-6 is involved in various disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion.

The cytokine IL-1 beta also participates in the inflammatory response. It stimulates the proliferation of thymocyte, the activity of fibroblast growth factor, and the release of prostaglandin from synovial cells. High or unregulated levels of the cytokine IL-1 beta have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory fatigue syndrome (Meduri et al., Chest 107: 1061- 73, 1995), allergy (Hastie et al., Cytokine 8: 730-8, 1996), Alzheimer's disease (O'Barr et al., J Neuroimmunol 109: 87-94, 2000), anorexia (Laye et al., Am J Physiol Regul Integr Comp Physiol 279: R93-8, 2000), asthma (Sousa et al., Thorax 52: 407-10, 1997), arteriosclerosis (Dewberry et al., Artherioscler Thromb Vasc Biol 20: 2394-400, 2000), tumors Brain (Ilyn et al., Mol Chem Neuropathol 33: 125-37, 1998), cachexia (Nakatani et al., Res Commun Mol Pathol Pharmacol 102: 241-9, 1998), (Ikemoto et al., Anticancer Res 20: 317-21 , 2000), chronic arthritis (van den Berg et al., Clin Exp Rheumatol 17: S105-14, 1999), fatig syndrome to chronic (Cannon et al., J Clin Immunol 17: 253-61, 1997), CNS trauma (Herx et al., J. Immunol 165: 2232-9, 2000), epilepsy (De Simon et al., Eur J Neurosci 12 : 2623-33, 2000), fibrotic pulmonary diseases (Pan et al., Pathol Int 46: 91-9, 1996), fulminant hepatic failure (Sekiyama et al., Clin Exp Immunol 98: 71-7, 1994), gingivitis (Biesbrock et al., Monogr Oral Sci 17: 20-31, 2000), glomerulonephritis (Kluth et al., J Nephrol 12: 66-75, 1999), Guillain-Barre syndrome (Zhu et al., Clin Immunol Immunopathol 84: 85-94 , 1997), thermal hyperalgesia (Opree et al., J Neurisci 20: 6289-93, 2000), hemorrhage and endotoxemia (Parsey et al., J. Immunol 160: 1007-13, 1998), inflammatory bowel disease (Olson et al. J Pediatr Gastroenterol Nutr 16: 241-6, 1993), leukemia (Estrov et al., Leuk Lymphoma 24: 379-91, 1997), leukemic arthritis (Rudwaleit et al. , Arthritis Rheum 41: 1695-700, 1998), generalized lupus erythematosus (Mao et al., Autoimmunity 24: 71-9, 1996), multiple sclerosis Martin et al., J Neuroimmunol 61: 241-5, 1995), osteoarthritis (Hernvann et al., Osteoarthritis Cartilage 4: 139-42, 1996), osteoporosis (Zheng et al., Maturitas 26: 63-71, 1997), Parkinson's disease (Bessler et al., Biomed Pharmacother 53: 141-5, 1999), syndrome from POEMS (Gherardi et al., Blood 83: 2587-93, 1994), preterm labor (Dudley, J Reprod Immunol 36: 93-109, 1997), psoriasis (Bonifati et al., J. Biol Regul Homeost Agents 11: 133- 6, 1997), reperfusion injury (Clark et al., J Surg Res 58: 675-81, 1995), rheumatoid arthritis (Seitz et al., J Rheumatol 23: 1512-6, 1996), septic shock (van Deuren et al. , Blood 90: 1101-8, 1997), generalized vasculitis (Brooks et al., Clin Exp Immunol 106: 273-9, 1996), mandibular union disease. poral (Nordahi et al., Eur J Oral Sci 106: 559-63, 1998), tuberculosis (Tsao et al., Tuber Lung Dis 79: 279-85, 1999), viral rhinitis (Roseler et al., Eur Arch Otorhinolaryngol Suppl l: S61-3, 1995), the contents of which are incorporated herein by reference, and pain and / or inflammation resulting from deformation, sprain, trauma, surgery, infection or other disease processes. Since the overproduction of IL-6 beta is associated with numerous disease states, it is desirable to develop compounds that inhibit the production or activity of IL-1 beta. Cytooxygenase is an enzyme that catalyzes a speed determining step in the biosynthesis of prostaglandins, which are important mediators of inflammation and pain. The enzyme is found as at least two different isomers, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 isomer is constitutively expressed in the gastric mucosa, platelets and other cells and is involved in the maintenance of homeostasis in mammals, which includes protecting the integrity of the digestive tract. The COIX-2 isomer, on the other hand, is not constitutively expressed but instead is induced by various agents, such as cytokines, mitogens, hormones and growth factors. In particular, COX-2 is induced during the inflammatory response (DeWitt DL, Biochim Biophys Acta, 1083: 121-34, 1991; Seibert et al., Receptor, 4: 17-23, 1994). Aspirin and other conventional non-steroidal anti-inflammatory drugs (NSAIDs) are non-selective inhibitors of both COX-1 and COX-2. They can be effective in reducing inflammatory pain and swelling, but, since they prevent the protective action of COX-1, they produce side effects of gastrointestinal pathology. Accordingly, agents that selectively inhibit COX-2 but not COX-1 are preferable for the treatment of inflammatory diseases. Recently, a diarylpyrazole sulfonamide (celecoxib) that selectively inhibits COX-2 has been approved by the FDA for use in the treatment of osteoarthritis and adult rheumatoid arthritis (Luong et al., Ann Pharmacother, 34: 743-60, 2000; Penning et al., J Med Chem, 40: 1347-65, 1997). Another selective COX-2 inhibitor, rofecoxib, has been approved by the FDA for the treatment of osteoarthritis, acute pain and acute dysmenorrhea (Scott and Lamb, Drugs, 58: 499-505, 1999; Morrison et al., Obstet Gynecol, 94 : 504-8, 1999; Saag et al., Arch Fam Med, 9: 1124-34, 2000). COX_2 is also expressed in many cancers and precancerous lesions, and there is growing evidence that selective COX-2 inhibitors may be useful for treating and preventing colon, breast, and other cancers (Taketo MM, J. Nati Cancer Inst, 90 : 1609-20, 1998, Fourmier et al, J Cell Biochem Suppl, 34: 97-102, 2000, Masferrer et al, Cancer Res, 60: 1306-11, 2000), the contents of each of which are incorporated to the present as a reference. In 1999 celecoxib was approved by the FDA as an adjunct to the usual care for patients with familial adenomatous polyposis, a condition that, if left untreated, usually leads to colon cancer. The production of nitric oxide by iNOS has been associated with both beneficial and detrimental effects in inflammation, inflammatory diseases and related disorders. For example, detrimental effects have been implicated in the pathogenesis of abdominal aortic aneurysms (Johanning et al., J. Vasc Surg 33: 579-86, 2001), acute endotoxemia (Henningsson et al., Am J Physiol Cell Physiol 280: C1242- 5, 2001), amyotrophic lateral sclerosis (Sasaki et al., Neurosci Lett 291: 44-8, 2000), arteriosclerosis (Behr-Roussel et al., Circulation 102: 1033-8, 2000), bladder cancer (Wolf et al., Virchows Arch 437: 662-6, 2000), colon cancer (Watanabe et al., Biofactors 12: 129-33,2000), cystitis (Alfieri et al., Naunyn Schmiedebergs Arch Pharmacol 363: 353-7, 2001, HIV-1 encephalitis (Zhao et al., J Neuroimmunol 115: 182-91,2001), inflammatory bowel disease (Singer et al., Gastroenterology 111: 871-85. , 1996), multiple sclerosis (Pozza et al., Brain Reser 855: 39-46, 2000), osteoarthritis (Pelletier et al., Osteoarthritis Cartilage 7: 416-8, 1999), osteoporosis Armor et al., J Bone Miner Res 14: 2137-42, 1999), portal hypertension (Schroeder et al., Dig Dis Sci Dec 45: 2405-10, 2000) pulmonary edema in endotoxin shock (Lee et al., Clin Exp Pharmacol Physiol 28: 315-20, 2001), rheumatoid arthritis (vant Hoff et al., Rheumatology (Oxford) 39: 1004-8, 2000), sepsis (Nishina et al., Anesth Analg 92:95 9-66, 2001), damage from severe burns / smoke inhalation (Soejima et al., J Respir Crit Care Med 163: 745-52, 2001), and ulcerative colitis (Ikeda et al., Am J Gastroenterol 92: 1339-41 , 1997), the contents of each of which are incorporated herein by reference. Since the production of nitric oxide by means of iNOS has been implicated in the pathogenesis of related inflammatory and immunological diseases, it is desirable to develop compounds that inhibit the activity or expression of iNOS. Phosphodiestearases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP), which convert these second reporters into their inactive forms. There are eleven major families of PDEs, designated PDE1 to PDE11. Phosphodiesterase type 4 (PDE4) is found in smooth muscle cells of the respiratory tract and in immune and inflammatory cells. PDE4 activity has been associated with a wide variety of inflammatory and autoimmune diseases, and PDE4 inhibitors have been studied as potential therapeutic agents for diseases such as asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis and type 2 diabetes ( Bumouf and Pruniaux, Current Pharm Des, 8: 1255-96, 2002; Dal Piaz and Giovannoni, Eur J Med Chem, 35: 463-80, 2000). Phosphodiesterase type 3 (PDE3) is located in platelets and vascular and cardiac smooth muscle cells. PDE3 inhibitors have been proposed as possible drugs for the treatment of acute respiratory fatigue syndrome (Schemuly et al., J Pharmacol Exp Ther, 292: 512-20, 2000), cancer (Shimizu et al., Anticancer Drugs, 13: 875 -80, 2002; Murata et al., Anticancer Drugs, 12: 79-83, 2001), cardiomyopathy (Alharethi and Movsesian, Expert Opin Investig Drugs, 11: 1529-36, 2002), congestive heart failure (Movsesian, J Am Coll Cardiol, 34: 318-24, 1999), erectile dysfunction (Kuthe et al., Curr Opin Investig Drugs, 3: 1489-95, 2002), and autoimmune disorders mediated by T cells (Bielekova et al. J Immunol 164: 1117-24 , 2000), the contents of each of which are incorporated herein by reference. Lymphocyte activation and the macrophage immune response to pathogens involve complex intracellular signaling pathways involving a cascade of several phosphorylating enzymes, kinases that ultimately regulate cytokine production and cellular apoptosis. Key kinases include the MAP kinase p44 / 42 (also known as ERK1 / ERK2), MAP kinase P38, MEK, and IRAK / NFKB. Although different processes use different aspects of the pathway, the LPS protein derived from the bacterial coat has been shown to activate the multiple mitogen-activated protein kinases, which include the regulated receptor ERK1 and ERK2 kinases of the extracellular signal. The production of TNF-α induced by LPS by means of human monocytes involves the activation of ERK1 / ERK2 (van der Bruggen et al., Infect. Immun, 67: 3824-9, 1999). As TNF-alpha is a key mediator of autoimmune diseases, blocking the ERK pathway has potential for the treatment of inflammatory and immunological diseases such as lupus (Yi et al., J Immunol, 165: 6627-34, 2000), Rheumatoid arthritis (Neff et al., Cell Microbiol, 3: 703-12, 2001; Schett et al., Arthritis Rheum, 43: 2501-12, 2000), psoriasis (van der Bruggen et al., Infect Immun, 67: 3824-9, 1999) and the destruction of beta cells of the pancreatic islet in Type 1 diabetes (Pavlovic et al., Eur Cytokine Netw 11: 267-74, 2000), the contents of each of which are incorporated herein by reference. From the foregoing it will be appreciated that, although there have been extensive prior efforts to provide compounds to inhibit, for example, TNF-alpha, IL-lbeta, IL-6, COX-2, PDE4 or other agents considered responsible for inflammation or inflammatory diseases, for example, arthritis, there remains a need for improved and new compounds to effectively treat or inhibit such diseases. A principal object of the invention is to provide compounds that are effective for such treatments, as well as for the treatment of, for example, diabetes, coronary heart disease, insulin resistance and related disorders.

SUMMARY OF THE INVENTION The invention is directed to compounds, for example, heterocyclic derivatives of acyl urea, thiourea, carbamate and thiocarbamate compounds, to provide a variety of useful pharmacological effects. The compounds are useful, for example, in lowering blood glucose levels in hyperglycemic disorders, such as diabetes mellitus, and in treating related disorders, such as obesity and hyperlipidemia. In addition, these compounds are useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, and for the treatment of inflammation and immune diseases, particularly those mediated by pro-inflammatory cytokines (such as TNF). -alpha, IL-1 beta and IL-6), phosphodiesterase type 4 (PDE4), phosphodiesterase type 3 (PDE3), protein kinase (MAP) activated by mitogen p44 / 42, cyclooxygenase-2 (COX-2) and / or inducible nitric oxide synthase (iNOS). In particular, the invention describes compounds of Formulas I-XIII as well as pharmaceutically acceptable salts and solvates thereof.

?? Where the stereocenters marked with an asterisk (*) can be R- or S-; the link represented by a broken line plus a solid line can be a double link or a single link, and when the link is a double link it can be in the E or Z configuration, and when the link is a single link the resulting stereocenters they may have the R- or S- configuration; and Ri, R2, R3, R4, Rs, e and R7 are independently selected from the group consisting of H; C1-C20 optionally substituted linear or branched alkyl including chloroalkyl or fluoroalkyl; C2-C2 optionally substituted straight or branched alkenyl; C6-C20 optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR wherein R is H, C1-C20 optionally substituted alkyl, optionally substituted C2-C2o alkenyl or optionally substituted Ce-Cio aryl, sodium, potassium or other pharmaceutically acceptable counterions such as calcium, magnesium, ammonium, tromethamine and the Similar; COOR'R ", wherein R 'and R" are independently H, C1-C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or C6-Cio optionally substituted aryl or where NR'R "represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; Ci-C6 optionally substituted amidoalkyl; NH2; C1-C20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH: C1-C20 optionally substituted alkoxy including trifluoromethoxy and the like; C1-C20 alkanoyl optionally substituted; C1-C20 optionally substituted acyloxy; halo; C1-C20 alkylcarboxylamino optionally substituted; cyano; nitro; S02NR '' ', R "" where R' "and R" "are independently H, C1-C20 alkyl or aryl; S02R "'where R"' is H, C1-C20 alkyl or aryl; S03R '"where R"' is H,?! -? 20 alkyl or aryl; and C4-C8 heterocycles such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, indolyl and the like; and wherein when the individual aromatic rings possess adjacent substituents, these substituents can be joined together to form a ring such as a methylenedioxy or ethylenedioxy group, and the like, including lactones and lactams; R8 and Rg are independently selected from the group consisting of H; Ci-C2o optionally substituted straight or branched alkyl; C2-C2o optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; COOR where R is optionally substituted H, C1 -C20 alkyl; C 2- C20 optionally substituted alkenyl or C6-Ci or optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counterion such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", wherein R' and R" are independently H.alkoxy, C1-C20 alkyl optionally substituted, C2-C2o optionally substituted alkenyl, C3-C10 cycloalkyl or optionally substituted cycloalkenyl or C6-Cio aryl or optionally substituted heteroaryl, preferably 2-, 3- or 4- pyridyl; or wherein NR 'R "represents a cyclic moiety such as morpholine, piperidine, hydroxypiperidine, imidazole, piperazine, methylpiperazine and the like; NH2; Ci-C2o alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20 alkoxy C 1 -C 20 alkanoyl; C 1 -C 20 acyloxy; halo C 1 -C 20 alkylcarboxylamino; cyano; nitro; S 2 NR '"' R" "wherein R" 'and R "" are independently H, C 1 -C 20 alkyl or aryl; SO R "'where R"' is H, C1-C20 alkyl or aryl; S03R "'where R' '' is H, C1-C20 alkyl or aryl, and tetrazolyl, and wherein R8 and R9 together may be joined to form a heterocyclic C4-C8 ring, which includes lactone or lactam; Ri o and R 11 are independently from each other, selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl; C2-C? 0 optionally substituted straight or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; COOR where R is H, Ci -C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or C6-Ci0 optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R" are independently H, C! -C2o optionally substituted alkyl, C2-C2o optionally substituted alkenyl or optionally substituted aryl C6-Ci0 or where NR 'R "represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; Ci-C20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20 alkoxy; C1-C20 alkanoyl; Ci-C2o acyloxy; halo; Ci-C20 alkylcarboxylamino; cyano; nitro; S02NR '' 'R "" wherein R' "and R" "are independently H, Ci-C20 alkyl or aryl; S02R '' 'where R' '' is H, C: -C2o alkyl or aryl; SO3R Where R "'is H, Ci-C20 alkyl or aryl, and tetrazolyl, and wherein Rio and Rn together may be joined to form a heterocyclic C4-C8 ring, including lactone or lactam; Ri?, Ria r? e? R <9> and R <2o> are independently selected from the group consisting of H, optionally substituted linear or branched C1-C20 alkyl, C2-C20 linear or branched alkenyl optionally replaced; C6-C10 optionally substituted aryl or heteroaryl; COOR where R is Ci-C20 optionally substituted alkyl, optionally substituted C2-C20 alkenyl; or C6-Ci or optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R3 are independently H, C1-C20 optionally substituted alkyl, C2-C20 optionally substituted alkenyl or C6-Cm optionally substituted aryl or where NR 'R" represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; C1-C20 alkanoyl; C1-C20 alkylamido; C6-C2o aroyl or heteroaroyl; SO2R '' 'wherein R' "is H, C1-C20 alkyl or aryl; morpholinocarbonylmethyl; piperazinecarbonylmethyl; and piperadinocarbonylmethyl; Ri- and R13 may be absent, or R12 and together may be an optionally substituted heterocyclic ring, preferably morpholine, piperidine, piperazine, and N-methyl piperidine. R14 is selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl and fluoroalkyl; C2-C20 optionally substituted linear or branched alkenyl; C6-Ci or optionally substituted aryl or heteroaryl; COOR where R is H, C1-C20 optionally substituted alkyl, C2-C20 optionally substituted alkenyl or C3-C10 optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R" are independently H, Ci-C? 0 optionally substituted alkyl, C2-C20 optionally substituted alkenyl or optionally substituted aryl C6-C10 or where NR 'R "represents a cyclic moiety such as morpholine , piperidine, piperazine and the like; cyano; and tetrazolyl; R15, R16 and R17 are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl and fluoroalkyl; C2-C20 linear alkenyl or optionally substituted branched; C6-C10 optionally substituted aryl or heteroaryl; COOR where R is H, C1-C20 optionally substituted alkyl, C2-C20 optionally substituted alkenyl or C6-Ci or optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counter ion such as calcium, magnesium, ammonium, tromethamine and the like; CONR'R ", wherein R 'and R" are independently selected from optionally substituted H, C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted aryl C6-Ci0 or where NR'R "represents a cyclic moiety such as morpholine , piperidine, piperazine and the like; NH2; C1-C20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH, Ci-C20 alkoxy; Ci-C2r alkanoyl; C1-C20 acyloxy; halo; C1-C20 alkylcarboxylamino; cyano; nitro; S02NR "'R" "where R"' and R "" are independently H, C! -C2o alkyl or aryl; S02R '"where R'" is H, C1-C20 alkyl or aryl; S03R "' where R "'is H, C1-C20 alkyl or aryl, and tetrazolyl; X is independently selected from the group consisting of O; N; S; S = 0; S02; or NR'" ", where R" "'may H or C1-C20 optionally substituted alkyl, C-: - C2o optionally substituted alkenyl, Ci-C? or optionally substituted acyl, Ci-C? or optionally substituted acyloxy and Ci-C2o alkoxycarbonyl optionally replaced body; And it is independently 0, S, or NH; Z is 0 Ra where Ra is selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C20 optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; Ce-Cao optionally substituted aryl or heteroaryl; C1-C20 optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, Ci-C2o alkyl or aryl; or Z is NRbRc where Rb and Rc are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C20 optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; C3-C10 optionally substituted cycloalkyl or cycloalkenyl; COOZi where Zi is optionally substituted C1-C20 alkyl, optionally substituted C2-C2o alkenyl or optionally substituted C6-Ci0 aryl; C6-C2o optionally substituted aroyl or heteroaroyl; Ci -Cone optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, Ci-C20 alkyl or aryl; and wherein R and Rc together can be joined to form a 3-6-element ring such as aziridine, morpholine, piperidine, piperazine and the like; or Z is CRdReRf where R¿, Re and Rf are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C25 optionally substituted straight or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; C3-C10 optionally substituted cycloalkyl or cycloalkenyl; COOR where R is H, C1-C20 optionally substituted alkyl, optionally substituted C2-Cro alkenyl or optionally substituted C6-Ci0 aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; NH2; C1-C20 alkylamino, bis (alkylamino); cycloalkylamino or cyclic amino; OH; Ci-C20 optionally substituted alkoxy including trifluoromethoxy and the like; Ci-optionally substituted alkanoyl; C1-C20 optionally substituted acyloxy; C6-C2o optionally substituted aroyl or heteroaroyl; halo; cinao; nitro; C1-C 0 optionally substituted alkylcarboxylamino; S02NR '' 'R "" wherein R' "and R" "are independently H, C1-C20 alkyl or aryl; S02R '' 'where R' "is H, C1-C20 alkyl or aryl; and SO3R '' 'is H, C1-C20 alkyl or aryl; and wherein Rd and Re together can be joined to form a ring of 3-6 elements such as aziridine, morpholine, piperidine, piperazine and the like; and the resulting stereocenter may have the R- or S- configuration; o The grouping C (= Y) Z can represent hydrogen or R12 or may be absent. Q is QRa where Ra is selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C2o optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; C6-C20 optionally substituted aroyl or heteroaroyl; Ci-C20 optionally substituted alkanoyl; and S02R "'where R"' is H, C1-C20 alkyl or aryl; or Q is NRbRc where Rb and Rc are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C20 optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; C3-CiU optionally substituted cycloalkyl or cycloalkenyl; COOZi wherein Zi is optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted aryl C6-C10; C6-C2o optionally substituted aroyl or heteroaroyl; CL-C20 optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, C1-C20 alkyl or aryl; and wherein Rb and Rc together can be joined to form a 3-6-element ring such as aziridine, morpholine, piperidine, piperazine and the like; or Q is SRg, S0RQ or S02Rg where Ra is selected from the group consisting of H; Ci-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C20 optionally substituted linear or branched alkenyl; Ci-C20 optionally substituted acyl; Ci-C20 optionally substituted alkoxycarbonyl; C2-C20 alkoxy; C6-Ci0 optionally substituted aryl or heteroaryl; and optionally substituted C6-Ci0 aroyl or heteroaroyl. Group A is C2-C20 optionally substituted straight or branched alkenyl; C6-C20 optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl, optionally substituted heteroaryls such as pyridine, indole, morpholine, piperidine, piperazine, tetrazoyl and the like; COR wherein Ri is Ci-C2o or optionally substituted straight or branched alkyl; C2-C20 optionally substituted linear or branched alkenyl; C6-C20 optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally substituted heteroaryls such as pyridine, indole, morpholine, piperidine, piperazine, tetrazolyl and the like; Group B is OH, Ci-C20 alkoxy; S02R where R can be H or Ci-C20 linear or branched alkyl. The Het Group represents a heterocyclic ring which is pyridyl, indolyl, tetrazolyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl, thiophenyl or the like. These compounds are useful for treating diabetes and other diseases linked to insulin resistance, such as coronary artery disease and peripheral vascular disease, and also for treating or inhibiting inflammation or inflammatory diseases such as inflammatory arthritis and vascular collagen diseases. , which are caused by, for example, cytokines or by inducible enzymes such as TNF-alpha, IL-1, IL-6, iNOS and / or COX-2. The compounds are also useful for treating or preventing other diseases mediated by cytokines, iNOS and / or COX-2, such as cancer. Another aspect of the invention is a method of treating diabetes and related diseases comprising the step of administering to a subject suffering from a diabetic or diabetes-related condition a therapeutically effective amount of a compound of Formulas I-XIII. Additionally, the invention provides a method of treating inflammation or inflammatory diseases or diseases mediated by cytokines, iNOS, PDE4, PDE3, MAP kinase p44 / 42 and / or COX-2 by administering to a subject in need of such treatment an effective amount of a compound in accordance with Formulas I-XIII. Additionally, pharmaceutical compositions are also provided that contain a therapeutically effective amount of one or more compounds according to Formulas I-XIII together with a pharmaceutically or physiologically acceptable carrier for use in the treatment contemplated herein.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a graph of the increase in dose-dependent glucose uptake in 3T3-L1 adipocytes treated with varying concentrations of a compound according to the invention. Figure 2 shows a graph of the improvement in glucose uptake in 3T3-L1 adipocytes treated with a compound according to the invention to vary insulin concentrations. Figure 3 shows a graph of the abatement of glucose levels in ob / ob mice treated with a compound according to the invention. Figures 4A and 4B show graphs of serum triglyceride depletion and free fatty acid levels, respectively, in ob / ob mice treated with a compound according to the invention.

Figure 5 shows a graph of the inhibition of TNF-alpha production induced by LPS in mouse RAW264.7 cells treated with varying concentrations of a compound according to the invention. Figure 6 shows a graph of inhibition of LPS-induced IL-1 beta production in mouse RAW264.7 cells treated with varying concentrations of a compound according to the invention. Figure 7 shows a graph of the inhibition of IL-6 production induced by LPS in mouse RAW264.7 cells treated with varying concentrations of a compound according to the invention. Figure 8 shows photos of Western stains demonstrating the inhibition of COX-2 and iNOS production induced by LPS in mouse RAW264.7 cells treated with varying concentrations of a compound according to the invention. Figure 9 shows a graph of median clinical ratings over time demonstrating the improvement of collagen-induced arthritis in mice using varying concentrations of a compound according to the invention.

DETAILED DESCRIPTION OF THE INVENTION The invention is based on the discovery that the compounds described herein are useful in the treatment of diabetes and other diseases linked to insulin resistance, such as coronary artery disease and peripheral vascular disease, and also for the treatment or inhibition of inflammation or inflammatory diseases such as inflammatory arthritides and vascular diseases by collagen, which are caused by, for example, inducible enzymes or cytokines such as TNF-alpha, IL-1, IL-6 , PDE4, PDE3, MAP kinase p44 / 42, iNOS and / or COX-2. Definitions As used herein, the following terms, unless otherwise indicated, should be understood to have the following meanings: "Alkyl" alone or in combination, means a branched or straight chain alkyl radical that preferably contains 1-20 carbon atoms, more preferably 1-10 carbon atoms, and more preferably 1-6 carbon atoms. Exemplary alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, iso-amyl, hexyl and the like. "Alkenyl", alone or in combination, means a branched chain or straight chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably a double bond, and preferably containing 2-20 atoms of carbon, more preferably 2-10 carbon atoms, and even more preferably 2-6 carbon atoms. Exemplary alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, n-butenyl, isobutenyl, and include groups containing multiple sites of unsaturation such as 1,3-butadiene and 1,4-butadienyl and the like. "Alkoxy", alone or in combination, means a radical of type "R-0-", wherein R can be hydrogen, linear or branched alkyl, or linear or branched alkenyl as previously defined and "0" is a oxygen atom. Exemplary alkoxy radicals include, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. "Alkoxycarbonyl", alone or in combination, means a radical of the type "ROC (O) -" where "R-0-" is an alkoxy radical as previously defined and "C (0) -" is a carbonyl radical . Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. "Alkylcarboxylamino" means an RCON® group - where R can independently be hydrogen, linear or branched alkyl, or straight or branched alkenyl as previously defined. "Alkanoyl", alone or in combination, means a radical of type "R-C (O) -" wherein "R" is an alkyl radical as previously defined and "-C (O) -" is a carbonyl radical. Exemplary alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl and the like. "Halo" or "Halogen", alone or in combination, means the chlorine, bromine, fluorine or iodine radicals. "Aryl", alone or in combination, means an aromatic carboxylic radical containing about 6 to about 10 carbon atoms, which are optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro , cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N, N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl , oxo and the like. Exemplary aryl radicals include phenyl, o-tolyl, 4-methoxyphenyl, 2- (tert-butoxy) phenyl, 3-methyl-4-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3- acetamidophenyl, 2-amino-3- (aminomethyl) phenyl, 6-methyl-2-aminophenyl, 2-amino-3-methylphenyl, 4,6-dimethyl-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl 4- (2-methoxyphenyl) phenyl, 2-amino-1-naphthyl, 2-naphthyl, 1-methyl-3-amino-2-naphthyl, 2, 3-diamino-1-naphthyl, 4,8-dimethoxy 2- naphthyl and the like. "Acyloxy" or "Acylamino" group means an oxygen or amino group, respectively, linked to an acyl group (RCO) where R can be hydrogen, linear or branched alkyl, or straight or branched alkenyl. "Alqui lido" means the group RN (H) C0- where R can be hydrogen, linear or branched alkyl, or linear or branched alkenyl, as previously defined. The reference to "optionally substituted" in the definition of the compounds in the course of this description is intended to include any substituent that does not adversely affect the activity of the compounds. Typical substitution includes, for example, (C1-C6) lower alkyl; halogen such as fluorine, chlorine and bromine; nitro; Not me; lower alkylamino; carboxylate, lower alkyl carboxylate, hydroxy, lower alkoxy, sulfonamide, cyano, or the like. The invention is directed to compounds, for example, heterocyclic derivatives of acyl urea, thiourea, carbamate and thiocarbamate compounds, which provides a variety of useful pharmacological effects. The compounds are useful, for example, in lowering blood glucose levels in hyperglycemic disorders, such as diabetes mellitus, and in treating disorders, such as obesity and hyperlipidemia. In addition, these compounds are useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, and for the treatment of inflammation, inflammatory and immunological diseases, particularly those mediated by pro-inflammatory cytokines (such as TNF). -alpha, IL-1 beta and IL-6), phosphodiesterase type 4 (PDE4), phosphodiesterase type 3 (PDE3), mitogen-activated protein kinase (MAP) p44 / 42, cyclooxygenase-2 (COX-2) and / or inducible nitric oxide synthase (iNOS). In particular, the invention describes compounds of Formulas I-XIII as well as the pharmaceutically acceptable salts and solvates thereof: ?? wherein the stereocenters marked with an asterisk (*) can be R- or S-; the link represented by a dotted line plus a solid line can be a double bond or a single link, and when the link is a double bond it can be in the E or Z configuration, and when the link is a single link the resulting stereocenters can have the R- or S- configuration; and Rií R-2f R-3 / R 5, R 6 and 7 are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl; C2-C2o optionally substituted linear or branched alkenyl; C6-C20 optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR wherein R is H, C1-C20 optionally substituted alkyl, C2-C20 optionally substituted alkenyl or optionally substituted Ce-Cio aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; COOR'R ", wherein R 'and R" are independently H, C1-C20 optionally substituted alkyl, C2-C2o optionally substituted alkenyl or C6-Cio optionally substituted aryl or wherein NR'R "represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; Ci-C6 optionally substituted amidoalkyl; NH2; Ci-C2u alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH: Ci-C20 optionally substituted alkoxy including trifluoromethoxy and the like; C1-C-0 optionally substituted alkanoyl; optionally substituted Ci-C20 acyloxy; halo; Ci-C20 optionally substituted alkylcarboxylamino; cyano; nitro; S02NR '' 'R "" wherein R' "and R" "are independently H, C1-C20 alkyl or aryl; S02R "'where R"' is H, C1-C20 alkyl or aryl; SO3R "'where R'" is H, C: -C2o alkyl or aryl; and C4-C8 heterocycles such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, indolyl and the like; or when the individual aromatic rings possess adjacent substituents, these substituents can be joined to form a ring such as a methylenedioxy or ethylenedioxy group, and the like, including lactones and lactams; R8 and Rg are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl; C2-C2o optionally substituted linear or branched alkenyl; C6-C10 optionally substituted aryl or heteroaryl; COOR where R is optionally substituted H, C1 -C20 alkyl; C2-C2o optionally substituted alkenyl or C6-Cio optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counterion such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R" are independently H, alkoxy, optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 3 -C 10 cycloalkyl or cycloalkenyl or optionally substituted Ce-Cio aryl or heteroaryl , preferably 2 -, 3 - or 4-pyridyl; or wherein NR 'R "represents a cyclic moiety such as morpholine, piperidine, hydroxypiperidine, imidazole, piperazine, methylpiperazine and the like; NH2; Ci-C20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH; C 1 -C 20 alkanoyl; C 1 -C 20 acyloxy; halo C 1 -C 20 alkylcarboxylamino; cyano; nitro; S 2 NR '' 'R "" wherein R' "and R" "are independently H, C 1 -C 20 alkyl or aryl; S02R "'where R"' is H, Ci-C20 alkyl or aryl; S03R "'where R'" is H, C1-C20 alkyl or aryl; and tetrazolyl; wherein Re and Rg together can be joined to form a heterocyclic C4-C8 ring, which includes lactone or lactam; Ri or y n are independently of each other, selected from the group consisting of H; C1 -C20 optionally substituted straight or branched alkyl; C2-C2o optionally substituted linear or branched alkenyl; C6-C10 optionally substituted aryl or heteroaryl; COOR where R is H, C 1 -C 20 optionally substituted alkyl, optionally substituted C 2 -C 20 alkenyl or optionally substituted C 6 -C 0 aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R" are independently H, C1-C20 optionally substituted alkyl, C2-C2o optionally substituted alkenyl or C6-Ci or optionally substituted aryl or where NR 'R "represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; C1-C20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20 alkoxy; C1-C20 alkanoyl; C1-C20 acyloxy; halo; Ci-C-alkylcarboxylamino; cyano nitro; S02NR '' 'R "" wherein R' "and R" "are independently H, C1 -C20 alkyl or aryl; S02R '' 'where R' '' is H, C1-C20 alkyl or aryl; SO3R '' 'where R' "is H, C1-C20 alkyl or aryl; and tetrazolyl; and wherein R10 and Rn together can be joined to form a heterocyclic C4-C8 ring, including lactone or lactam; Ri2 Ri3 > Rie / R19 and R20 are selected, independently of each other from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl; C2-C or optionally substituted straight or branched alkenyl; C6-Ci 0 optionally substituted aryl or heteroaryl; COOR where R is optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl; or C6-C10 optionally substituted aryl, sodium, potassium or other pharmaceutically acceptable counterions such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R" are independently H, C1-C20 optionally substituted alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-Cio aryl or where NR 'R "represents a cyclic moiety such as morpholine, piperidine, piperazine and the like, C1-C20 alkanoyl, C1-C20 alkylamido, C6-C2o aroyl or heteroaroyl, S02R '' 'where R' '' is H, C1-C20 alkyl or aryl, morpholinocarbonylmethyl, piperazinocarbonylmethyl, and piperadinocarbonylmethyl; R 13 may be absent, or R 2 and R 13 together may be an optionally substituted heterocyclic ring, preferably morpholine, piperidine, piperazine, and N-methyl piperidine R 14 is selected from the group consisting of optionally H-C 1 -C 20 straight or branched alkyl substituted including chloroalkyl and fluoroalkyl, C2-C2o or optionally substituted straight or branched alkenyl, Ce-Cio aryl or optionally substituted heteroaryl, COOR where R is H, C1-C20 alkyl optionally substituted optionally substituted C -C20 alkenyl or optionally substituted C6-C10 aryl, sodium, potassium or other pharmaceutically acceptable counterions such as calcium, magnesium, ammonium, tromethamine and the like; CONR'R ", wherein R 'and R" are independently H, Ci-C20 alkyl optionally substituted, C2-C2o optionally substituted alkenyl or C6-C10 optionally substituted aryl or where NR' R "represents a cyclic moiety such as morpholine, piperidine , piperazine and the like; cyano; and tetrazolyl; i5 / Ri6 and Rn are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl and fluoroalkyl; C2-C20 straight or branched alkenyl optionally substituted C6-C10 optionally substituted aryl or heteroaryl, COOR where R is H, C1-C20 optionally substituted alkyl, optionally substituted C2-C2o alkenyl or optionally substituted aryl GC-CIO, sodium, potassium or other pharmaceutically acceptable counter ion such as calcium, magnesium, ammonium, tromethamine and the like; CONR 'R ", where R' and R" are independently selected from H, C 1 -C 20 alkyl optionally substi optionally substituted C2-C20 alkenyl or optionally substituted aryl C6-C10 or where NR 'R "represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; C1-C20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH, C1-C20 alkoxy; Ci -C:, > alkanoyl; C1-C20 acyloxy; halo; Ci-C20 alkylcarboxylamino; cyano; nitro; S02NR '' 'R "" where R' "and R" "are independently H, Ci-C20 alkyl or aryl; S02R '' 'where R"' is H, C1-C20 alkyl or aryl; S03R "'where R"' is H, C1 -C20 alkyl or aryl; and tetrazolyl; X is independently selected from the group consisting of O; N; S; S = 0; S02; or NR "'"', where R "" 'may be H or Ci-C20 optionally substituted alkyl, C: - C2o optionally substituted alkenyl, C1-C20 optionally substituted acyl, optionally substituted CL-C20 acyloxy and Ci-C2o optionally substituted alkoxycarbonyl: Y is independently O, S, or NH; Z is ORa wherein Ra is selected from the group consisting of H; Ci-C2o or optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C20 linear alkenyl or optionally substituted branched C6-Ci or optionally substituted aryl or heteroaryl, C6-C20 optionally substituted aroyl or heteroaroyl, optionally substituted C1-C20 alkanoyl, and SO2R '' 'where R' '' is H, Ci-C20 alkyl or aryl or Z is NRRc where R and Rc are independently selected from the group consisting of optionally substituted C1-C20 linear or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C? or linear alkenyl or branched optionally substituted; C6-Ci0 optionally substituted aryl or heteroaryl; COOZi where Zi is Ci-C2o alkyl optionally substituted, C2-C20 optionally substituted alkenyl or Cfi-Cio aryl optionally substituted; C6-C20 optionally substituted aroyl or heteroaroyl; Ci -C20 optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, C1-C20 alkyl or aryl; and wherein Rb and Rc together can be joined to form a ring of 3-6 elements such as aziridine, morpholine, piperidine, piperazine and the like; or Z is CRdReRf where Ra, Re and f are independently selected from the group consisting of H; Ci -C2o optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C20 optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; COOR where R is H, C i -C20 optionally substituted alkyl, optionally substituted C2-C2o alkenyl or optionally substituted C6-Cio aryl, sodium, potassium or other pharmaceutically acceptable counter ions such as calcium, magnesium, ammonium, tromethamine and the like; NH ?; C1-C20 alkylamino, bis (alkylamino); cycloalkylamino or cyclic amino; OH; C1-C20 optionally substituted alkoxy including trifluoromethoxy and the like; Ci-C2 or optionally substituted alkanoyl; C1-C20 acyloxy optionally substituted; C6-C20 optionally substituted aroyl or heteroaroyl; halo; cyano; nitro; C i -C20 alkylcarboxylamino optionally substituted; SC > 2NR '' 'R "" where R "' and R" "are independently H, C: -C20 alkyl or aryl; S02R" 'where R "' is H, Ci-C20 alkyl or aryl; and S03R '' 'where R '' 'is H, C1-C20 alkyl or aryl, and where Rd and Re together can be joined to form a 3-6-element ring such as aziridine, morpholine, piperidine, piperazine and the like, and the resulting stereocenter can having the configuration R- or S-, or the grouping C (= Y) Z may represent hydrogen or R12 or may be absent Q is 0Ra where Ra is selected from the group consisting of H; C1-C20 linear or branched alkyl optionally substituted including chloroalkyl or fluoroalkyl and the like; C2-C2o optionally substituted straight or branched alkenyl; C6-Ci0 aryl or optionally substituted heteroaryl; C5-C2o optionally substituted aroyl or heteroaroyl; optionally substituted C1-C20 alkanoyl; and S02R "'where R "'is H, C1 -C20 alkyl or aryl, or Q is NRbRc where Rb and Rr. are selected inde independently of the group consisting of H; C1 -C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C2o optionally substituted linear or branched alkenyl; C6-Ci0 optionally substituted aryl or heteroaryl; C3-C10 optionally substituted cycloalkyl or cycloalkenyl; COOZ i wherein Z i is optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 2 or alkenyl or optionally substituted C 6 -Cio aryl; C6-C2o optionally substituted aroyl or heteroaroyl; C1-C20 optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, C1-C20 alkyl or aryl; and wherein Rb and Re together can be joined to form a 3-6-element ring such as aziridine, morpholine, piperidine, piperazine and the like; or Q is SRg, SORg or S02Rg where Rg is selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including chloroalkyl or fluoroalkyl and the like; C2-C2o optionally substituted linear or branched alkenyl; Ci-C20 optionally substituted acyl; C1-C20 optionally substituted alkoxycarbonyl; C2-C20 alkoxy; C6-Ci0 optionally substituted aryl or heteroaryl; and optionally substituted C6-Cio aroyl or heteroaroyl. Group A is C2-C20 optionally substituted straight or branched alkenyl; C6-C20 optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl, optionally substituted heteroaryls such as pyridine, indole, morpholine, piperidine, piperazine, tetrazoyl and the like; COR wherein Ri is C1-C20 linear or branched alkyl optionally substituted; C2-C20 optionally substituted linear or branched alkenyl; C6-C20 optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally substituted heteroaryls such as pyridine, indole, morpholine, piperidine, piperazine, tetrazolyl and the like; Group B is OH, C1-C20 alkoxy; S02R where R can be H or C1-C20 linear or branched alkyl. The Het Group represents a heterocyclic ring which is pyridyl, indolyl, tetrazolyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl, thiophenyl or the like. These compounds are useful for treating diabetes and other diseases linked to insulin resistance, such as coronary artery disease and peripheral vascular disease, and also for treating or inhibiting inflammation or inflammatory diseases such as inflammatory arthritis and vascular collagen diseases. , which are caused by, for example, cytokines or by inducible enzymes such as TNF-alpha, IL-1, IL-6, PDE4, PDE3, MAP kinase p44 / 42, iNOS and / or COX-2. The compounds are also useful for treating or preventing other diseases mediated by cytokines, PDE4, PDE3, MAP kinase p44 / 42, iNOS and / or COX-2, such as cancer. As indicated above, the compounds of the invention include bonds, designated in Formulas I-XIII with a dotted line plus a solid line, which may be either a double bond or a single bond. When such a link is a double bond it can be either in the E or Z configuration. On the other hand, when such a link is a single link, the resulting stereocenters can be in the R- and / or S- configurations. Similarly, the compounds of the invention with other stereocenters, designated in Formulas I-XIII with an asterisk may be R- and / or S- stereoisomers. The invention contemplates racemic mixtures of said stereoisomers as well as individual, separate stereoisomers. Individual stereoisomers can be obtained through the use of an optically active resolving agent. Alternatively, a desired enantiomer can be obtained by stereospecific synthesis using an optically pure starting material of known configuration. Generally, R- or S- refers to the configuration of the stereoisomers. The determination of whether the configuration is R- (rectus) or S- (sinister) is based on the priority of atoms in a compound. In a similar way, the E- or Z- configuration is used when compounds are described with double bonds and where the determination is based on the priority of the atom on each carbon of a double bond. The following compounds are representative of preferred compounds according to Formula I: 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} -acrylic (1); 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylic (6); 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-Ethoxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} - acrylic (8); 2- (4- [4- (3-Benzoyloxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl] -3- (3, 5-dimethoxyphenyl) -acrylic acid methyl ester (9); (3,5-dimethoxyphenyl) -2- {4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - propionic (10); 3- (3,5-dimethoxyphenyl) ) - 2- {4- [4- (3-oxo-3-ureidopropenyl) -phenoxy] -phenyl} - acrylic (11) 3- (3,5-dimethoxyphenyl) -2-ethyl ester - { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} -acrylic (12); 3- (3,5-dimethoxyphenyl) - N, N-dimethyl- 2- {. 4- [4-vinyl] -phenyl} - benzamide (67); 2- {4- [4- (1-dimethylcarbamoyl-2-pyridin-3-yl-vinyl) -phenoxy] - benzyl.) - malonamide (71); 3- {4- [4- (2-benzo [l, 3] dioxol-5-yl-1-dimethylcarbamoyl-vinyl) -phenoxy] -phenyl ester. .) - propionic (69); 3-benzo [l, 3] dioxol-5-yl-2- {4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} - N, N - dimethyl acrylamide (72); N, N-dimethyl-2-. {4- [4- (3-ox o- 3- ureidopropyl) -phenoxy] -phenyl} 3- pyridin-3-yl-acrylamide (73); The following are the most preferred compounds for their antidiabetic properties: 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-ethoxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} - acrylic (8); (4- {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoyl-vinyl] -phenoxy} -benzyl) -carbamic acid methyl ester (29); 2- . { 4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} - 3- (3, - dimethoxyphenyl) - N, N-dimethylarilamide (31); 3- (3,5-dimethoxyphenyl) - N, N-dimethyl- 2-. { 4- [4- (3-morpholin-4-yl-3-oxopropyl) -phenoxy] -phenyl} acrylamide (40); [3- (4- { 4- [2- (3,5-dimethoxyphenyl) -1- (piperidin-1-carbonyl) -vinyl] -phenoxy} - phenyl) -propionyl] -urea (51); 2- . { 4- [4- (3-acetylamino-3-oxopropyl) -phenoxy] -phenyl} 3- (4-fluorophenyl) -N, N-dimethylacrylamide (56); 3- (3,5-dimethoxyphenyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - N-pyridin-4-ylacrylamide (60); N- (4-chlorophenyl) -3- (3,5-dimethoxyphenyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide (61); 3- (3,5-dimethoxyphenyl) - N, N-dimethyl-2- (4-. {4- [2- (2-morpholin-4-yl-2-oxoethylcarbamoyl) -ethyl] -phenoxy}. phenyl) -acrylamide (63); 3- (3, 5-dimethoxyphenyl) -?,? - dimethyl-2- (4-. {4- [3- (4-methyl-piperazin-1-yl) -3-oxopropyl] -phenoxy} - phenyl ) -acylamide (6); However, it will be appreciated that the invention also contemplates the supply and use of other compounds in accordance with Formulas I-XIII. The compounds according to the present invention can be combined with a physiologically acceptable carrier or vehicle to provide a pharmaceutical composition, such as lyophilized powder in the form of a tablet or capsule with various fillers or binders. Similarly, the compounds can be co-administered with other agents. Co-administration means the administration of at least two agents to a subject so as to provide the beneficial effects of the combination of both agents. For example, agents can be administered simultaneously or sequentially over a period of time. The active dosage of a compound in the composition can vary widely according to the selection of those skilled in the art and can be determined empirically. In addition, the compounds of the present invention can be used alone or in combination with one or more additional agents depending on the indications and the desired therapeutic effect. For example, in the case of diabetes, insulin resistance and associated conditions and complications, including obesity and hyperlipidemia, said additional agents can be selected from the group consisting of: insulin or an imitation insulin, a sulfonylurea (such such as acetohexamide, chlorpropamide, glimepyridine, glizipiride, glyburide, tolbutamide and the like) or other insulin secretagogues (such as nateglinide, repaglinide and the like), a thiazolidinedione (such as pioglitazone, rosiglitazone and the like) or other gamma receptor agonists activated (PPAR) by the peroxisome proliferator, a fibrate (such as bezafibrate, chlorfibrate, fenofibrate, gemfibrozole, and the like) or other PPAR alpha agonists, a delta agonist of PPAR, a biguanidine (such as metformin), a statin ( such as fluvastatin, lovastatin, pravastatin, simvastatin and the like) or other inhibitors of hydroxymethylglutaryl (HMG) CoA reductase, an inhi alpha-glucosidase bidor (such as carbose, miglitol, voglibose and the like), a bile acid binding resin (such as cholestyramine, celestipol and the like), a high density lipoprotein (HDL) breaker such as apolipoprotein Al (apoAl), niacin and the like, probucol and nicotinic acid. In the case of inflammation, inflammatory diseases, autoimmune diseases and others such as cytokine-mediated disorders, the additional agents can be selected from the group consisting of: a nonsteroidal anti-inflammatory drug (NSAID) (such as diclofenac, difunisal, ibuprofen , naproxen and the like), a cyclooxygenase-2 inhibitor (such as celecoxib, rofecoxib and the like), a corticosteroid (such as prednisone, methylprednisone and the like) or another immunosuppressive agent (such as methotrexate, leflunomide, cyclophosphamide, azathioprine and the like), a disease modifying antirheumatic drug (DMARD) (such as injectable gold), penicillamine, hydroxychloroquine, lfasalazine and the like), a TNF-alpha inhibitor (such as etanercept, infliximab and the like), other cytokine inhibitors (such as the soluble cytokine receptor, the anti-cytokine antibody and the similar), other immune modulating agents (such as cyclosporin, tacrolimus, rapamycin, and the like) and a narcotic agent (such as hydrocodone, morphine, codeine, tramadol, and the like). The combination therapy contemplated by the invention includes, for example, the administration of the compound of the invention and additional agents in a single pharmaceutical formulation as well as the administration of the compound of the invention and additional agents in separate pharmaceutical formulations. Another aspect of the invention is a method of treating diabetes and related diseases, comprising the step of administering to a subject suffering from a diabetic or related condition a therapeutically effective amount of a compound of Formulas I-XIII. Additionally, the invention provides a method of treating inflammation or inflammatory diseases or diseases mediated by cytokines, PDE4, PDE3, MAP kinase p44 / 42, iNOS and / or COX-2 by administering to the subject in need of such treatment an effective amount of a compound in accordance with Formulas I-XIII. Additionally, pharmaceutical compositions containing a therapeutically effective amount of one or more compounds in accordance with Formulas I-XIII together with a pharmaceutically or physiologically acceptable carrier for use in the treatments contemplated herein are also provided. The compounds of the invention are useful for the treatment of diabetes, characterized by the presence of elevated blood glucose levels, that is, hyperglycemic disorders such as diabetes mellitus, which include both types of diabetes type 1 and type 2, as well as other related hyperglycemic disorders such as obesity, increasing cholesterol, hyperlipidemia such as hypertriglyceridemia, kidney-related disorders and the like. The compounds are also useful for the treatment of disorders linked to insulin resistance and / or hyperinsulinemia, which also include diabetes, hyperandrogenic conditions such as polycystic ovarian syndrome (Ibañez et al., J Clin Endocrinol Metab, 85: 3526 -30, 2000; Taylor A.E., Obstet Gynecol Clin North Am, 27: 583-95, 2000), coronary artery disease such as arteriosclerosis and vascular restenosis, and peripheral vascular disease. Additionally, the compounds of the present invention are also useful for the treatment of inflammation and immunological diseases including those mediated by the signaling pathways linked to pro-inflammatory cytokines, such as rheumatoid arthritis, ankylosing sponditis, multiple sclerosis, inflammatory bowel diseases , psoriasis, and atopic and contact dermatitis. By "treatment", it is meant that the compounds of the invention are administered in an amount which is at least sufficient to, for example, reduce the blood glucose level in a patient suffering from a hyperglycemic disorder or to inhibit or prevent the development of the pro-inflammatory cytokine or similar responses in a patient suffering from inflammatory or immunological diseases. In the case of diabetes, the compound is usually administered in an amount sufficient to reduce the blood glucose level, the level of free fatty acids, the level of triglycerides and / or the similar level sufficient to improve or alleviate the symptoms and / or reduce the risk of complications associated with high levels of these parameters. A variety of subjects that can be treated with the compounds herein to reduce blood glucose levels such as cattle, rare and wild animals, pets, as well as humans. The compounds can be administered to a subject suffering from hyperglycemic disorders using any convenient administration technique, including intravenous, intradermal, intramuscular, subcutaneous, oral and the like. However, daily oral dosage is preferred. The dosage released into the host will necessarily depend on the route by which the compound is released, but generally ranges from about 0.1 to about 500 mg / kg of human body weight or typically from about 0.1 to about 50 mg / kg of human body weight . In general, similar types of administration and dosages are also contemplated, when the compounds of the invention are used to treat immunological and inflammatory diseases. The compounds of this invention can be used in formulations using pharmaceutical carriers acceptable for enteral or parenteral administration, such as, for example, water, alcohol, gelatin, gum arabic, lactose, amylase, magnesium stearate, talc, vegetable oils, polyalkylene glycol, and the similar ones. The compounds may be formulated in solid form, for example, as tablets, capsules, dragees and suppositories, or in the liquid form, such as, for example, solutions, suspensions and emulsions. The preparations can also be released transdermally or by topical application. The synthesis of representative compounds according to the present invention are illustrated in Reaction Schemes I and II. Additional examples illustrating the synthesis of additional compounds according to the present invention are also given below, Reaction Scheme I Reaction scheme 1 details the synthesis of compounds 1-6. The reaction scheme 2 details the synthesis of 17. It will be understood that the reaction schemes 1 and 2 are representative schemes and are not intended to be limiting of the disclosed compounds. Reaction Scheme II 17 The following examples are provided to further illustrate the present invention and are not intended in any way to be limiting of the invention. EXAMPLE 1 Synthesis of 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylic (1) [see Reaction Scheme I] (a) Step 1: Synthesis of 3- (3,5-dimethoxyphenyl) -2- (4-hydroxyphenyl) -acrylic acid (2). To a mixture of 3,5-dimethoxybenzaldehyde (120 g, 0.72 mol) and p-hydroxyphenyl acetic acid (110 g, 0.72 mol) were added acetic anhydride (240 ml) and triethylamine (161 ml, 1.6 equiv.). The non-homogeneous mixture upon heating became homogeneous at ~ 70 ° C. After being stirred at 130 ° C for 4 hours, the mixture was cooled to room temperature. HC1 (15%, 500 ml) was added to the reaction mixture, slowly in 30 min, keeping the temperature below 5-10 ° C. The solid was dissolved in 3 N aqueous NaOH solution (1.2 1) and stirred for 0.5 hour. The filtrate was acidified maintaining a temperature at 25-30 ° C, with HC1 conc. (~ 700 ml) at pH 1. The precipitated product was filtered and washed with water to give the crude product (~ 300 g, wet cake). The crude product was dissolved by heating in ethanol and recrystallized by the addition of an equal volume of water. The product was dried overnight in a vacuum oven at 40 ° C. Product: 161 g, 74%. Analysis: ^ MR (DMS0-d6): d 12.48 (br, 1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 6.35 (t, J = 2.2 Hz, 1H), 6.27 (d, J = 2.2 Hz, 2H), 3.56 (s, 6H). (b) Step 2: Synthesis of 3- (3,5-dimethoxyphenyl) -2- [4- (4-formylphenoxy) -phenyl] -acrylic acid (3). 2 (64.0 g, 0.21 mole) was dissolved in 320 ml of anhydrous DMSO under nitrogen, and potassium tert-butoxide (48.0 g, 0.43 mole) was added in batches. When the solution became homogeneous, p-fluorobenzaldehyde (27 ml, 0.22 mol) was added and the mixture was heated at 100 ° C for 5 hours. After cooling to room temperature, the solution was poured into 1 l of water and extracted with ether (2 x 500 ml). The aqueous phase was acidified with 5% HC1 to a pH of ~4 and the precipitated product was collected by suction filtration. The wet filter cake was dissolved in a minimum of boiling acetone and recrystallized with the addition of water. After cooling to 4 ° C for 3 hours, the solid was collected by vacuum filtration. The product was dried overnight at 40 ° C in a vacuum oven. Product: 62 g, 73%. Analysis: lK NMR (DMSO-d6): d 12.87 (s, 1H), 9.94 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.42 (t, J = 1.6 Hz, 1H), 6.29 (d, J = 2.0 Hz , 2H), 3.60 (s, 6H). (c) Step 3: Synthesis of 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (2-ethoxycarbonyl-vinyl) -phenoxy] -phenyl} - acrylic (4). Triethyl phosphonoacetate (7.14 ml, 36 mmol) was added to a suspension of NaH (60% in mineral oil, 2.64 g, 66 mmol) in anhydrous THF (100 ml) at 0 ° C under argon, and the mixture was stirred by 15 minutes. A solution of aldehyde 3, (12.12 g, 30 mmol) in THF (100 ml) was added and the mixture was stirred for 1 hour. The reaction of the mixture was quenched with saturated aqueous solution of ammonium chloride (5 ml), diluted with ethyl acetate (300 ml) and acidified with 5% aqueous solution of HC1 to pH 1. The film layer was separated. ethyl acetate, and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO 4, filtered and concentrated. The crude product was purified by recrystallization from a chloroform / methanol mixture. The compound was suspended in hot methanol (200 ml) and a minimum volume (~ 30-40 ml) of chloroform was added., to produce 4. Product: 12.39 g, 87.1 ¾. Analysis:: H NMR (DMSO-d6): d 7.77 (d, J = 8.4 Hz, 2H), 7.69 (s.1H), 7.65 (d, J = 16 Hz, 2H), 7.23 (d, 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 16 Hz, 2H), 6.41 (t, J = 2 Hz, 1H) , 6.28 (d, J = 1.6 Hz, 2H), 4.18 (q, J = 1.2 Hz, 2H), 3.59 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H). (d) Step 4: Synthesis of 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (2-ethoxycarbonyl-ethyl) -phenoxy] -phenyl} - acrylic (5). To a suspension of Raney nickel (10.0 g, Raney nickel 2800 in aqueous active catalyst) in ethanol-dioxane (2: 1, 50 ml) was added a solution of 4 (13.0 g, 27.4 mmol) in an ethanol mixture. dioxane (2: 1400 ml), and the resulting mixture was stirred vigorously for 15 hours under hydrogen at atmospheric pressure. The completion of the reaction was monitored by HPLC (several times with the stirring speed). The catalyst was filtered through a bed of diatomaceous earths of Celite®, the bed was washed with ethanol-dioxane (2: 1, 200 ml), and the solvent was evaporated. The solid obtained was dissolved in hot toluene (150 ml) and cooled to 4 ° C overnight. The separated solid was filtered and washed with ice-cold toluene (50 ml) and dried at 55 ° C for 6 hours. Product: 11.61 g, 90.5%. Analysis:: H MR (DMSO-d6): d 12.75 (s, 1 H), 7.68 (s, 1 H), 7.26 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H ), 6.39 (t, J = 2.0 Hz, 1 H), 6.27 (d, J = 1.6 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 3.57 (s, 6H), 2.84 (t, J = 8 Hz, 2H), 2.60 (t, J = 8 Hz, 2H), 1.1 5 (t, J = 8 Hz, 3H). (e) Stage 5; Synthesis of 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (3-oxo-3-ureido-propyl) -phenoxy] -phenyl} - acrylic (6). To a solution of sodium ethoxide in ethanol (21%, by weight, 65 ml) under argon was added ethyl acetate (3.12 ml), then refluxed for 20 minutes. Urea (18 g, 0.3 mmol) was dissolved in the above solution of sodium ethoxide in ethanol at 75 ° C. To this solution was added 5 (13 g, 0.027 mol) in a batch. After all was dissolved, the resulting mixture was stirred at 75 ° C for another 5 minutes, cooled rapidly in 15 minutes at 15-20 ° C, TFA (13 mL) was added, and then adjusted to pH 4- 5 with HC1 at 5%. After stirring at room temperature for 1 hour, the mixture was slowly added to water (520 ml). The separated solid was filtered and refluxed in 10% isopropanol in ethyl acetate (150 ml) for 20 minutes. The mixture was allowed to cool to room temperature, then incubated overnight at 4 ° C. The mixture was filtered and the solid dried. Product: 8.5 g. Analysis: ? NMR (DMSO-d6): d 12.35 (br, 1H), 10.20 (s, 1H), 7.75 (br, 1H), 7.68 (s, 1H), 7.26 (d, J = 8, Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.39 (t, .J = 2.4 Hz, 1H), 6.27 (d, J-2.4 Hz, 2H), 3.57 (s, 6H) , 2.81 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H). (f) Step 6: Synthesis of 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-oxo-3-ureido-propyl) -phenoxy] -phenyl} - acrylic (1). To a stirred solution of 6 (5 g, 0.01 mol) in dry DMF (35 mL) under argon was added K7CO3 (1.38 g, 0.01 mol). To this was added dimethyl sulfate (3.8 g, 0.03 mol) and stirred at room temperature for 30 minutes. The reaction mixture was acidified with 5% aqueous solution of HC1 and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The oily residue was dissolved in hexane / ethyl acetate (2: 3, 30 ml) with stirring, and incubated overnight at 4 ° C by crystallization. The solid was collected by vacuum filtration and dried. Product: 3.3 g, 65%. Analysis: XH MR, (DMSO-d6): d 10.17 (br, 1H), 7.72 (br, 2H), 7.72 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 6.8 Hz, 2H), 7.21 (s, superimposed 1H), 7.01 (d, J = 6.8 Hz , 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 2H), 3.73 (s, 3H), 3.57 (s) , 6H), 2.84 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H). EXAMPLE 2 Synthesis of 3- (3,5-dimethoxy-enyl) -2- methyl ester. { 4- [4- (3-ethoxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} - acrylic (8) The 2- methyl ester was obtained. { 4- [4- (2-carbamoyl-ethyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -acrylic (7) as a by-product in the synthesis of 3- (3,5-dimethoxy-phenyl) -2- methyl ester. { 4- [A- (2, 4-dioxothiazolidin-5-ylmethyl) -phenoxy] -phenyl} - acrylic, was effected essentially as shown in PCT / US99 / 09982 (WO 99/58127). 7 (460 mg, 1.0 mmol) in dry THF (6 mL) was taken and cooled to -78 ° C. To this solution, lithium diisopropyl amide was added (LDA) (2, 0.55 ml, 1.1 mmol) and stirred for 10 minutes. Ethyl chloroformate (0.11 ml, 1.2 mmol) was added and stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and ethyl acetate (50 ml) was added. The organic layer was washed with brine (2 x 20 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (7: 3) Product: 264 mg, 49.8%.

Analysis: H MR (DMSO-d6): d 10.52 (s, 1H), 7.70 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8, Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.40 (t, J = 2.1 Hz, 1H), 6.27 (d, J = 2.1 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.56 (s, 6H), 2.76 (m, 4H), 1.19 (t, J = 7.2 Hz, 3H). EXAMPLE 3 Synthesis of 2- methyl ester. { 4- [4- (3-benzoyloxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -acrylic (9) 7 (1.38, 3.0 mmol) prepared as in Example 2 was taken up in dry THF (20 mL) and cooled to -78 ° C. To this solution, LDA (2 M, 1.8 mL, 3.6 mmol) was added and stirred for 10 minutes. Benzyl chloroformate (0.67 g, 39 mmol) was added and stirred overnight at room temperature. The reaction was quenched with saturated aqueous solution of ammonium chloride, and ethyl acetate (150 mL) was added. The organic layer was washed with brine (2 x 25 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (7: 3). Product: 0.68 g, 37.3%.

Analysis: LH NMR (DMSO-de): d 10.65 (s, 1H), 7.72 (s, 1H), 7.38-7.39 (m, 5H), 7.25 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.00 (di J = 8.4 Hz, 2H), 6.94 (d , J = 8.4 Hz, 2H), 6.41 (t, J = 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 2H), 5.12 (s, 2H), 3.72 (s, 3H), 3.57 (s) , 6H), 2.79 (m, 4H). EXAMPLE 4 Synthesis of 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - propionic (10) 3- (3,5-Dimethoxyphenyl) -2- acid was dissolved. { 4- [4- (2-ethoxycarbonylvinyl) -phenoxy] -phenyl} - acrylic (4, 2.37 g, 5.0 mmol) in a dioxane-ethanol mixture (2: 1, 150 ml), and palladium-charcoal (10%, 500 mg) was added. The mixture was stirred under hydrogen for 15 hours. The catalyst was then removed by filtration, and the solvent was evaporated under reduced pressure to yield 3- (3,5-dimethoxy-phenyl) -2- (4- [4- (2-ethoxycarbonylethyl) -phenoxy] -phenyl acid} - propionic (18) quantitatively urea was dissolved in sodium ethoxide (2.7 M, 2.2 ml, 5.92 mmol) at 80 ° C under argon, and added to this solution of 18 (1.13 g, 2.37 mmol) in ethanol Anhydrous (15 mL) and heated at this temperature for 13 hours.The ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by means of a 5% aqueous solution of HC1 and extracted with ethyl acetate (50 mL) The organic layer was washed with water (2 x 25 mL), brine (2 x 20 mL), dried over anhydrous magnesium sulfate and evaporated The crude product was purified by gel chromatography of silica and eluted with ethyl acetate-hexane (3: 7) containing acetic acid (1%), followed by recrystallization from ethanol Product: 256 mg, 22.8%. 18 10 Analysis: LH NMR (DMSO-d6): d 12.37 (s, 1H), 10.17 (s, 1H), 7.74 (br, 1H), 7.31 < d, J = 9.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8 Hz, 2H), 6.33 (d , J = 2.0 Hz, 2H), 6.29 (t, J = 2.0 Hz, 1H), 3.83 (t, J = 8.0 Hz, 1H), 3.68 (s, 6H), 3.19 (dd, J = 14.4 & Hz, 1H), 2.88-2.80 (m, 3H), 2.59 (t, J = 8.0 Hz, 2H). EXAMPLE 5 Synthesis of 3- (3, 5-dimethoxy-enyl-2- (4- [4- (3-oxo-3-ureidopropenyl) -phenoxy] -phenyl} -acrylic acid (11) Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2 ml, 5.92 mmol) at 80 ° C under argon, and this solution of 4 (1.14 g, 2.37 mmol) in anhydrous ethanol was added ( 15 ml) and heated at this temperature for 13 hours. The ethanol was evaporated under reduced pressure, water (20 ml) was added, acidified to H 1 by means of 5% aqueous solution of HC1 and extracted with ethyl acetate (50 ml). The organic layer was washed with water (2 x 25 mL), brine (2 x 20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (3: 7) containing acetic acid (1%), followed by recrystallization from ethanol. Product: 187 mg, 14.4.

Analysis: XH NMR (DMSO-d6): d 12.51 (br, 1H), 10.30 (s, 1H), 7.92 (br, 1H), 7.77 (d, J = 9.2 Hz, 2H), 7.68 (s, 1H ), 7.65 (d, J = l 6.0 Hz, 1H), 7.30 (br, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.40 (t, J = 2.0 Hz, 1H), 6.28 (d, J = 2 Hz, 2H), 3.59 (s, 6H) . EXAMPLE 6 Synthesis of the 3- (3,5-dimethoxyphenyl) -2- ethyl ester. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylic (12) To a stirred solution of 6 (0.40 g, 0.81 mmol) in dry DMSO (3 mL) was added K2CO3 (0.14 g, 0.98 mmol). To this, diethyl sulfate (0.115 g, 0.91 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography on silica gel and eluted with ethyl acetate-hexane (3: 1). Product: 0.39 g, 92.2%.

Analysis: XH MR (DMSO-d6): d 10.17 (s, 1H), 7.74 (br, 1H), 7.70 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.24 (superimposed, 1H) , 7.18 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.41 (t, J = 1.6 Hz, 1H) , 6.28 (d, J = 1.6 Hz, 2H), 4.19 (q, J = 8.0 Hz, 2H), 3.57 (s, 6H), 2.83 (t, J = 7.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.25 (t, J = 8.0 Hz, 3H). EXAMPLE 7 Synthesis of 3- (3,5-dimethoxyphenyl) -N, N-dimethyl-2-. { 4- [4- (3-oxo-3-ureido-propyl) -phenoxy] -phenyl} - acrylamide (13) To a stirred solution of 6 (1.68 g, 3.43 mmol) in Dry DMF (30 mL) was added carbonyldiimidazole (1.1 g, 6.86 mmol), and the reaction mixture was heated at 60 ° C for 1 hour. The reaction mixture was cooled to 0 ° C and a solution of dimethylamine in THF (2M, 8.6 ml, 17.2 mmol) was added and stirred for 18 hours. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml). The organic phase was then stirred sequentially with 10% citric acid (2 x 50 mL), water (2 x 50 mL), and brine (20 mL), then dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate-hexane (3: 7) containing 1% acetic acid. Product: 1.77 g, 100%.

Analysis: 2H NMR (DMSO-d6): d 10.17 (br, 1H), 7.74 (br, 1H), 7.27 (d, J = 9.2 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.23 (br, 1H), 6.79 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.34 (t, J = 2 Hz, 1H), 6.29 (s, 1H), 6.28 (s, 1H), 3.58 (s, 6H), 3.05 (br, 3H), 2.90 (br, 3H), 2.82 (t, J = 7.2 Hz, J = 8.0 Hz, 2H) , 2.59 (t, J = 8.0 Hz, J = 7.2 Hz, 2H). EXAMPLE 8 Synthesis of 2- (4- {4- [3- (3-cyclohexylureido) -3-oxopropyl] -phenoxy} - phenyl) -3- (3,5-dimethoxyphenyl) -acrylic acid (14 ) Cyclohexylurea (1.3 g, 9 mmol) was dissolved in sodium ethoxide in ethanol (21% by weight, 3 mL) at 75 ° C. To this solution was added 5 (0.5 g, 1.1 mmol) in one batch. The resulting mixture was stirred at 75 ° C for 5 minutes, then rapidly cooled to 40-50 ° C. TFA (0.5 ml) was added and then 5% aqueous solution of HC1 (1 N, 0.6 ml). After stirring at room temperature for 1 hour, the mixture was left overnight at 4 ° C. The separated solid was filtered and refluxed in ethyl acetate (40 mL) for 20 minutes. The mixture was allowed to cool to room temperature, filtered and the crude product was purified by chromatography on silica gel using ethyl acetate-hexane (1: 1). Product: 0.27 g, 45%.

Analysis: XH NMR (DMSO-d6): d 12.74 (s, 1H), 10.30 (s, 1H), 8.32 (br, 1H), 7.67 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H) , 7.16 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.34 (t, J = 2.4 Hz, 1H), 6.27 (d, J = 2.4 Hz, 2H), 3.58 (s, 6H), 2.83 (t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.78 (m, 2H), 1.61 (m, 2H), 1.51 (m, 1H), 1.32-1.16 (m, 5H). EXAMPLE 9 Synthesis of [3- (4-phenoxyphenyl) -propionyl] -urea (15) 4-Phenoxybenzaldehyde was reacted with triethyl phosphonoacetate to produce the 3- (4-phenoxyphenyl) -acrylic acid ethyl ester, which was then reduced with H2 using palladium on carbon catalyst to produce the 3- (4-phenoxyphenyl) -propionic acid methyl ester (19). Urea (1.20 g, 19.99 mmol) was dissolved in sodium ethoxide (2 M, 6.7 mL, 13.4 mmol) at 80 ° C under argon, and added to this solution of 19 (1.71 g, 6.67 mmol) in anhydrous ethanol ( 8 ml) and heated at this temperature for 1 hour. The ethanol was evaporated under reduced pressure, water (20 ml) was added, acidified to pH 1 by means of 5% aqueous solution of HC1 and extracted with ethyl acetate (50 ml). The organic layer was washed with water (2 x 25 mL), brine (2 x 20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (1: 1) containing acetic acid (1%) followed by recrystallization from ethanol. Product: 113 mg, 5.6%.

Analysis: XH MR (DMSO-d6): d 10.18 (s, 1H), 7.74 (br, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H) , 6.97 (d, J = 7.2 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.59 (t, J = 7.2 Hz, 2H). EXAMPLE 10 Synthesis of the 2- methyl ester. { 4- [4- (3-acetylureidomethyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -acrylic (17) [see Scheme II] (a) Step 1: Synthesis of methyl 3- (3,5-dimethoxyphenyl) -2- [4- (4-methyl ester hydroxymethyl-phenoxy) -phenyl] -acrylic (22). The 2- (3-methyl) methyl ester was first prepared, 5- dimethoxyphenyl) -2- [4- (4-formylphenoxy) -phenyl] -acrylic acid (21) by conversion of the corresponding free acid (3) to the methyl ester by addition of DMF, K2C03 and dimethyl sulfate in an analogous manner to Example 1 (f) above. Sodium borohydride (0.125 g, 3.3 mmol) was added to a suspension of 21 (1.26 g, 3 mmol) in ethanol and stirred at room temperature for 1 hour. The reaction was quenched with 5% aqueous solution of HC1, and the ethanol was evaporated under reduced pressure. The residue was taken up in lime acetate (50 ml) and washed with brine (2 x 20 ml), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (1: 1). Product: 1.14 g, 95.0%. Analysis: * H NMR (DMSO-d6): d 7.72 (s, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.41 (t, J-2.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 2H), 5.18 (t, J = 6.4 Hz, 1H), 4.49 (d, J = .8 Hz, 2H), 3.72 (s, 3H), 3.57 (s, 6H). (b) Step 2: Synthesis of 2- [4- (4-bromoethylphenoxy) -phenyl] -3- (3,5-dimethoxyphenyl) -acrylic acid methyl ester (23). To a stirred solution of 22 (1.05 g, 2.5 mmol) in dichloromethane (10 ml) at 10 ° C, PBrj (1 M, 3.75 ml) was added and stirred for 1 hour. The reaction was stopped with saturated aqueous sodium bicarbonate solution. The organic layer was washed with water (20 ml), brine (2 x 30 ml), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel and eluted with ethyl acetate-hexane (4: 1). Product: 0.85 g, 70.4%. Analysis: ^ NMR (DMSO-d6): d 7.73 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8. Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.42 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 2H), 4.74 (s, 2H), 3.73 ( s, 3H), 3.58 (s, 6H). (c) Synthesis of 2- methyl acid ester. { 4- [4- (3-acetylureidomethyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -acrylic (17). To a stirred suspension of sodium hydride (60% in oil, 0.11 g, 2.8 mmol) in dimethylformamide (2 mL), N-acylurea (0.11 g, 1.12 mmol) was added and stirred at room temperature for 30 minutes. It was added to a solution of 23 (0.54 g, 1.12 mmol) in dimethylformamide (3 mL) and heated overnight at 80 ° C. The reaction was quenched with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 25 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (3: 7) containing 1% acetic acid. Product: 0.16 g, 28.4%. Analysis: l MR (DMSO-d6): d 8.34 (t, J = 5.6 Hz, 1H), 7.72 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz , 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.42 (t, 8.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 2H), 4.24 (d, J = 5.2 Hz), 3.73 (s, 3H), 3.57 (s, 6H), 1.87 (s, 3H). General Procedure for the Conversion of Carboxylic Acids to Amides A mixture of carboxylic acid (1.1 mmol) and carbonyldiimidazole (1.3 mmol) in DMF (20 mL) was heated at 60 ° C for 30 minutes. After the reaction mixture was cooled to room temperature, a solution of amine (2 M, 1 mL, 2.0 mmol) was added and stirred for 18 hours. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (3 x 60 mL). The organic phase was washed with 10% citric acid (20 ml), water (2 x 50 ml), and brine (50 ml), then dried over anhydrous magnesium sulfate and the solvent was removed. The crude product was purified by chromatography on silica gel.

EXAMPLE 11 Synthesis of N, N-dimethyl 2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acetamide (26) Urea (0.78 g, 13 mmol) and 3- [4- (4- (4-carboxymethylphenoxy) -phenyl] -propionic acid ethyl ester, 24 (0.5 g, 1.5 mmol) were dissolved in sodium ethoxide in ethanol (2M, 6.5 ml, 13 mmol) at 80 ° C under argon, and the reaction mixture was heated at this temperature for 1 hour. The reaction was stopped by TFA (0.5 ml) after cooling to 5 ° C. Water (40 ml) was added to the reaction mixture. The crude product was filtered and purified by chromatography on silica gel and eluted with ethyl acetate-hexane (1: 1) containing acetic acid (1%) followed by recrystallization from the produced toluene (0.28 g, 54%). . Analysis: ^ NMR (DMSO-d6): d 12.28 (br, 1H), 7.73 (br, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.23 (br, 1H) 7.21 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.54 (s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.58 ( t, J = 7.2 Hz, 2H). Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethylamine as the amine, it was converted to 26 with 97% yield. Analysis: LH NMR (DMSO-d6): d 10.17 (s, 1H), 7.73 (s, 1H), 7.22 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 3.65 (s, 2H), 3.00 (s, 3H), 2.81 (t, J = 8.0 Hz, 2H), 2.58 (t, J = 8.0 Hz, 2H). 24 25 26 EXAMPLE 12 Synthesis of (4- {4- [2- (3, 5-dimethoxy-enyl) -1-dimethylcarbamoyl-vinyl] -phenoxy} -benzyl) -carbamic acid methyl ester (29) Was after the reaction of 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (2, 4-dioxothiazolidin-3-ylmethyl) -phenoxy] -phenyl} - acrylic, 27, (0.4 g, 0.77 mmol) with 5% LiOH (2 mL) in methanol (19 mL) at room temperature for 18 hours. The reaction mixture was acidified to pH 3 by means of 5% aqueous solution of HC1 and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with water (2 x 50 mL), brine (2 x 20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel and eluted with ethyl acetate-hexane (1: 1) containing acetic acid (1%). Product (28): 0.31 g, 83%. Analysis: XH MR (DMS0-d6): d 12.75 (br, 1H), 7.68 (t, J = 4.6 Hz, 1H), 7.67 (s, 1H), 7.28 (d, J-8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.39 (t, J = 2.8 Hz, 1H), 6.27 (d , J = 2.4 Hz, 2H), 4.17 (d, J = 6.4 Hz, 2H), 3.58 (S, 6H), 3.55 (s, 3H). Following the general procedure of conversion of carboxylic acids to amides mentioned above and using dimethylamine as amine, 28 was converted to 29 with 96% yield. Analysis: 2H NMR (DMSO-d6): d 7.68 (t, J = .6 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8Hz, 2H), 6.98 ( d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.57 (s, 1 H), 6.35 (t, J = 2.8 Hz, 1H), 6.28 (d, J = 2.4 Hz , 2H), 4.16 (d, J = 6.4 Hz, 2H), 3.59 (S, 6H), 3.55 (s, 3H), 3.05 (br, 3H), 2.91 (br, 3H).

EXAMPLE 13 Synthesis of 2-. { 4- [4- (2-carbamoylmethyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -N, N-dimethylacrylamide (31) Urea (0.78 g, 13 mmol) and 3- (3,5-dimethoxyphenyl) -2- were dissolved. { 4- [4- (2-ethoxycarbonylethyl) -phenoxy] -phenyl} - acrylic 5 (0.45 g, 1.5 mmol) in sodium ethoxide in ethanol (2 N, 6.5 ml, 13 mmol) at 80 ° C under argon, and the reaction mixture was heated at this temperature for 5 hours. The reaction was then stopped by TFA (0.5 ml) after cooling to 5 ° C. Water (40 ml) was added to the reaction mixture. The crude product was filtered and purified by chromatography on silica gel and eluted with ethyl acetate-hexane (1: 1) containing acetic acid (1). Product (30): 0.39 g, 93%. Analysis: H NMR (DMSO-d6): d 12.73 (br, 1H), 7.68 (s, 1 H), 7.29 (br, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.78 (br, 1H), 6.39 (t, J = 2.Hz, 1H) , 6.27 (d, J = 2 Hz, 2H), 3.57 (s, 6H), 2.79 (t, J = 8.0 Hz, 2H), 2.35 (t, J = 8.0 Hz, 2H). Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethyl amine as an amine, it was converted to 31 in 98% yield.

Analysis: XH NMR (DMSO-d6): d 7.30 (br, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (br, 1H), 6.56 (s, 1H), 6.34 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2 Hz, 2H), 3.58 (s, 6H), 3.05 (br, 3H), 2.90 (br, 3H), 2.77 (t, J = 8.0 Hz, 2H), 2.34 (t, J = 8.0 Hz, 2H) .

EXAMPLE 14 Synthesis of 2- [4- (4-acetylaminophenoxy) -phenyl] -3- (3,5-dimethoxyphenyl) -N, N-dimethylacrylamide (34) Compound 2 was reacted with 1-fluoro-4-nitrobenzene in the presence of NaH in DMF to give 3- (3,5-dimethoxyphenyl) -2- [4- (4-nitrophenoxy) -phenyl] -acrylic acid (32). The reduction of 32 (10 g, 24 mmol) with zinc powder (15 g, 230 mmol) in acetic acid (100 ml) at 120 ° C for 15 hours was achieved, the mixture was cooled to room temperature. Water (250ml) was slowly added to the reaction mixture. The precipitated product was filtered and washed with water (70 ml) to give crude product. The product was recrystallized from toluene. Product (33): 9.7 g, 94 Analysis: * H NMR (DMSO-d6): d 12.35 (br, 1H), 9.96 (s, lH), 7.67 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.34 (t, J = 2.8 Hz, 1H ), 6.28 (d, J = 2.4 Hz, 2H), 3.58 (S, 6H), 2.03 (s, 3H). Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethylamine as an amine, 33 was converted to 34 in 98% yield. Analysis: XH NMR (DMSO-d6): d 9.96 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8Hz, 2H), 6.97 (d, J = 8.8 Hz , 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.55 (s, 1H), 6.34 (t, J = 2.8 Hz, 1 H), 6.28 (d, J = 2.4 Hz, 2H), 3.58 ( S, 6H), 3.04 (br, 3H), 2.90 (br, 1 3H), 2.03 (s, 3H). 32 33 34 EXAMPLE 15 Synthesis of 3- (3, 5-dimethoxyphenyl) -2- [4- (4-methanesulfonylphenoxy) -phenyl] - N, N-dimethylacrylamide (36) Compound 2 (3 g, 10 mmol) was dissolved in anhydrous DMF (70 ml) under nitrogen, and potassium carbonate (1.4 g, 10 mol) was added in batches. When the solution became homogeneous, 4-fluorophenyl methyl sulfone (1.74 g, 10 mmol) was added and the mixture was heated to 150 ° C for 2 hours. After cooling to room temperature, the solution was poured into water (150 ml). The mixture was acidified with 5% HC1 to pH of about 4 and the solidified product was collected by suction filtration. The crude product was recrystallized with toluene. Product (35): 4.3 g, 96%. Analysis: lH NMR (DMSO-d6): d 12.72 (br, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.72 (s, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.42 (t, J = 2.8 Hz, 1H), 6.28 (d, J = 2.4 Hz, 2H), 3.59 (S , 6H), 3.21 (s, 3H). Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethylamine as an amine, it was converted to 36 with 96% yield. 7 Analysis:: H NMR (DMS0-d6): d 7.93 (d, J = 8.8 Hz, 2H), 7. 38 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 6.36 (t, J = 2.8 Hz, 1H), 6.29 (d, J = 2.4 Hz, 2H), 3.59 (S, 6H), 3.20 (s, 3H), 3.08 (br, 3H), 2.92 (br, 3H).

EXAMPLE 16 Synthesis of 3- (4- {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy} - phenyl) -propionic acid ethyl ester (37) Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethyl amine as the amine, it was converted to 37 with 97% yield. Analysis: LH NMR (DMSO-d6): d 7.28 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 (d , J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.34 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2 Hz, 2H), 4.04 (q, J = 6.8 Hz, 2H ), 3.58 (s, 6H), 3.05 (br, 3H), 2.90 (br, 3H), 2.84 (t, J = 8. Hz, 2H), 2.61 (t, J = 8.4 Hz, 2H), 1.15 ( t, J = 6.4 Hz, 3H).

EXAMPLE 17 Synthesis of 2-. { 4- [4- (N-ureido-2-carbéunoylmethyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -N, N-dimethylacrylamide (39) Hydrolysis of 13 with 1 N NaOH yielded 38. The 1- 1 -carbonyl-diimidazole derivative (CDI) was prepared by the procedure for the conversion of carboxylic acids to amides mentioned above. The CDI intermediate of 38 was converted to 39 by reacting it with semicarbazide with 73% yield. Analysis: LH NMR (DMSO-d6): d 9.48 (br, 1H), 7.72 (br, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.25 (d, J-8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.34 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2 Hz , 2H), 5.86 (s, 2H), 3.58 (s, 6H), 3.05 (br, 3H), 2.90 (br, 3H), 2.77 (t, J = 8.0 Hz, 2H), 2.39 (t, J = 8.0 Hz, 2H). 38 39 EXAMPLE 18 Synthesis of 3- (3,5-dimethoxyphenyl) -N, N-dimethyl-2-. { 4- [4- (3-morpholin-4-yl-3-oxopropyl) -phenoxy] -phenyl} - acrylamide (40) The COI intermediate of 38 was converted to 40 by reacting with morpholine with 94% yield. Analysis: aH NMR (DMSO-d6): d 7.27 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 (d , J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.34 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2 Hz, 2H), 3.58 (s, 6H), 3.49 (m , 4H), 3.41 (m, 4H), 3.05 (br, 3H), 1 2.90 (br, 3H), 2.77 (t, J = 8.0 Hz, 2H), 2.39 (t, J = 8.0 Hz, 2H). 38 40 EXAMPLE 19 Synthesis of 2- (4- {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy} - benzyl) -malonic acid dimethyl ester (43) The condensation of with dimethyl ester of malonic acid in the presence of sodium hydride as a base resulted in 41, which by reduction with acetic acid / zinc produced 42. The conversion of 42 to 43 was achieved by the general procedure for the conversion of carboxylic acids to amides mentioned above with 94% yield. Analysis: XH NMR (DMSO-d6): d 7.29 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.92 (d , J = 8.8 Hz, 2H), 6.57 (s, 1H), 6.34 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2 Hz, 2H), 3.87 (t, J = 8 Hz, 1H) 3.61 (s, 6H), 3.58 (s, 6H), 3.08 (d, J = 7.6 Hz, 2H), 3.05 (br, 3H), 2.91 (br, 3H).

EXAMPLE 20 Synthesis of N-. { 4- [2- (3, 5-dimethoxyphenyl) -1- dimethylcarbamoylvinyl] -phenyl} - 3-hydroxybenzenamide (44) A mixture of 2- (4-aminophenyl) -3- (3,5-dimethoxyphenyl) -N, N-dimethylacrylamide, 43 (0.59 g, 1.5 mol), benzotriazole-1-yloxytris- (dimethylamino) hexafluorophosphate was stirred. phosphonium (BOP, 0.88 g, 2.0 mmol), 3- hydroxybenzoic acid (0.28 g, 2.0 mmol), triethylamine (0.2 g, 2.0 mmol) in DMF (8.0 ml) for 3 hours at room temperature. The reaction mixture was poured into water (50 ml) and the separated solid was filtered, dried and the purity verified by HPLC (97.6%). Analysis: ? NMR (DMSO-d6): 6 10.29 (s, 1H), 9.81 (s, 1H), 7.79 (d, J = 6.8Hz, 2H), 7.43 (d, J = 8.0Hz, 1H), 7.37 ( t, J = 7.6Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 7.02 (m, 1H), 6.60 (s, 1H), 6.40 (t, J = 2.0Hz, 1H), 6.36 ( d, J = 2.0Hz, 2H), 3.63 (s, 6H), 3.08 (brs, 3H), 2.96 (brs, 3H). 43 44 EXAMPLE 21 Synthesis of N, N-dimethyl-2-. { 4- [4- (3-oxo-3-ureidopropenyl) -phenoxy] -phenyl} 3-pyridin-3-ylacrylamide (47) Synthesis of 45 from 3-pyridinecarboxaldehyde was carried out, following Reaction Scheme I. Urea (0.78 g, 13 mmol) and 2- acid were dissolved. { 4- [4- (2-ethoxycarbonyl-vinyl) -phenoxy] -phenyl} 3-pyridin-3-ylacrylic, 45 (0.5 g, 1.2 mmol) in sodium ethoxide in ethanol (2 M, 6.5 ml, 13 mmol) at 80 ° C under argon, and the reaction mixture was heated to this temperature for 1 hour. The reaction was then stopped by TFA (0.5 ml) after cooling to 5 ° C. Water (40 ml) was added to the reaction mixture. The crude product was filtered and purified by chromatography on silica gel and eluted with ethyl acetate-hexane (1: 1) containing acetic acid (1%) followed by recrystallization from toluene. Product (46): 0.33 g, 63%. Analysis: lE NMR (DMSO-d6): d 12.78 (br, 1H), 10.29 (s, 1 H), 8.42 (dd, J = 4.8, 1.6 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H ), 7.92 (br, 1H), 7.66 (d, J = 1 6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.36 (tt, J = 8.4, 1.6 Hz, 1H), 7.30 ( br, 1H), 7.28 (m, 1H), 7.23 (d, L- J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 16 Hz, 1H). Following the general procedure for the conversion of carboxylic acids to amides mentioned above, 46 was converted to 47. Analysis: 1H NMR (DMSOd6): d 10.30 (s, 1H), 8.39 (dd, J = 4.8, 1.6 Hz, 1H) , 8.34 (d, J = 2.4 Hz, 1H), 7.92 (br, 1H), 7.66 (d, J = 16 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.45 (tt, J = 8.4, 1.6 Hz, 1H), 7.32 (br, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.26 (m, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 16 Hz, 1H), 6.70 (s, 1H), 3.07 (br, 3H), 2.93 (br, 3H). 45 46 47 EXAMPLE 22 Synthesis of 3- (3,5-dimethoxyphenyl) -2- (4-hydroxyphenyl) -N, N-dimethylacrylamide (49) Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethylamine as amine, 2 was converted to 49. Analysis:: H NMR (DMSO-d6): d 9.59 (s, 1H), 7.07 (d, J = 8.8, 2H), 6.73 (d, J = 8.8Hz, 2H) , 6.43 (s, 1H), 6.23 (t, J = 2.4Hz, 1H), 6.29 (d, J = 2.4Hz, 2H), 3.57 (s, 6H), 2.99 (brs, 3H), 2.89 (brs, 3H).

EXAMPLE 23 Synthesis of [3- (4- { 4- [2- (3,5-dimethoxyphenyl) -1- (piperidin-1-carbonyl) -vinyl] -phenoxy} - phenyl) -propionyl] - urea (51) Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using piperidine as amine, 6 was converted to 51. Analysis: 2H NMR (DMSO ~ d6): d 10.16 (s, 1H), 7.73 ( brs, IH), 7.26 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.55 (s, 1H), 6.34 (t, J = 2.4Hz, 1H), 6.29 (d, J = 2.4Hz, 2H), 3.58 (s, 6H), 3.50 (br, 4H), 2.82 ( t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.58 (br, 2H) 1.40-1.45 (br, 4H). 51 EXAMPLE 24 Synthesis of 3- (3,5-dimethoxyphenyl) - N, N-diethyl- 2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide (53) Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using diethylamine as amine, 6 was converted to 53. Analysis: H NMR (DMSO-d6): d 10.17 (s, 1H), 7.70 (brs, 1H), 7.26 (d superimposed, J = 8.8 Hz, 2H), 7.23 (d superimposed, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 6.34 (t, J = 2.0 Hz, 1H), 6.29 (d, J = 2.0 Hz, 2H), 3.32-3.37 (br, 4H), 3.59 (s, 6H), 2.82 (t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.03 (br, 3H), 0.92 (br, 3?).

EXAMPLE 25 Synthesis of 2-. { 4- [4- (3-acetylamino-3-oxopropyl) -phenoxy] -phenyl} 3- (4-fluorophenyl) -N, N-dimethylacrylamide (56) To an acid solution. { 4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} acetic, 54, (0.45 g, 1.5 min) in acetic anhydride (15 mL) were added 4-fluorobenzaldehyde (0.17 mL, 1.6 mmol) and potassium acetate (0.17 g, 1.8 mmol) and refluxed overnight. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The crude product was purified by chromatography on silica gel to produce 55. Analysis: * H NMR (DMSO-d6): d 12.50 (br, 1H), 10.64 (s, 1H), 7.74 (s, 1H), 7.27 (d, J = 8 Hz, 2H), 7.10-7.15 (m, 6H), 6.99 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 2.81 (d, J = 6.8 Hz, 2H), 2.76 (d, J = 6.8 Hz, 2H), 2.15 (s, 3H).

Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using dimethylamine as an amine, it was converted to 56. Analysis: JH NMR (DMS0-d6): d 10.62 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 2.81 (d, J = 6.8Hz, 2H), 2.76 (d, J = 6.8 Hz, 2H), 2.15 (s, 3H). 54 55 56 EXAMPLE 26 Synthesis of 2- (4- {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy} - benzyl) -malonic acid (58) and 2- (4-. {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy} - benzyl) -malonamide (59) To a solution of 2- (4- (4- [2] dimethyl ester - (3,5-dimethoxyphenyl) -1- dimethylcarbamoylvinyl] -phenoxy.} - benzyl) -malonic acid, 43 (0.40 g, 0.73 mmol) in DMF (6 ml) and ethanol (10 ml), ammonium hydroxide was added (20 mL, 28%) and 1 N NaOH (0.36 mL, 0.36 mmol) and stirred overnight at room temperature The solvent was evaporated and the crude product was purified by chromatography on silica gel to yield 58 and 59. Analysis: H NMR (DMSO-d6 + D20) of 58: d 7.20 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.51 (s, 1H) , 6.29 (t, J = 2.0 Hz, 1H), 6.21 (d, J = 2.0 Hz, 2H), 3.53 (s, 6H), 3.13 (br, 1 H), 3.01 (brs, 3H), 2.92 (br , 2H), 2.86 (brs, 3H). Analysis: XH NMR (DMSO-d6) of 59: d 7.28 (d, J = 8.8 Hz, 2H), 7.26 (br, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.03 (br, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.56 (s, 1 H), 6.34 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2 Hz, 2H), 3.58 (s, 6H), 3.29 (t, J = 8 Hz, 1H), 3.05 (br, 3H), 2.95 (d, J = 7.6 Hz, 2H), 2.91 (br, 3H).

EXAMPLE 27 Synthesis of 3- (3,5-dimethoxyphenyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} N-pyridin-4-ylacrylamide (60) Following the general procedure for the conversion of carboxylic acids to amides, mentioned above and using 4-aminopyridine as amine, 6 was converted to 60. Analysis:: H NMR (DMS0-d6) : d 10.17 (s, 1H), 8.24 (brs, 1H), 7.71 (br, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.25 (d, J = 8.4 Hz , 2H), 7.22 (br, 1H), 7.03 (d, J = 9.2 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 2.4 Hz, 2H), 6.43 (t , J = 2.4 Hz, 2H), 3.65 (s, 6H), 2.83 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H).

EXAMPLE 28 Synthesis of N- (4-chlorophenyl) -3- (3, 5-dimethoxy-enyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide (61) Following the general procedure for conversion of carboxylic acids to amides mentioned above and using 4-chloroaniline as amine, 6 was converted to 61. Analysis: XH NMR (DMSO-d6): d 10.16 (s, 1H), 8.24 (brs, 1H), 7.65 (brs, 1H), 7.53 (d, J = 8.8 Hz, 2H) , 7.44 (s, 1 H), 7.25 (d, J = 8.8 Hz, 2H), 7.22 (br, 1H), 7.03 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H ), 6.47 (d, J = 2.4 Hz, 2H), 6.43 (d, J = 2.4 Hz, 1H), 3.66 (s, 6H), 2.83 (t, J = 8.0 Hz, 2H), 2.60 (t, J) = 8.0 Hz, 2H).

EXAMPLE 29 Synthesis of 3- (3,5-dimethoxyphenyl) -N, N-dimethyl-2- (4-. {4- [2- (2-morpholin-4-yl-2-oxoethylcarbamoyl) -ethyl] - phenoxy.}. phenyl) -acrylamide (63) Following the general procedure for the conversion of carboxylic acids to amides mentioned above and using 2-amino-1-morpholin-4-yl-ethanone as amine, 3- (4 -. {4- [2- (3, 5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy}. Phenyl) -propionic, 38, was converted to 63.

Analysis: lH NMR (DMSO-d6): d 7.99 (t, J = 5.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.97 (d , J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 6.34 (t, J = 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 2H ), 3.93 (d, J = 5.6 Hz, 2H) 3.56 (s, 6H), 3.52-3.56 (m, 4H), 3.40-3.42 (m, 4H), 3.05 (brs, 3H), 2.91 (brs) , 3H), 2.80 (t, J = 7.6 Hz, 2H), 2.46 (t, J = 7.6 Hz, 2H). 38 63 EXAMPLE 30 Synthesis of 3- (3,5-dimethoxyphenyl) -N, N-dimethyl-2- (4-. {4- [3- (4-methyl-piperazin-1-yl) -3-oxopropyl] -phenoxy)} - phenyl) -acrylamide (64) Following the general procedure for conversion of carboxylic acids to amides mentioned above and using 4-methylpiperazine as amine, 3- (4-. {4- [2- (3, 5 dimethoxyphenyl) -1- dimethylcarbamoylvinyl] -phenoxy.] - phenyl) -propionic, 38, was converted to 64. Analysis:? H NMR (DMSO-d6): d 7.28 (d, J = 2.8Hz, 2H), 7.25 (d, J = 2.8 Hz, 2H), 6.96 (d, J = 8.8Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.56 (s, 1H), 6.34 (t, J = 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 2H), 6.19 (s, 6H), 3.40 (dt, 2 = 18.0 and 4.8Hz), 3.04 (brs, 3H), 2.90 (brs, 3H), 2.79 (t, J = 8.0, 2H), 2.60 (t, J = 8.0 Hz, 2H), 2.20 (t, J = 5.2 Hz, 2H), 2.14 (s, 3H).

EXAMPLE 31 Synthesis of 3- (3, 5-dimethoxyphenyl) -, N-dimethyl-2- [4- (pyridin-2-yloxy) -phenyl] -acrylamide (66) A solution of 3- (3, 5-dimethoxyphenyl) -2- (4-hydroxyphenyl) -acrylic, 2, (0.6 g, 2.0 mmol), 2-fluoropyridine (0.19 g, 2.0 mmol) in dimethyl acetamide (4.0 ml), in the presence of potassium carbonate ( 0.28 g, 2.0 mmol) at 175 ° C for 2 hours, and then the reaction was quenched with water (25 mL), neutralized with dilute HC1 and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried and evaporated. The crude product was purified by chromatography on silica gel to yield 65 (0.15 g, 19.9%). A mixture of 3- (3, 5-dimethoxyphenyl) -2- [4- (pyridin-2-yloxy) -phenyl] -acrylic acid, 65, (0.11 g, 0.3 mmol), benzothiazole-1-yloxytris- hexafluorophosphate (dimethylamino) -phosphonium (BOP), 0.15 g, 0.35 mmol), dimethylamine in THF (2 M, 0.5 ml, 1.0 mmol), triethylamine (0.035 g, 0.35 mmol) in DMF (6.0 ml) was stirred for 3 hours at room temperature. The reaction mixture was poured into water (50.0 ml) and extracted with ethyl acetate (2 x 50 ml). The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to produce 66. Analysis: XH MR (DMSO-d6): d 8.14 (m, 1H), 7.88 (m, 1H), 7.33 (d , J = 8.8 Hz, 2H), 7.14 (m, 3H), 7.05 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 6.34 (t, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 2H), 3.58 (s, 6H), 3.10 (brs, 3H), 2.92 (brs, 3H). 65 66 EXAMPLE 32 Measurement of Increased Glucose Uptake in 3T3-L1 Adipocytes Treated With a Compound of the Present Invention The effect of treatment with 1 on glucose uptake was measured in differentiated adipocytes of 3T3-L1. the assay was conducted essentially in accordance with the method of Tafuri SR, Endocrinology, 137, 4706-4712 (1996). The adipocytes were incubated with different concentrations of the test compound for 48 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), then washed and incubated in glucose free serum free medium. for 60 minutes at 37 ° C. Then 14C-deoxyglucose was added and the cells were incubated for 30 minutes at room temperature. After washing, the cells were lysed (0.1 SDS) and the radioactivity was measured to determine the amount of glucose captured. Glucose uptake was calculated as a percentage of the baseline level seen in cells not treated with the drug. As shown in Figure 1, treatment with 1, resulted in a dose-dependent increase in glucose uptake. EXAMPLE 33 Measurement of Enhanced Glucose Uptake in 3T3-L1 Adipocytes Treated with Insulin in Combination with a Compound of the Present Invention The ability of 1 to improve insulin-stimulated glucose uptake was evaluated in 3T3-L1 adipocytes essentially as described in Example 32. The adipocytes were incubated either with vehicle (0.1% DMSO) or with test compound (5 uM of 1) for 48 hours in DMEM plus 10% FBS. The cells were then hypoalimentated with serum, incubated for 30 minutes with different concentrations of insulin, and then the glucose uptake was carried out for 10 minutes at room temperature. When compared to vehicle treatment, treatment with 1 improved the stimulation of glucose uptake by insulin (see Figure 2). EXAMPLE 34 Measurement of the Effect of Glucose Decrease in Ob / ob Mice Treated with a Compound of the Present Invention The glucose-knocking effect of 1 was measured in ob / ob mice, an animal model for type 2 diabetes. Diabetes, seven-week-old male ob / ob mice received daily oral doses either from vehicle (0.5% CMC) or from 1 (10 mg / kg) per tube for seven days. Blood glucose levels were measured on day 0 (24 hours before the first dose was administered), on day 1 (immediately before the first dose), and on days 2, 4, 6 and 8 (24 hours after the administration of the previous dose). There were significant decreases in blood glucose levels on day 6 (decrease of 36%), p <; 0.05) and on day 8 (decrease of 23 ¾, p <0.05) in the animals treated with drug versus those treated with vehicle (see Figure 3). EXAMPLE 35 Measurement of the Effects of Lipid Decrease on Ob / ob Mice Treated with a Compound of the Present Invention The effects of lipid decrease of 1 on ob / ob mice were also measured after one week of treatment. In the experiment described above in Example 34, concentrations of serum triglycerides and free fatty acids were determined on day 8. Significant decreases in serum triglyceride levels were observed (49% decrease, p <0.05). and free fatty acids (19% decrease, p <0.05) in the drug-treated versus vehicle-treated mice (see Figure 4). EXAMPLE 36 Measurement of TNF-alpha Production Induced by LPS in RAW264.7 Cells Treated with a Compound of the Present Invention The ability of 1 to inhibit the production of TNF-alpha induced by LPS in the cell line RA 264.7 macrophage was evaluated of mouse. The RAW cells were preincubated with either 1? of dexamethasone (Dex) or 10, 30 or 100 uM of 1 per 1 hour at 37 ° C in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 μg / ml) was added and the cells were incubated an additional 6 hours. The cell supernatant was then collected, aliquoted and frozen at -70 ° C, and an aliquot was used to determine the concentration of TNF-alpha by ELISA. As shown in Figure 5, treatment with 1 significantly inhibited TNF-alpha production induced by LPS. The inhibitory effect approximated to that seen with dexamethasone. EXAMPLE 37 Measurement of Inhibition of IL-1 Beta Production Induced by LPS in RAW264.7 Cells Treated with a Compound of the Present Invention The ability of 1 to inhibit the production of beta-IL-1 induced by LPS was also examined. RAW264.7 cells. The RW cells were preincubated with either 1 μ? of dexamethasone (Dex) or 10, 30 or 100 uM of 1 per 1 hour at 37 ° C in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 μg / ml) was added and the cells were incubated an additional 6 hours. The cell supernatant was then collected, aliquoted and an aliquot was used to determine the concentration of beta IL-1 by ELISA. As shown in Figure 6, treatment with 1 significantly inhibited the production of beta IL-1 induced by LPS. The inhibition seen with 1 was of the same approximate magnitude as the dexamethasone view. EXAMPLE 38 Measurement of Inhibition of IL-6 Production Induced by LPS in RA Cells 264.7 Treated with a Compound of the Present Invention The ability of 1 to inhibit IL-6 production induced by LPS in RAW264 cells was also measured. 7 The RAW cells were pre-incubated with either 1 uM of dexamethasone (Dex) or with 10, 30 or 100? of 1 for 1 hour at 37 ° C in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 μ? / P ??) was added and the cells were incubated an additional 6 hours. The cell supernatant was then collected, aliquoted and frozen at -70 ° C, and an aliquot was used to determine the concentration of IL-6 by ELISA. As shown in Figure 7, treatment with 1 significantly inhibited the production of IL-6 induced by LPS. The inhibitory effect was greater than that observed with dexamethasone. EXAMPLE 39 Measurement of the Inhibition of COX-2 and iNOS Production Induced by LPS in RAW Cells Treated with a Test Compound of the Present Invention The ability of 1 to inhibit the production of iNOS was also measured in RAW264.7 cells. and of COX-2 induced by LPS. The RAW cells were preincubated with either 1 μ? of dexamethasone (Dex) or with 10, 30 or 100 μ? of 1 (Cpd of Test) or another reference compound (Cpd A of Ref or Cpd B of Ref) for 1 hour at 37 ° C in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 g / ml) was added and the cells were incubated an additional 6 hours. The cells that did not receive the treatment with the drug, incubated with or without LPS, served as controls. The cells were used and electrophoresed 25 μ? / ??????? of total protein in SDS Tris-glycine gels 4-20 S. Proteins were transferred to nitrocellulose membrane, and the resulting stain was probed with antibody to iNOS, then trapped and re-probed with COX-2 antibody, and then they were trapped and re-probed with antibody to COX-1. As shown in Figure 8, treatment with 1 exhibited dose-dependent inhibition of iNOS production induced by LPS. In addition, treatment with 1 selectively inhibited the production of COX-2 but not COX-1 in cells stimulated with LPS. EXAMPLE 40 Inhibition of TNF-alpha Liberation Induced by LPS by Human Monocytes With Compounds of the Present Invention Frozen human decanted monocytes (Advanced Biotechnologies Incorporated) were thawed and each 1 ml vial was mixed with approximately 12 ml of complete medium of 10% FBS (10% thermal inactivated fetal bovine serum in RPMI 1640 medium supplemented with 100 U / ml penicillin, 100 μ? / p ?? streptomycin and 50 μ? 2-mercaptoethanol). The cells were centrifuged at 800 rpm for 10 minutes at room temperature using a Beckman GS-6 centrifuge with GH-3.8 rotor, and the cell compaction was resuspended in complete 20% FBA medium (20% thermally inactivated FBS in medium RPMI 1640 supplemented with 100 U / ml penicillin, 100 μg / ml streptomycin and 50 μ? 2-mercaptoethanol) and centrifuged again at 800 rpm for 10 minutes at room temperature. The cell compaction was resuspended in complete medium of 20% FBS, and the cell suspensions were combined and passed through a 70 micron cell sieve to remove any agglomerate or agglomerate. The cell suspension was adjusted to 2.5 x 10 b cells / ml in complete 20% FBS medium. The cell suspension (160 μ ?, 4 × 10 5 cells) was added in each well of a polystyrene plate treated for 96 well tissue culture and incubated at 37 ° C for 1 - 2.5 hours. Cells were pretreated with vehicle (DMSO) or test compound (0.3, 1.0, 3.0, 10 or 30 μ) in complete medium of 20% FBS for 1 hour at 37 ° C. After pretreatment, lipopolysaccharides (LPS) of Salmonella typhi urium were added to the cells in complete 20% FBS medium. The final concentrations were 0.1% DMSO and 10 ng / ml LPS in a final volume of 200 μl / well. The cells were incubated for 20 hours at 37 ° C, and then the supernatants were harvested and aliquots of the supernatant were frozen at -80 ° C for subsequent analysis. The cells were tested on the plates for cell viability using the MTS / PMS assay (Cory AH et al., Cancer Commun 3: 207-212, 1991). The concentration of TNF-alpha in the cell supernatants was determined using the quantitative immunoassay of the sandwich enzyme for human TNF-alpha (R & amp; amp; amp;; D Systems). The average percent inhibition of TNF-alpha release relative to the vehicle was calculated for each concentration of test compound from multiple determinations. As shown in Table 2, the compounds of the invention caused significant inhibition of TNF-alpha release induced by LPS by means of human monocytes.

TABLE 2 TABLE 2 (Continued) Compound% of Inhibition of TNF-alpha Release of 10 μ Test 30 μ? 49 47% 54% 31 83% 86% 37 65% 78% 13 78% 78% 51 57% * 56 - 54% 66 - 84% 67 - 89% 44 - 91% 71 - 65% 69 - 50% 58 - 53% 59-80% EXAMPLE 41 Stimulation of Glucose Uptake in 3T3-L1 Adipocytes With Compounds of the Present Invention Adipocyte differentiation of mouse 3T3-L1 was carried out using the method of Greenberg AS, et al. J Biol Chem 276: 45456-61, 2001. In summary, 3T3-L1 fibroblasts were differentiated from adipocytes by incubation in DMEM containing 10% FBS, 12 μ? / P ?? of porcine insulin, 0.5 mM of 3-isobutylmethylxanthine (IBMX) and 400 mg / ml of dexamethasone for 2 x 48 hours at 37 ° C. The differentiated cells were maintained in medium containing 10% FBS without insulin, IBMX or dexamethasone until they were used for experiments. The effect of the treatment with compounds of the invention on the uptake of glucose by means of differentiated adipocytes was evaluated essentially in accordance with the method of Tafuri SR, Endocrinology 137: 4706-12, 1996. The adipocytes were incubated with vehicle (0.1 DMSO). %) or test compound (0.1, 1.0 or 10 μ?) for 48 hours in DMEM containing 10% FBS, then washed and incubated in higher glucose, serum free medium for 3 hours at 37 ° C. The cells were then washed, incubated for 20 minutes in serum free medium, free of glucose containing 100 nM insulin, then supplemented with 2.5 μ ?? / p ?? of 1 C-deoxyglucose in 0.1 iriM of cold deoxyglucose and further incubated for 10 minutes at room temperature. After washing, the cells were lysed with 0.5% SDS and the radioactivity was measured in a scintillation counter to determine the amount of glucose captured. The average percent stimulation of glucose uptake in relation to the vehicle (adjusted to 100%) was calculated for each concentration of test compound from triplicate determinations. As shown in Table 3, the compounds of the invention caused significant stimulation of glucose uptake in differentiated adipocytes. TABLE 3 Compound% Stimulation of Test Glucose Uptake 0.1 μp? 1.0 um 10 um 31 107% 119% 161% 8 115% 132% 171% 60 93 5 120% 229% 61 93% 120% 229% 51 93% 107% 136% 29 106% 124% 120% 40 126% 117 % 126% 63 107% 112% 139% 64 108% 113% 127% 56 83% 100% 126% EXAMPLE 42 Inhibition of PDE4 and PDE3 Activity With a Compound of the Present Invention Compound 13 was examined for its ability to inhibit the activity of PDE4 and PDE3 enzymes. Partially purified PDE4 was used from human U-937 promonocitic cells and partially purified PDE3 from human platelets. The test compound (1, 10 or 30 μ?) Or the vehicle (0.1% DMSO) were incubated with 0.2? of the PDE4 enzyme or 1 μ? of the PDE3 enzyme and 1 μ? of cAMP containing 0.01 μg of [3 H] cAMP in Tris pH 7.5 regulator for 20 minutes at 30 ° C. The reaction was terminated by boiling for 2 minutes and the resulting AMP was converted to adenosine by addition of 10 mg / ml viper venom nucleosidase and further incubation at 30 ° C for 10 minutes. Unhydrolyzed cAMP was bound to the AGI-X2 resin, and the [H] adenosine remaining in the aqueous phase was quantified by scintillation counting. The average percent inhibition of PDE4 or PDE3 activity was calculated from the determinations in duplicate (Table 4). Compound 13 exhibited significant inhibition of both the activity of the enzyme PDE4 (IC50 <1 M) and PDE3 (IC50 = 13.6 uM).

TABLE 4 EXAMPLE 43 Inhibition of LPS-induced Phosphorylation of MAP kinase p44 / 42 With a Compound of the Present Invention Compound 13 was examined for its ability to inhibit phosphorylation of MAP kinase p44 / 42 induced by LPS / IF-gamma and induced by LPS. RAW 264.7 NO (-) range cells were seeded at 1 x 106 / well (2 ml / well) in 6-well tissue culture plates one day before the experiment. When starting the experiment, cells were washed 2 x with RPMI 1640 medium, 0.5% FBS, 100 U / ml penicillin, 100 μ? / p ?? of streptomycin, 1 mM sodium pyruvate, and then pretreated with vehicle (0.1% DMSO) or test compound (10 or 30 μ?) at 37 ° C for 1 hour. After pretreatment the cells were incubated in RPMI 1640 medium, 10 100 FBS / ml penicillin, 100 g / ml streptomycin, 1 mM sodium pyruvate, containing 10 mg / ml LPS or LPS (10 μg / ml). ng / ml) / IFN-gamma (10 U / ml) at 37 ° C for 15 minutes. The cells were then washed 2X with cold PBS (pH 7.4) and used in 20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM of sodium pyrophosphate, 1 mM of beta-glycerophosphate, 1 mM of Na3vO4, 1 μg of leupeptin, 1 mM of PMSF on ice for 10 minutes. The lysed cells were collected and centrifuged at approximately 20,800 x g for 10 minutes at 4 ° C. Supernatants (Used) were collected, aliquoted, and stored frozen at -80 ° C until used. The lysates (29 μg of total proteins per sample) were subjected to electrophoresis on SDS-polyacrylamide gel (4- 20%), and the separated proteins were transfected into nitrocellulose membranes. The membranes were blocked with 5% defatted dehydrated milk at 5 ¾, 10 mM Tris-HCl (pH 8.0), 150 mM NaCl, 0.1% Tween® 20 at room temperature for 1 hour and then stained with mAb against MAP kinase phospho-p44 / 42 (Thr 202 / Tyr 204) at room temperature for 1 hour. The membranes were then washed and incubated with a secondary anti-mouse antibody linked to horseradish peroxidase at room temperature for 1 hour. The signals were detected using reagents for detection by Western ECL staining. The results showed that Compound 13 inhibited the phosphorylation of MAP kinase p44 / 42 induced by LPS at 30 μ? but not at 10 μ ?, while the compound inhibited the phosphorylation of p44 / 42 induced by LPS / IFN-gamma in a dose-dependent manner at 30 μ? and 10 μ? (the data is not shown). EXAMPLE 44 Inhibition of Lymphocyte Proliferation Stimulated by Anti-CD3 / Anti-CD28 With a Compound of the Present Invention Compound 13 was examined for its ability to inhibit lymphocyte proliferation stimulated by anti-CD3 / anti-CD28. The binding of antigen, or antibodies, to the initiation activation of CD3 / CD28 and the proliferation of T lymphocytes, which are key stages involved in increasing an immune response (Abbas, Lichtman &; Pober, Cellular and Molecular Immunology, 3a. Edition, W. B. Saunders Company, Philadelphia, 1997). The mesenteric lymph nodes of BALB / c mice (females, approximately 8 weeks old) were collected, and the cells were isolated in PBS (pH 7.4) and mixed with culture medium (RPMI 1640 medium, 10% FBS, 100 U / ml penicillin, 100 g ml streptomycin, 50 uM 2-mercaptoethanol). The cell suspension was centrifuged at 900 rpm for 10 minutes at room temperature using a Beckman GS-67 centrifuge with GH-3.8 rotor. After centrifugation, the cell compacts were resuspended in culture medium and centrifuged again at 900 rpm for 10 minutes at room temperature. The cell compacts were resuspended in culture medium and the cells were counted, 2 x 10 5 lymph node cells were added per well in a 96-well cell culture plate. For the treatment (n = 4), vehicle (DMSO) or test compound was added to the cells. The cells were treated with purified anti-mouse CD28 monoclonal antibodies (0.2 μg / ml) and purified hamster anti-mouse CD3e (2 g / ml) or culture medium. The final concentrations were 1% DMSO and 10 μ? of test compound in a final volume of 200 μ? by pocilio. The cells were incubated at 37 ° C for 67 hours, and then the cells were centrifuged on the plates at 900 rpm for 10 minutes at room temperature using a Beckman Centrifuge GS-6 with GH-3.8 rotor. 150 μ? of the supernatant from each well were subsequently harvested and frozen at -80 ° C for further analysis (ELISA). For cells in the plate, 150 μ? of culture medium in each of the wells to replace the harvested supernatants and 40 μ? of MTS / PMS solution in each of the wells. After further incubation at 37 ° C for 140 minutes, the plates were read at 505 nm in a microplate spectrophotometer. The values of O.D., after subtracting the O.D. medium of the control wells) were used to compare the proliferation of the treated cells. As shown in Table 5, 10 μ? of Compound 13 caused approximately 50% inhibition of proliferation of mouse mesenteric lymph node cells stimulated by anti-CD3 / anti-CD28 monoclonal antibodies. Inhibition of CD3 / CD28 mediated T cell proliferation demonstrates that Compound 13 is capable of blocking an immunologically relevant cell response, probably via interaction with a step in a cascade of signal transduction. This indicates that Compound 13 has immunomodulatory activity, which may be useful for the treatment of immunoproliferative disorders. TABLE 5 EXAMPLE 45 Improvement of Collagen-Induced Arthritis in Mice Using a Compound of the Present Invention Collagen-induced arthritis (CIA) was induced in 45 DBA / 1 J mice using immunization with chicken type II collagen. The induction procedure was as follows: on Day 0, 100 g 100 μ? in Complete Freund's Adjuvant (CFA), intradermally; on Day 21, 100 μg / 100 μ? of Freund's Adjuvant Complete subcutaneously; on Day 31, 100 μg / μl in CFA subcutaneously; all occurred at the base of the queue. On Day 35 the animals received lipopolysaccharides (detoxified serotype 0111: B4 from E. Coli; 40 μg ml) intraperitoneally. When signs of arthritis appeared, the mice were assigned into four treatment groups; control with vehicle (0.5% carboxymethylcellulose (CMC), compound 31 (40 mg / kg suspension in CMC), compound 31 (100 mg / kg in CMC), positive control (dexamethasone, 5 mg / kg). dosed orally, twice daily for 14 days, at a dose volume of 250 μ? per mouse per dose.The study was scored blind for the different treatment groups.The mice were weighed and the arthritis scored three times per week Arthritis was classified as an account of affected limbs and digits, evaluated as: erythema and swelling of the tarsal, the ankle to the metatarsal joint to the restriction of movement and deformation of the joints. 4 hours after the final dose, to measure the circulating drug levels Finally, the animals were euthanized and the hind limbs removed for histopathological examination, the hind limbs were collected in Ormalin: The disqualified tissue was sectioned longitudinally parallel to the bones, and sections stained with eosin and hematoxylin were graded using a standard rheumatoid arthritis rating system by a veterinary histopathologist who was blinded to the treatment groups. Animals in all groups had moderate arthritis before the start of dosing (Day 0) as shown in Figure 9. The vehicle group exhibited an increase in severity over the course of the study with a tendency to stable from about Day 10. Low dose of Compound 31 had no apparent effect on animals compared to vehicle controls. The high dose prevented the increase in severity, in approximately the same extent as dexamethasone. Histology showed that the group with vehicle and the group with the low dose of Compound 31 had marked chronic inflammation of the synovium with formation of pannus and destruction of bone and cartilage, whereas in the group with dexamethasone the joints were within normal limits . At high dose of Compound 31 there was a reduction in the incidence and severity of pannus formation, infiltration of cell inflammation and bone / cartilage damage. Thus, a dose-dependent effect of Compound 31 was observed in both soft tissue and bone and cartilage, consistent with a disease modifying activity of the compound in this model - From the foregoing, it will be obvious that the compounds in accordance with the present invention not only decreased the blood glucose level, the triglyceride level and the free fatty acid level in diabetic conditions, but also inhibited the production of TNF-alpha, IL-6, IL-1 beta, COX-2 and iNOS in inflammation, as well as inhibited the activity of PDE4 and PDE3, the phosphorylation of MAP kinase p44 / 42 and the proliferation of lymphocytes. The properties demonstrated above indicate that the compounds of the invention should be useful in the treatment of disorders associated with insulin resistance, hyperglycemia, hyperlipidemia, coronary artery disease and peripheral vascular diseases and for the treatment of inflammation., inflammatory diseases, immunological diseases, proliferative diseases and cancer, especially those mediated by cytokines, cyclooxygenase, phosphodiestearase and / or MAP kinase. EXAMPLE 46 Synthesis of N-. { 4- [2- (3, 5-dimethoxyphenyl) -1- dimethylcarbamoylvinyl] -phenyl} - benzamide (67) A mixture of 2- (4-aminophenyl) -3- (3, 5-dimethoxyphenyl) -N, N-dimethylacrylamide, 43, (0.49 g, 1.2 mmol) and benzoyl chloride (0.26 g) was heated. , 1.8 mmol) in anhydrous benzene (18.0 ml) at 90 ° C for 2 hours. The solvent was evaporated and the crude product was purified by chromatography on silica gel. Analysis: LH MR (DMSO-d6): d 10.33 (s, 1H), 7.96 (d, J = 8.8Hz, 2H), 7.76 (d, J = 8.8Hz, 1H), 7.51-7.62 (m, 3H) , 7.26 (d, J = 9.2 Hz, 2H), 6.55 (s, 1H), 6.35 (t, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 2H), 3.58 (s, 6H) , 3.03 (brs, 3H), 2.91 (brs, 3H). 43 67 EXAMPLE 47 Synthesis of the 3- ethyl ester. { 4- [4- (2-benzo [l, 3] dioxol-5-yl-1-dimethylcarbamoylvinyl) -phenoxy] -phenyl} - propionic (69) A mixture of 3- acid was heated. { 4- [4- (2-ethoxycarbonylethyl) -phenoxy] -phenyl} - 2-oxopropionic, 24 (1.0 g, 3.0 mmol), piperonal (0.67 g, 0.45 mmol), triethylamine (5.12 ml) and acetic anhydride (5 ml) at 80 ° C for 3 hours. The reaction mixture was poured into water (50 ml). The separated solid was filtered and boiled in toluene, cooled and filtered. The crude solid was purified by chromatography on silica gel to yield 68, 0.35 g (product, 25.0%). A mixture of 4-benzo [l, 3] dioxol-5-yl-3- acid was stirred. { 4- [4- (2-ethoxycarbonylethyl) -phenoxy] -phenyl} - 2-oxobut-3-enoic, 68, (0.08 g, 0.17 mmol), benzotriazole-1-yloxytris- (dimethylamino) -phosphonium hexafluorophosphate (BOP, 0.09 g, 0.21 mmol), triethylamine (36 μ ?, 0.25 mmol) ), dimethylamine in THF (2, 0.25 ml, 0.5 mmol) in DMF (2.0 ml) for 10 minutes at room temperature. The reaction mixture was poured into water (20 ml). The separated solid was filtered and boiled in toluene, cooled and filtered. The crude solid was purified by chromatography on silica gel to produce 69. Analysis: lE NMR (DMS0-d6): d 7.24 (d, J = 8.8 Hz, 4H), 6. 95 (d superimposed, J = 8.8 Hz, 4H), 6.80 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.51 (s, 1H) , . 96 (s, 2H), 4.05 (q, J = .0 Hz, 2H), 3.05 (brs, 3H), 2.85 (brs, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H) and 1.15 (t, J = 4.0 Hz, 3H). 24 68 69 EXAMPLE 48 Synthesis of 2-. { 4- [4- (1-dimethylcarbamoy1- 2-pyridin-3-ylvinyl) -phenoxy] -benzyl} - malonamide (71) To a solution of 2-dimethyl ester. { 4- [4- (1- Dimethylcarbamoyl-2-pyridin-3-ylvinyl) -phenoxy] -benzyl} - malonic, 70 (0.49 g, 1.0 mmol), in DMF (5 mL), ammonium hydroxide (28% in water, 12 mL) was added and stirred overnight at room temperature. The reaction mixture was poured into water (30 ml) and extracted with chloroform (5 x 25 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel to yield 71, 0.23 g (yield, 24.5%). Analysis: * H NMR (CDC13 + CD30D): 6 8.32 (m, 2H), 7.40 (m, 1H), 7.18 (d superimposed, J = 8.0 Hz, 2H), 7.20 (d superimposed, J = 8.0 Hz, 2H), 7.12 (m, 1H), 6.92 (d, J = 8.0 Hz, 2H) , 6.84 (d, J = 8.0 Hz, 2H), 6.60 (s, 1H), 3.22 (d, J = 12.0 Hz), 3.12 (brd, J = 12.0 Hz), 2.98 (brs, 3H), 2.96 (brs , 3H). 70 71 It will be appreciated that various modifications may be made to the invention as described above and as defined in the following claims wherein:

Claims (36)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore the content of the following claims is claimed as property: 1. A compound characterized in that it has a structure selected from Formulas I-XIII: ?? wherein the stereocenters marked with an asterisk (*) can be R- or S-; the link represented by a dotted line plus a solid line is a double bond or a single link; and wherein Ri, R2, R3, R4 R5, R6 and T are selected, independently of each other from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl, chloroalkyl or fluoroalkyl; C2-C2o optionally substituted linear or branched alkenyl; C6-C2o optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR wherein R is H, C1-C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or optionally substituted aryl-CG-CI0, sodium, potassium, calcium, magnesium, ammonium, tromethamine; COOR'R ", wherein R 'and R" are independently H, C1-C20 optionally substituted alkyl, C2-C2o optionally substituted alkenyl or Cf.-Cm optionally substituted aryl or where NR'R "represents a selected cyclic portion of morpholine piperidine, piperazine, Ci-C6 optionally substituted amidoalkyl, NH2; Ci-C2o alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH: C1-C20 optionally substituted alkoxy; C1-C20 optionally substituted alkanoyl; C1-C20 acyloxy optionally substituted; halo; halo; C 1 -C 20 alkylcarboxylamino optionally substituted; cyano; nitro; S02NR '"' R" "wherein R" 'and R "" are independently H, C 1 -C 20 alkyl or aryl; S02R '' 'where R' "is H, C1-C20 alkyl or aryl, S03R '" where R "' is H, C1-C20 alkyl or aryl, and C4-C8 heterocycles such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, and indolyl, Rs and R9 are independently selected from the group consisting of H, optionally substituted straight or branched alkyl C1-C20, optionally substituted C2-C2o straight or branched alkenyl, optionally substituted C6-Ci0 aryl or heteroaryl, COOR where R is H, C1-C20 optionally substituted alkyl, C2 ~ C2o optionally substituted alkenyl or optionally substituted C6-Ci0 aryl, sodium, potassium, calcium, magnesium, ammonium, tromethamine; CONR'R ", where R 'and R" are independently H , alkoxy, Ci-C20 alkyl optionally substituted, C2-C20 alkenyl optionally substituted, C3-C10 cycloalkyl or cycloalkenyl optionally substituted or C5-Cio aryl or optionally substituted heteroaryl, or where NRf R "represents a selected cyclic portion of raorfoline, pip eridine, hydroxypiperidine, imidazole, piperazine or methylpiperazine; NH2; C: -C2o alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20 alkoxy; Ci-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20 alkylcarboxylamino; cyano; nitro; S02NR '' 'R "" wherein R' "and R" "are independently H, Ci-C20 alkyl or aryl; S02R '"where R"' is Hf Ci-C2o alkyl or aryl; S03R '"wherein R' '' is H, C1-C20 alkyl or aryl, and tetrazolyl; Ri and R11 are independently from each other, selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl; C2-C20 optionally substituted linear or branched alkenyl, C6-Ci0 optionally substituted aryl or heteroaryl, COOR where R is H, C1-C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or C6-C10 aryl, sodium, potassium, calcium, magnesium, ammonium , tromethamine, CONR 'R ", where R' and R" are independently H, Ci-C2o optionally substituted alkyl, optionally substituted C2-C20 alkenyl or C6-Ci or optionally substituted aryl or where NR 'R "represents a selected cyclic portion of morpholine, piperidine or piperazine; NH2; Ci-C2o alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20 alkoxy; C1-C20 alkanoyl; CL-C2o acyloxy; halo; C1-C20 alkylcarboxylamino; cyano; nitro; S02 R 'r' R "" wherein R '"and R" "are independently H, C 1 -C 20 alkyl or aryl; S02R "'where R"' is H, Ci -C20 alkyl or aryl; S0 R "'where R' '' is H, C1-C20 alkyl or aryl, and tetrazolyl, R12, R1 3, Ie / R19 R20 are independently selected from the group consisting of H; optionally substituted branched C2-C2o optionally substituted straight or branched alkenyl, C6-Ci or optionally substituted aryl or heteroaryl, COOR where R is Ci-C2o optionally substituted alkyl, optionally substituted C2-C2 or alkenyl, or optionally substituted C6-Cio aryl, sodium, potassium, calcium, magnesium, ammonium or tromethamine; CONR 'R ", where R' and R" are independently H, C1-C20 alkyl optionally substituted, C2-C2o optionally substituted alkenyl or C6-Ci0 optionally substituted aryl or where NR 'R' represents a selected cyclic portion of morpholine, piperidine and piperazine; C1-C20 alkanoyl; C1-C20 alkylamido; C6-C2o aroyl or heteroaroyl; SO2R '' 'where R "' is H, C1-C20 alkyl or aryl, morpholinocarbonylmethyl, piperazinecarbonylmethyl, and piperadinocarbonylmethyl, R12 and R13 may be absent, or Ri2 and R13 together may be an optionally substituted heterocyclic ring, selected from morpholine, piperidine , piperazine, and N-methyl piperidine RIA is selected from the group consisting of H, C1-C20 optionally substituted straight or branched alkyl including chloroalkyl and fluoroalkyl; C2-C20 optionally substituted straight or branched alkenyl; C6-Cio aryl or heteroaryl optionally substituted, COOR where R is H, C1-C20 optionally substituted alkyl, optionally substituted C2-C2o alkenyl or optionally substituted aryl C6-CIO, sodium, potassium, calcium, magnesium, ammonium or tromethamine; CONR'R ", where R 'and R "are independently H, C1-C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or C5-C10 optionally substituted aryl or where NR 'R" represents a a selected cyclic portion of morpholine, piperidine, and piperazine; cyano; and tetrazolyl; Ri5 / i6 and i are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl including eloroalkyl and fluoroalkyl; C- or optionally substituted straight or branched alkenyl; Cfe-Cio optionally substituted aryl or heteroaryl; COOR where R is H, C1-C20 optionally substituted alkyl, C2-C20 optionally substituted alkenyl or C6-C1 or optionally substituted aryl, sodium, potassium, calcium, magnesium, ammonium and tromethamine; CONR'R ", wherein R 'and R" are independently H, Ci-C2o optionally substituted alkyl, optionally substituted C2-C20 alkenyl or optionally substituted aryl C6-C10 or where NR' R "represents a selected cyclic portion of morpholine, piperidine and piperazine; NH 2; C 1 -C 20 alkylamino, bis (alkylamino), cycloalkylamino or cyclic amino; OH, CI-CJO alkoxy; C 1 -C 20 alkanoyl; C 1 -C 20 acyloxy; halo; C 1 -C 20 alkylcarboxylamino; cyano; nitro; S02NR ' "R" "wherein R '" and R "" are independently H, C 1 -C 20 alkyl or aryl, S 0 R "' where R" 'is H, Ci-C 2 or alkyl or aryl; S 0 R "' where R '' ' is H, 0: -? 2? alkyl or aryl; and tetrazolyl; X is selected independently of O; N; S; S = 0; S02; or NR "" ', wherein R' "" may be H or C1-C20 optionally substituted alkyl, C2-C2o optionally substituted alkenyl, C1-C20 optionally substituted acyl, Ci-C2o optionally substituted acyloxy and Ci-C20 optionally substituted alkoxycarbonyl; And it is independently O, S, or NH; Z is selected from the group consisting of ORa where Ra is selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl, chloroalkyl or fluoroalkyl; C2-C20 optionally substituted linear or branched alkenyl; Optionally substituted aryl or heteroaryl; C6-C20 optionally substituted aroyl or heteroaroyl; Ci-C20 optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, d-C2o alkyl or aryl; NRbRc where Rb and Rc are independently selected from the group consisting of H; Ci ~ C2o optionally substituted linear or branched alkyl, chloroalkyl or fluoroalkyl; C2-C20 optionally substituted linear or branched alkenyl; C6-Cio optionally substituted aryl or heteroaryl; C3-C10 optionally substituted cycloalkyl or cycloalkenyl; COOZi where Zi is optionally substituted C1-C20 alkyl, optionally substituted C2-C2o alkenyl or optionally substituted C6-Ci0 aryl; C6_C2o optionally substituted aroyl or heteroaroyl; C1.-C20 optionally substituted alkanoyl; and S02R "'where R'" is H, C1-C20 alkyl or aryl; and wherein Rb and Rc together can be joined to form a ring of 3-6 elements selected from aziridine, morpholine, piperidine and piperazine; and CRd eRf where Rd, Re and Rf are independently selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl, chloroalkyl or fluoroalkyl; C2-C2o optionally substituted linear or branched alkenyl; Ce-Cio optionally substituted aryl or heteroaryl; C3-C10 optionally substituted cycloalkyl or cycloalkenyl; COOR where R is H, Ci-C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or C6-Ci or optionally substituted aryl, sodium, potassium, calcium, magnesium, ammonium or tromethamine; NH2; Ci -C2u alkylamino, bis (alkylamino); cycloalkylamino or cyclic amino; OH; C1-C20 optionally substituted alkoxy, trifluoromethoxy; C1-C20 optionally substituted alkanoyl; C1-C20 optionally substituted acyloxy; C6-C2o optionally substituted aroyl or heteroaroyl; halo; cyano; nitro; C1-C20 optionally substituted alkylcarboxylamino; S02NR "'R" "where R"' and R "" are independently H, Ci-C20 alkyl or aryl; S02R '' 'where R' "is H, C1-C20 alkyl or aryl, and S03R" 'where R "' is H, C1-C20 alkyl or aryl, the grouping C (= Y) Z may represent hydrogen or R12 or may be absent Q is selected from the group consisting of 0Ra where Ra is selected from the group consisting of H; C1-C20 optionally substituted straight or branched alkyl, chloroalkyl or fluoroalkyl; C2-C20 optionally substituted straight or branched alkenyl; C10 optionally substituted aryl or heteroaryl, C6-C2o optionally substituted aroyl or heteroaroyl, Ci-C20 optionally substituted alkanoyl, and SO2R '' 'where R' '' is H, Ci-C20 alkyl or aryl, and NRbRc where Rb and Re are independently selected from the group consisting of optionally substituted H, C -Co straight or branched alkyl, chloroalkyl or fluoroalkyl; C2-C20 optionally substituted straight or branched alkenyl; C6-C i 0 aryl or optionally substituted heteroaryl; C3-C10 cycloalkyl or cycloalkenyl opc only replaced; COOZ i where Z i is C i -C20 alkyl optionally substituted, C2-C20 optionally substituted alkenyl or C6-Ci or optionally substituted aryl; C6-C2o optionally substituted aroyl or heteroaroyl; C1-C20 optionally substituted alkanoyl; and S02R '' 'wherein R' "is H, C1-C20 alkyl or aryl; and wherein Rb and Rc together can be joined to form a 3-6-element ring such as aziridine, morpholine, piperidine, piperazine and the like; and SRg, SORg or S02Rq where, is selected from the group consisting of H; C1 -C20 optionally substituted straight or branched alkyl, chloroalkyl or fluoroalkyl; C2-C20 optionally substituted linear or branched alkenyl; C1-C20 optionally substituted acyl; Ci-C2u optionally substituted alkoxycarbonyl; C2 -C2o alkoxy; Ce-Cio optionally substituted aryl or heteroaryl; and C6-C10 optionally substituted aroyl or heteroaroyl. Group A is C2-C2o or optionally substituted straight or branched alkenyl; C6-C2o optionally substituted aryl, linear or branched alkylaryl / linear or branched alkenylaryl, optionally substituted heteroaryls selected from pyridine, indole, morpholine, piperidine, tetrazolyl and piperazine; COR wherein R is C1-C20 linear or branched alkyl optionally substituted; C2-C20 optionally substituted linear or branched alkenyl; C6-C2o optionally substituted aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally substituted heteroaryls selected from pyridine, indole, morpholine, piperidine, piperazine and tetrazolyl; Group B is OH, C! -C2o alkoxy; S02R where R can be H or C1-C20 linear or branched alkyl. The Het Group represents a heterocyclic ring selected from pyridyl, indolyl, tetrazolyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl and thiophenyl.
2. 2. The compound in accordance with the claim 1, characterized in that the link represented by a dotted line plus a solid line is a double bond and is in the E or Z configuration.
3. 3. The compound according to claim 1, characterized in that the bond represented by a dotted line plus a Solid line is a link only where the resulting stereocenters have the R- or S- configuration.
4. The compound according to claim 1, characterized at least in that at least one aromatic ring possesses more than one adjacent substituent, and in that the substituents are linked to form a ring.
5. 5. The compound according to claim 1, characterized in that Ra and 9 together join to form a heterocyclic C4-C8 ring.
6. 6. The compound according to claim 1, characterized in that Rio and Ru together join to form a heterocyclic C4-C8 ring.
7. 7. The compound in accordance with the claim 1, characterized in that Rd and Re together merge to form a ring of 3-6 elements and because the resulting stereocenter has an R- or S- configuration.
8. 8. The compound according to claim 1, characterized in that it is of Formula I.
9. 9. The compound according to claim 8, characterized in that it is selected from the group consisting of: methyl ester of 3- (3, 5) acid. - dimethoxyphenyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} -acrylic; 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylic; 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-ethoxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} - acrylic; 2-methyl ester. { 4- [4- (3-benzoyloxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} -3- (3,5-dimethoxyphenyl) -acrylic acid; 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - propionic; 3- (3,5-dimethoxyphenyl) -2- acid. { 4- [4- (3-oxo-3-ureidopropenyl) -phenoxy] -phenyl} - acrylic; Ethyl 3- (3,5-dimethoxyphenyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} -acrylic; 3- (3,5-dimethoxyphenyl) - N, N-dimethyl- 2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide; 2- (4-. {4- [3- (3-cyclohexylureido) -3-oxopropyl] -phenoxy} - phenyl) -3- (3,5-dimethoxyphenyl) -acrylic acid.
10. 10. The compound according to claim 1, characterized in that it is of Formula II.
11. 11. The compound according to claim 10, characterized in that it is selected from the group consisting of [3- (4-phenoxyphenyl) -propionyl] -urea; and (3- [4- (4-methoxyphenoxy) -phenyl] -acryloyl} - urea 12.
12. The compound according to claim 1, characterized in that it is of Formula III 13.
13. The compound according to claim 12, characterized in that it is selected from the group consisting of 2- {4- [4- (3-acetylurethomethyl) -phenoxy] -phenyl} - 3- (3,5-dimethoxyphenyl) -acrylic acid methyl ester. 2- {4- [4- (3-acetylthioureidomethyl) -phenoxy] -phenyl} - 3- (3,5-dimethoxyphenyl) -acrylic acid 14.
14. The compound according to claim 1, characterized because it is of Formula IV 15.
15. The compound according to claim 14, characterized in that it is selected from the group consisting of l-acetyl-3- [4- (4-methoxyphenoxy) -benzyl] -urea; 3- [4- (3, 4-dimethoxyphenoxy) -benzyl] -urea 16.
16. A composition characterized in that it comprises the compound according to claim 1 and a pharmaceutically acceptable carrier.
17. A method of treating diabetes characterized in that it comprises the co-administration of the compound according to claim 1 and an agent selected from the group consisting of: insulin or an insulin mimic, a sulphonylurea or other insulin secretagogue, a thiazolidinedione , a fibrate or other PPAR-alpha agonist, a PPAR-delta agonist, a biguanidine, a statin, or another inhibitor of hydroxymethylglutaryl (HMG) CoA reductase, an alpha-glucosidase inhibitor, a resin binding to a bile acid, apoAl, niacin probucol, and nicotinic acid.
18. 18. A method of treating inflammatory or immunological diseases characterized in that it comprises the co-administration of the compound according to claim 1 and an agent selected from the group consisting of: a non-steroidal anti-inflammatory drug (NSAID), an inhibitor of cyclooxygenase-2, a corticosteroid or other immunosuppressive agent, a disease-modifying anti-rheumatic drug (DMARD), an inhibitor of TNF-alpha, another cytokine inhibitor, another immunomodulatory agent, and a narcotic agent.
19. A method of treating inflammatory or immunological diseases characterized in that it comprises the step of administering to a subject in need of said treatment a therapeutically effective amount of the compound according to claim 1.
20. 20. The method according to claim 19, characterized in that the compound is administered in combination with an agent selected from the group consisting of NSAID, cyclooxygenase-2 inhibitor, immunosuppressive agent, DMARD, TNF-alpha inhibitor, cytokine inhibitor, immuno-modulating agent and a narcotic agent.
21. 21. The method according to claim 20, characterized in that the agent is corticosteroid or methotrexate.
22. 22. A method of treatment for diabetes characterized in that it comprises the step of administering to a subject suffering from a diabetic condition a therapeutically effective amount of the compound according to claim 1.
23. 23. The method according to claim 20, characterized in that the compound is administered in combination with an agent selected from the group consisting of: insulin, insulin mimic, insulin secretagogue, PPAR-gamma agonist, PPAR-alpha agonist, a PPAR-delta agonist, biguanidine , HMG CoA reductase inhibitor, alpha-glucosidase inhibitor, bile acid binding resins, apoAl, niacin, probucol and nicotinic acid.
24. 24. The method of compliance with the claim 21, characterized in that the agent is selected from the group consisting of sulfonylurea, thiazolidinedione, fibrate, and statin.
25. 25. The method of compliance with the claim 22, characterized in that the agent is sulfonylurea.
26. 26. A method of inhibiting the activity of TNF-alpha, IL-1, IL-6, PDE4, PDE3, MAP kinase p44 / 42, iNOS or COX-2 characterized in that it comprises administering to a host in need of inhibition an amount Therapeutically effective of the compound according to claim 1.
27. 27. A method of inhibiting the undesired action of cytokine, phosphodiestearase. MAP kinase or cyclooxygenase, characterized in that it comprises administering to a host in need of treatment a therapeutically effective amount of the compound according to claim 1.
28. 28. A method of treating hyperlipidemia characterized in that it comprises administering to a host in need of treatment an effective amount The method of treating coronary heart disease characterized in that it comprises administering to a host in need of treatment a therapeutically effective amount of the compound according to claim 1. 30. A method of treating cancer or a proliferative disease characterized in that it comprises administering to a host in need of treatment a therapeutically effective amount of the compound according to claim 1. 31. The method according to claim 19, characterized in that the Inflammatory or immunological disease is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, asthma, acute respiratory fatigue syndrome, chronic obstructive pulmonary disease, and multiple sclerosis. 32. A compound of the formula characterized in that the compound is 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylic. 33. A compound of the formula characterized in that the compound is 3- (3,5-dimethoxyphenyl) -N, N-dimethyl-2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide. 34. An anti-inflammatory composition characterized in that it comprises an effective amount of a compound selected from the group consisting of 3- (3,5-dimethoxyphenyl) -N, N-dimethyl-2-. { 4- [4- oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide (13); 2- . { 4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} 3- (3,5-dimethoxyphenyl) -N, N-dimethylacrylamide (31); 3- (4. {4- [2- (3,5-dimethoxy phenyl) -1-dimethylcarbamoylvinyl] -phenoxy] -phenyl) -propionic acid ethyl ester (37); N-. { 4- [2- (3, 5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenyl} - 3-hydroxybenzenamide (44); 3- (3,5-dimethoxyphenyl) -2- (4-hydroxyphenyl) -N, N-dimethylacrylamide (49); [3- (4- { 4- [2- (3,5-dimethoxyphenyl) -1- (piperidin-1-carbonyl) -vinyl] -phenoxy} - phenyl) -propionyl] -urea (51); 2- . { 4- [4- (3-acetylamino-3-oxopropyl) -phenoxy] -phenyl} - 3- (4- fluorophenyl) - N, N-dimethylacrylamide (56); 2- (4- { 4- [2- (3,5-Dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy} - benzyl) malonic acid (58); 2- (4-. {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoylvinyl] -phenoxy} - benzyl) -malonamide (59); 3- (3,5-dimethoxyphenyl) - N, N-dimethyl-2- [4- (pyridin-2-yloxy) -phenyl] -acrylamide (66); N, N-dimethyl-2-. { 4- [4- (3-oxo-3-ureidopropenyl) -phenoxy] -phenyl} 3- pyridin-3-ylacrylamide (47); N- (4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoyl-vinyl] -phenyl} - benzamide (67); 2- . { 4- [4- (1-dimethylcarbamoyl-2-pyridin-3-yl-vinyl) -phenoxy] -benzyl} - malonamide (71); 3-ethyl ester. { 4- [4- (2-Benzo [l, 3] dioxol-5-yl-1-dimethylcarbamoyl-vinyl) -phenoxy] -phenyl} - propionic (69); 3-benzo [l, 3] dioxol-5-yl- 2-. { 4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} - N, N-dimethyl acrylamide (72); N, N- dimethyl- 2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} 3- pyridin-3-yl-acrylamide (73); 35. An anti-diabetic composition characterized in that it comprises an effective amount of a compound selected from the group consisting of: 3- (3,5-dimethoxyphenyl) -2- methyl ester. { 4- [4- (3-ethoxycarbonylamino-3-oxo-propyl) -phenoxy] -phenyl} - acrylic (8); (4- {4- [2- (3,5-dimethoxyphenyl) -1-dimethylcarbamoyl-vinyl] -phenoxy} -benzyl) -carbamic acid methyl ester (29); 2- . { 4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} - 3- (3, 5- dimethoxyphenyl) - N, N-dimethylarilamide (31); 3- (3,5-dimethoxyphenyl) - N, N-dimethyl- 2-. { 4- [4- (3-morpholin-4-yl-3-oxopropyl) -phenoxy] -phenyl} acrylamide (40); [3- (4- { 4- [2- (3,5-dimethoxyphenyl) -1- (piperidin-1-carbonyl) -vinyl] -phenoxy} - phenyl) -propionyl] -urea (51); 2- . { 4- [4- (3-acetylamino-3-oxopropyl) -phenoxy] -phenyl} 3- (4-fluorophenyl) -N, N-dimethylacrylamide (56); 3- (3,5-dimethoxyphenyl) -2-. { 4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - N-pyridin-4-ylacrylamide (60); N- (4-chlorophenyl) -3- (3, 5-dimethoxyphenyl) -2- (4- [4- (3-oxo-3-ureidopropyl) -phenoxy] -phenyl} - acrylamide (61); - (3,5-dimethoxyphenyl) - N, N-dimethyl-2- (4-. {4- [2- (2-morpholin-4-yl-2-oxoethylcarbamoyl) -ethyl] -phenoxy} - phenyl) -acrylamide (63); 3- (3, 5-dimethoxyphenyl) -?,? - dimethyl-2- (4-. {4- [3- (4-methyl-piperazin-1-yl) -3-oxopropyl) ] - phenoxy] - phenyl) - acrylamide (64); 36. 2- {4- [4- (2-carbamoylethyl) -phenoxy] -phenyl} - 3- (3, 5-dimethoxyphenyl) - N, N-dimethylacrylamide (31).