Title of Invention

PYRIMIDINE CARBOXIMIDES

Abstract The present invention relates to novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions, their metabolites and prodrugs thereof. The present invention more particularly relates to novel pyrimidine carboxamides of the general formula (I). Also included is a method of prophylaxis or treatment of a pain disorder, immunological diseases, inflammation, rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic beta cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; muscle degeneration; cachexia; asthma; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection in a mammal comprising administering an effective amount of a compound of formula (I) as described above.
Full Text

Field of the Invention
The present invention relates to novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions, their metabolites and prodrugs thereof. The present invention more particularly relates to novel pyrimidine carboxamides of the general formula (I).

The present invention also provides a process for the preparation of the above said novel compounds of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. This invention also relates to intermediates useful in the preparation of such compounds.
The novel compounds of the present invention are useful for the treatment of inflammation and immunological diseases; particularly those mediated by cytokines such as TNF-ct, IL-1, IL-6, IL-lβ, IL-8, IL-12 and cyclooxygenases such as COX-2 and COX-3 and diseases mediated by thromboxane synthase.
The compounds of the present invention are also useful for the treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic P cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis;

anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
Background of Invention
Signals necessary for cell growth, differentiation, response to bioregulatory molecules, infectious agents and physiological stress involve changes in the rates of gene expression. The ability to respond appropriately to such signaling events challenges the survival of the cell and ultimately the organism. Pertrubations in the normal regulation of these specific genetic responses can result in pathogenic events that lead to acute and chronic diseases. In certain autoimmune diseases or chronic inflammatory states, continuous activation of T-cells eventually leads to a self-perpetuating destruction of normal tissues or organs. This caused by the induction of adhesion molecules, chemotaxis of leukocytes, activation of leukocytes and the production of mediators of inflammation, all of these events are regulated at the level of transcription for the production of new proteins, including cytokines. The production of cytokines, as well as a number of other cellular regulators, is controlled by a family of proteins, known as transcription factors (TFs). These transcription factors, when activated, bind to specific regions on the DNA and act as molecular switches or messengers to induce or upregulate gene expression. The activation of these TFs is caused by a variety of external signals including physiological stress, infectious agents and other bioregulatory molecules. Once the plasma membrane receptors are activated, a cascade of protein kinases and second messengers are induced which, in turn, result in the production of RNA transcripts. The end result is

the production of RNA transcripts, and proinflammatory proteins via translation and processing of the RNA transcripts.
The activation system can, at times, be very robust. For example, a specific set of external signals could result in a single transcription factor to induce many proteins responsible for a given disease. Therefore, regulating this process by disrupting the production of activated TF(s) has the potential to attenuate the production of the associated pathological proteins, thereby halting or reversing the course of the disease.
Two transcription factors, NFkB and AP-1, have been show to regulate the production of many proinflammatory cytokines and related proteins that are elevated in immunoinflammatory diseases. These TFs regulate interleukin-1 (IL-1), interleukin-2 (IL-2), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in a variety of cell types. For example, NFkB and other related complexes are involved in the rapid induction of genes whose products function in the protective and proliferative responses upon exposure of cells to external stimuli. Similarly, AP-1 has a significant role in the regulation of IL-2 and TNF-a transcription during T-cell activation. In addition, TNF-a and IL-1 are strong activators of collagenase, gelatinase and stromelysin gene expression, which require a single AP-1 binding site in the promoter region of these genes. Therefore, an inhibitor of NFkB and/or AP-1 activation would coordinately repress the activities of a series of proteinases. In addition, cell adhesion molecules are also controlled by these TFs. All of these proteins have shown to play a role in diseases, including osteoarthritis, transplant rejection, ischemia, reperfusion injury, trauma, certain cancers, viral disorders, and autoimmune diseases such a rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus and juvenile diabetes, In summary, the role of these TFs is to act as a transducer for certain stimuli that lead to immune, inflammatory, and acute phase responses.

Since many diseases are caused by the inappropriate production of proteins, conventional therapeutic approaches have focused on inhibiting function or activity of individual effector proteins. These treatments have not always proved to be effective and, at times, are associated with many undesirable side effects. Therefore, there is a need for new therapies for the prevention and/or treatment of immunoinflammatory and autoimmune diseases. More specifically, there is a need for compounds that prevent, preferably by inhibiting transcription at an early stage, the production of proteins associated with immunoinflammatory and autoimmune diseases. Furthermore, these compounds should inhibit the kinase(s) that regulate the activation of TFs such as NFkB and AP-1. The present invention fulfulls these needs and provides further related advantages.
The present invention is concerned with the treatment of immunological diseases or inflammation, notably such diseases are mediated by cytokines or cyclooxygenases. The principal 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 are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and provide the necessary "help" for T cell stimulation and proliferation. Most importantly macrophages make IL-1, IL-12 and TNF-ot all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFNy). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.

Cytokines are molecules secreted by the immune cells and large numbers of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including IL-1, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation rely at least in part on the activation of an enzyme on the cell signalling pathway, a member of the MAP known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents.
Cytokines are molecules secreted by the immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine, TNF-a, plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory diseases. TNF-a is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-a participates in the protective inflammatory response by activating leukocytes and promoting their migration to the extravascular sites of inflammation (Moser et al., J Clin Invest, 83, 444-55,1989). At higher concentrations, TNF-a 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-a also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-a mediates the cytokine cascade that leads to joint damage and

destruction (Arend et aly Arthritis Rheum, 38, 151-60, 1995). Inhibitors of TNF-a, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21, 75-87, 1999) and anti-TNF-a antibody (infliximab) (Luong et al.9 Ann Pharmacother, 34, 743-60, 2000), have been recently approved by the U.S.FDA as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-ct have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis etc.
Elevated levels of TNF-a and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes
zoster are also exacerbated by TNF-a.
It can be seen that inhibitors of TNF-a are potentially useful in the treatment of a wide variety of diseases. Compounds that inhibit TNF-a have been described in several patents. Excessive production of IL-6 is implicated in several disease states, and it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S Patents: 6004813, 5527546 and 5166137.

The cytokine IL-1β also particβates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandins from synovial cells. Elevated or unregulated levels of the cytokine IL-lp have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome, allergy, Alzheimer's disease etc. Since overproduction of IL-lp is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-β.
In rheumatoid arthritis models in animals, multβle intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382, 1990). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than TNF-a. (Firestein, Am. J. Pathol. 140, 1309, 1992). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration have been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531, 1994).
In rheumatoid arthritis, both IL-1 and TNF-a induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen-induced arthritis i.e.CIA in rats and mice) intra-articular administration of TNF-a either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253, 1992; and Cooper, Clin. Exp.Immunol. 898, 244, 1992).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into the sites of inflammation or injury (e.g., ischemia) is mediated; chemotactic nature of IL-8, including, but is not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress

syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminish, neutrophil infiltration.
It has been reported that Cyclooxygenase enzyme exists in three isoforms, namely, COX-1, COX-2 and COX-3. COX-1 enzyme is essential and primarily responsible for the regulation of gastric fluids, whereas COX-2 enzyme is present at the basal levels and is reported to have a major role in the prostaglandin synthesis for inflammatory response. These prostaglandins are known to cause inflammation in the body. Hence, if the synthesis of these prostaglandins is stopped by way of inhibiting COX-2 enzyme, inflammation and its related disorders can be treated. COX-3 possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and COX-2 demonstrated, that this enzyme is selectively inhibited by analgesic/antβyretic drugs such as acetaminophen, phenacetin, antβyrine, dβyrone, and is potently inhibited by some nonsteroidal anti¬inflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. Earlier reports prior to Coxib's development show that inhibitors of COX-1 enzyme cause gastric ulcers, whereas selective COX-2 and COX-3 enzyme inhibitors are devoid of this function and hence are found to be safe. But, recent reports show that the selective COX-2 inhibitors (Coxib's) are associated with cardiovascular risks. So, inhibition of COX-2 without causing cardiovascular risks and gastric ulcers due to inhibition of COX-1 is shown to be safe and is concerned in the present invention.
Cardiovascular pathologies that remain the leading cause of mortality and morbidity in western society include several diseases, such as ishemic cardiopathy of which myocardial infarction represents the most important form. Ischemic cardiopathy is characterized by an inadequacy between supply and demand in

oxygenated blood correlated with a diminution of coronary blood flow due to coronary artery stenosis or occlusion. This artery occlusion often caused by atherosclerous lesions, acute thrombosis, edema, ballooning of atheromatous plaque, or bleeding (Pearson et al., Am J.Pathol, 86, 657-664, 1977; HoR1e etal, Br Heart J. 40: 153 - 161, 1978; Koenig, Cardiol.Review, 9:31-35, 2001). TXA2 is a potent platelet activator and constR1ctor of vascular and bronchial smooth muscles. TXA2 is a short live lβidic mediator generated by the cyclooxygenase pathway, is mainly produced by platelets, macrophages, and lung parenchyma. TXA2 is a potent platelet activator and constR1ctor of vascular and bronchial smooth muscles. It has been demonstrated that drugs able to antagonize TXA2 receptors or to inhibit thromboxane synthase (TS) reduce the seveR1ty of myocardial ischemia (Schror etal, Am J.Physiol, 238: 87 -92, 1980; Burke etal, Br J Clin Pharmacol, 15:97S- 101S, 1983; Hock etal, Eur. J. Pharmacol, 122:213-219, 1986; Brezinsky etal, J.Cardio-vasc Pharmacol, 9:65-71, 1987) and is also concerned in the present invention. Few pR1or art references, which disclose the closest compounds, are given below: i) WO 2005/084368 discloses novel compounds of formula,

wherein, each -^ independently represents a single or double bond; either (a) A, B and E are independently CR1, C(R1)2, NR1 or N; or (b) B is joined with A or E to form a fused 5- to 8- membered partially satured R1ng that is substituted with 0 to 3 substituents, independently selected from Ru and the other of A or E is CR1, C(R1)2, NR1 or N; D and G are independently CRh C(R1)2, NR1; W, X, Y and Z are

independently CR1 and N; P5 Q, T and V are independently CR,, C(R1)2, N or NF; or Q is taken together with V or P to form a fused 5-to 7- membered carbocycle or heterocycle that is substituted with from 0 to 4 substitutents, independently chosen from Rb; R1 is independently chosen at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro and groups of the formula L-M; L is independently chosen at each occurrence from a single covalent bond, O, C(=0), OC(=0), C(=0)0, OC(=0)0, S(0)m, N(RX), C(=0)N(Rx), N(Rx)C(=0), N(Rx) S(0)m, S(0)m N(Rx) and N[S(0)mRx]S(0)m; wherein m is independently selected at each occurrence from 0, 1 and 2 and M is independently selected at each occurrence from (a) hydrogen; and (b) C\-C$ alkyl, C2-C8alkenyl, C2-C8alkynyl, mono- and di-(Ci-C4alkyl)aminoCo-C4alkyl, phenylC0-C4alkyl, C3-C8cycloalkylC1C4alkyl, (5-membered heteroaryl)C0-C4alkyl, and (5- to 7- membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from 0-5 substitutents independently selected from Rb; Ji chosen form O, NH and S; U is C1-C3alkyl, substituted with from 0 to 3 substitutents independently chosen from oxo and C1-C3alkyl, or two substitents are taken together to form a 3- to 7- membered cycloalkyl or heterocycloalyl. The invention further relates to the use of such compounds for treating conditions related to capsaicin receptor activation, for identifying other agents that bind to capsaicin receptor, and as probes for the detection and localization of capsaicin receptor. An example of these compounds is shown below in formula (1)

ii) US patent 5811428 discloses the following general structure,


wherein A is C-R6 when B is N, and A is N when B is C-R1, and wherein Ru R2, R4, R5 and R6 are as defined below. Thus, when A is C-R6 and B is N, structure (I) is a pyR1midine-containing compound having structure (II), and when A is N and B is C-R1, structure (I) is a pyrazine containing compound having structure (III). The inventions relates generally to compounds that block intracellular signal transduction and activation of transcrβtion factors, and to methods for preventing or treating



aralkyl. Compounds and compositions are provided which are useful for the treatment of viral infections particularly human cytomegalovirus infection. Examples of these compounds are shown below,





Objective of the Invention
We have focused our research to identify cytokine inhibitors, predominantly acting through the inhibition of TNF-a, which are devoid of any side effects normally associated with TNF-a inhibitors or/ blockers. Our sustained efforts have resulted in novel compounds of the formula (I). The deR1vatives may be useful in the treatment of inflammation and immunological diseases. Particularly the compounds of the present invention are useful for the treatment of immunological diseases those mediated by cytokines such as TNF-a, IL-1, IL-6, IL-1 [5, IL-8, IL-12 and inflammation. The compounds of the present invention are also useful in the treatment of rheumatoid arthR1tis; osteoporosis; multβle myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic p-cell destruction; osteoarthR1tis; rheumatoid spondylitis; gouty arthR1tis; inflammatory bowel disease; adult respiratory distress syndrome; psoR1asis; Crohn's disease; allergic rhinitis; ulcerative colitis;

anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; bone resorption diseases; ischemia reperfusion injury; brain trauma; multβle sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.

their deR1vatives, analogs, tautomeR1c forms, stereoisomers, polymorphs, hydrates, solvates, and pharmaceutically acceptable salts and compositions; wherein R1ngs represented by A is selected from aryl or heteroaryl; wherein R1ngs represented by B is selected from aryl or heteroaryl; R independently represents hydrogen, hydroxyl, amino, azido, alkyl, alkyloxy, aryloxy, heteroaryloxy, SR6, S(0)pR7, haloalkyl, aminocycloalkyl, aminoalkyl, aminodialkyl, -NH(C1C5)n-X, X represents aryl, heteroaryl, heterocyclyl, aminoheterocyclyl; aminoalkanols represent -NH-(CH2)qOH (the methylene group may be further substituted for e.g. by alkyl, -OH and the like); hydrazine, alkylhydrazine; R1 independently represents hydrogen, SR6 and S(0)pR7; R2 independently represents hydrogen, hydroxyl, halogen, nitro, cyano, azido, amino, alkyl, haloalkyl, alkoxy, aminoalkyl, aminodialkyl, aminoacyl, alkoxycarbonyl, alkoxyalkyl groups, COR8, carboxylic acid and its deR1vatives; R3 independently represents hydrogen, SR6 andJS(0)pR7; R4 independently represents hydrogen, hydroxyl, halogen, nitro, cyano, azido, amino, alkyl, haloalkyl, alkoxy, aminoalkyl, aminodialkyl, aminoacyl, alkoxycarbonyl, alkoxyalkyl groups, COR8,

carboxylic acid and its deR1vatives; R5 independently represents hydrogen, hydroxyl, amino, azido, alkyl, alkyloxy, aryloxy, heteroaryloxy, SR^, S(0)pR7, haloalkyl, aminocycloalkyl, aminoalkyl, aminodialkyl, -NH(C1-C5)n-X, X represents aryl, heteroaryl, heterocyclyl, aminoheterocyclyl; aminoalkanols represent -NH-(CH2)qOH, hydrazine, alkylhydrazine; R6 represents hydrogen, alkyl, aryl, alkylhalide, alkylester; R7 represents amino, hydroxyl, hydrazine, halogen, alkyl, alkylhydrazine, acylhydrazide, aminoacyl, aryl, aminoaryl, aminoheteroaryl, aminoheterocyclyl; R8 represents hydrogen, hydroxyl, amino, halogen, alkyl, haloalkyl, alkoxy, aryloxy, aminoalkyl, dialkylamino, arylamino, heteroarylamino, acylamino; m and n is an integer in the range of 0 to 4, p is an integer in the range of 1 to 2 and q is an integer in the range of 1 to 10.
The foregoing merely summaR1zes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their

their deR1vatives, analogs, tautomeR1c forms, stereoisomers, polymorphs, hydrates, solvates, and pharmaceutically acceptable salts and compositions; wherein suitable R1ng systems represented by A is selected from phenyl, naphthyl, pyR1dyl, thienyl, pyR1midinyl, and the like which may be substituted. Suitable R1ng systems

represented by B is selected from phenyl, naphthyl, pyR1dyl, thienyl, pyR1midinyl, and the like which may be substituted.
R independently represents hydrogen, halogen (such as fluoR1ne, chloR1ne, bromine, iodine), hydroxyl, azido, amino, linear or branched (C1-C4) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, tR1fluoromethyl, tR1fluoroethyl, dichloromethyl, dichloroethyl and the like; SR6, S(0)qR7; aminocycloalkyl groups such as -NH-cylcopropyl, -NH-cyclopentyl, -NH-cyclohexyl and the like; monoalkylamino groups such as -NHCH3, -NHC2H5, -NHC3H7, -NHC6H13, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; -NH(C1-C5)n-X, wherein linear or branched (C1-C5) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; X is aryl or heteroaryl, aryl groups such as phenyl, naphthyl and the like and heteroaryl groups such as pyR1dyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, tR1azolyl, thiadiazolyl, tetrazolyl, pyR1midinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl groups such as pyrrolidinyl, morpholinyl, thiomorpholinyl, pβeR1dinyl, pβerazinyl, and the like; aminoheterocyclyl groups such as aminopβerazinyl, and the like; aminoalkanols such as -NH-(CH2)qOH (the methylene group may be further substituted for e.g. by alkyl, -OH and the like); hydrazine; alkylhydrazines such as -N(CH3)NH2, -N(C2H5)NH2, -N(C3H7)NH2 and the like.
Suitable groups represented by R1 are selected from hydrogen, SR6 and S(0)pR7.
Suitable groups represented by R2 are selected from hydrogen, hydroxyl, halogen atoms such as fluoR1ne, chloR1ne, bromine, iodine; hydroxyl, nitro, cyano, azido, amino, linear or branched (C1-C4) alkyl groups such as methyl, ethyl, n-propyl,

isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, tR1fluoromethyl, tR1fluoroethyl, dichloromethyl, dichloroethyl and the like; linear or branched (C1-C6) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aminoalkyl groups such as -NHCH3, -NHC2H5, -NHC3H7 and the like; aminodialkyl groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; acyl groups such as -C(=0)CH3, -C(=0)CF3, -C(=0)C2H5, -C(=0)C3H7, -C(=S)CH3, -C(=S)CF3, -C(=S)C2H5, -C(=S)C3H7) benzoyl; aminoacyl groups such as -NHC(0)CH3, -NHC(=0)CF3, -NHC(=0)C2H5, -NHC(-0)C3H7, and the like; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; COR8; carboxylic acid and its deR1vatives such as esters, amides, acid halides and the like.
Suitable groups represented by R3 are selected from hydrogen, SR^ and S(0)pR7.
Suitable groups represented by R4 are selected from hydrogen, hydroxyl, halogen atoms such as fluoR1ne, chloR1ne, bromine, iodine; hydroxyl, nitro, cyano, azido, amino, linear or branched (C1-C4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, tR1fluoromethyl, tR1fluoroethyl, dichloromethyl, dichloroethyl and the like; linear or branched (C1C6) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aminoalkyl groups such as -NHCH3, -NHC2H5, -NHC3H7 and the like;

alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; alkoxyalkyl groups such as

methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; COR8; carboxylic acid and its deR1vatives such as esters, amides, acid halides and the like.
R5 independently represents hydrogen, hydroxyl, azido, amino, linear or branched (C1-C4) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, tR1fluoromethyl, tR1fluoroethyl, dichloromethyl, dichloroethyl and the like; SRe, S(0)qR7; aminocycloalkyl groups such as -NH-cylcopropyl, -NH-cyclopentyl, -NH-cyclohexyl and the like; monoalkylamino groups such as -NHCH3, -NHC2H5, -NHC3H7, -NHC6H13, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; -NH(C1-C5)n-X, wherein linear or branched (C1-C5) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; X is aryl or heteroaryl, aryl groups such as phenyl, naphthyl and the like and heteroaryl groups such as pyR1dyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, tR1azolyl, thiadiazolyl, tetrazolyl, pyR1midinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl groups such as pyrrolidinyl, morpholinyl, thiomorpholin pβeR1dinyl, pβerazinyl, and the like; aminoheterocyclyl groups such as aminopβerazinyl, and the like; aminoalkanols such as -NH-(CH2)qOH; hydrazine; alkylhydrazines such as -N(CH3)NH2, -N(C2H5)NH2, -N(C3H7)NH2 and the like.
Suitable groups represented by R6 are selected from hydrogen, linear or branched (C1-C6) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl groups such as phenyl, naphthyl and the like; alkylhalides such as -CH2C1, -CH2CH2C1 and the like; alkylesters such as -CH2OCOC2H5, -CH2OCOC3H7 and the like.
Suitable groups represented by R7 are selected from amino, hydroxyl, hydrazine, halogen atoms such as fluoR1ne, chloR1ne, bromine, iodine; linear or

branched (C1C6) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; alkylhydrazine groups such as -N(CH3)NH2, -N(C2H5)NH2 and the like; acylhydrazide groups as -NHNH(C=0)CH3, -NHNH((>0)CF3 and the like; arninoacyl groups such as -NHC(=0)CH3, -NHC(=0)CF3, -NHC(=0)C2H5, -NHC(=0)C3H7j -NHC(=0)C6H13; aminoalkanols such as -NH-(CH2)qOH; aryl groups such as phenyl, naphthyl and the like; aminoaryl groups such as phenyl amino, naphthyl amino and the like; aminoheteroaryl groups such as thienylamino, pyR1dylamino, pyR1midyl amino and the like; aminoheterocyclyl groups such as aminopβerazine, aminomorpholine and the like.
Suitable groups represented by R8 are selected from hydrogen, hydroxyl, amino, halogen atoms such as fluoR1ne, chloR1ne, bromine, iodine; linear or branched (C1-C4) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like; haloalkyl groups such as chloromethyl, chloroethyl, tR1fluoromethyl, tR1fluoroethyl, dichloromethyl, dichloroethyl and the like; linear or branched (C1-C4) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryloxy groups such as phenoxy, napthoxy and the like; aminoalkyl groups such as -NHCH3, -NHC2H5, -NHC3H7, -NHC6Hi3, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; arylamino groups such as phenyl amino, naphthyl amino and the like; heteroarylamino groups such as thienylamino, pyR1dylamino, pyR1midyl amino and the like, acylamino groups such as -NHC(=0)CH3, -NHC(=0)CF3, -NHC(=0)C2H5, -NHC(=0)C3H7, -NHC(=0)C6H13 and the like.
m and n are integers ranging from 0 to 4; p is an integer of 1 or 2; q is an integer in the range of 1 to 10.
When the groups R, Rl9 R2, R3, R4 and R5 are substituted, the term substituted means that one or more hydrogen atoms are replaced by a substituent including, but

not limited to, halogen, hydroxy, nitro, cyano, azido, nitroso, amino, amidino, hydrazine, formyl, alkyl, aryl, cycloalkyl, alkoxy, aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aralkoxy (e.g., benzyloxy), acyl, acyloxyacyl, carboalkoxy (e.g., acyloxy), carboxyalkyl (e.g., esters), carboxamido, aminocarbonyl, carbonyl, alkylenedioxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, sulfanyl, sulfinyl, sulfonyl, sulfamoyl, thio, alkoxyalkyl groups, carboxylic acids and its deR1vatives. In addition, the substituent may be substituted.
Furthermore when A and B are cyclic R1ngs, they represent substituted or unsubstituted 5 to 10 membered R1ng systems, and also the R1ngs may be monocyclic or bicyclic, saturated, partially saturated or aromatic, containing 1 to 4 hetero atoms selected from O, S and N and the like.
The term analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms. Hence, a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
The term stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
The term tautomers include readily interconvertible isomeR1c forms of a compound in equilibR1um. The enol-keto tautomeR1sm is an example.
The term polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
The term pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
The term deR1vative refers to a compound obtained from a compound according to formula (I), an analog, tautomeR1c form, stereoisomer, polymorph,

hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate
thereof, by a simple chemical process converting one or more functional groups, such
as, by oxidation, hydrogenation, alkylation, esteR1fication, halogenation, and the like.
Pharmaceutically acceptable salts of the present invention include alkali metal
salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of
organic bases such as diethanolamine, a-phenylethylamine, benzylamine, pβeR1dine,
morpholine, pyR1dine, hydroxyethylpyrrolidine, hydroxyethylpβeR1dine, guanidine,
choline and the like, ammonium or substituted ammonium salts, aluminum salts.
Salts also include amino acid salts such as glycine, alanine, cysteine, lysine, arginine,
phenylalanine etc. Salts may include sulphates, nitrates, phosphates, perchlorates,
borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, oxalates,
palmoates, methanesulphonates, tosylates, benzoates, salicylates,
hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or compR1sing of other solvents of crystallization such as alcohols.











Preferred salts for the list of compounds above are hydrochloR1de, phosphonate, mesylate, besylate, tosylate, and oxalate.
According to another embodiment of the present invention, there is provided a process for the preparation of novel pyR1midines of the formula (I) wherein all the symbols are as defined earlier. Scheme I:
Reacting a compound of the formula (la) as disclosed in our US Patent 2004-259891, with substituted or unsubstituted alkylamines to produce a compound of formula (I).


(Compound of the formula (la) as disclosed in our US Patent 2004-259891:
wherein X represents oxygen, sulfur or NR, wherein R represents hydrogen, hydroxyl, acyl, alkyl, alkoxy, aryl, amino, hydroxylamino, alkylamino, arylamino, acylamino, alkoxyamino group; the R1ngs represented by A and B are selected from aryl or heteroaryl; R1 and R3 may be same or different and independently represent hydrogen, SR7, S(0)pR8; R2 and R4 may be same or different and independently represent hydrogen, halogen, hydroxyl, nitro, cyano, azido, nitroso, amino, formyl, alkyl, haloalkyl, acyl, alkoxy, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl, SR, S(0)pR , alkoxyalkyl groups or carboxylic acids or its deR1vatives; R5 and R6 may be same or different and independently represent hydrogen, halogen, hydroxyl, nitro, cyano, azido, nitroso, amino, formyl, alkyl, aryl, aralkyl, haloalkyl, acyl, alkoxy, aryloxy, aralkoxy, heteroaryl, heterocyclyl,
7 R
monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl, SR, S(0)pR,
O "7 8
alkoxyalkyl groups or COR ; R represents hydrogen, alkyl or aryl; R represents
halogen, alkyl, amino, acylamino, arylamino or aryl group; R9 represents hydrogen,
hydroxyl, amino, halogen, alkyl, alkoxy, aryloxy, monoalkylamino, dialkylamino,
acylamino, arylamino, groups; m is an integer and is in the range of 0 to 4; n is an
integer and is in the range of 0 to 4; p represents an integer of 1 or 2; with a proviso
that when R represents hydrogen R is not hydrogen.)
Scheme II; Compound of formula (I) may also be prepared by following steps: Step; I



Reacting the compound of the formula (I, wherein R is halogen) to give a compound of formula (I) wherein all the other symbols are as defined earlier using suitable nucleophiles.

The reactions descR1bed in the processes outlined above are performed by using the methods descR1bed herein:
Scheme 1:
The reaction of compound of formula (la) with substituted or unsubstituted
alkylamines may be carR1ed out using appropR1ate solvents like water, toluene, xylene, THF, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitR1le, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, pyR1dine, ethanol, methanol, isopropylalcohol, tert-butylalchol, acetic acid, propionic acid etc, a mixture thereof or by neat reactions. The condensation reaction may be carR1ed out under acidic conditions using mineral/organic acids, or basic conditions viz. carbonates, bicarbonates, hydR1des, hydroxides, alkyls and alkoxides of alkali metals and alkaline earth metals. The reaction may be carR1ed out in presence of phase transfer catalysts viz. tR1ethylbenzylammonium chloR1de, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tR1caprylmethylammonium chloR1de (aliquat 336) and the like. The reaction is usually carR1ed out under cooling to reflux conditions. The final product is puR1fied by using chromatographic techniques or by recrystallization. The reaction may be carR1ed out for a peR1od in the range of 30 minutes to 20

The conversion of formula (la) may be carR1ed out in the presence of basic
conditions viz. with one or more equivalents of carbonates, bicarbonates, hydR1des,
hydroxides, alkyls and alkoxides of alkali metals and alkaline earth metals and the
like in appropR1ate solvents like water, ethanol, methanol, isopropylalcohol, tert-
butylalchol, toluene, xylene, THF, dioxane, chloroform, dichloromethane,
dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitR1le, dimethyl
formamide, dimethyl sulphoxide, pyR1dine a mixture thereof or the like. The reaction
can also be carR1ed out in presence of phase transfer catalysts viz.
tR1ethylbenzylammonium chloR1de, tetrabutylammonium bromide,
tetrabutylammonium hydrogensulphate, tR1caprylmethylammonium chloR1de (aliquat
336) and the like. The reaction is usually carR1ed out under cooling to reflux
conditions for a peR1od in the range of 30 minutes to 20 hours. The final product is
puR1fied by chromatographic techniques or by recrystallization.
Step 2:
The conversion of the compound of formula (II) to compound of formula (III), wherein R represents hydroxyl is carR1ed out by using dry hydrogen chloR1de gas in solvents such as ethanol, methanol, dioxane, toluene, xylene, THF, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, dβhenyl ether and the like or a mixture thereof or by using reagents such as phosphorus oxychloR1de, thionyl chloR1de, phosphorus tR1chloR1de, phosphorus pentachloR1de, oxalyl chloR1de or and the like or a mixture thereof in the presence or absence of solvents such as toluene, xylene, THF, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, dβhenyl ether and the like or a mixture thereof, in presence or absence of dimethyl formamide, N,N-dimethylaniline, N,N-diethylaniline and the

like. The reaction is carR1ed out at a temperature in the range of 20 °C to reflux temperature for a peR1od in the range of 2 to 12 hours Step 3:
The conversion of compounds of formula (III) to compound of formula (IV), wherein R represents halogen is carR1ed out using reagents such as phosphorus oxychloR1de, thionyl chloR1de, phosphorus tR1chloR1de, phosphorus pentachloR1de, oxalyl chloR1de and the like or mixtures of the above in the presence or absence of solvents such as toluene, xylene, THF, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, dβhenyl ether and the like or a mixture thereof, in presence or absence of dimethyl formamide, N,N-dimethylaniline, N,N-diethylaniline and the like. The reaction can be carR1ed out at a temperature in the range of 20 °C to reflux temperatures for a peR1od in the range of 2 to 12 hours. Step 4:
The conversion of formula (IV) may be carR1ed out in the presence of one or
more equivalents of a metal azide such as LiN3, NaN3, tR1alkyl silylazide and the like
or hydrazine hydrates or substituted hydrazines or alkylamines or aminoalkanols or
heterocyclylamines or cyclic amines or benzylamines or aryl or heteroarylamines or
ammonia. The reaction may be carR1ed out in the presence of solvents such as
toluene, xylene, THF, dioxane, chloroform, dichloromethane, dichloroethane, o-
dichlorobenzene, acetone, ethylacetate, acetonitR1le, dimethyl formamide, dimethyl
sulphoxide, ethanol, methanol, isopropylalcohol, tert-butylalcohol, dβhenyl ether
and the like or a mixture thereof. The condensation reaction may be carR1ed out under
acidic conditions using mineral/organic acids, or basic conditions viz. carbonates,
bicarbonates, hydR1des, hydroxides, alkyls and alkoxides of alkali metals and alkaline
earth metals. The reaction may be carR1ed out by using phase transfer catalysts viz.
tR1ethylbenzylammonium chloR1de, tetrabutylammonium bromide,
tetrabutylammonium hydrogensulphate, tR1caprylmethylammonium chloR1de (aliquat

336) and the like. The reaction may be carR1ed out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably in the range of 80°C to 100°C. The reaction time may range from 0.5 to 18 hours.
According to yet another embodiment of the present invention there is provided a process for the conversion of novel pyR1midines of the formula (I), wherein any of the groups R or R5 or R1 or R3 represent SR6 and wherein R According to yet another embodiment of the present invention there is provided a process for the conversion of novel pyR1midines of the formula (I), wherein any of the groups R or R5 or R\ or R3 represent SR$ and wherein R According to yet another embodiment of the present invention there is provided a process for the conversion of novel pyR1midines of the formula (I), wherein R or R5 or R1 or R3 represent S(0)pR7 and wherein p is 1 or 2 and R7

represents alkyl; to novel pyR1midines of the formula (I) wherein Ry or R3 represent S(0)pR7, where p is 1 or 2 and R7 represents amino; by using the procedure descR1bed in the literature (Huang etal. Tetrahedron Lett., 39, 7201, 1994).
Alternatively, a process for the preparation of novel pyR1midines of the formula (I), wherein either of R1 or R3 represent S(0)PR7, wherein R7 independently represents the amino, alkylamino, hydrazine, alkylhydrazine, arylhydrazino group, p represents an integer of 1 or 2 and all the other symbols are as defined earlier, compR1ses of reacting the compound of formula (V) wherein either of

R1 or R3 represents hydrogen and wherein all the symbols are as defined earlier, with chlorosulfonic acid, followed by reaction with nucleophilic reagents such as ammonia, alkylamines, hydrazines, alkylhydrazines, arylhydrazines and the like.
The reaction of the compound of formula (V) with chlorosulfonic acid and ammonia may be carR1ed out in the presence of solvents such as acetic acid, dichloromethane, acetone, THF, dioxane, ethyl acetate, chloroform, water, an alcohol and the like or a mixture thereof or in the absence of solvents. The reaction may be carR1ed out at a temperature in the range of 0°C to reflux temperature for a time peR1od in the range of 2 to 24 hours.
The N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., tR1fluoroacetic acid, per maleic acid, perbenzoic acid, peracetic acid, meta-chloroperbenzoic acid, or the like) in a suitable inert organic solvent (e.g.,

a halogenated hydrocarbon such as dichloromethane) at approximately 0°C. Alternatively, the N-oxides can be prepared from the N-oxide of appropR1ate starting mateR1al.
It is appreciated that in any of the above-mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropR1ate to the molecule being protected. Protecting groups are removed under conditions, which will not affect the remaining portion of the molecule.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydR1de, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases such as diethanolamine, a-phenylethylamine, benzylamine, pβeR1dine, morpholine, pyR1dine, hydroxyethylpyrrolidine, hydroxyethylpβeR1dine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts. Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloR1c acid, hydrobromic acid, nitR1c acid, sulfuR1c acid, phosphoR1c acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citR1c acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaR1c acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.

It should be noted that compounds of the invention may contain groups that may exist in tautomeR1c forms, and though one form is named, descR1bed, displayed and/or claimed herein, all the tauomeR1c forms are intended to be inherently included in such name, descrβtion, display and/or claim.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeR1c form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeR1c salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaR1c acid, lactic acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their deR1vatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compounds of the formula (I) may be converted to a 1:1 mixture of diastereomeR1c amides by treatment with chiral amines, aminoacids, aminoalcohols deR1ved from aminoacids; conventional reaction conditions may be employed to convert acids into amides; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of the compounds of formula (I) may be prepared by hydrolysing the pure diastereomeR1c amides.
Prodrugs of the compounds of formula (I) are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.

VaR1ous polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; vaR1ous modes of cooling, ranging from very fast to very slow cooling duR1ng crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning caloR1metry and powder X-ray diffraction or other such techniques.
The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their deR1vatives, their analogs, their tautomeR1c forms, their stereoisomers, their polymorphs, their hydrates, their metabolites, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carR1ers, diluents and the like, useful for the treatment of inflammation, arthR1tis, pain, fever, psoR1asis, allergic diseases, asthma, inflammatory bowel syndrome, gastro-intestinal ulcers, cardiovascular disorders including ischemic heart disease, atherosclerosis, cancer, ischemic-induced cell damage, particularly brain damage caused by stroke and other pathological disorders associated with free radicals.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carR1ers or diluents, or in suitable steR1le media to form injectable solutions or suspensions. The compositions may be pepared by processes known in the art. The amount of the active ingredient in the composition may be less than 70% by weight. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the

remainder of the composition being pharmaceutical^ acceptable carR1ers, diluents, excβients or solvents.
Suitable pharmaceutical^ acceptable carR1ers include solid fillers or diluents and steR1le aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as descR1bed above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carR1er or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excβients and the like. For parenteral administration, the compounds can be combined with steR1le aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intrapeR1toneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The pharmaceutical compositions of the invention are effective in loweR1ng TNF-a and IL-6 levels, COX-2 activity without ulcers, platelet aggregation inhibition and anticancer acitivity as shown by tests in in-vitro as well as in animal models. The pharmaceutical compositions of the invention are thus effective for treating rheumatoid arthR1tis, osteoarthR1tis, rheumatoid spondylitis, gouty arthR1tis, inflammatory bowel disease, psoR1asis, Crohn's disease, allergic rhinitis, ulcerative colitis, bone resorption diseases, and osteoporosis. The pharmaceutical compositions of the invention are also effective in the treatment of ischemic heart disease, ischemic-induced cell damage, ischemia reperfusion injury, atherosclerosis, brain trauma, multβle sclerosis, sepsis, septic shock, toxic shock syndrome, fever, and

myalgias due to infection. The pharmaceutical compositions of the present invention are also effective in treating cancer, acute and chronic myelogenous leukemia, multβle myeloma, and pancreatic p cell destruction. Furthermore, pharmaceutical compositions of the present invention are useful for the treatment of disorders, which includes adult respiratory distress syndrome (ARDS), anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, type I and type II diabetes. Generally, the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician duR1ng treatment to alleviate the symptoms or indications of the condition or disease. Generally, a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropR1ate for administration to obtain effective results. The daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescR1bed daily dose. Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other therapies to a mammal in need of such treatment. More specifically, it is that amount that is sufficient to lower the cytokines such as TNF-a, IL-1, IL-6, IL-


mediated by thromboxane synthase to treat autoimmune diseases, inflammation, immunological diseases, and cancer. The term "animal" as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the seveR1ty of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
The term "treatment" or "treating" means any treatment of a disease in a mammal, including:
a) Preventing the disease, that is, causing the clinical symptoms of the disease
not to develop;
b) Inhibiting the disease, that is, slowing or arresting the development of clinical
symptoms; and/or
c) Relieving the disease, that is, causing the regression of clinical symptoms.
From the foregoing descrβtion, once skilled in the art can easily ascertain the essential characteR1stics of this invention, and without departing from the spiR1t and scope thereof, can make vaR1ous changes and modifications of the invention to adapt it to vaR1ous usages and conditions.
The present invention is provided by the examples given below, which are provided by the way of illustration only, and should not be considered to limit the scope of the invention. VaR1ation and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, which are defined in the appended claims.


To a suspension of 5-Cyano-1 -(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyR1midine (2.5g, 6.59 mmol) in ethanol (30 ml) was added anhydrous potassium carbonate (1.3g, 9.4 mmol) under continous stirR1ng, and at an ambient temperature. The suspension was heated slowly to 60°C under stirR1ng for 5 hours. Subsequently the reaction mixture was filtered, and washed with water then with ethanol and dR1ed under vacuum to yield the title compound (2.12g, 80.8%, m.p.: 173-175°C, puR1ty 91.6% by HPLC). !H-NMR (CDC13) 5 (ppm): 2.34 (s, 3H), 2.53 (s, 3H), 2.69 (s, 3H), 7.16-7.18 (d, 2H), 7.26-7.37 (m, 4H), 7.92-7.94 (d, 2H), 14.0 (s, 1H, D20 exchangeable). IR (KBr) cm"1: 3311, 2201, 1702 (-CO). MS m/z: 398.5 (M++l).


by following the same procedure as descR1bed in preparation 1, 8.1g, 77.45% yield, m.p.: 163-166°C, puR1ty 99.7% by HPLC. !H-NMR (DMSO-ds) 5 (ppm): 2.03 (s, 3H), 2.08 (s, 3H), 2.15 (s, 3H), 2.49(s, 3H), 6.90-6.92 (d, 2H), 6.97 (s, 1H), 7.06-7.08 (d, 2H), 8.01-8.03 (d, 2H), 11.73 (s, 1H, D20 exchangeable). IR (KBr) cm'1: 3430, 2186, and 1628 (-00). MS m/z: 412.1 (M++l).

Dry HC1 gas was passed through a solution of Af-[(l£)-2-Cyano-3-[(4-methylphenyl)amino]-1 -(methylthio)-3-oxoprop-1 -en-1 -yl]-4-(methylthio)benzamide (2g, 5 mmol, prepared according to the procedure descR1bed in preparation 1) in ethanol (50 ml) at 0°C for 4 hours.The reaction mixture was then refluxed for 4 hours until completion; subsequently the resultant solid was filtered and washed with ethanol. The solid thus obtained was suspended in dichloromethane (50 ml), filtered, and finally dR1ed under vacuum to yield the title compound (1.8g, 90%, puR1ty 99.78% by HPLC), m.p.: 302-305°C. *H-NMR (CDC13) 8 (ppm): 2.29 (s, 3H), 2.33 (s, 3H), 2.63 (s, 3H), 7.12-7.14 (d, 2H), 7.23-7.26 (m, 2H), 7.47-7.49 (d, 2H), 8.13-8.15 (d, 2H), 11.38 (s, 1H, D20 exchangeable), 12.45 (s, 1H, D20 exchangeable). IR (KBr) cm'1: 3436, 3320, and 1646. MS m/z: 398.1(M++1). Example 2:
Synthesis of 4-Hydroxy-7V-(3,4-dimethylphenyl)-6-(methylthio)-2-[4-(methyIthio) phenyl]pyR1midine-5-carboxamide


The title compound was obtained from 7V-[(li?)-2-Cyano-3-[(3,4-dimethylphenyl)amino]-1 -(methylthio)-3-oxoprop-1 -en-1 -yl]-4-(methylthio) benzamide (4.4g, 10 mmol, prepared according to the procedure descR1bed in preparation 1) by following the procedure descR1bed in example 1, 3.3g, yield 75%, and puR1ty 99.89% by HPLC, mp 303~305°C. 1H-NMR (DMSO-cfc) 8 (ppm): 2.18-2.22 (d, 6H), 2.51-2.56 (d, 6H), 7.08-7.10 (d, 1H), 7.38-7.45 (q, 4H), 8.20-8.22 (d, 2H), 11.69 (s, 1H, D20 exchangeable), 13.35 (s, 1H, D20 exchangeable). IR (KBr) cm-1: 3281, 2920, 2852 and 1650. MS m/z: 412.1 (M++l).



4-Hydroxy-A^-(4-methylphenyl)-6-(methylthio)-2-[4-(methylthio)phenyl] pyR1midine-5-carboxamide (0.5g, 1.25 mmol) was refluxed in phosphorus oxychloR1de (10 ml) for 3 hours and subsequently cooled to room temperature. The reaction mixture was poured onto ice-water mixture, neutralised with saturated sodium bicarbonate solution and the solid thus separated was extracted with ethylacetate. The organic layer was washed with water; dR1ed over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound, 0.3g, yield 57%. 2H-NMR (CDC13) 5 (ppm): 2.35 (s, 3H), 2.55 (s, 3H), 2.69 (s, 3H), 7.19-7.21 (d, 2H), 7.3-7.32 (d, 2H), 7.51-7.53 (m, 3H, 1H D20 exchangeable), 8.35-8.37 (d, 2H). IR (KBr) cm1: 3436, 3276, and 1648. MS m/z: 416 (M++l).

(methylthio)phenyl]-6-oxo-1,6-dihydropyR1midine (2g, 5.3 mmol, prepared according to the procedure disclosed in our US patent 2004/0259891) in DMF was added methylamine (0.32g, 10.5 mmol) under stirR1ng. The solution was slowly warmed to 45 °C, and maintainted at this temperature for 1 hour. The completion of the reaction confirmed by TLC using ethylacetate: hexane (1:1) as a solvent system. The resulted

reaction mass was poured onto ice and filtered, the crude solid thus obtained was puR1fied by column chromatography using ethylacetate: hexane to give the title compound, 0.8g, yield 37%, puR1ty 99.5% by HPLC, m.p.: 228-230°C. !H-NMR (CDCI3) 8 (ppm): 2.35 (s, 3H), 2.54 (s, 3H), 2.73 (s, 3H), 3.1 -3.13 (d, 3H), 7.17-7.20 (d, 2H), 7.30-7.32 (d, 2H), 7.48-7.5 (d, 2H), 7.9 (bs, 1H)3 8.35 (bs, 1H), and 8.4-8.42 (d, 2H). IR (KBr) cm-1: 3358, 3270, and 1625. MS m/z: 411.1 (M++l). Example 5 can be alternatively synthesized as follows:
To a solution of 4-Chloro-7V-(4-methylphenyl)»6-(methylthio)-2-[4-(methylthio)phenyl]pyR1midine-5-carboxamide (0.05g, 0.12 mmol, obtained according to the procedure descR1bed in example 4) in THF (5ml) was added 10% methylamine in THF (5 ml, prepared by purging methylamine gas into THF at 0°C to get a 10% solution) at 0°C under stirR1ng. The reaction mixture was stirred at this temperature until completion (TLC) and was subsequently poured onto ice-water mixture and extracted with ethylacetate. The organic layer was dR1ed over anhydrous sodium sulphate and distilled under vacuum to yield the title compound, 0.03g, yield 61%. MS m/z: 411.1 (M++l).


under stirR1ng at -20°C. The resultant reaction mass was stirred at the same temperature until the completion of the reaction was confirmed by TLC using ethylacetate: hexane (1:1). Subsequently the reaction mixture was poured onto ice-water mixture under vigorous stirR1ng, until a solid separated out, which was filtered, and washed thoroughly with cold water to yield the title compound 1.47g, yield 84.44%, puR1ty 96.6% by HPLC, m.p.: 184-197°C. 'H-NMR (DMSO-de) 5 (ppm): 2.72 (s, 3H), 3.11-3.13 (d, 3H), 3.8 (s, 3H), 6.92-6.94 (m, 2H), 7.37-7.41 (m, 1H), 7.51-7.53 (m, 2H), 7.90 (s, 1H, D20 exchangeable), 8.37 (s, 1H, D20 exchangeable), 8.68-8.70 (m, 2H), 9.65 (s, 1H). IR (KBr) cm"1: 3285,1642. MS m/z: 382.4 (M++l).

pyR1din-3-yl-l,6-dihydropyR1midine (0.6g, 1.72 mmol, prepared according to the procedure disclosed in our US Patent 2004/0259891) in THF was added methylamine (0.36g, 11.6 mmol) under stirR1ng at an ambient temperature, and the reaction mixture was maintainted at this temperature for 4 hours until completion of the reaction was confirmed by TLC using ethylacetate: hexane (1:1). The resultant reaction mass was poured onto ice and filtered. The crude solid thus obtained was puR1fied by column chromatography using ethylacetate: hexane to give the title compound, 0.23g, yield 38.44%, puR1ty 94.3% by HPLC, m.p.: 285-286°C. 'H-NMR (CDC13) 5 (ppm): 2.26-2.29 (d, 6H), 2.72 (s, 3H), 3.09-3.12 (d, 3H), 6.5 (bs, 1H, D20 exchangeable), 7.13-7.15 (d, 1H), 7.26-7.39 (m, 3H, 1H, D20 exchangeable), 7.88-7.93 (bs, 1H), 8.37

(bs, 1H, D20 exchangeable), 8.66-8.7 (m, 2H), and 9.62-9.65 (m, 1H). IR (KBr) cm" 1 3246, and 1641. MS m/z: 363.2 (M++l). General Procedure:
To the suspension/solution of l,2-Diaryl-5-cyano-4-methylthio-l,6-dihydro-pyR1midin-6-one (prepared according to the procedure disclosed in our US patent 2004-259891) in appropR1ate solvents like DMF, acetonitR1le, ethanol, isopropanol, dioxane, THF, dichloromethane, chloroform or mixture thereof was added 1 to 30 molar quatities of methylamine/ethanolamine or substituted alkylamine under stirR1ng at -20°C to reflux temperature in presence or absence of a catalytic amount of anhydrous potassium carbonate. The reaction mass was stirred until completion of reaction (as confirmed by TLC). Subsequently the resultant solid thus separated was filtered, washed with water and dR1ed to yield crude product, which was puR1fied by column chromatography to yield the title compounds. The following compounds are prepared by the general procedure given above:



































Example 59:
To the clear solution of N-(4-Methoxyphenyl)-4-(methylamino)-6-(methylthio)-2-pyR1din-3-ylp3nimidine-5-carboxamide (2.5g, 6.55 mmol, prepared according to the procedure descR1bed in example 5) in acetone (250 ml) was added orthophosphoR1c acid ( 1-6 g, 16.38 mmol) in one portion under stirR1ng. The stirR1ng was continued until the solid separates out. The resultant solid was filtered and washed slowly and dropwise with acetone (5 ml). The solid obtained was dR1ed under vacuum to yield the desired salt 3.78 g, yield 97.8%, assay of base 68.3% by HPLC and phosphate content 30.09% by assay, m.p.: 222-225°C. !H-NMR (DMSO-d^ 8 (ppm): 2.59 (s, 3H), 2.96-2.98 (d, 3H), 3.74 (s, 3H), 6.91-6.94 (m, 2H), 7.12-7.14 (m, 1H, D20 exchangeable), 7.54-7.57 (m, 1H), 7.61-7.63 (m, 2H), 8.67-8.71 (m, 2H), 9.53 (s, 1H), 10.39 (s, 1H, D20 exchangeable). IR (KBr) cm"1: 3788.5, 3388, 1722, 1686, 1657, 1615, 1580 and 1548. MS m/z: 382.1 (M++l).

General Procedure for making Salts:
To the suspension/solution of N,2-Diaryl-4-(methylamino)-6-(methylthio)-pyR1midine-5-carboxamide (prepared according to the procedure descR1bed in the above examples) in a suitable solvents like ethanol, isopropanol, dichloromethane, ethylacetate, hexane, THF, acetone, ether, acetonitR1le, dioxane or the combination/mixture of solvents mentioned in 1:1 to 1:10 ratio was added 3 to 10 molar quantities of acid which includes aqueous hydrochloR1c acid or dry hydrogen chloR1de gas, orthophosphoR1c acid, nitR1c acid, sulphuR1c acid, succinic acid, oxalic acid, citR1c acid, salicylic acid, methane sulfonic acid, p-toluene sulfonic acid, benzoic acid etc of inorganic/organic oR1gin under stirR1ng at an ambient temperature to reflux temperature. Subsequently a solid separated out or was precβitated out by adding a suitable solvent, it was filtered or the solvent was removed under vacuum. This resulted in the target salts as mono or di or tR1 salts in a pure form. The salts thus formed were characteR1zed by using analytical techniques and estimations. The following salts are prepared by the general procedure given above.





DescR1bed below are the examples of pharmacological assays used for finding out the efficacy of the compounds of the present invention wherein their protocols and results are provided.
In vitro evaluation of Cyclooxygenase-2 (COX-2) inhibition activity
The compounds of this invention exhibited in vitro inhibition of COX-2. The COX-2 inhibition activities of the compounds illustrated in the examples were determined by the following method. Human Whole Blood Assay
Human whole blood provides a protein and cell R1ch milieu appropR1ate for the study of biochemical efficacy of anti-inflammatory compounds such as selective COX-2 inhibitors. Studies have shown that normal human blood does not contain COX-2 enzyme. This is correlating with the observation that COX-2 inhibitors have

no effect on prostaglandin E2 (PGE2) production in normal blood. These inhibitors were active only after incubation of human blood with lβopolysacchaR1de (LPS), which induces COX-2 production in the blood.
Fresh blood was collected in tubes containing sodium hepaR1n by vein puncture from healthy male volunteers. The subjects should have no apparent inflammatory conditions and should have not taken NSAIDs for at least 7 days pR1or to blood collection. Blood was pre-incubated with aspiR1n in vitro (12jig/ml, at time zero) to inactivate COX-1 for 6 hours. Then test compounds (at vaR1ous concentrations) or vehicle were added to blood. After that blood was stimulated with LPS B: 4 (10 fig/ml) and incubated for another 18 hours at 37°C water bath. After which the blood was centR1fuged, plasma was separated and stored at -80°C (J. Pharmacol. Exp.Ther, 271, 1705, 1994; Proc. Natl. Acad. Sci. USA., 96, 7563, 1999). The plasma was assayed for PGE2 using Cayman ELISA kit as per the procedure outlined by the manufacturer (Cayman Chemicals, Ann Arbor, USA). Representative results of COX-2 inhibition are shown in the Table I. Table I:

COX-1 and COX-2 enzyme based assay
COX-1 and COX-2 enzyme based assays were carR1ed out to check the inhibitory potential of test compounds on the production of prostaglandin by puR1fied recombinant COX-l/COX-2 enzyme (Proc. Nat. Acad. Sci. USA, 88, 2692-2696,

1991; J. Clin. Immunoassay 15, 116-120, 1992) In this assay, the potential of the test compound to inhibit the production of prostaglandin either by COX-1 or COX-2 from arachidonic acid (substrate) was measured. This was an enzyme based in-vitro assay to evaluate selective COX inhibition with good reproducibility.
Arachidonic acid was converted to PGH2 (Intermediate product) by COX1/COX-2 in presence or absence of the test compound. The reaction was carR1ed out at 37°C and after 2 minutes it was stopped by adding 1M HC1. Intermediate products PGH2 was converted to a stable Prostanoid product PGF2a by SnCl2 reduction. The amount of PGF2a produced in the reaction was inversely proportional to the COX inhibitory potential of the test compound. The prostanoid product was quantified via enzyme immunoassay (EIA) using a broadly specific antibody that binds to all the major forms of Prostaglandin, using Cayman ELISA kit as per the procedure outlined by the manufacturer Cayman Chemicals, Ann Arbor, USA). Representative results of inhbition are shown in the Table II. Table II:

In vitro measurement of Tumor Necrosis Factor Alpha (TNF-cO
This assay determines the effect of test compounds on the production of TNF-a in human Perβheral Blood Mononuclear Cells (PBMC). Compounds were tested

for their ability to inhibit the activity of TNF-a in human PBMC. PBMC were isolated from blood (from healthy volunteers) using BD Vacutainer CPT™ (Cell preparation tube, BD Bio Science) and suspended in RPMI medium (Physiol. Res. 52: 593-598, 2003). The test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37°C and then stimulated with LβopolysacchaR1de (EscheR1chia colt B4; 1 |uig/ml) for 18 hours at 37 °C in 5% C02. The levels of TNF-a in the cell culture medium were estimated using enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer (R&D Systems, Inc. 614 McKinley Place NE, Minneapolis, MN 55413, USA). Representative results of TNF-a inhibition are shown in Table III. Table III;

In vitro measurement of Interleukin-6 (IL-6) & Interleukin-IB IIL1B)
This assay determines the effect of test compounds on the production of IL-6 and IL1 β in human PBMC (Physiol. Res. 52: 593-598, 2003). Compounds were

tested for their ability to inhibit the activity of IL-6 and IL1 p in human PBMC. PBMC were isolated from blood using BD Vacutainer CPT Cell preparation tube (BD Bio Science) and suspended in RPMI medium. The test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37°C and then stimulated with LβopolysacchaR1de (EscheR1chia colt B4; 1 |ig/ml) for 18 hours at 37°C in 5% C02. The levels of IL-6 and IL1 p in cell culture medium were estimated using enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer (R&D Systems, Inc. 614 McKinley Place NE5 Minneapolis, MN 55413, USA). Representative results of IL-6 and IL-lp inhibition are shown in Table IV.

Carrageenan induced Paw Edema test in Rat
The carrageenan paw edema test was performed as descR1bed by Winter et al (Proc.Soc.Exp.Biol.Med, 111, 544, 1962). Male wistar rats were selected with body weights equivalent within each group. The rats were fasted for eighteen hours with free access to water. The rats were dosed orally with the test compound suspended in vehicle containing 0.25% carboxymethylcellulose and 0.5% Tween 80. The c™trr»1

rats were administered with vehicle alone. After an hour, the rats were injected with 0.1 ml of 1% Carrageenan solution in 0.9% saline into the sub-plantar surface of the R1ght hind paw. Paw volume was measured using digital plethysmograph before and after 3 hours of carrageenan injection. The average of foot swelling in drug treated animals was compared with that of control animals. Anti-inflammatory activity was expressed as the percentage inhibition of edema compared with control group [Arzneim-Forsch/Drug Res., 43 (I), 1,44-50,1993; Otterness and Bliven, Laboratory Models for Testing NSAIDs, In Non-Steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed.1985)]. Representative results of edema inhibition are shown in Table V. Table V
Ulcerogenic potential
In order to evaluate compound's role on the ulcer formation, the animals were sacR1ficed and the stomach was taken out and flushed with 1% formalin. Animals (male wistar 200gm) were fasted for 18 hours free access to water and the test compounds were suspended in 0.5% Tween 80 and 0.25% CMC (carboxymethylcellulose) solution to make a uniform suspension. After 4 hours of oral administration of test compounds, all the animals were sacR1ficed by cervical dislocation. Dissect the stomach carefully and filled up with a steR1le saline solution and embedded in 6% formalin solution. Finally cut the stomach longnitudinaly and ulcer lesions were observed with computeR1zed stereomicroscope. Compare the test

compound treated groups with the vehicle treated groups. Dose selected: 50, 100, 200mg/kg (Marco Romano et al, Journal of clinical Investigation, 1992; 2409-2421)
Inhibitory Action on Adjuvant ArthR1tis in rats
Compounds were assayed for their activity on rat adjuvant induced arthR1tis model according to Theisen-Popp et al., (Agents Actions, 42, 50-55,1994). Six to seven weeks old, wistar rats were weighed, marked and assigned to groups [a negative control group in which arthR1tis was not induced (non-adjuvant control), a vehicle-treated arthR1tis control group, test substance treated arthR1tis group]. Adjuvant induced arthR1tis was induced by an injection of 0.1ml of MycobacteR1um butyR1cum (Difco) suspended in mineral oil (5mg/ml) into the sub-plantar region of the R1ght hind paw (J.Pharmacol.Exp.Ther., 284, 714, 1998). Body weight, paw volumes were measured at vaR1ous days (0, 4, 14, 21) for all the groups. The test compound or vehicle was administered orally beginning post injection of adjuvant ('O'day) and continued for 21 days (pretreatment group). In post treatment group, the test compound or vehicle was administered starting from day 14th to 21st day. On day 21, body weight and paw volume of both R1ght and left hind paw were taken. Spleen, and thymus weights were determined. In addition, the radiographs of both hind paws were taken to assess the tibio-tarsal joint integR1ty. Hind limb below the stifle joint was removed and fixed in 1% formalin saline for the histopathological assessment. At the end of the expeR1ment, serum samples were analysed for inflammatory mediators. The presence or absence of lesions in the stomach was also observed. Two-factor ('treatment5 and 'time') analysis of vaR1ance with repeated measures on 'time5 was applied to the percentage (%) changes for body weight and foot volumes. A post hoc Dunnett's test was conducted to compare the effect of treatments to vehicle control. A one-way analysis of vaR1ance was applied to the thymus and spleen weights followed by the Dunnett's test to compare the effect of treatments to vehicle.

Dose-response curves for percentage inhibition in foot volumes on days 4, 14 and 21 were fitted by a 4-parameter logistic function using a nonlinear least Squares* regression. IC50 was defined as the dose corresponding to a 50% reduction compared to vehicle control and was deR1ved by interpolation from the fitted 4-parameter equation.
LPS induced sepsis for measurement of TNF-q inhibition in mice
The LPS induced sepsis model in mice was performed as descR1bed by Les sekut et al (J Lab Clin Med 1994; 124:813-20). Female Swiss albino mice were selected with their body weights being equivalent within each group. The mice were fasted for 20 hours with free access to water. The mice were dosed orally with the test compound suspended in vehicle containing 0.5% Tween 80 in 0.25% Carboxy-methylcellulose sodium salt. The control mice were administered the vehicle alone. After 30 minutes of oral dosing, the mice were injected with 500|ig of LβopolysacchaR1de (EscheR1chia coli, LPS: B4 from Sigma) in phosphate buffer saline solution into the intrapeR1toneal cavity of the mice. After 90 minutes of LPS administration, the mice were bled via retro-orbital sinus puncture. Blood samples were stored overnight at 4°C. Serum samples were collected by centR1fuging the samples at 4000 rpm for 15 minutes at 4°C. Immediately the serum samples were analysed for TNF-a levels, using commercially available mouse TNF-a ELISA kit (Amersham Biosciences) and assay was performed by the manufacturer instruction. Representative results of TNF-a inhibition are shown in Table VI. Table VI:


Anti-cancer screen:
ExpeR1mental drugs are screened for anti-cancer activity in three cell lines for their GI50, TGI and LC50 values (using five concentrations for each compound). The cell lines are maintained in DMEM containing 10% fetal bovine serum. 96 well microtiter plates are inoculated with cells in 100 (aL for 24h at 37°C, 5% C02, 95% air and 100% relative humidity. 5000 HCT116 cells/well, 5000 NCIH460 cells/well, 10000 U251 cells/well and 5000 MDAMB231 cells/well are plated. A separate plate with these cell lines is also inoculated to determine cell viability before the addition of the compounds (T0). Addition of expeR1mental drugs
Following 24 hours incubation, expeR1mental drugs are added to the 96 well plates. Each plate contains one of the above cell lines and the following in trβlicate: five different concentrations (0.01, 0.1, 1, 10 and 100 (iM) of four different compounds, appropR1ate dilutions of a cytotoxic standard and control (untreated) wells. Compounds are dissolved in dimethylsulfoxide (DMSO) to make 20 mM stock solutions on the day of drug addition and frozen at -20°C. SeR1al dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 \xL of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100 μM can be added to the cells in trβlicate. Standard drugs whose anti-cancer activity has been well documented and which are regularly used are doxorubicin and SAHA.

End-point measurement
Cells are incubated with compounds for 48 hours followed by the addition of 10 \xL 3-(4,5-Dimethyl-2-thiazolyl)-2,5-dβhenyl-2H-tetrazolium (MTT) solution per well and a subsequent incubation at 37°C, 5% C02, 95% air and 100% relative humidity, protected from light. After 4 hours, well contents are aspirated carefully followed by addition of 150 μL DMSO per well. Plates are agitated to ensure solution of the formazan crystals in dimethylsulphoxide and absorbance read at 570 nm.
Calculation of GI50, TGI and LC50
Percent growth is calculated for each compound's concentration relative to the control and zero measurement wells (T0; viability R1ght before compound addition). If a test well's O.D. value is greater than the T0 measurement for that cell line % Growth = (test - zero) / (control - zero) X 100
If a test well's O.D. value is lower than the T0 measurement for that cell line, then
% Growth = (test - zero) / zero X 100
Plotting % growth versus expeR1mental drug concentration, GI50 is the concentration required to decrease % growth by 50%; TGI is the concentration required to decrease % growth by 100% and LC50 is the concentration required to decrease % growth by 150%. Representative results of growth are shown in Table VII and VIII.






We Claim:
1. The present invention relates to novel compounds of the formula (I),

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, and pharmaceutically acceptable salts and compositions; wherein suitable ring systems represented by A is selected from phenyl, naphthyl, pyridyl, thienyl, pyrimidinyl, and the like which may be substituted. Suitable ring systems represented by B is selected from phenyl, naphthyl, pyridyl, thienyl, pyrimidinyl, and the like which may be substituted.
R independently represents hydrogen, halogen (such as fluorine, chlorine, bromine, iodine), hydroxyl, azido, amino, linear or branched (Q-C4) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; SR^, S(0)qR7; aminocycloalkyl groups such as -NH-cylcopropyl, -NH-cyclopentyl, -NH-cyclohexyl and the like; monoalkylamino groups such as -NHCH3, -NHC2H5, -NHC3H7, -NHC6H13, and the like, which may be substituted; dialkylamino groups suet like; -NH(C1-C5)n-X, wherein linear or branched (C1-C5) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; X is aryl or heteroaryl, aryl groups such as phenyl, naphthyl and the like and heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl,

triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl groups such as pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like; aminoheterocyclyl groups such as aminopiperazinyl, and the like; aminoalkanols such as -NH-(CH2)qOH (the methylene group may be further substituted for e.g. by alkyl, -OH and the like); hydrazine; alkylhydrazines such as -N(CH3)NH2, -N(C2H5)NH2, -N(C3H7)NH2 and the like.
Suitable groups represented by R\ are selected from hydrogen, SR$ and S(0)pR7.
Suitable groups represented by R2 are selected from hydrogen, hydroxyl, halogen atoms such as fluorine, chlorine, bromine, iodine; hydroxyl, nitro, cyano, azido, amino, linear or branched (C1-C4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; linear or branched (C1-C6) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy

alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; COR8; carboxylic acid and its derivatives such as esters, amides, acid halides and the like.
Suitable groups represented by R3 are selected from hydrogen, SR$ and S(0)pR7.

Suitable groups represented by R4 are selected from hydrogen, hydroxyl, halogen atoms such as fluorine, chlorine, bromine, iodine; hydroxyl, nitro, cyano, azido, amino, linear or branched (Q-C4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; linear or branched (C1-C6) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aminoalkyl groups such as -NHCH3, -NHC2H5, -NHC3H7 and the like;

alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; COR8; carboxylic acid and its derivatives such as esters, amides, acid halides and the like.
R5 independently represents hydrogen, hydroxyl, azido, amino, linear or branched (Q-C4) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; SR^, S(0)qR7; aminocycloalkyl groups such as -NH-cylcopropyl, -NH-cyclopentyl, -NH-cyclohexyl and the like; monoalkylamino groups such as -NHCH3, -NHC2H5, -NHC3H7) -NHC6H13, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; -NH(CrC5)n-X, wherein linear or branched (C1-C5) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; X is aryl or heteroaryl, aryl groups such as phenyl, naphthyl and the like and heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl,

benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl groups such as pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like; aminoheterocyclyl groups such as aminopiperazinyl, and the like; aminoalkanols such as -NH-(CH2)qOH; hydrazine; alkylhydrazines such as -N(CH3)NH2, -N(C2H5)NH2, -N(C3H7)NH2 and the like.
Suitable groups represented by R6 are selected from hydrogen, linear or branched (C1-C6) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl groups such as phenyl, naphthyl and the like; alkylhalides such as -CH2C1, -CH2CH2C1 and the like; alkylesters such as -CH2OCOC2H5, -CH2OCOC3H7 and the like.
Suitable groups represented by R7 are selected from amino, hydroxyl, hydrazine, halogen atoms such as fluorine, chlorine, bromine, iodine; linear or branched (C1-C6) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; alkylhydrazine groups such as -N(CH3)NH2, -N(C2H5)NH2 and the like; acylhydrazide groups as -NHNH(C=0)CH3, -NHNH(C=0)CF3 and the like; arninoacyl groups such as -

aminoalkanols such as -NH-(CH2)qOH; aryl groups such as phenyl, naphthyl and the like; aminoaryl groups such as phenyl amino, naphthyl amino and the like; aminoheteroaryl groups such as thienylamino, pyridylamino, pyrimidyl amino and the like; aminoheterocyclyl groups such as aminopiperazine, aminomorpholine and the like.
Suitable groups represented by R8 are selected from hydrogen, hydroxyl, amino, halogen atoms such as fluorine, chlorine, bromine, iodine; linear or branched (C1-C4) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like; haloalkyl groups such as chloromethyl, chloroethyl,

tR1fluoromethyl, tR1fluoroethyl, dichloromethyl, dichloroethyl and the like; linear or branched (C1-C4) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryloxy groups such as phenoxy, napthoxy and the like; aminoalkyl groups such as -NHCH3, -NHC2H5, -NHC3H7, -NHC6Hi3, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; arylamino groups such as phenyl amino, naphthyl amino and the like; heteroarylamino groups such as thienylamino, pyR1dylamino, pyR1midyl amino and the like, acylamino groups such as -NHC(=0)CH3, -NHC(0)CF3, -NHC(=0)C2H5, -NHC(=0)C3H7, -NHC(=0)C6H13 and the like.
m and n are integers ranging from 0 to 4; p is an integer of 1 or 2; q is an integer in the range of 1 to 10.
When the groups R, R1, R2, R3, R4 and R5 are substituted, the term substituted means that one or more hydrogen atoms are replaced by a substituent including, but not limited to, halogen, hydroxy, nitro, cyano, azido, nitroso, amino, amidino, hydrazine, formyl, alkyl, aryl, cycloalkyl, alkoxy, aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aralkoxy (e.g., benzyloxy), acyl, acyloxyacyl, carboalkoxy (e.g., acyloxy), carboxyalkyl (e.g., esters), carboxamido, aminocarbonyl, carbonyl, alkylenedioxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, sulfanyl, sulfinyl, sulfonyl, sulfamoyl, thio, alkoxyalkyl groups, carboxylic acids and its deR1vatives. In addition, the substituent may be substituted.
Furthermore when A and B are cyclic rings, they represent substituted or unsubstituted 5 to 10 membered ring systems, and also the R1ngs may be monocyclic or bicyclic, saturated, partially saturated or aromatic, containing 1 to 4 hetero atoms selected from O, S and N and the like. 2. Novel compounds as claimed in claim 1, are selected from a group compR1sing of:












and pharmaceutically acceptable salts thereof.
4. A compound as claimed in claim 3, wherein said pharmaceutically acceptable salt is selected from the group compR1sing of a hydrochloR1de, phosphonate, mesylate, besylate, tosylate, and oxalate salt.
5. A pharmaceutical composition comprising a compound of formula (I) as claimed in claims 1-4, as an active ingredient along with a pharmaceutically acceptable carR1er, diluent, excipient or solvate.
6. A pharmaceutical composition as claimed in claim 5, wherein the pharmaceutical composition is a tablet, capsule, powder, syrup, solution, aerosol or suspension.

7. A pharmaceutical composition as claimed in claim 5, wherein the amount of the compound of claim 1 in the composition is less than 70% by weight.
8. A method of prophylaxis or treatment of a pain disorder, inflammation, and immunological diseases in a mammal compR1sing administeR1ng an effective amount of, a compound according to any of claim 1-7, to the mammal in need thereof.
9. A method of prophylaxis or treatment of rheumatoid arthR1tis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic beta cell destruction; osteoarthR1tis; rheumatoid spondylitis; gouty arthR1tis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoR1asis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; muscle degeneration; cachexia; asthma; bone resorption diseases; ischemia reperfiision injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome;

fever, and myalgias due to infection in a mammal compR1sing administeR1ng an effective amount of, a compound according to any of claim 1-7, to the mammal in need thereof.
10. A method of loweR1ng plasma concentrations of anyone or a combination or all of
TNF-a and IL (1)8, 1, 6, 8, 12) comprising administeR1ng an effective amount of a
compound according to any of claim 1-7, to the mammal in need thereof.
11. A method of treating immunological diseases, those mediated by cytokines such as TNF-a and IL (1b, 1, 6, 8, 12) compR1sing administeR1ng an effective amount of a compound according to any of claim 1-7, to the mammal in need thereof.
12. A method of decreasing Cyclooxygenase enzyme activity (COX-2) in a mammal comprising administering an effective amount of a compound according to any of claim 1-7, to the mammal in need thereof.


Documents:

1302-CHE-2005 AMENDED PAGES OF SPECIFICATION 10-04-2013.pdf

1302-CHE-2005 AMENDED CLAIMS 10-04-2013.pdf

1302-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 10-04-2013.pdf

1302-CHE-2005 FORM-1 10-04-2013.pdf

1302-CHE-2005 AMENDED CLAIMS 07-05-2012.pdf

1302-CHE-2005 AMENDED PAGES OF SPECIFICATION 07-05-2012.pdf

1302-CHE-2005 CORRESPONDENCE OTHERS 27-03-2012.pdf

1302-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 07-05-2012.pdf

1302-CHE-2005 FORM-1 07-05-2012.pdf

1302-CHE-2005 FORM-13 05-09-2006.pdf

1302-che-2005 form-3 06-09-2010.pdf

1302-CHE-2005 FORM-3 07-05-2012.pdf

1302-CHE-2005 FORM-3 27-03-2012.pdf

1302-che-2005-abstract.pdf

1302-che-2005-claims.pdf

1302-che-2005-correspondnece-others.pdf

1302-che-2005-description(complete).pdf

1302-che-2005-description(provisional).pdf

1302-che-2005-form 1.pdf

1302-che-2005-form 3.pdf

1302-che-2005-form 5.pdf

abs-1302-che-2005.jpg


Patent Number 256019
Indian Patent Application Number 1302/CHE/2005
PG Journal Number 17/2013
Publication Date 26-Apr-2013
Grant Date 19-Apr-2013
Date of Filing 15-Sep-2005
Name of Patentee ORCHID RESEARCH LABORATORIES LTD
Applicant Address ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI 600 034,
Inventors:
# Inventor's Name Inventor's Address
1 RAVIKUMAR TADIPARTHI ORCHID CHEMICALS AND PHARMACEUTICALS LTD., 476/14, OLD MAHBALIPURAM ROAD, SHOLINGANALLUR, CHENNAI 600119, TAMIL NADU, INDIA
2 PAWAN AGGARWAL ORCHID CHEMICALS AND PHARMACEUTICALS LTD., 476/14, OLD MAHBALIPURAM ROAD, SHOLINGANALLUR, CHENNAI 600119, TAMIL NADU, INDIA
3 VENKATESAN PARAMESWARAN ORCHID CHEMICALS AND PHARMACEUTICALS LTD., 476/14, OLD MAHBALIPURAM ROAD, SHOLINGANALLUR, CHENNAI 600119, TAMIL NADU, INDIA
4 SAPPANIMUTHU THITUNAVUKKARASU ORCHID CHEMICALS AND PHARMACEUTICALS LTD., 476/14, OLD MAHBALIPURAM ROAD, SHOLINGANALLUR, CHENNAI 600119, TAMIL NADU, INDIA
5 RAJIB BARIK ORCHID CHEMICALS AND PHARMACEUTICALS LTD., 476/14, OLD MAHBALIPURAM ROAD, SHOLINGANALLUR, CHENNAI 600119, TAMIL NADU, INDIA
6 SRIRAM RAJGOPAL ORCHID CHEMICALS AND PHARMACEUTICALS LTD., 476/14, OLD MAHBALIPURAM ROAD, SHOLINGANALLUR, CHENNAI 600119, TAMIL NADU, INDIA
PCT International Classification Number A61K31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA