PT1360178E - Novel heterocyclic analogs of diphenylethylene compounds - Google Patents

Description

ΡΕ1360178 1

DESCRIPTION " NEW HETEROCYCLIC ANALOGS OF DIFENYLETHYLENE COMPOUNDS "

Background of the Invention The present application is directed to novel compounds formed by chemical coupling of diphenylethylene compounds, and derivatives thereof, with intermediates thiazolidine or oxazolidine. These compounds are effective to provide a variety of useful pharmacological effects. For example, the compounds are useful in lowering blood glucose levels, serum insulin and triglycerides in animal models of type II diabetes. Surprisingly it has been found that these compounds increase the level of leptin and are not toxic to the liver.

In addition, these compounds are useful for the treatment of disorders associated with insulin resistance, such as polycystic ovarian syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease, and for the treatment of inflammation and immunological diseases, particularly those mediated by cytokines and cyclooxygenase, such as TNF-alpha, IL-1, IL-6 and / or COX-2. 2 ΡΕ1360178

The causes of type I and type II diabetes are still unknown, although genetics and environment appear to be important factors. Insulin-dependent type I and non-insulin dependent type II are the known types. Type I is an autoimmune disease in which the responsible autoantigen is still unknown. Type I patients need to receive insulin, either parenterally or subcutaneously, to survive. However, type II diabetes, the most common form, is a metabolic disorder resulting from the inability of the body to produce a sufficient amount of insulin or to appropriately use the insulin that is produced. Insulin secretion and insulin resistance are considered the main deficiencies, but the precise genetic factors involved in the mechanism remain unknown.

Patients with diabetes generally have one or more of the following deficiencies:

Less production of insulin by the pancreas;

Excessive secretion of glucose from the liver;

Independent of glucose uptake by skeletal muscles;

Deficiencies in glucose transporters, desensitization of insulin receptors; and

Deficiencies in the metabolic degradation of polysaccharides.

In addition to the parenteral or subcutaneous application of insulin, there are about 4 classes of oral hypoglycemic agents used. 3 ΡΕ1360178

Class Approved Agents Mechanisms of Limitations Sulfonylurea 4 (Ia generation) and 2 (2nd generation) acts in the pancreas to release more insulin development of resistance Biguanides Metformin reduces the production of glucose by the liver; improves insulin sensitivity liver problems, lactic acidosis Alpha-glucosidase inhibitor Acarbose interferes with the digestive process; reduces glucose absorption only useful at the postprandial level Thiazolidine-dione Troglitazone (withdrawn) rosiglitazone pioglitazone reduces insulin resistance " additive " with insulin; not useful for people with heart and liver disease

As is clear from the above table, each of the standard agents available for use in the treatment of diabetes has certain disadvantages. Accordingly, there is continued interest in the identification and development of novel agents, particularly water-soluble agents that can be administered orally, for use in the treatment of diabetes. The class of thiazolidinediones listed in the above table has been used more widely in recent years for the treatment of type II diabetes, exhibiting particular utility as an insulin sensitizer for 4 ΡΕ1360178 to combat " insulin resistance ", a state in which the patient responds less to the effects of insulin. However, the known thiazolidinediones are not effective in a significant portion of the patient population. In addition, the first drug in this class to be approved by the FDA, troglitazone, has been withdrawn from the market due to liver toxicity problems. Thus, there is a continuing need for non-toxic and more widely effective insulin sensitizers.

Thiazolidinedione compositions are pharmaceuticals and methods employing described in the patents 6,133,295; 6,117,893; 6,103,742; 6,030,973; 5,990,139; 6,133,293; 6,114,526; 6,080,765; RE 36,575; 5,985,884; 6,130,216; 6,110,951; 6,046,222; 6,011,036; 5,972,973 and 6,121,295; 6,110,948; 6,046,202; 6,011,031; others. Nos. 6,121,294; 6,107,323; 6,034,110; 6,008,237; help

As indicated above, the present invention also relates to the treatment of immune diseases or inflammation, especially cytokine or cyclooxygenase-mediated diseases. The major elements of the immune system are macrophages or antigen presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells is known, but their role in primary immune is right. Macrophages are important mediators in inflammation and in achieving " assistance " necessary for stimulation and proliferation of T cells. More importantly, macrophages produce IL-1, IL-12 and TNFÎ ±, all of which are potent pro-inflammatory molecules and also provide support for T-cells. In addition, activation of macrophages leads to the induction of enzymes, such as cyclooxygenase II (COX-2), inducible nitric oxide synthase (iNOS), and the production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and gamma interferon (IFNγ). Phospho-tyrosine kinases (PTKs) and other undefined cellular kinases are believed to be involved in the activation process.

Macrophages collect and degrade antigens in small fragments. These fragments then associate with the major histocompatibility complex II (MHC II). This complex of antigen and MHC II fragments is recognized by the T cell receptor. Associated with appropriate costimulation signals, this receptor-ligand interaction leads to T cell activation and proliferation. Depending on the route of administration of the antigen, its dose and the conditions under which the macrophages are activated, the immune response may result in B-cell aid and antibody production or in the development of a cell-mediated response. Since macrophages are sentinels of 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. 6 ΡΕ1360178

Cytokines are molecules secreted by immune cells that are important in mediating immune responses. The production of cytokines can lead to the secretion of other cytokines, altered cell function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathological inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor alpha (TNF-alpha) plays a central role in the inflammatory response and was considered a point of intervention in inflammatory disease. 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., 3: 444-55, 1989). At higher concentrations, TNF-alpha can act as potent pyrogen and induce the production of other proinflammatory 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 acute phase proteins. In rheumatoid arthritis, a chronic, progressive inflammatory disease affecting about 1% of the US adult population, TNF-alpha mediates the cytokine cascade leading to damage and destruction of the joints (Arend et al., Arthritis Rheum., 1998 : 151-60, 1995). Inhibitors of TNF-alpha, including soluble receptors of TNFα (etanercept) (Goldenberg, Clin. Ther., 21, 75-87, 1999) and anti-TNF-alpha antibodies (infliximab) (Luong et al., Ann. Pharmacother., 34: 743-60, 2000) 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 were also implicated in many other disorders and disease states, including cachexia (Fong et al., Am. J. Physiol., 256: R659-65, 1989), septic shock syndrome (Tracey et al. 200: 233-9 (1992)), osteoarthritis (Venn et al., Arthritis Rheum., 36: 819-26, 1993), inflammatory bowel disease, as a disease of Crohn's disease and ulcerative colitis (Murch et al., Gut, 32: 913-7, 1991), Behcet's disease (Akoglu et al., J. Rheumatol., 117: 1107-8, 1990), Kawasaki's disease (Matsubara et al. Immunopathol, 56p 29-36, 1990), cerebral malaria (Grau et al., N. Engl. J. Med., 320: 1586-91, 1989), adult respiratory distress syndrome (Millar et al., Lancet 2: 712-4, 1989), asbestosis and silicosis (Bissonnette et al.

Inflammation, 13: 329-39, 1989), pulmonary sarcoidosis (Baughman et al., J. Lab. Clin., 115: 36-42, 1990), asthma (Shah et al., Clin Exp Exp. 25: 1038-44, 1995), AIDS (Dezube et al., J. Acquire Immune Deficit Syndr., 5p 1099-104, 1992), meningitis (Waage et al., Lancet, 1: 355-7, 1987 ), psoriasis (Oh et al., J. Am. Acad. Dermatol., 42: 829-30, 2000), graft versus host reaction (Nestel et al., J. Exp. Med., 175: 405-13, 1992), multiple sclerosis ΡΕ1360178 (Sharief et al., N. Engl. J. Med., 325: 467-72, 1991), systemic lupus erythematosus (Maury et al., Int. J. Tissue React., 11: 189 -93, 1989), diabetes (Hotamisligil et al.

Science, 259: 87-91, 1993) and atherosclerosis (Bruunsgaard et al., Clin Exp. Immunol., 121: 255-60, 2000).

From the references cited above it can be seen that TNF-alpha inhibitors are potentially useful in the treatment of a wide variety of diseases. Compounds which inhibit TNF-alpha have been described in U.S. Patent Nos. 6,090,817; 6,080,763; 6,080,580; 6,075,041; 6,048,841; 6,046,319; 6,046,221; 6,040,329; 6,057,369; 6,034,100; 6,028,086; 6,022,884; 6,015,558; 6,004,974; 5,990,119; 5,981,701; 5,977,122; 5,972,936; 5,968,945; 5,962,478; 5,958,953; 5,958,409; 5,955,480; 5,948,786; 5,935,978; 5,935,977; 5,929,117; 5,925,636; 5,900,430; 5,900,417; 5,891,883, 5,869,677 and others. Interleukin-6 (IL-6) is another proinflammatory 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 liver response and is a powerful stimulator of the hypothalamic-pituitary-adrenal axis that is under the negative control of glucocorticoids. IL-6 promotes the secretion of growth hormone but inhibits the release of thyroid stimulating hormone. Elevated levels of IL-6 are observed in a number of inflammatory diseases, and inhibition of the IL-6 cytokine subfamily has been suggested as a strategy to improve ΡΕ1360178 rheumatoid arthritis therapy (Carroll et al., Inflamm. Res., 47: 1 -7, 1998). Additionally, IL-6 has been implicated in the progression of atherosclerosis and in the pathogenesis of coronary heart disease (Yudkin et al., Atherosclerosis, 148: 209-14, 1999). IL-6 overproduction is also seen in steroid deprivation syndrome, conditions related to dysregulated vasopressin secretion and osteoporosis associated with increased bone resorption, as in cases of hyperparathyroidism and sexual steroid deficiency (Papanicolaou et al. Ann. Intern. Med., 128: 127-37, 1998).

Since overproduction of IL-6 is implicated in various disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S. Patent Nos. 6,004,813; 5,527,546 and 5,166,137. Cyclooxygenase is an enzyme that catalyzes a rate-determining step in the biosynthesis of prostaglandins, which are important mediators of inflammation and pain. The enzyme occurs in the form of at least two distinct isomers, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 isomer is constitutively expressed in the gastric mucosae, platelets and other cells and is involved in the maintenance of homeostasis in mammals, including protection of the integrity of the digestive tract. The COX-2 isomer, on the other hand, is not constitutively expressed; rather, it is induced by various agents, such as cytokines, mitogens, hormones and growth factors. In particular, COX-2 is induced during the inflammatory response (DeWitt D.L., 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 COX-1 and COX-2 inhibitors. They may be effective in reducing inflammatory pain and swelling but, since they attenuate the protective action of COX-1, they produce undesirable side effects of gastrointestinal pathology. Accordingly, agents that selectively inhibit COX-2 but not COX-1 are preferred for the treatment of inflammatory diseases. Recently, a diarylpyrazol sulfonamide (celecoxib) that selectively inhibits COX-2 has been approved by the FDA for use in the treatment of rheumatoid arthritis (Luong et al., Ann. Pharmacother., 34: 743-60, 2000; Penning et al. Med. Chem., 40: 1347-65, 1997). COX-2 is also expressed in many precancerous cancers and lesions and there is increasing evidence that selective COX-2 inhibitors may be useful in the treatment and prevention of colorectal, breast and other cancers (Taketo MM, J. Natl. The present invention relates to a method for the preparation of a pharmaceutical composition comprising the preparation of a pharmaceutical composition comprising the preparation of a medicament for the treatment of cancer, Cancer Inst. ). In 1999, celecoxib was approved by the FDA as an adjunct to the usual treatment of patients with familial adenomatous polyposis, a condition that, if left untreated, generally leads to colorectal cancer.

Compounds that selectively inhibit COX-2 were 11? 1360178 described in U.S. Patent Nos. 5,344,991; 5,380, 738; 5,434,178; 5,466,823; 5,474,995; 5,510,368; 5,521, 207; 5,521,213; 5,536,752; 5,550,142; 5,552,422; 5,604,260; 5,639,780; 5,643,933; 5,677,318; 5,691,374; 5,698, 584; 5,710,140; 5,733,909; 5,789,413; 5,811,425; 5,817,700; 5,849,943; 5,859,257; 5,861,419; 5,905,089; 5,922, 742; 5,925,631; 5,932,598; 5,945,539; 5,968,958; 5,981, 576; 5,994,379; 5,994,381; 6,001,843; 6,002,014; 6.004, 950; 6,004,960; 6,005,000; 6,020,343; 6,034,256; 6,046, 191; 6,046,217; 6,057,319; 6,071,936; 6,071,954; 6,077, 850; 6,077,868; 6,077,869 and 6,083,969. The IL-1 beta cytokine also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and prostaglandin release from synovial cells. Elevated or dysregulated IL-1 beta cytokine levels have been associated with some inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome (Meduri et al., Chest 107: 1062-73, 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. Asthma (Sousa et al., Thorax 52: 407-10, 1997), atherosclerosis (Dewberry et al., Arterioscler, Thromb. Vasocol., 2: 0: 2394-400, 2000), brain tumors (Ilyin et al., 12 ΡΕ1360178

Mol. Chem. Neuropathol. 33: 125-37, 1998), cachexia (Nakatani et al., Res. Commun. Mol. Pathol. Pharmacol. 102: 241-9, 1998), carcinoma (Ikemoto et al., Anticancer Res. 20: 317-21 , 2000), chronic arthritis (van den Berg et al.

Clin. Exp. Rheumatol. 11: S105-14, 1999), chronic fatigue syndrome (Cannon et al., J. Clin Immunol, 107: 253-61, 1997), CNS trauma (Herx et al., J. Immunol 165: 2232 -9, 2000), epilepsy (De Simoni et al., Eur. J.

Neurosci. 12: 2623-33, 2000), fibrotic lung 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 (Zhu et al.,

Clin. Immunol. Immunopathol. 8, 4: 85-94, 1997), thermal hyperalgesia (Opree et al., J. Neurosci., 2000, 6289-93, 2000), haemorrhages and endotoxemia (Parsey et al., J. Immunol 160: 1007-13, 1998 ), inflammatory bowel disease (Olson et al., J. Pediatr Gastroenterol, Nutr., 1996, 241-6, 1993), leukemia (Estrov et al., Leuk, Lymphoma 24: 379-91, 1997), leukemic arthritis (Rudwaleit et al., Arthritis Rheum, 41: 1695-700, 1998), systemic lupus erythematosus (Mao et al.

Autoimmunity 2_4: 71-9, 1996), multiple sclerosis (Martin et al., J. Neuroimmunol, 6: 241-5, 1995), osteoarthritis (Hernvann et al., Osteoarthritis Cartilage A 139-42, 1996), osteoporosis (Zheng et al., Maturitas 26: 63-71, 1997), Parkinson's disease (Bessler et al., Biomed.

Pharmacother. (Gherardi et al., Blood 83: 2587-93, 1994), preterm delivery (Dudley, 13, pp. 1360178, J. Reprod Immunol 36: 93-109, 1997) , Psoriasis (Bonifati et al., J. Biol. Regul. Homeostasis 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), systemic vasculitis (Brooks et al., Clin Immunol 106: 273-9, 1996), temporomandibular joint disease (Nordahl et al., Eur. J. Oral, 106: 559-63, 1998), tuberculosis (Tsao et al. (Roseler et al., Eur. Arch. Otorhinolaryngol. Suppl., 1: S61-3, 1995) and pain and / or inflammation resulting from excessive exertion, sprain , trauma, surgery, infection or other disease processes.

Since overproduction of IL-1 beta is associated with numerous disease states, it is desirable to develop compounds that inhibit the production or activity of IL-1β. Methods and compositions for inhibiting IL- IL-1 beta are described in U.S. Patent Nos. 6,096,728; 6,090,775; 6,083,521; 6,036,978; 6,034,107; 6,034,100; 6,027,712; 6,024,940; 5,955,480; 5,922,573; 5,919,444; 5,905,089; 5,874,592; 5,874,561; 5,874,424; 5,840,277; 5,837,719; 5,817,670; 5,817,306; 5,792,778; 5,780,513; 5,776,979; 5,776,954; 5,767,064; 5,747,444; 5,739,282; 5,731,343; 5,726,148; 5,684,017; 5,683,992; 5,668,143; 5,624,931; 5,618,804; 5,527,940; 5,521,185; 5,492,888; 5, 488,032 and others. 14 ΡΕ1360178

From the foregoing, it will be appreciated that, having undertaken extensive prior efforts to provide compounds for inhibiting, for example, TNF-alpha, IL-1, IL-6, COX-2 or other agents considered to be responsible for the immune response, inflammation or inflammatory diseases , for example, arthritis, new and improved compounds are still required to effectively treat or inhibit such diseases. A primary object of the invention is to provide compounds which are effective for such treatments, as well as for the treatment of, for example, insulin resistance, hyperlipidemia, coronary heart disease, multiple sclerosis and cancer.

Summary of the Invention

In one aspect of the invention there is provided a compound selected from: 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} acrylamide, 3- 3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} -N, N-dimethylacrylamide, 3- (3,5-dimethoxyphenyl) -2- { 4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} -N-methoxy-N-methylacrylamide.

These compounds are useful for the treatment of diabetes, hyperlipidemia 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 arthritis, and Collagen-related vascular diseases, which are caused, for example, by cytokines or cyclooxygenase, such as TNF-alpha, IL-1, IL-6 and / or COX-2. The compounds are also useful for the treatment or prevention of other cytokine and / or cyclooxygenase mediated diseases, such as cancer.

Accordingly, the scope of the invention also includes the use of a compound according to the invention in the preparation of a medicament for the treatment of diabetes, inflammation, arthritis, inflammatory disease, inhibition of TNF-alpha, IL-1, IL-6 or COX-2, multiple sclerosis treatment, cancer or heart disease.

Also provided are pharmaceutical compositions containing a therapeutically effective amount of one or more compounds according to the invention together with a pharmaceutically or physiologically acceptable carrier for use in the treatments contemplated herein.

Brief Description of the Drawings

FIGS. 1A and 1B show graphs of blood glucose levels and body weights, respectively, of db / db (spontaneously diabetic) male mice that received compound VIII over a period of 15 days. 16 ΡΕ1360178

FIGS. 2A and 2B show graphs of blood glucose levels and body weights of ob / ob (genetically obese and spontaneously diabetic) male mice that received compound VIII over a period of 15 days.

FIGS. 3A and 3B show graphs of blood glucose levels of db / db and ob / ob mice, respectively, which received compound VIII over a period of 20-25 days. FIG. 4 shows a graph of the blood glucose level of db / db mice for 72 hours after a dosage of compound VIII.

FIGS. 5A, 5B, 5C and 5D show graphs of triglyceride levels, free fatty acid levels, glyc-Hb levels and serum leptin levels of compound VIII treated db / db mice.

FIGS. 6A, 6B, 6C, and 6D are graphs showing serum insulin levels, triglyceride levels, free fatty acid levels, and serum Glyc-Hb levels of ob / ob mice treated with compound VIII.

FIGS. 7A and 7B show the liver enzyme assays in mice 21 days after treatment with compound VIII. FIG. 8 shows uptake of glucose in 3T3-L1 cells to compound VIII. FIG. 9 shows a graph comparing compound VIII with rosiglitazone for inhibition of LPS-induced TNF production. FIG. 10 is a graph comparing compound VIII with rosiglitazone for inhibition of LPS induced IL-6 production. FIG. 11 is a graph comparing compound VIII with rosiglitazone for inhibition of LPS-induced IL-1-beta production.

FIGS. 12A and 12B show a comparison of compound VIII (FIG 12A) with rosiglitazone (FIG 12B) for inhibition of LPS-induced COX-2 activity.

FIGS. 13A, 13B, 13C and 13D illustrate the suppression of collagen-induced arthritis using compound VIII. FIG. 14 shows the suppression of experimental allergic encephalomyelitis (EAE) by use of compound VIII. 18 ΡΕ1360178

Description of Preferred Embodiments

The compounds of the present invention may be combined with a physiologically acceptable carrier or carrier to form a pharmaceutical composition, such as lyophilized powder in the form of tablets or capsules with various fillers and binders. The effective dosage of a compound present in the composition may vary greatly, being selected by those customarily skilled in the art and can be determined empirically.

As was previously indicated, the compounds of the invention are useful for the treatment of diabetes, characterized by the presence of increased blood glucose levels, i.e., hyperglycemic disorders such as diabetes mellitus, including type I and type II diabetes, as well as other disorders related to hyperglycemia, such as obesity, increased cholesterol, hyperlipidemia, such as hypertriglyceridemia, disorders related to the kidneys and the like. The compounds are also useful for the treatment of disorders related to insulin resistance and / or hyperinsulinemia, which include, in addition to diabetes, hyperandrogenic conditions, such as polycystic ovarian syndrome (Ibanez et al., J. Clin. Endocrinol. Metab., 15: 3526-30, 2000, Taylor AE, Obstet Gynecol Clin North Am. 27: 583-95, 2000), coronary artery disease such as atherosclerosis and vascular restenosis, and vascular disease peripheral In addition, the compounds of the present invention are also useful for the treatment of inflammation and immunological diseases which include those mediated by signaling pathways linked to pro-inflammatory cytokines such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and contact and atopic dermatitis.

By " treatment " it is meant that the compounds of the invention are administered in an amount that is at least sufficient, for example, to reduce the blood glucose level in a patient suffering from hyperglycaemic disorder or to inhibit or prevent the development of prokaryotic cytokine responses, inflammatory or related disorders in a patient suffering from inflammatory or immunological disease. In the case of diabetes, the compound is usually administered in an amount sufficient to reduce blood glucose level, free fatty acid level, cholesterol level and the like to an acceptable range, where an acceptable range means + or - 10% and usually + or - 5% of the normal mean blood glucose level and related level of the subject, or sufficient to attenuate the symptoms and / or reduce the risk of complications associated with increased levels of these parameters. A variety of subjects can be treated with the present compounds to reduce blood glucose levels such as cattle, wild or rare animals, pets as well as humans. The compounds may be administered to a subject suffering from hyperglycaemic disorder using any convenient delivery technique, including intravenous, intradermal, intramuscular, subcutaneous, oral and the like. However, daily oral dosing is preferred. The dosage delivered to the host will necessarily depend on the route by which the compound is administered, but generally ranges from about 0.1 - 500 mg / kg body weight or typically from about 1 to 50 mg / kg body weight of the human body. In general, administration types and similar dosages are also contemplated when the compounds of the invention are used to treat inflammatory or immunological diseases.

The compounds of this invention may 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 like. The compounds may be formulated in solid form, for example in the form of tablets, capsules, dragees and suppositories, or in liquid form, for example, solutions, suspensions and emulsions. The preparations may also be delivered transdermally or by topical application. The following is compound VIII, which is 5- (4- (4- (1-carbomethoxy) -2- (3,5-dimethoxyphenyl) ethyl) phenoxy) benzyl) -2,4- thiazolidinedione. Compound VIII is not according to the invention. Scheme IA below illustrates the preparation of compound VIII, while Scheme 1B more generally describes a method of synthesis which may be used to synthesize compounds according to the invention. ΡΕ1360178 21 SCHEMA ΙΑ

ΡΕ1360178 22

SCHEME 1B

Referring to Scheme IA, aldehyde (II) and acid (III) can be condensed into acetic anhydride and triethylamine to form the unsaturated (IV) acid. After esterification of the acid to give Compound (V), the phenolic hydroxy group is transformed into an ether (VI) with p-23 ΡΕ1360178 fluorobenzaldehyde. The aldehyde (VI) is then condensed with the thiazolidinedione to give Compound (VII) and the exo bond to the heterocycle of Compound (VII) is reduced with hydrogen to form the objective Compound (VIII).

The steps of Scheme IA are generalized in Scheme 1B. The general formulas IIb, IIIb, IVb, VIb, VIIb and VIIIb correspond respectively to formulas II, III, IV, VI, VII and VIII of Scheme IA.

Example 1 (a) Synthesis of 3- (3,5-dimethoxyphenyl) -2- (4-hydroxyphenyl) acrylic acid (Compound IV) To a mixture of 3,5-dimethoxybenzaldehyde (500 g, 3 mol) and p-hydroxyphenylacetic acid (457 g, 3 mol) was added acetic anhydride (1 L) and triethylamine (420 mL). Upon heating, this homogeneous mixture becomes homogeneous at ~ 70 ° C. After being stirred at 130-140 ° C for 6 hours, the mixture was cooled to room temperature. To the reaction mixture was added concentrated HCl (1 L) slowly over 50 minutes, maintaining the temperature between 20-30 ° C. The obtained light yellow precipitate was filtered and rinsed with water D1 in the Buchner funnel. The solid was dissolved in 3N NaOH (5 L), stirred for 1 hour and filtered. The filtrate was acidified, maintaining the temperature at 25-30 ° C, with concentrated HCl to pH 1. The precipitated product was filtered and washed with 24 4 E 1360178 water to give the crude product. The crude product was recrystallized from MeOH-H2 O and then dried at 40 ° C for 6 hours. Yield: pale yellow solid 428 g (47%). 1H NMR (DMSO-d6): δ 12.48 (broad, 1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J = , 6.26 (d, J = 8.0 Hz, 2H), 6.35 (t, J = 2.2 Hz, 1H), 6.27 (d, 56 (s, 6H). (b) Synthesis of 3- (3,5-dimethoxy-phenyl) -2- (4-hydroxyphenyl) acrylic acid methyl ester (Compound V)

Methanol (3 L) was added to extensively dried Compound IV (427.5 g, 1.42 mol) under argon. To this stirred suspension was added concentrated sulfuric acid (100 mL) and the system was refluxed for 20 hours under argon. The methanol was evaporated under reduced pressure at 30 ° C. The residue was taken up in ethyl acetate (3 L) and washed with water (2 x 1 L), saturated aqueous NaHCO 3 (pH 8, 2 x 1 L), brine (2 x 1 L) . The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated. The crude product obtained was extensively dried under high vacuum and was used as such in the next step. Yield: white solid, 433.6 g (97%). 1 H NMR (CDCl 3): δ 7.72 (s, 1H), 7.06 (d, Cl II -J > , 6.38 (d, J = 2.2 Hz, 2H), 5.74 (s, 1H), 3.81 (s, 3H) 60 (s, 6H). (C) Synthesis of 3- (3,5-dimethoxy-phenyl) -2- [4- (4-formylphenoxy) phenyl] acrylic acid methyl ester (Compound VI)

Under argon, Compound V (433 g, 1.37 mol) was dissolved in dry DMF (1.6 L) and to this system sodium hydride (60% in oil, 60.4 g, 1.51 mol). To the resulting orange solution was added p-fluorobenzaldehyde (185 mL, 1.71 mol) and the system was heated at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3 L) and extracted with water (3 x 1 L), then brine (1 x 1 L). The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated. The residue was suspended in methanol (3 L) and stirred overnight. The suspension was cooled and then filtered. The solid obtained was dried under vacuum at 40 ° C. Yield 445 g (77%). 1 HNMR (CDCl 3): δ 9.94 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.80 (s, 1H), 7.28 (d, J = (D, J = 2, 9 Hz, 2H), 7.08 (d, J = 2.9 Hz, 2H), 6.36 (t, J = 2 Hz, 1H), 6.25 (d, J = 2.2 Hz, 2H), 3.83 (s, 3H), 3.63 (s, 6H). (d) Synthesis of 3- (3,5-dimethoxy-phenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylidenemethyl) phenoxy] phenyl} acrylic acid methyl ester (Compound VII) To a stirred suspension of Compound VI (352 g, 0.82 mol) in anhydrous toluene (2.5 L) were sequentially added 2,4-thiazolidinedione (98.6 g, 0.84 mol), benzoic acid (134 g, 1.10 mol) and piperidine (107.4 g, 1.26 mol) 26 ΡΕ1360178 and the system was heated to reflux temperature with continuous removal of water with the aid of a Dean-Stark apparatus for 5 hours . Toluene (1 L) was removed from the reaction mixture and the mixture was placed overnight in a cold room at 4 ° C. The separated solid was removed by filtration and the mother liquor was evaporated to dryness under reduced pressure. The obtained residue was redissolved in a mixture of MeOH-diethyl ether (1: 1.3 L). By standing overnight at 4 ° C, the solution gave more solids. The solid was filtered; the two fractions collected were pooled and dried overnight in a vacuum oven at 40 ° C.

Yield: 362.5 g (86%). 1 H NMR (DMSOd 6): δ 12.53 (broad, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.63 (d, J = 7.25 (d, J = 9.2 Hz, 2H), 7.15 (d, J = 4.3 Hz, 2H), 7.12 (d, J = 4.3 Hz, 2H), 6.42 (t, J = 2.2 Hz, 1H), 6.27 (d, J = 2.2

2H), 3.73 (s, 3H) and 3.59 (s, 6H). (e) Synthesis of 5- (4- (4- (1-carbomethoxy) -2- (3,5-dimethoxyphenyl) ethenyl) phenoxy) benzyl) -2,4-thiazolidinedione, also called Compound VII (30 g, 58 mmol) was dissolved in dichloromethane (30 ml) and recrystallized from dichloromethane was dissolved in warm dioxane (900 mL), transferred to a 2 L hydrogenation bottle and 10% Pd-C (-50% water, 15 g) was added thereto, having been hydrogenated in a Parr hydrogenation apparatus at 60 psi for 24 hours. After this time, an additional 15 g of Pd-C was added and left 27 ΡΕ1360178 if hydrogenation was continued for a further 24 hours. The catalyst was filtered on a Celite bed and the solvent was evaporated. The residue was taken up in acetonitrile (500 mL) and adsorbed onto C-18 silica (50 g). The adsorbed material was placed on top of a column containing C-18 reverse phase silica gel (400 g). The column eluted with CH 3 CN in H 2 O (45%, 2 L), CH 3 CN in H 2 O (50%, 2 L), CH 3 CN in H2 O (55%, 2 L) to elute the undesired fractions. Fractions were collected by eluting with 60% CH 3 CN in H 2 O to give the desired compound. The fractions were pooled based on their HPLC purity. The acetonitrile was evaporated under reduced pressure. The water was removed by lyophilization.

Yield: 12 g (40%). White solid; P. f. 126-128 ° C. 1 H NMR (DMSO-d 6) δ 12.01 (broad, 1H), 7.73 (s, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.19 (d, J J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), (5.40 (t, J = = 2.2 Hz, 1H), 6.27 (d, J = 2.2 Hz, 2H), 4.92 (dd, J = 9.2 and 4.4 Hz, 1H), 3.73 (s 3H), 3.57 (s, 6H), 3.37 (dd, J = 14.8 and 4.3 Hz, 1H) and 3.12 (dd, J = 14.8 and 9.4 Hz, 1H), IR (KBr) Î »max 3200, 1950, 2850, 1700, 160C), 1,500, 1350, 1150 and 850Â ° C; EIMS: m / z, 518, [M-H] +, 265, 249 and 113.

Referring to the drawings, Compound VIII was administered in a single oral dose (50 mg / kg body weight) for 15 days to male db / db mice as shown in FIG. IA. A substantial reduction in blood glucose was observed. No increase in body weight 28 ΡΕ1360178 was observed in the treatment group compared to the vehicle treated control without the active ingredient, FIG. 1B. The compound was administered orally to ob / ob mice in a single oral dose (50 mg / kg body weight). As shown in FIG. 2A, there was a 62% decrease in blood glucose level and, similarly to db / db mice, there was no significant increase in body weight between the control and treatment groups, as shown in FIG. 2B. This contrasts with the treatment of diabetic animals with thiazolidine-dione compounds which are known to be associated with increased body weight. See Okuno et al., J. Clin. Invest., 101, 1354-1361 (1998), and Yoshioka et al., Metabolism, 42, 75-80 (1993). Upon completion of treatment after day 15 in both models an increase in glucose level was observed, as shown in FIGs. 3A and 3B. The time course of drug effect is shown in FIG. 4. Oral administration of a single dose of the compound to db / db mice was effective for more than 24 hours.

Triglyceride levels were also measured. Triglycerides, which are esters of fatty acids and glycerol, do not circulate freely in plasma but are bound to proteins and transported in the form of macromolecular complexes called lipoproteins. The triglycerides were measured by the enzymatic method described by McGowen et al., 1983, with a modification to determine triglyceride levels in db / db and ob / ob mice. A ΡΕ1360178 24% reduction in triglyceride levels in db / db mice (FIG 5A) was observed after 15 days of treatment with the compound and, in ob / ob mice, a 65% decrease in triglycerides was observed in comparison with the control (Figure 6B) after treatment for 10 days.

Free fatty acids (FFA) were measured enzymatically using coenzyme A in the presence of acyl-CoA synthase (Wako Chemicals, U.S.A.). The free fatty acid levels of db / db and ob / ob mice treated with the compound were significantly lower compared to control animals. A 34% reduction of FFA levels in db / db mice (FIG 5B) was observed after 15 days of treatment with the compound. In ob / ob mice, after 10 days of treatment, there was a 33% decrease in FFA compared to control (FIG 6C). The percentage of glycohemoglobin (GHb) in the blood reflects the average concentration of glucose in the blood. It is a measure of overall diabetic control and can be used to monitor mean blood glucose levels. Glycosylation of hemoglobin occurs continuously in red blood cells. But since the reaction is non-enzymatic and irreversible, the concentration of glycohemoglobin in a cell reflects the average blood glucose levels observed by the cell during its life. An assay was run using boronate affinity chromatography as described by Abraham et al., J. Lab. Clin. Med., 102, 187 (1983). There is a decrease of 30 ΡΕ1360178 0.7% of the GHb level in db / db mice (FIG.5C) after 15 days of treatment with the compound, and in ob / ob mice, after 14 days of treatment, a decrease of 1.3% (FIG 6D) of the level of GHb compared to the control.

The level of insulin in the blood was measured by ELISA following a standard protocol. A 58% reduction of serum insulin in ob / ob mice (FIG 6A) was observed after 10 days of treatment with the compound, thus demonstrating its ability to act as an insulin sensitizer. Obesity is considered a major risk factor for several adult diseases, such as diabetes and heart disease. Leptin, a gene product related to obesity, has been identified from the ob / ob mice investigation, where leptin is absent due to a mutation of this gene (Zhiang et al., Nature, 372, 425 (1994)). . Leptin is a protein of about 16 kDa which is expressed in adipose tissue and promotes weight loss by suppressing appetite and stimulating metabolism. Leptin is now believed to play a key role in the obesity syndrome. In db / db mice, according to the experiment, the level of leptin was measured by ELISA following a standard protocol. After 15 days of treatment with the compound a 23% increase (Figure 5D) of the serum leptin level was observed compared to the control group.

The enzymes of the liver transaminase glutamic oxazine / aspartate aminotransferase (AST / GOT) and glutamic pyruvic transaminase / alanine aminotransferase (ALT / GPT) were evaluated in sera from ob / ob mice after 21 days of treatment (orally, 50 mg / kg) with the test compound. The test was also conducted using troglitazone. The levels of these enzymes are increased in various types of liver disorders or liver necrosis. As shown in FIG. 7A, the level of AST in mice was not increased in comparison to untreated or troglitazone treated mice. Similarly, FIG. 7B shows that the level of ALT did not increase compared to untreated mice or troglitazone treated mice.

Referring to FIG. 8, glucose uptake into differentiated 3T3-L1 adipocytes was measured after treatment with the test compound. The assay was conducted according to the method of Tafuri, Endocrinology, 137, 4706-4712 (1996). Serum-depleted cells were treated with the test compound for 48 hours at different concentrations, then washed and incubated in medium without glucose for 30 minutes at 37øC. 14 C-deoxyglucose was then added and the uptake monitored for 30 minutes with incubation. After washing, the cells were lysed (0.1% SDS) and counted. As shown in FIG. 8, there is a 3.5 to 4 fold increase in glucose uptake at the indicated concentrations of test compound relative to baseline levels. 32 ΡΕ1360178

Referring to FIG. 9, RAW cells were preincubated with Compound VIII or rosiglitazone (0.1, 1, 10, 50 or 100 μΜ) for 1 hour at 37øC in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 μg / ηηΑ) was added and the cells were incubated for a further 6 hours. Thereafter, cell supernatant was collected, aliquoted and frozen at -70øC, and an aliquot was used to determine TNF-alpha concentration by ELISA. Compound VIII was better TNF-alpha inhibitor than rosiglitazone.

Referring to FIG. 10, RAW cells were preincubated with Compound VIII or rosiglitazone (0.1, 1, 10, 50 or 100 μΜ) for 1 hour at 37øC in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 μg / ml) was added and the cells were incubated for a further 6 hours. Thereafter, cell supernatant was collected, aliquoted and frozen at -70 ° C, and an aliquot was used to determine IL-6 concentration by ELISA. Compound VIII was better inhibitor of IL-6 than rosiglitazone.

Referring to FIG. 11, RAW cells were preincubated with Compound VIII or rosiglitazone (0.1, 1, 10, 50 or 100 μΜ) for 1 hour at 37øC in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 μg / ml) was added and the cells were incubated for a further 6 hours. Thereafter, cell supernatant was collected, aliquoted and frozen at -70 ° C, and an aliquot was used to determine IL-1-beta concentration by ELISA. Compound VIII inhibited IL-1-beta better than rosiglitazone. 33 ΡΕ1360178

Referring to FIGs. 12A and 12B, RAW cells were preincubated with Compound VIII (12A) or rosigli-tazone (12B) (0.1, 1, 10, 50 or 100 μΜ) for 1 hour at 37øC in RPMI-1640 containing FBS 10%. After 1 hour LPS (0.1 μg / π) was added and the cells incubated for a further 6 hours. Thereafter, cell supernatant was collected, aliquoted and frozen at -70 ° C, and aliquots were used to determine the COX-1 and COX-2 activity. Compound VIII, but not rosiglitazone, inhibited COX-2 activity (as measured by PEG2 production in a 50 μ amostra sample). No compound inhibited the activity of COX-1. The transcription factor NF-kappaB coordinates the activation of many genes involved in the response to pro-inflammatory cytokines and, as a consequence, plays a key role in the development of inflammatory diseases. NF-kappaB is activated by phosphorylation of the IkapB inhibitor protein. To examine the effect of compound VIII on the LPS-stimulated phosphorylation of IkapaB, RAW 264.7 cells were preincubated with vehicle only, 15-deoxy-Δ12,14-prostaglandin J2 (3 μΜ) as positive control, compound VIII (3, 10 or 30 μΜ) or rosiglitazone (3, 10 or 30 μΜ) for 1 hour at 37øC. The cells were then treated with or without LPS (10 ng / ml) plus IFN-gamma (10 U / ml) for 5 minutes or 15 minutes at 37øC. The cells were lysed and the cell lysates (27 μg / lane) were separated by electrophoresis on a 4-20% polyacrylamide gel, stained on a nitrocellulose membrane and probed with anti-phosphot-IkappaB antibody. Results 34 ΡΕ1360178 revealed that compound VIII, but not rosiglitazone, exhibited dose-dependent inhibition of IkapaB phosphorylation.

Figures 13A-D illustrate the suppression of collagen-induced arthritis by treatment with Compound VIII. Arthritis was induced by intradermal administration of collagen (100 μg / mouse) in complete adjuvant in 7-week old DBA / ILac male mice. Reinforcement immunization (100 μg / mouse) in incomplete adjuvant was administered subcutaneously on Day 21. Two days later, when the arthritis scores were close to 1, the animals were divided into two groups. One group received a dose of 50 mg / kg per day of Compound VIII orally for 17 days. The second group received 10% PEG in water and was used as vehicle treated group. Body weight (Figure 13Ά), Clinical score (Figure 13B), Affected joints (Figure 13C) and Leg thickness (Figure 13D) were monitored 24 hours after drug administration at different time intervals. As shown in the Figures, the Compound VIII treated mice exhibited significantly lower clinical scores, affected joints and leg thickness compared to the vehicle treated group. No change in body weight was observed between vehicle groups and treatment. Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory demyelinating disease of the central nervous system. EAE exhibits many of the clinical and pathological manifestations of human sclerosis (MS) 35 ΡΕ1360178 and is an animal model for testing potential therapeutic agents for MS (Scolding et al., Prog Neurobiol 43: 143-73, 2000). Figure 14 illustrates the suppression of EAE by Compound VIII. Active EAE was induced in SJL / J mice essentially according to the method of Owens and Sriram (Neurol. Clin., 13: 51-73, 1995). Unmanaged mice were immunized subcutaneously with 400 μg each of mouse spinal cord homogenate in complete Freund's adjuvant on day 0 and day 7. Then the mice were treated once daily by subcutaneous injection of 50 μρ or 200 μρ of Compound VIII or only with vehicle. The paralysis was scored according to the numerical scale indicated. As evidenced by the dramatic reduction of clinical score shown in Figure 14, treatment with the 200 μg dose of Compound VIII was highly effective in improving EAE.

From the foregoing it will be apparent that the compounds of the present invention not only lower blood glucose level, triglyceride level, free fatty acid level, glycohemoglobin and serum insulin, but also increase the level of leptin, not exhibiting a significant increase in body weight or liver toxicity. The compounds also inhibit the production of TNF-alpha, IL-6 and IL-β and the activity of COX-2 in vitro and, as shown by Figures 13A-13D and 14, the compounds can be used to suppress arthritis and potentially to multiple sclerosis, respectively. The properties shown above indicate that the compounds of the invention 36 ΡΕ1360178 should be useful in the treatment of disorders associated with insulin resistance, hyperlipidemia, coronary artery disease and peripheral vascular disease and for the treatment of inflammation, inflammatory diseases, immunological diseases and cancer, especially those mediated by cytokines and cyclooxygenase.

While the invention has been exemplified above with reference to the preparation and use of compound VIII, it is to be understood that the invention is of broader application consistent with the scope of the compounds of formula I. This includes, for example, compound VII, which is not only useful as an intermediate for the preparation of compound VIII as shown but also demonstrates useful biological activity per se consistent with the activities of compound VIII. The synthesis of other compounds according to the invention is illustrated by the following examples:

Example 2 Synthesis of 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} acrylic acid (Compound XVII) Compound XVII, a metabolite of Compound VIII can be prepared by hydrolysis of compound VIII according to the following reaction scheme. 37 ΡΕ1360178

To a stirred and cooled suspension to 3-10 g of 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl (50 mL) was added aqueous sodium hydroxide (2 N, 50 mL) and the system was stirred for 15 h at room temperature. The resulting pale yellow solution was cooled to 10 ° C and acidified with aqueous HCl (5%, 115 mL). The separated solid was filtered and washed with water (3 x 30 mL), recrystallized from methanol and dried, yielding a product characterized as follows: 1 H NMR (DMSO-d 6) δ 7.69 (s, 1H 7,28 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.41 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 2H) 92 (dd, J = 9.2 and 4.4 Hz, 1H), 3.58 (s, 6H), 3.38 (dd, J = 14.0 and 4.0 Hz, 1H) and 3.13 (dd, J = 14.4 and 9.2 Hz, 1H).

Example 3 Synthesis of 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxo-thiazolino-5-ylmethyl) -phenoxy] -phenyl} -acrylamide (Compound XVIII) Compound XVIII, which can be represented by the formula: ΡΕ1360178 38

k -H 8 'ΐγ O-v- ^ ./

. y was prepared as follows from compound (XVII):

A dry, clean flask with a stir bar was charged with compound (XVII) (0.423 g, 0.837 mmol) and dry DMF (10 mL). Carbonyldiimidazole (0.271 g, 1.67 mmol) was then added with stirring and the reaction was warmed to 60 ° C for 1 hour while being vented by means of an oil bubbler. The reaction mixture was cooled to 0 ° C and 2M ammonia in methanol (2.1 mL, 4.2 mmol) was added. The reaction was worked up by partitioning the mixture with 10% citric acid (10 mL), ethyl acetate (50 mL) and water (40 mL). The organic phase was then rinsed sequentially with water (2 x 30 mL) and brine (1 x 20 mL) and dried with anhydrous magnesium sulfate. Concentration of the organic compounds gave the crude product. The crude product was purified by silica gel chromatography using gradient elution of ethyl acetate - hexanes (1: 1) in 1% acetic acid to ethyl acetate - hexanes (3: 2) in 1% acetic acid. Concentration of the appropriate fractions gave 200 mg (47%) of the white to pale yellow primary amide as a solid. Analysis: 1H NMR, 400 MHz (DMSO-d6): δ 12.06 (broad, 1H), 7.40 (s, 1H), 7.34 (broad, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.05 39 ΡΕ1360178 CM II Hz, 2H), 6.98 (d, 2H), 6.93 (broad, 1H), 6.36 (m, 1H), 6.20 (s, 1H), 6.19 (s, 1H), 4.91 (dd, (m, 1H), 3.57 (s, 6H), 3.12 (dd, J = 9.2 Hz, 1H).

Example 4 Synthesis of 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxo-thiazolino-5-ylmethyl) -phenoxy] -phenyl} -N, N-dimethylacrylamide (Compound XIX ) Compound (XIX), represented by the formula:

was prepared as follows:

A dry, clean flask with a stir bar was charged with compound (XVII) (0.422 g, 0.835 mmol) and dry DMF (10 mL). Carbonyldiimidazole (0.271 g, 1.67 mmol) was then added with stirring and the reaction was warmed to 60 ° C for 1 hour while being vented by means of an oil bubbler. The reaction mixture was cooled to 0 ° C and a solution of 2M dimethylamine in THF (2.1 mL, 4.2 mmol) was added. The reaction was worked up by partitioning the mixture with 10% citric acid (10 mL), ethyl acetate (50 mL) and water (40 mL). Then, the organic phase was rinsed sequentially with water (2 x 30 mL) and brine (1 x 20 mL) and 40 ΡΕ1360178 was dried with anhydrous magnesium sulfate. Concentration of the organic compounds gave the crude product. The crude product was purified by silica gel chromatography using elution with ethyl acetate - hexanes (3: 2) in 1% acetic acid. Concentration of the fractions gave 381 mg (86%) of the off-white tertiary dimethylamide as a solid. Analysis: 1 H-NMR, 400 MHz (DMSO-d 6): δ 11.7 (broad, 1H), 7.29 (d, 2H), 7.27 (d, d, J = 8.8 Hz), 6.95 (d, J = 8.8 Hz, 2H), 6.57 (s, 1H) , 6.35 (m, 1H), 6.29 (s, 1H), 6.28 (s, 1H), 4.91 (dd, J = 4.4Hz, 1H), 3.58 (s , 6.12 (d, J = 9.2 Hz, 1H), 3.05 (broad, 3H), 2.91 (s, 3H).

Example 5 Synthesis of 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxo-thiazolino-5-ylmethyl) phenoxy] phenyl} -N-methoxy- N -methyl- acrylamide (Compound XX) Compound (XX) was prepared as follows:

A dry, clean flask with a stir bar was charged with compound (XVII) (0.450 g, 0.890 mmol) and dry DMF (10 mL). Carbonyldiimidazole (0.29 g, 1.78 mmol) was added with stirring and the reaction was warmed to 60 ° C for 1 hour while being vented by means of an oil bubbler. The reaction mixture was cooled to 0 ° C, N-methyl-N-methoxyhydroxylamine hydrochloride (0.43 g, 4.45 mmol) was added in water (10 mL) and triethylamine (0.62 mL ) and the system was stirred overnight. The reaction was worked up by subjecting the mixture to 41 ΡΕ1360178 with 10% citric acid (10 mL), ethyl acetate (50 mL) and water (40 mL). The organic phase was then rinsed sequentially with water (2 x 30 mL) and brine (1 x 20 mL) and dried with anhydrous magnesium sulfate. Concentration of the organic compounds gave the crude product. The crude product was purified by silica gel chromatography using elution with ethyl acetate - chloroform (1: 5). Concentration of the appropriate fractions gave 400 mg (82%) of off-white tertiary N-methyl-N-methoxyamide as a solid. Analysis: 1 H-NMR, 400 MHz (DMSO-d 6): δ 12.06 (broad, Î'7.17 (d, J = 9.2 Hz, 2H), 7.26 (d, J = J = 8.8 Hz), 6.95 (d, J = 8.4 Hz, 2H), 6.57 (s, 1H), 6.97 (d, 1H), 6.28 (s, 1H), 4.91 (dd, J = 4, 4 Hz, 1H), 3.58 (s, 1H), 6.29 (s, 1H), 6.28 (s, 1H). Compound (XX) can be shown structurally as follows: â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ 8 J 1. o

Lisbon, March 3, 2009

Claims (11)

A compound selected from: 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} acrylamide, 3- (3,4- Dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} -N, N-dimethylacrylamide, 3- (3,5-dimethoxyphenyl) -2- {4- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy] phenyl} -N-methoxy-N-methylacrylamide. A pharmaceutical composition for the treatment of diabetes, comprising a therapeutically effective amount of a compound, or mixture of compounds, according to Claim 1 on a physiologically acceptable carrier. Use of a compound according to Claim 1 in the preparation of a medicament for the treatment of diabetes. Use of a compound according to Claim 1 in the preparation of a medicament for the treatment of inflammation, arthritis or inflammatory disease. A pharmaceutical composition for the treatment of inflammation, arthritis or inflammatory disease, comprising a therapeutically effective amount of a compound, or mixture of compounds, according to Claim 1 in a physiologically acceptable carrier. Use of a compound according to Claim 1 in the preparation of a medicament for the inhibition of TNF-alpha, IL-1, IL-6 or COX-2. A pharmaceutical composition for the inhibition of TNF-alpha, IL-1, IL-6 or COX-2, comprising a therapeutically effective amount of a compound, or mixture of compounds, according to Claim 1 in a physiologically acceptable carrier. Use of a compound according to Claim 1 in the preparation of a medicament for the treatment of multiple sclerosis. A pharmaceutical composition for the treatment of multiple sclerosis, comprising a therapeutically effective amount of a compound, or mixture of compounds, according to Claim 1 on a physiologically acceptable carrier. 10. Use of a compound according to Claim 1 in the preparation of a medicament for the treatment of cancer or heart disease. 3 ΡΕ1360178 treatment of an amount or mixture of 1 in a trans- A pharmaceutical composition for cancer or cardiac disease, comprising therapeutically effective of a compound, compounds according to the physiologically acceptable carrier claim. Lisbon, March 3, 2009