Field of the Invention
The present invention relates to novel condensed pyrimidones of the general formula (I), their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them. The present invention more particularly provides novel condensed pyrimidone derivatives of the general formula (I).
The present invention also provides a process for the preparation of the above said novel condensed pyrimidones of the formula (I) pharmaceutically acceptable salts, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
The novel condensed pyrimidones of the present invention are useful for the treatment of inflammation and immunological diseases. Particularly the compounds of the present invention are useful for the treatment of inflammation and immunological diseases those mediated by cytokines such as TNF-a, IL-1, IL-6, IL-1 (3, IL-8 and cyclooxygenase such as COX-2 and COX-3. 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 (3 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; and as diuretic; and diseases mediated by HIV-1; HIV-2; HIV-3; cytomegalovirus (CMV); influenza; adenovirus; the herpes viruses (including HSV-1, HSV-2) and herpes zoster viruses.
Background of Invention
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/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. Recent reports show that inhibitors of COX-1 enzyme causes gastric ulcers, where as selective COX-2 and COX-3 enzyme inhibitors are devoid of this function and hence are found to be safe.
The present invention is concerned with treatment of immunological diseases or inflammation, notably such diseases are mediated by cytokines or cyclooxygenase. 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 providing the necessary "help" for T cell stimulation and proliferation. Most importantly macrophages make IL-1, IL-12 and TNF-a 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 (IFN y). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
Cytokines are molecules secreted by 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 tumor necrosis factor-alpha (TNF-a) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. 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 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 al., 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., Ann Pharmacother, 34, 743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-a have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel disease 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 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; 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 viruses 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, it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S. Pat. Nos. 6,004,813; 5,527,546 and 5,166,137.
The cytokine IL-1 (3 also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandin from synovial cells. Elevated or unregulated levels of the cytokine IL-ip 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-1 p.
In rheumatoid arthritis models in animals, multiple 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 has 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 (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 in filtration into sites of inlammation or injury (e.g., ischemia) is mediated chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowl disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 has also has ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
Objective of the Invention
We have focused our research to identify selective COX-2 and COX-3 inhibitors, which are devoid of any side effects normally associated with anti¬inflammatory agents. Our sustained efforts have resulted in novel condensed pyrimidones of the formula (I). The derivatives may be useful in the treatment of inflammation and immunological diseases. Particularly the compound of the present invention are useful for the treatment of inflammation and immunological diseases those mediated by cytokines such as TNF-a, IL-1, IL-6, IL-lp, IL-8 and cyclooxygenase such as COX-2 and COX-3. The compound 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 (3 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; and diseases mediated by HIV-1; HIV-2; HIV-3; cytomegalovirus (CMV); influenza; adenovirus; the herpes viruses (including HSV-1, HSV-2) and herpes zoster viruses.
Summary of the Inventions
The present invention relates to novel condensed pyrimidones of the formula (I)
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions, wherein X represents O or S; Ar1 and Ar may be same or different and independently represent substituted or unsubstituted cycloalkyl, aryl, five to seven membered heteroaryl or heterocyclylgroup; Ri and R2 may be same or different and independently represent hydrogen, hydroxy, thiol, nitro, nitroso, formyl, azido, cyano, halo or substituted or unsubstituted groups selected from alkyl, halo alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl, acyl, acyloxy, cycloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, arylsulfonyl, alkylsulfmyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives.
Detailed Description of the Invention
Suitable groups represented by Ri and R2 are selected from hydrogen, hydroxy, thiol, nitro, nitroso, formyl, azido, cyano, halogen atom such as fluorine, chlorine, bromine or iodine; substituted or unsubstituted linear or branched (Q- C6) alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; halo alkyl such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl, difluoromethyl, and the like, which may be substituted; aryl group such as phenyl or naphthyl, the aryl group may be substituted; cyclo (C3- C6) alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; acyl group such as -C(=0)CH3, - C(=0)C2H5, -C(=0)C3H7, -C(=0)C6H13, -C(=S)CH3J -C(=S)C2H5, -C(=S)C3H7 - C(=S)C6Hi3, benzoyl and the like, which may be substituted; linear or branched (Ci-Ce) alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryloxy group such as phenoxy, napthoxy, the aryloxy group may be substituted; arylalkoxy group such as benzyloxy, phenethyloxy and the like, which may be substituted; acyloxy group such as MeCOO-, EtCOO-, PhCOO- and the like, which may be substituted; heterocyclyl groups such as pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like, the heterocyclyl group may be substituted; heteroaryl group may be mono or fused ring system such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazine, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like, the heteroaryl
group may be substituted; aralkyl group such as benzyl, phenyl ethyl, phenyl propyl and the like, which may be substituted; amino, which may be substituted; hydrazine, which may be substituted; monoalkylamino group such as -NHCH3, - NHC2H5, -NHC3H7; -NHC6HI3, and the like, which may be substituted; dialkylamino group such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like; acylamino group such as -NHC(=0)CH3, -NHC(=0)C2H5, -NHC(=0)C3H7> - NHC(=0)C6HI3, and the like, which may be substituted; alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like, the alkoxycarbonyl group may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthoxycarbonyl, the aryloxycarbonyl group may be substituted; alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl and the like, the alkylsulfonyl group may be substituted; arylsulfonyl group such as phenylsulfonyl or naphthylsulfonyl, the arylsulfonyl group may be substituted; alkylsulfmyl group such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso- propylsulfinyl and the like, the alkylsulfinyl group may be substituted; arylsulfinyl group such as phenylsulfinyl or naphthylsulfinyl, the arylsulfinyl group may be substituted; alkylthio group such as methylthio, ethylthio, n- propylthio, iso-propylthio and the like, the alkylthio group may be substituted; arylthio group such as phenylthio, or naphthylthio, the arylthio group may be substituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; sulfamoyl; carboxylic acid or its derivatives such as esters, amides and acid halides.
Suitable groups represented by Ar1 and Ar2 are selected from substituted or unsubstituted aryl such as phenyl, naphthyl and the like; (C3-C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl and the like, which may be substituted; heterocyclyl group such as pyrrolidinyl, thiazolidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like, the heterocyclyl group may be substituted.
1 7
The groups represented by Ar and Ar may be substituted by one to four substituents selected from hydroxy, thiol, nitro, nitroso, formyl, azido, cyano, halo or substituted or unsubstituted groups selected from alkyl, halo alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl, acyl, acyloxy, cycloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives. These groups are as defined above.
Pharmaceutically acceptable salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, a-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, per chlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates,
benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Representative compounds according to the present invention include: 5,7-Diamino-3-(4-methylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- d]pyrimidin-4(3//)-one;
5,7-Diamino-3-(3,4-dimethylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- cT|pyrimidin-4(3//)-one;
5,7-Diamino-3 - [4-(methylthio)phenyl] -2-phenylpyrimido [4,5 -^pyrimidin-4(3//)- one;
5,7-Diamino-3-(4-isopropylphenyl)-2-(4-methylthiophenyl)pyrimido[4,5- cf]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-methoxyphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- i/]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-fluorophenyl)-2-phenylpyrimido[4,5-J]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-ethylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5-
c?]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-trifluoromethylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- ^pyrimidin- 4(3//)-one;
5,7-Diamino-3-(4-chlorosulfonylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- c/]pyrimidin- 4(3//)-one;
5,7-Diamino-3-(4-sulfonylaminophenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- d]pyrimidin- 4(3//)-one;
5,7-Diamino-3-[4-(methylthio)phenyl]-2-[4-trifluoromethylphenyl]pyrimido[4,5- f/]pyrimidin-4(3//)-one;
5-Amino-7-methyl-3-(4-methylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- cT|pyrimidin-4(3//)-one;
5-Amino-3-(3,4-dimethylphenyl)-7-methyl-2-[4-methylthio)phenyl]pyrimido[4,5- cT|pyrimidin-4(3//)-one;
5-Amino-7-methyl-3-[4-(methylthio)phenyl]-2-phenylpyrimido[4,5-J]pyrimidin- 4(3//)-one;
5-Amino-3-(4-methylphenyl)-2-[4-(methylthio)phenyl]-7-phenyl-pyrimido[4,5- cT|pyrimidin-4(3//)-one and
5-Amino-3-(3,4-dimethylphenyl)-2-[4-(methylthio)phenyl]-7-phenyl- pyrimido[4,5-^pyrimidin-4(3//)-one.
According to another embodiment of the present invention, there is provided a process for the preparation of novel compounds of the formula (I)

where R2 represents amino and other symbols are as defined earlier which comprises condensing a compound of formula (la)
wherein R3 represents SCH3 or S02CH3 and all other symbols are as defined earlier with a compound of 1
where Riis as defined above through the formation of an intermediate
_ w —
R1 N N Ar2
to produce compounds of formula (I).
The reaction of compound of formula (la) with compound of formula (lb) may be carried out using solvents such as toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethylacetate, acetonitrile, dimethylformamide, DMAc, dimethylsulfoxide, ethanol, methanol, isopropyl alcohol, tert-butylalcohol etc., a mixture thereof or the like or by neat reactions. The condensation reaction is carried out under acidic condition using organic acids, or basic conditions viz. carbonate, bicarbonates, hydrides, hydroxides, alkyls and alkoxides of alkali metals and alkaline earth metals or by neat reaction. The reaction is carried out by using phase transfer catalysts viz. triethylbenzylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like. The reaction is usually carried out under cooling to refluxing conditions.
According to another embodiment of the present invention, there is provided a process for the conversion of novel condensed pyrimidone derivative of the formula (I) wherein any of the groups represent alkylthio or arylthio to novel pyrimidone derivatives of the formula (I) wherein any of the groups Rj or R2 represent arylsulfinyl, alkylsulfinyl, arylsulfonyl or alkylsulfonyl using suitable oxidizing agent. The oxidizing agent may be selected from potassium peroxymonosulfate (Oxone), hydrogen peroxide, tert-butylperoxide, Jones reagent, per acid [e.g. per acetic acid, per benzoic acid, m-chloroperbenzoic acid etc], chromic acid, potassium permanganate, alkali metal periodate [e.g sodium periodate, etc], magnesium mono peroxypthalate, osmium tetroxide / N- methylmorpholine-N-oxide, sodium tungstate, and the like. The oxidation is usually carried out in a solvent which does not adversely influence the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, an alcohol [eg. methanol, ethanol, etc.], a mixture thereof or the like. The reaction temperature is usually carried out under cooling to refluxing conditions.
According to yet another embodiment of the present invention, there is provided a process for the preparation of novel compounds of the formula (I) wherein any of the groups represent arylsulfonyl or alkylsulfonyl may be converted to novel condensed pyrimidone derivatives of the formula (I) wherein Ri or R2 represent sulfomyl by using the procedure described in the literature (Huang et.al. Tetrahedron Lett., 39, 7201, 1994).
The compounds of formula (I) wherein R represents hydroxy or thiol, the compound exists in tautormeric forms as given below:

wherein R represents O or S; R represents hydrogen or conventional nitrogen protecting group.
The present invention is provided by the examples given below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
The compound of formula (la) is prepared according to the procedure described in our PCT publication no/ 084938
Example 1
Synthesis of 5,7-diamino-3-(4-methylphenyl)-2-[4-(methylthio)phenyl] pyrimido[4,5-]pyrimidin-4(3//)-one
nh2 O r^VCH3 ^sch3
Anhydrous potassium carbonate (1.82g, 13mmol) was added to DMF (20ml) containing guanidine hydrochloride (1.26g, 13mmol) and 5-cyano-l-(4- methylphenyl)-4-methylthio-2-(4-methylthiophenyl)-l,6-dihydro-pyrimidin-6- one (5g, 13mmol) under stirring at room temperature. The reaction mass was heated at 150°C for fourteen hours then poured onto ice-water mixture. The precipitate thus obtained was filtered, washed with water and dried. The crude product thus obtained was purified by recrystallisation using ethyl acetate as solvent to yield the title compound (1.2g, 23.3.0%, mp >285 0 C, purity 98.4 % by HPLC). !H- NMR (DMSO-de): 8 2.25 (s, 3H), 2.41 (s, 3H), 6.75 (bs, 2H, D20 exchangeable), 7.06 - 7.16 (m, 6H), 7.26 - 7.28 (m, 2H), 7.75 (s, 1H, D20 exchangeable), 8.0 (s, 1H, D20 exchangeable). IR (KBr) cm"1: 3452, 3383, 3319, 3136, 1671. MS m/z: 391.6 (M+).
Example 2
Synthesis of 5,7-diamino-3-(4-isopropylphenyl)-2-(4-methylthiophenyl) pyrimido[4,5-rf]pyrimidin-4(3/7)-one

Anhydrous potassium carbonate (1.49g, 10.8 mmol) was added to DMF (20ml) containing guanidine hydrochloride (1.03g, 10.8 mmol) and 5-cyano-l-(4- isopropylphenyl)-4-methylthio-2(4-methylthiophenyl)-l,6-dihydro-pyrimidin-6- one (4g, 9.8 mmol) under stirring at room temperature. The reaction mass was heated to 150°C for eight hours, poured onto ice-water mixture. The precipitate thus obtained was filtered, washed with water and dried. The crude product thus obtained was purified by recrystallization using ethylacetate as solvent to yield the title compound (1.5g, 36.5%, mp >285°C, purity 98 % by HPLC). 'H- NMR (CDC13): 5 1.21 - 1.27 (m, 6H), 2.42 (s, 3H), 2.90 (m,lH), 5.25 (bs, 2H, D20 exchangeable), 5.45 (s, 1H, D20 exchangeable), 6.98 - 7.06 (m, 4H), 7.22 - 7.32 (m, 4H), 8.5 (s, 1H, D20 exchangeable). IR (KBr) cm"1: 3405,3334,3144,1671. MS m/z: 419.2 (M+).
Example-3
Synthesis of 5,7-diamino-3-[4-(methylthio)phenyl]-2-phenylpyrimido[4,5- d\ pyrimidin-4(3//)-one
Anhydrous potassium carbonate (1.66g, 12mmol) was added to DMF (20ml) containing guanidine hydrochloride (1.15g, 12mmol) and 5-cyano-l-(4- methylthiophenyl)-4-methylthio-2-phenyl-1,6-dihydro-pyrimidin-6-one (4g, 11 mmol) under stirring at room temperature. The reaction mass was heated to 150°C for eight hours, poured onto ice-water mixture. The precipitate thus obtained was filtered, washed with water and dried. The crude product thus obtained was purified by column chromatography (silica gel 60-120 mesh) using hexane ethyl acetate mixture as eluent to yield the title compound (0.75g, 18.18%, mp >285°C, purity 97.6 % by HPLC). lU- NMR (DMSO-d*): 5 2.41 (s, 3H), 6.85 (bs, 2H, D20 exchangeable), 7.12 - 7.36 (m, 9H), 7.63 (s, 1H, D20 exchangeable), 8.08 - 8.09 (d, 1H, D20 exchangeable). IR (KBr) cm"1: 3365,3035,1667. MS m/z: 377.2 (M+).
Example 4
Synthesis of 5,7-diamino-3-(3,4-dimethylphenyl)-2-[4-(methylthio)phenyI] pyrimido [4,5 -d\ pyrimidin-4(3i/)-one

Anhydrous potassium carbonate (0.885g, 64mmol) was added to DMF (15ml) containing guanidine hydrochloride (0.6lg, 64mmol) and 5-cyano-l- (3,4- dimethylphenyl)-4-methylthio-2-(4-methylthiophenyl)-l,6-dihydro-pyrimidin-6- one (2.5g, 64mmol) under stirring at room temperature. The reaction mass was heated to 150°C for fourteen hours, poured onto ice-water mixture. The precipitate thus obtained was filtered, washed with water and dried. The crude product thus obtained was purified by recrystallization using ethyl acetate as solvent to yield the title compound (1.2g, 47.0%, mp >285 °C, purity 93.2 % by HPLC). lU- NMR (DMSO-dfi): 5 2.13-2.16 (d, 6H), 2.51 (s, 3H), 6.75 (bs, 2H, D20 exchangeable), 6.9 (m, 1H), 7.04 - 7.07 (m, 4H), 7.28 - 7.30 (d, 2H), 7.5 (s, 1H, D20 exchangeable), 8.0 (s, 1H, D20 exchangeable). IR (KBr) cm"1: 3458, 3317, 3140, 1675. MS m/z: 405.3 (M+).
Described 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.
Rat Carrageenan Paw Edema Test
The carrageenan paw edema test is performed as described by Winter et al (Proc.Soc.Exp.Biol.Med, 111, 544, 1962). Male Wistar rats are selected and the body weights are equivalent within each group. The rats are fasted for eighteen hours with free access to water. The rats are dosed orally with the test compound suspended in vehicle containing 0.5% methylcellulose. The control rats are administered the vehicle alone. After an hour, the rats are injected with 0.1 ml of 1% Carrageenan solution in 0.9% saline into the sub-plantar surface of the right hind paw. Paw volume is measured using water plethysmograph before and after 3 hours of carrageenan injection. The average of foot swelling in drug treated animals is compared with that of control animals. Anti-inflammatory activity is expressed as the percentage inhibition of edema compared with control group [Arzneim-Forsch/Drug Res., 43(1), 1, 44-50,1993; Otterness and Bliven, Laboratory Models for Testing NSAIDs, In Non-Steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed.1985)]. In order to evaluate their role on the ulcer formation, the animals are sacrificed and the stomach is taken out and flushed
i 1% formalin. The stomach is opened along the greater curvature. The naemorrhagic puncta and sulci are identified microscopically and images are captured. The stomach lesions are calculated.
In vitro evaluation of Cycloxygenase-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 are determined by the following method.
Human Whole Blood Assay
Human whole blood provides a protein and cell rich milieu appropriate 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 are active only after incubation of human blood with lipopolysaccharide (LPS), which induces COX-2 production in the blood.
Method
Fresh blood is collected in tubes containing potassium EDTA by vein puncture from male volunteers. The subjects should have no apparent inflammatory conditions and not taken NSAIDs for atleast 7 days prior to blood collection. Blood is treated with aspirin in vitro (10|ig/ml, at time zero) to inactivate COX-1, and then with LPS (10|ig/ml) along with test agents or vehicle. The blood is incubated for 24 h at 37 °C, after which the tubes are centrifuged, the plasma is separated and stored at -80 °C (J.Pharmacol.Exp.Ther, 271, 1705, 1994;
Proc.Natl.Acad.Sci. USA., 96, 7563, 1999). The plasma is 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 Table I.

Tumor Necrosis Factor Alpha (TNF-a)
This assay determines the effect of test compounds on the production of TNF alpha in human whole blood. TNF-alpha assay is carried out as described by Armin hatzelmann and Christian Schudt (J Pharm Exp Ther 297, 261,2001). Compounds are tested for their ability to inhibit the activity of TNF alpha in human whole blood. The test compounds are pre-incubated for 15 minutes at 37° C and then stimulated with Lipopolysaccharide (Salmonella abortus equi, 1 jug/ml) for 4 h at 37 0 C in 5% C02. The levels of TNF alpha are estimated using Enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer. (Cayman Chemical, Ann Arbor, USA). Representative results of TNF-a inhibition are shown in Table II.
1 025 43.84
3 (U 13.57
3 025 14.98
InterIeukin-6 (IL-6)
This assay determines the effect of test compounds on the production of IL-6 from human whole blood. Compounds are tested for their ability to downregulate the production of IL-6 in activated whole blood. The test compounds are pre- incubated for 15 minutes at 37° C and then stimulated with Lipopolysaccharide (Salmonella abortus equi, 1 /Jg/ml) for 4 h at 37 ° C in 5% C02. The levels of Interleukin-6 are estimated using Enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer. (Cayman Chemical, Ann Arbor, USA). Representative results of IL-6 inhibition are shown in Table III.
Table III
Example No. Cone. (p.M) IL-6 Inhibition (%)
1 1 52.57 1 10 62.20
2 1 29^8
2 10 52.94
3 1 14.19 3 10 25.30
Inhibitory Action on Adjuvant Arthritis
Compounds are assayed for their activity on rat adjuvant induced arthritis according to Theisen-Popp et al., (Agents Actions, 42, 50-55,1994). Six to seven weeks old, Wistar rats are weighed, marked and assigned to groups [a negative control group in which arthritis is not induced (non-adjuvant control), a vehicle- treated arthritis control group, test substance treated arthritis group]. Adjuvant induced arthritis is induced by an injection of Mycobacterium butyricum (Difco) suspended in liquid paraffin into the sub-plantar region of the right hind paw (J.Pharmacol.Exp.Ther., 284, 714, 1998). Body weight, contra-lateral paw volumes are measured at various days (0, 4, 14, 21) for all the groups. The test compound or vehicle is administered orally beginning post injection of adjuvant and continued for 21 days. On day 21, body weight and paw volume of both right and left hind paw, spleen, and thymus weights are determined. In addition, the radiographs of both hind paws are taken to assess the tibio-tarsal joint integrity. Hind limb below the stifle joint is removed and fixed in 1% formalin saline. At the end of the experiment, plasma samples are analysed for cytokines, interleukins and prostaglandins. The presence or absence of lesions in the stomach is also observed.
Two-factor ('treatment' and 'time') Analysis of Variance with repeated measures on 'time' is applied to the % changes for body weight and foot volumes. A post hoc Dunnett's test is conducted to compare the effect of treatments to vehicle. A one-way Analysis of Variance is 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 % inhibition in foot volumes on days 4, 14 and 21 are fitted by a 4-parameter logistic function using a nonlinear Least Squares' regression. ID50 is defined as the dose corresponding to a 50% reduction from the vehicle and is derived by interpolation from the fitted 4- parameter equation.
DTP Human Tumor Cell Line Screen Methodology Of The In Vitro Cancer Screen
The three cell lines, one-dose prescreen carried out which identifies a large proportion of the compounds that would be inactive in multi-dose 60 cell line screening. The current assay utilizes a 384 well plate format and fluorescent staining technologies resulting in greater screening capacity for testing of synthetic samples. Cell Lines
The cell lines of the cancer-screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. For a typical screening experiment, cells are inoculated into 96 well microtiter plates in 100 fiL. After cell inoculation, the microtiter plates are incubated at 37° C, 5 % C02, 95 % air and 100 % relative humidity for 24 h prior to addition of experimental drugs. The cells are plated a densities of 5000 cells/well (MCF7), 1000 cells/well (NCI-H460), and 7500 cells/well (SF-268) to allow for varying doubling time of the cell lines. Each plate contains all three cell lines, a series of dilutions of standard agents, total kill wells and appropriate controls. Plates are incubated under standard conditions for 24 hours prior to addition of experimental compounds or extracts.
Addition of Experimental Agents (Pure Compounds)
Experimental compounds are solubilized in dimethyl sulfoxide (DMSO) at 400-times the desired maximum test concentration (maximum final DMSO concentration of 0.25%) and stored frozen. Compounds are then diluted with complete media with 0.1% gentamicin sulfate (5 jj.1 of test sample in 100% DMSO is added to 565 (il of complete medium). 20 |il of this solution is then dispensed into test wells containing 50 |xl of cell suspension to yield a test concentration of 1.00E-04M.
Two standard drugs, meaning that their activities against the cell lines are well documented, are tested against each cell line: NSC 19893 (5-FU) and NSC 123127 (Adriamycin).
Endpoint Measurement
After compound addition, plates are incubated at standard conditions for 48 hours, 10 |xl/well Alamar Blue is added and the plates are incubated for an additional 4 hours. Fluorescence is measured using an excitation wavelength of 530 nm and an emission wavelength of 590 nm.
Calculation of Percent Test Cell Growth/Control (untreated) Cell Growth (T/q
Percent growth is calculated on a plate-by-plate basis for test wells relative to control wells. Percent Growth is expressed as the ratio of fluorescence of the test well to the average fluorescence of the control wells x 100.

We claim:
1. Novel condensed pyrimidones of formula (I)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions, wherein X represents O or S; Ar1 and Ar may be same or different and independently represent substituted or unsubstituted cycloalkyl, aryl, five to seven membered heteroaryl or
i
• heterocyclylgroup; R1 and R2 may be same or different and independently
I represent hydrogen, hydroxy, thiol, nitro, nitroso, formyl, azido, cyano, halo or
(substituted or unsubstituted groups selected from alkyl, halo alkyl, alkoxy, aryl,
aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl, acyl, acyloxy, cycloalkyl,
amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl,
arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl,
aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives.
Novel condensed pyrimidones as claimed in claim 1, wheirne the groups
represented by Ar1 and Ar2 are selected from substituted or unsubstituted phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, 1 tetrahydroisoquinolinyl, pyrrolidinyl, thiazolidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl.
3. Novel condensed pyrimidones as claimed in claim 1, selected from:
5,7-Diamino-3-(4-methylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5-
d]pyrimidin-4(3//)-one;
5,7-Diamino-3-(3,4-dimethylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- d]pyrimidin-4(3//)-one;
5,7-Diamino-3-[4-(methylthio)phenyl]-2-phenylpyrimido[4,5-J]pyrimidin-4(3//) one;
5,7-Diamino-3-(4-isopropylphenyl)-2-(4-methylthiophenyl)pyrimido[4,5- ]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-methoxyphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- J]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-fluorophenyl)-2-phenylpyrimido[4,5-J]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-ethylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5-
d]pyrimidin-4(3//)-one;
5,7-Diamino-3-(4-trifluoromethylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- d/]pyrimidin- 4(3//)-one;
5,7-Diamino-3-(4-chlorosulfonylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- cdpyrimidin- 4(3//)-one;
5,7-Diamino-3-(4-sulfonylaminophenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5- d]pyrimidin- 4(3H)-onc;
5,7-Diamino-3-[4-(methylthio)phenyl]-2-[4-trifluoromethylphenyl]pyrimido[4,5- ]pyrimidin-4(3//)-one;
5-Amino-7-methyl-3-(4-methylphenyl)-2-[4-(methylthio)phenyl]pyrimido[4,5-