Title of Invention

NOVEL COMPOUNDS

Abstract The present invention relates to novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and their pharmaceutically acceptable salts and compositions. The present invention more particularly provides novel pyrimidones of the general formula (I).
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 and their pharmaceutically acceptable salts and compositions. The present invention more particularly provides novel pyrimidones 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, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and their pharmaceutically acceptable salts and compositions.
The novel compounds 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-α, IL-1, IL-6, IL-lβ , IL-8 IL-12 and cyclooxygenase such as COX-2 and COX-3. The compounds of the present invention are also useful for the treatment 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; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
Background of Invention
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 proinflammatory 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 immune cells, and a large number of chronic and acute conditions have been recognized to be associated with pertrubation 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 relies at least in part on the activation of an enzyme on the cell-signaling 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 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 a/., Ann Pharmacother, 34, 743-60, 2000), have recently been approved by the U.S (FDA) as agents for the treatment of rheumatoid arthritis.

Elevated levels of TNF-ot 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-ct 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 (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 reperflision 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; it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in the U.S. Patents 6,004,813; 5,527,546 and 5,166,137.
The cytokine IL-lβ 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-iβ 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-1 (3 is associated with

numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-1 β .
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 infiltration into sites of inflammation or injury (e.g., ischemia) is mediated. Chemotactic nature of IL-8, includes, but is not limited to, the following: asthma, inflammatory bowl disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperflision 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, 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/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. Reports earlier to COXIBs development show that inhibitors of the COX-1 enzyme cause gastric ulcers, where as 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 (COXIBs) 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 of concern in the present invention.
Few prior art references, which disclose the closest compounds, are given here:
i) US Patents 5,726,124 and 5,300,477 disclose novel herbicidal compounds of formula (Ila)
R2 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaromatic group (e.g. a heteroaromatic ring structure having four to five carbon

atoms and one heteroatom selected from the group consisting of nitrogen, sulfur and
oxygen); R3 is an alkyl, haloalkyl, polyhaloalkyl, haloalkenyl, polyhaloalkenyl,
alkenyl, alkynyl, haloalkynyl, polyhaloalkynyl, alkoxyalkyl, dialkoxyalkyl,
haloalkoxyalkyl, oxoalkyl, trimethylsilylalkynyl, cyanoalkyl or aryl group; R5 is a
hydrogen, halo, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkoxyalkyl,
alkoxyimino, alkoxycarbonylalkyl, dialkoxyalkyl, formyl, haloalkyl, haloalkenyl,
haloalkynyl, haloalkoxy, hydroxyalkyl, hydroxyimino, polyhaloalkyl,
polyhaloalkenyl, polyhaloalkynyl, polyhaloalkoxy, trimethylsilylalkynyl,
alkoxyalkoxy, aminocarbonylalkyl, alkylaminocarbonylalkyl,
dialkylaminocarbonylalkyl, cyanoalkyl, hydroxy or cyano group; and ^ is a hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, haloalkylthio, polyhaloalkyl, polyhaloalkenyl, polyhaloalkynyl, polyhaloalkoxy, polyhaloalkylthio, cycloalkyl, aryl, aryloxy, heterocyclyl, aralkyl, alkylamino, dialkylamino, dialkylaminocarbonyl, or cyano group; and X is oxygen or sulfur.
An example of these compounds is shown in formula (lib)

ii) US Patent 5,474,996 discloses novel compounds of formula (lie) wherein


R5 is a single bond or ~(CH2)m —, -NH-, etc., m is an integer of 0 to 4; Y is Yi-B-Y2 is a monocyclic aryl of 5 to 6 ring member or condensed ring of 8 to 10 ring members optionally containing at least one heteroatom chosen from oxygen, nitrogen and sulfur; R10 and R11 together form oxo group; R2 is chosen from the group consisting of hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, formyl, benzoyl, acyl of 1 to 6 carbon atoms, alkyl, alkenyl, alkoxy, alkylthio of up to 10 carbon atoms, phenyl, phenoxy, naphthyl, benzyl, phenylthio, biphenyl, biphenylmethyl and indole; R3 is alkyl substituted with carboxy or esterified carboxy. An example of these compounds is shown in formula (IId)

iii) US Patents 6,420,385 and 6,410,729 disclose novel compounds of formula (IIe)
wherein

represents


X is O, S or NR5; R1 and R2 are each independently represent — Y or --Z--Y, and R3 and R4 are each independently — Z--Y or R3 is a hydrogen radical; provided that R4 is other than a substituted-aryl, (substituted-aryl)methyl or (substituted-aryl)ethyl radical; wherein each Z is independently optionally substituted alkyl, alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl; Y is independently a hydrogen; halo, cyano, nitro, etc., R5 is independently a hydrogen, optionally substituted alkyl, alkenyl, alkynyl etc., R11 and R12 each independently represent optionally substituted aryl or heteroaryl.
An example of these compounds is shown in formula (IIf)

iv) US Patent 4,771,040 discloses 6-oxopyrimidinyl(thiono)phosphate, pesticide compounds and intermediates of formula (Ilg)

wherein R2 represents hydrogen, optionally substituted alkyl, or alkoxy, alkylthio, dialkylamino or aryl; R3 represents alkyl or aryl; R4 represents hydrogen, halogen or alkyl
An example of these compounds is shown in formula (Ilh)


v) DE 2142317 discloses hypnotic uracil derivatives of formula (Hi)

wherein R1 is H, alkyl, alkenyl, dialkylaminoalkyl, or aralkyl; R2 is H, alkyl, aryl, or halogen; R3 is alkyl, alkenyl, cycloalkyl, aralkyl, aralkenyl, or aryl, R4 is alkyl, alkenyl, cycloalkyl, aralkyl, aryl, etc.
An example of these compounds is shown in formula (IIj)

vi) US Patent 5,470,975 discloses dihydropyrimidine derivatives of formula (Ilk)

wherein R1 is alkyl, alkenyl, alkynyl, cycloalkyl, NR4R5 etc., R2 is hydrogen, halogen, SR4, etc., R3 --COOR, --CONH2, CN, etc., R4 and R5 are independently

selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl etc., or R4 and R5 together with the carbon atoms to which they are attached form a carbonyl or a thiocarbonyl group; R6 is --CN, alkyl, acyloxy, S02NH2, aryl, furyl; R7 is H, halogen, etc., R8 is H, halogen, alkyl, alkoxy etc.,
An example of these compounds is shown in formula (III)

We have focused our research to identify cytokine inhibitors predominantly acting through the inhibition of tumour necrosis factor - a (TNF-a) which are devoid of any side effects normally associated with tumour necrosis factor -a (TNF-a) inhibitors. Our sustained efforts have resulted in novel compounds of the formula (I). The derivatives 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-lβ , IL-8, IL-12 and inflammation. The compounds of the present invention are also useful in 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; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
Summary of the Invention
The present invention relates to novel compounds of the formula (I)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, and their pharmaceutically acceptable salts and compositions; wherein X represents oxygen or sulfur; rings represented by A and B are selected from aryl or heteroaryl; R represents hydrogen, hydroxyl, amino, alkyl, haloalkyl; R1 and R3 may be same or different and independently represent hydrogen, SR , S(0)pR ; R and R4 may be same or different and independently represent hydrogen, hydroxyl, halogen, nitro, cyano, azido, amino, alkyl, haloalkyl, alkoxy, monoalkylamino, dialkylamino, acyl, acylamino, alkoxycarbonyl, SR5, S(0)pR6, alkoxyalkyl groups or -COR7 or carboxylic acid or its derivatives; Y represents -C(=NH)R8 or -C(=NR9)R8; Z represents -NR', -S(0)q; R5 represents hydrogen, amino, alkyl, haloalkyl, aryl, heteroaryl, acyl, arylamine, heteroarylamino, aryl-NH-CO-, aryl-NH-CS-, NH2CO-, NH2CS-,-(CH2)rOH; R5 represents hydrogen, alkyl or aryl, alkylhalide, alkylester; R6 represents amino, hydroxyl, hydrazine, halogen, alkyl, alkylhydrazine, acylhydrazide, acylamino, aryl, arylamino, heteroarylamino; R represents hydrogen, hydroxyl, amino, halogen, alkyl, haloalkyl, alkoxy, aryloxy,

alkylamino, dialkylamino, arylamino, heteroarylamino, acylamino; R8 and R9 may be same or different and independently represents hydrogen, amino, azido, halogen, monoalkylamino, dialkylamino, acylamino, arylamino groups, -NH(CH2)rOH, -NHCONH2, -NHCSNH2, -NHCSNHCOOC2H5, -NHCONH-aryl, -NHCSNH-aryl, -NHCONH-heteroaryl, -NHCSNH-heteroaryl, acyl, -CONH2, -CSNH2, -CSNHCOOC2H5.
m and n are integers in the range of 0-4; p is an integer in the range of 1-2; q is an integer in the range of 0-2; and r is an integer in the range of 1-5.
Detailed Description of the Invention
Suitable ring systems represented by A and B are selected from phenyl, naphthyl, pyridyl, thienyl, pyrimidinyl, and the like.
R represents hydrogen, hydroxyl, 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.
Suitable groups represented by R and R are selected from hydrogen, SR , or S(0)pR6.
Suitable groups represented by R and R 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 and the like; monoalkylamino groups such as NHCH3, NHC2H5, NHC3H7, and the like; dialkylamino 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; acylamino groups such as NHC(=0)CH3, NHC(00)CF3, NHC(=0)C2H5, NHC(=0)C3H7, and the like; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; SR5, or S(0)pR6; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; -COR7 or carboxylic acids or its derivatives such as esters, amides and acid halides,.
Suitable groups represented by R5 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 or naphthyl; alkylhalide groups such as -CH2C1, -CH2CH2C1 and the like; alkylester groups such as -CH2OCOC2H5, - CH2OCOC3H7 and the like.
Suitable groups represented by R6 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; acylamino groups such as NHC(=0)CH3, NHC(=0)CF3, NHC(0)C2H5, NHC(=0)C3H7, NHC(=0)C6H13 and the like; aryl groups such as phenyl or naphthyl and the like; arylamino groups such as phenyl amino, naphthyl amino and the like; heteroarylamino groups such as thienylamino, pyridylamino, pyrimidyl amino and the like.
Suitable groups represented by R 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,

trifluoromethyl, trifluoroethyl, 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; monoalkylamino groups 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; arylamino groups such as phenyl amino, naphthyl amino and the like; heteroarylamino groups such as thienylamino, pyridylamino, pyrimidyl amino and the like, acylamino group such as NHC(=0)CH3, NHC(=0)CF3, NHC(=0)C2H5, NHC(=0)C3H7, NHC(=0)C6H13 and the like.
X represents oxygen or sulfur.
Suitable groups represented by Y are selected from -C(=NH)R8 or C(=NR9)R8.
Suitable groups represented by R and R are selected from hydrogen, amino, azido, halogen atoms such as fluorine, chlorine, bromine, iodine; 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; acylamino groups such as NHC(=0)CH3, NHC(=0)CF3, NHC(=0)C2H5, NHC(=0)C3H7) NHC(=0)C6H13; arylamino groups such as phenyl amino, naphthyl amino and the like; NH(CH2)rOH groups such as NHCH2OH, NH(CH2)2OH, NH(CH2)3OH and the like; -NHCONH2, -NHCSNH2, -NHCSNHCOOC2H5, -NHCONH-aryl, -NHCSNH-aryl, -NHCONH-heteroaryl, -NHCSNH-heteroaryl, 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 and the like; other groups such as -CONH2, -CSNH2, -CSNHCOOC2H5.
Suitable groups represented by Z are selected from -NR\ -S(0)q; R5 represents hydrogen, amino, linear or branched (Q-C6) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl,

trifluoroethyl, dichloromethyl, dichloroethyl and the like; aryl groups such as phenyl, naphthyl and the like; heteroaryl groups such as pyridyl, thienyl, pyrimidinyl and the like; acyl groups such as -C(=0)CH3, -C(=0)CF3, -C(=0)C2H55 -C(=0)C3H7, -C(=S)CH3, -C(=S)CF3, -C(=S)C2H5, -C(=S)C3H7, -benzoyl and the like; arylamino groups such as phenylamine, napthylamine and the like; heteroarylamino groups such as thienylamine, pyridylamine, pyrimidylamine and the like; other derivatives such as Aryl-NH-CO-, Aryl-NH-CS-, NH2CO-, NH2CS- and the like; -(CH2)rOH groups such as -CH2OH, -(CH2)2OH, -(CH2)3OH and the like.
The groups represented by Y and Z may be substituted with the substituents selected from halogen, hydroxyl, nitro, cyano, azido, nitroso, amino, formyl, alkyl, aryl, aralkyl, haloalkyl, acyl, alkoxy, aryloxy, aralkoxy, heteroaryl, heterocyclyl, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, alkylsulfanyl, sulfamoyl, alkoxyalkyl groups or carboxylic acids or its derivatives. The substituents are as defined above.
m and n are integers in the range of 0-4; p is an integer in the range of 1-2; q is an integer in the range of 0-2; and r is an integer in the range of 1-5.
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, α-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, 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, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.

Pharmaceutically acceptable solvates may be hydrates or comprising of other solvents of crystallization such as alcohols.
Representative compounds according to the present invention include:
N-Methyl-1 -(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-
dihydropyrimidine-5-carboximidamide;
N-Methyl-l-(3,4-dimethylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-
l,6-dihydropyrimidine-5-carboximidamide;
TV-Methyl-1 -(4-isopropylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-
dihydropyrimidine-5-carboximidamide;
A^Methyl-l-(3,4,5-trimethoxyphenyl)«4-(methylthio)-2-[4-(methylthio)phenyl]-
oxo-1,6-dihydropyrimidine-5-carboximidamide;
TV-Methyl-1 -(4-ethylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-
dihydropyrimidine-5-carboximidamide;
1 -(4-Methoxyphenyl)-N-methyl-4-(methylthio)-6-oxo-2-pyridin-3-yl-1,6-
dihydropyrimidine-5-carboximidamide;
1 -(4-Fluorophenyl)-N--methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl-1,6-
dihydropyrimidine-5-carboximidamide;
TV-Methyl-1 -(3,4-dimethylphenyl)-4-(methylamino)-2- [4-(methylthio)phenyl] -6-oxo-
l,6-dihydropyrimidine-5-carboximidamide;
1 -(4-Chlorophenyl)-N-methyl-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-
dihydropyrimidine-5-carboximidamide;
N-Methyl-4-(methylthio)-l-[4-(methylthio)phenyl]-6-oxo-2-[4-
(trifluoromethyl)phenyl]-1,6-dihydropyrimidine-5-carboximidamide;
N-Methyl-4-(methylthio)-1 -[4-(methylthio)phenyl]-6-oxo-2-phenyl-1,6-
dihydropyrimidine-5-carboximidamide;

1 -(4-Fluorophenyl)-N-methyl-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-
dihydropyrimidine-5-carboximidamide;
2-(4-Fluorophenyl)-N-methyl-4-(methylthio)-1 - [4-(methylthio)phenyl]-6-oxo-l,6-
dihydropyrimidine-5-carboximidamide;
2-(4-Methoxyphenyl)-N-methyl-4-(methylthio)-1-[4-(methylthio)phenyl]-6-oxo-1,6-
dihydropyrimidine-5-carboximidamide;
1 -(4-Methoxyphenyl)-N-methyl-4-(methylamino)-6-oxo-2-pyridin-3-yl-1,6-
dihydropyrimidine-5-carboximidamide;
1 -(4-Ethylphenyl)-N-methyl-4-(methylamino)-6-oxo-2-pyridin-3-yl-1,6-
dihydropyrimidine-5-carboximidamide;
1 -(3,4-Dimethylphenyl)-N-methyl-4-(methylamino)-6-oxo-2-pyridin-4-yl-1,6-
dihydropyrimidine-5-carboximidamide;
N-(2-Hydroxyethyl)-4-[(2-hydroxyethyl)amino]-6-oxo-l-(3,4-dimethylphenyl-2-
pyridin-3-yl-1,6-dihydropyrimidine-5-carboximidamide;
1 -(4-Chlorophenyl)-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl-1,6-
dihydropyrimidine-5-carboximidamide;
N-(2-Hydroxyethyl)-2-[4-(dimethylammo)phenyl]-4-(methylthio)-6-oxo-l-(3,4-
dimethylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
n-Methyl-l-[4-(methylthio)phenyl]-4-(methylthio)-2-[4-methylthio)phenyl
l,6-dihydropyrimidine-5-carboximidamide;
2-[4-(Aminosulfonyl)phenyl]-n-methyl-4-(methylthio)-6-oxo-1 -phenyl-1 ,6-
dihydropyrimidine-5-carboximidamide;
2-[4-(Aminosulfonyl)phenyl]-n-methyl-4-(methylthio)-6-oxo-l-(4-methylphe^
l,6-dihydropyrimidine-5-carboximidamide;
2-[4-(Aminosulfonyl)phenyl]-n-methyl-4-(methylthio)-6-oxo-1 -(3,4-
dimethylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;

2-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-1-(4-fluorophenyl)-
l,6-dihydropyrimidine-5-carboximidamide;
1 -[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-phenyl-1,6-
dihydropyrimidine-5-carboximidamide;
l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-(4-methylphenyl)-
l,6-dihydropyrimidine-5-carboximidamide;
l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-(3,4-
dimethylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-(4-isopropylphenyl)-
l,6-dihydropyrimidine-5-carboximidamide;
1 -[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-pyridin-3-yl-1 ,6-
dihydropyrimidine-5-carboximidamide;
1 -[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl-1,6-
dihydropyrimidine-5-carboximidamide;
1 -[4-(Hydrazinosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl« 1,6-
dihydropyrimidine-5-carboximidamide;
l-[4-(Hydrazinosulfonyl)phenyl]-N-methyl-4-(methylamino)-6-oxo-2-pyridin-4-yl-
l,6-dihydropyrimidine-5-carboximidamide;
1 -(4-Methoxyphenyl)-iV-methyl-4-( 1 -methylhydrazino)-6-oxo-2-pyridin-4-yl-1,6-
dihydropyrimidine-5-carboximidamide and
2-(4-Mehtylthiophenyl)-N-methyl-4-( 1 -methylhydrazino)-1 -(4-methylphenyl)-6-oxo-
l,6-dihydropyrimidine-5-carboximidamide;
According to another embodiment of the present invention, there is provided a process for the preparation of novel pyrimidones of the formula (I) wherein all symbols are as defined earlier.

i) Reaction of the compound of formula (la) as disclosed in our US Patent 2004/0259891, with amines or hydrazines as defined above gave a compound of formula (I) wherein all symbols are as defined above according to scheme 1.

The reaction of the compound of formula (la) with amines / hydrazines may be carried out using appropriate solvents like toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, pyridine, ethanol, methanol, isopropylalcohol, tert-butylalchol, acetic acid, propionic acid etc, or a mixture thereof or even in the absence of solvents by neat reactions. The condensation reaction may be carried out under acidic conditions using mineral or organic acids, or basic conditions viz. carbonates, bicarbonates, hydrides, hydroxides, alkyls and alkoxides of alkali metals and alkaline earth metals. The reaction may be 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 reflux conditions, and for period in the range of 30 minutes to 20 hours. The final product may be purified by using chromatographic techniques or by recrystallization
According to yet another embodiment of the present invention there is
provided a process for the conversion of novel pyrimidones of the formula (I)
i 3
[wherein any of the groups Z or Y or R or R represent an amino functional group]

to novel pyrimidones of the formula (I) wherein any of the groups Z or Y represent -NHCONH2, -NHCSNH2, -NHCONH-aryl, -NHCONH-heteroaryl, NHCSNHCOOC2H5 by using alkylisothiocyanate or alkylisocyante or arylisocyanate or alkylisocyanate and the like. The reactions may be carried out according to the procedure given in the scheme 1.
According to yet another embodiment of the present invention there is provided a process for the conversion of novel pyrimidones of the formula (I) [wherein any of the groups R or R represent SR , wherein R represents hydrogen alkyl or aryl and wherein Z represents S(0)qR, R represents hydrogen, alkyl or aryl wherein q is an integer of "zero"] to novel pyrimidones of the formula (I), [wherein
any of the groups R or R represent S(0)pR , wherein p represents 1 or 2, and R represents alkyl or aryl; and wherein Z represents S(0)qR, and R represents hydrogen, alkyl or aryl, wherein q is an integer of 1 to 3]; by using a suitable oxidizing agent. The oxidizing agent may be selected from potassium peroxymonosulfate (Oxone), hydrogen peroxide, tert-butylperoxide, Jones reagent, peracids [e.g peracetic acid, perbenzoic acid, m-chloroperbenzoic acid etc], chromic acid, potassium permanganate, alkali metal periodates [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 such as, methanol, ethanol, isopropanol and the like or a mixture thereof. The reaction is usually carried out under cooling to reflux conditions.
According to yet another embodiment of the present invention there is provided a process for the conversion of novel pyrimidones of the formula (I) [wherein any of the groups Z or R or R represent SR , wherein R represents alkyl]

1 T
to novel pyrimidones of the formula (I) [wherein any of the groups Z or R or R represents -SCH2C1] by using sulfurylchloride under conventional conditions.
According to yet another embodiment of the present invention there is provided a process for the conversion of novel pyrimidones of the formula (I) [wherein Z, R or R represent S(0)pR , wherein p is 1 or 2, R represents alkyl or aryl] to novel pyrimidones of the formula (I) [wherein R or R represent S(0)PR , wherein p is an integer of 1 or 2, and R6 represents an amino group], by using the procedure described in literature (Huang et.aL Tetrahedron Lett, 39, 7201, 1994).
Alternatively, a process for the preparation of novel pyrimidones of the formula (I), wherein either of R1 or R3 represent S(0)pR65 wherein R6 represents an amino group and p represents an integer of 1 or 2 and all the other symbols are as defined earlier, comprises, reaction of the compound of formula (II) [wherein all the symbols are as defined earlier and wherein either of R or R represents hydrogen] with chlorosulfonic acid and ammonia


The reaction of compound of formula (II) with chlorosulfonic acid and ammonia may be carried out in the presence of solvents such as acetic acid, dichloromethane, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, water, an alcohol and the like or a mixture thereof or in absence of solvents. The reaction may be carried out at a temperature in the range of 0°C to reflux temperature for period in the range of 2 to 24 hours.
It is appreciated that in any of the above-mentioned reactions, any reactive group in the substrate molecule may be protected according to the 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 appropriate to the molecule being protected.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, 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 also be used. Organic bases such as diethanolamine, ct-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts may also be used. 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 hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric 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 diastereomeric salts formed with chiral acids such as mandelic acid,

camphorsulfonic acid, tartaric acid, lactic acid, and the like, wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compound of formula (I) may be converted to a 1:1 mixture of diastereomeric amides by treatment with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert an acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of the compound of formula (I) may be prepared by hydrolysing the pure diastereomeric amides.
Various polymorphs of the compound of general formula (I) forming a part of this invention may be prepared by crystallization of the compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling, during crystallizations. Polymorphs can be obtained by heating or melting the compound followed by cooling gradually or immediately. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or such other techniques.
The present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of inflammation, arthritis, pain, fever, psoriasis, 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, aerosols, suspensions and the like, may contain flavoring agents, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of the active compound, the remainder of the composition being the pharmaceutically acceptable carriers, diluents or solvents.
The invention is explained in details in the examples given below which are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1:
Synthesis of 7V-methyl-l-(4-methylphenyl)-4-(methylthio)-2-[4-
(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide

Methylamine solution (30ml, 40% aqueous solution) was added to 5-cyano-l-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine (Ig, 2.63mmol, prepared according to the procedure disclosed in our US Patent 2004-259891) at ambient temperature and under stirring. The reaction, when complete, as confirmed by TLC using ethyl acetate: hexane (1:1), was poured onto ice, and the solid obtained was filtered and purified by recrystallization to give the title compound 0.28g, yield 25.8%, purity 98% by HPLC, m.p. 196 - 198°C. 1H-

NMR (CDCI3) 5 (ppm): 2.17(s, 3H), 2.31(s, 3H), 2.54(s, 3H), 3.35 - 3.41 (d, 3H), 6.7
(s, 1H, D20 exchangeable), 7.10 - 7.12 (d, 2H), 7.31 - 7.34 (d, 2H), 7.47 - 7.5 (d,
2H), 7.61 - 7.63 (d, 2H), 13.2 (s, 1H, 1H, D20 exchangeable). IR (KBr) cm"1: 3436,
1649, and 1595. MS m/z: 411.2 (M++l).
Example 2:
Synthesis of N-methyl-l-(3,4-dimethyIphenyl)-4-(methyIthio)-2-[4-
(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide.

Methylamine solution (30ml, 40% aqueous solution) was added to 5-cyano-l-(3,4-dimethylphenyl)-4-(methylthio)-6-oxo-2-pyridin-3-yl-l,6-dihydropyrimidine (0.5g, 1.27mmol, prepared as described in example 4) , at an ambient temperature, and under stirring. The reaction was further followed up according to the procedure described in the example 3 to yield the title compound 0.14g, yield 26.02%, purity 93.8% by HPLC, m.p.: 205 - 207°C. !H-NMR (CDC13) § (ppm): 2.22 - 2.25 (d, 6H), 2.4 (s, 3H), 2.54 (s, 3H), 3.43 (s, 3H), 6.6 (s, 1H, D20 exchangeable), 7.05 - 7.07 (d, 1H), 7.32 - 7.34 (d, 2H), 7.42 - 7.44 (d, 1H), 7.48 - 7.5 (d, 2H), 7.58 (s, 1H), 13.7 (s, 1H, D20 exchangeable). IR (KBr) cm'1: 3331, 1648, and 1595. MS m/z: 425.2 (M++l). Example 3:
Synthesis of N-methyl-l-(3,4-dimethylphenyl)-4-(methylthio)-2-[4-
(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide.


Methylamine solution (30ml, 40% aqueous solution) was added to 5-cyano-l-(4-isopropylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl] -6-oxo-l,6-dihydropyrimidine (3g, 7.36mmol, prepared as described in example 4), at an ambient temperature, and under stirring. The reaction was further followed up according to the procedure described in example 3 to yield the title compound 0.78g, yield 24.16%, purity 98.3% by HPLC, m.p.: 193 - 195°C. 'H-NMR (CDC13) 6 (ppm): 1.22 - 1.26 (d, 6H), 2.39 (s, 3H), 2.54(s, 3H), 2.84 - 2.91 (m, 1H), 3.4 (s, 3H), 6.55 (s, 1H, D20 exchangeable), 7.15 - 7.18 (d, 2H), 7.31 - 7.33 (d, 2H), 7.47 - 7.49 (d, 2H), 7.63 - 7.65 (d, 2H), 13.73 (s, 1H, D20 exchangeable). IR (KBr) cm"1: 3435, 1590. MS m/z: 439.2 (M++l). Example 4:
Synthesis of ALmethyl-l-(3,4,5-trimethoxyphenyl)-4-(methyIthio)-2-[4-
(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide.

Methylamine solution (30ml, 40% aqueous solution) was added to 5-cyano-l-(3,4,5-trimethoxyphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine (0.5g, 1.09mmol, prepared as described in example 4), at an ambient temperature, and under stirring. The reaction was further followed up

according to the procedure described in the example 3 to yield the title compound
0.2g, yield 37.45 %, purity 96.4% by HPLC, m.p.: 214 - 218°C. !H-NMR (CDC13) 8
(ppm): 2.42 (s, 3H), 2.55 (s, 3H), 3.44 (s, 3H), 3.82 (s, 3H), 3.89 (s, 6H), 7.05 (s,
2H), 7.33 - 7.35 (d, 2H), 7.5 - 7.52 (d, 2H), 13.8 (s, 1H, D20 exchangeable). IR
(KBr) cm"1: 3435, 1602. MS m/z: 487 (M++l).
Example 5:
General procedure for the preparation of the compounds given in the Table 1
To the suspension or solution of l,2-diaryl-5-cyano-4-methylthio-l,6-dihydro-pyrimidin-6-one (prepared according to the procedure disclosed in our US Patent 2004/0259891) in appropriate solvents like dimethylformamide / ethanol / tetrahydrofuran/ water was added 3 to 10 molar quatities of methylamine / ethanolamine under stirring at a temperature in the range of ambient to reflux, and in the presence or absence of a catalytical amount of anhydrous potassium carbonate. The reaction mass was stirred until completion of reaction (as confirmed by TLC), and subsequently, the resultant solid that separated out was filtered, washed with water and dried to yield the crude product, which was purified by column chromatography to yield the title compounds.
The following compounds were prepared by the general procedure given in the Example 5












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.
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 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 the COX-2 enzyme. This correlates 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 lipopolysaccharide (LPS), which induces COX-2 production in the blood.
Fresh blood was collected in tubes containing sodium heparin, 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 prior to the blood collection. Blood was preincubated with aspirin in vitro (12(ig/ml, at

time zero) to inactivate COX-1 for 6 hours. Then test compounds (at various concentrations) or vehicle were added to blood. After that blood was stimulated with LPS B:4 (10 μ g/ml) and incubated for another 18 hours at 37 °C water bath. After which the blood was centrifuged, 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).
COX-1 and COX-2 enzyme based assay
COX-1 and COX-2 enzyme based assays were carried out to check the inhibitory potential of the test compounds on the production of prostaglandin by purified 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 COX 1/COX-2 in the presence or absence of the test compound. The reaction was carried out at 37°C and after 2 minutes it was stopped by adding 1M HC1. The intermediate product PGH2 was converted to a stable prostanoid product PGF2a by SnC12 reduction. The amount of PGF2ce 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 Table I.


In vitro measurement of Tumor Necrosis Factor Alpha (TNF- a)
This assay determines the effect of the test compounds on the production of TNF a in human Peripheral Blood Mononuclear Cells (PBMC). Compounds were tested for their ability to inhibit the activity of TNF a in human PBMC. PBMC were
rTy\Jf
isolated from blood (of 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 Lipopolysaccharide (Escherichia colt B4; 1 |ig/ml) for 18 hours at 37° C in 5% C02. The levels of TNFa 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 (Cayman Chemical, Ann Arbor, USA). Representative results of TNF-a inhibition are shown in Table II.



In vitro measurement of Interleukin-6 (IL-6)
This assay determines the effect of the test compounds on the production of IL-6 in human PBMC (Physiol. Res. 52: 593-598, 2003). Compounds were tested for their ability to inhibit the activity of IL-6 in human PBMC. PBMC were isolated
rT"f\ K
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 Lipopolysaccharide {Escherichia colt B4; 1 μ g/ml) for 18 h at 37 ° C in 5% C02. The levels of IL-6 in cell culture medium were 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.


Carrageenan induced Paw Edema test in Rats
The carrageenan paw edema test was performed as described 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 18 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 control 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 right 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 the 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)].
Ulcerogenic potential
In order to evaluate the compound's role on the ulcer formation, the animals were sacrificed and the stomach was taken out and flushed with 1% formalin. Animals (male wistar 200gm) were fasted for 18 hours with 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 the test compounds, all the animals were sacrificed by cervical dislocation. The stomach was dissected carefully and filled up with a sterile saline

solution and embedded in 6% formalin solution. Finally the stomach was cut longnitudinaly and the ulcer lesions were observed with a computerized stereomicroscope. The test compound treated groups were compared with the vehicle treated groups. Doses selected: 50, 100, 200mg/kg (Marco Romano et al, Journal of clinical Investigation, 1992; 2409-2421.)
Inhibitory Action on Adjuvant Arthritis in rats
Compounds were assayed for their activity on rat adjuvant induced arthritis 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 arthritis was not induced (non-adjuvant control), a vehicle-treated arthritis control group, test substance treated arthritis group]. Adjuvant induced arthritis was induced by an injection of 0.1ml of Mycobacterium butyricum (Difco) suspended in mineral oil (5mg/ml) into the sub-plantar region of the right hind paw (J.Pharmacol.Exp.Ther., 284, 714, 1998). Body weight, paw volumes were measured at various days (0, 4, 14, 21) for all the groups. The test compound or the vehicle was administered orally, beginning post injection of adjuvant ('0'day) and continued for 21 days (pretreatment group). In the post treatment group, the test compound or the vehicle was administered starting from day 14th to 21st. On day 21, the body weight and paw volume of both the right 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 integrity. Hind limb below the stifle joint was removed and fixed in 1% formalin saline for the histopathological assessment. At the end of the experiment, the serum samples were analysed for inflammatory mediators. The presence or absence of lesions in the stomach was also observed.

Two-factor ('treatment' and 'time') analysis of variance with repeated measures on 'time' 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 variance 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 derived 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 described by Les sekut et al (J Lab Clin Med 1994; 124:813-20). Female Swiss albino mice were selected and their body weights were 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 500jag of Lipopolysaccharide {Escherichia coli, LPS: B4 from Sigma) in phosphate buffer saline solution into the intraperitoneal cavity of the mice. After 90 minutes of LPS administration, the mice were bled via retro-orbital sinus puncture, and the blood samples were stored overnight at 4°C. The serum samples were collected by centrifuging the samples at 4000rpm for 15 minutes at 4°C. Immediately the serum samples were analysed for TNF-ct levels using commercially available mouse TNF-a ELISA kit (Amersham Biosciences) and an assay was performed as per the

manufacturer instruction. Representative results of TNF-α inhibition are shown in Table IV.

Anti-cancer screen:
Experimental 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 μ L 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 (To). Addition of experimental drugs:
Following 24-hour incubation, experimental drugs are added to the 96 well plates. Each plate contains one of the above cell lines and the following in triplicate: five different concentrations (0.01, 0.1, 1, 10 and 100 μ M) of four different compounds, appropriate 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. Serial dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 JIL

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 triplicate. 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 ^iL 3-(4,5-Dimethyl-2-thiazolyl)-255-diphenyl-2H-tetrazolium (MTT) solution per well and a subsequent incubation at 37°C, 5% CO2, 95% air and 100% relative humidity, protected from light. After 4 hours, the well contents are aspirated carefully followed by addition of 150 JIL DMSO per well. The plates are agitated to ensure solution of the formazan crystals in DMSO 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 right 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 experimental 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 V.





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

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, and their pharmaceutically acceptable salts and compositions; wherein X represents oxygen or sulfur; rings represented by A and B are selected from aryl or heteroaryl; R represents hydrogen, hydroxyl, amino, alkyl, haloalkyl; R and R may be same or different and independently represent hydrogen, SR , S(0)pR ; R and R4 may be same or different and independently represent hydrogen, hydroxyl, halogen, nitro, cyano, azido, amino, alkyl, haloalkyl, alkoxy, monoalkylamino, dialkylamino, acyl, acylamino, alkoxycarbonyl, SR5, S(0)pR6, alkoxyalkyl groups or -COR7 or carboxylic acid or its derivatives; Y represents -C(=NH)R8 or -C(=NR9)R8 ;Z represents -NR', -S(0)q; R' represents hydrogen, amino, alkyl, haloalkyl, aryl, heteroaryl, acyl, arylamine, heteroarylamino, aryl-NH-CO-, aryl-NH-CS-, NH2CO-, NH2CS-,-(CH2)rOH; R5 represents hydrogen, alkyl or aryl, alkylhalide, alkylester; R6 represents amino, hydroxyl, hydrazine, halogen, alkyl, alkylhydrazine, acylhydrazide, acylamino, aryl, arylamino, heteroarylamino; R represents hydrogen, hydroxyl, amino, halogen, alkyl, haloalkyl, alkoxy, aryloxy, alkylamino, dialkylamino, arylamino, heteroarylamino, acylamino; R and R may be same or different and independently represents hydrogen, amino, azido, halogen, monoalkylamino, dialkylamino, acylamino, arylamino groups, -NH(CH2)rOH, -NHCONH2, -NHCSNH2, -NHCSNHCOOC2H5, -NHCONH-aryl, -NHCSNH-aryl, -

NHCONH-heteroaryl, -NHCSNH-heteroaryl, acyl, -CONH2, -CSNH2, -
CSNHCOOC2H5.
m and n are integers in the range of 0-4; p is an integer in the range of 1-2; q is an
integer in the range of 0-2; and r is an integer in the range of 1-5.
2. Novel compounds as claimed in calim 1, wherein groups represented by A and B are selected from aryl groups such as phenyl or naphthyl, the aryl group may be substituted; heteroaryl groups may be mono or fused systems such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazine, piperazine, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as pyrrolidinyl, fhiazolidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like, the heterocyclyl group may be substituted.
3. Novel compounds as claimed in claim 1, are selected from:
1.N-Methyl-1 -(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboximidamide;
2. A^-Methyl-l-(3,4-dimethylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide;
3. TV-Methyl-1 -(4-isopropylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide;
4. N-Methyl-l-(3,4,5-trimethoxyphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboximidamide;
5. N-Methyl-1 -(4-ethylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboximidamide;

6. 1 -(4-Methoxyphenyl)-N-methyl-4-(methylthio)-6-oxo-2-pyridin-3-yl-1 ,6-dihydropyrimidine-5-carboximidamide;
7. 1 -(4-Fluorophenyl)-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl- 1,6-dihydropyrimidine-5-carboximidamide;
8. N-Methyl-l-(3,4-dimethylphenyl)-4-(methylamino)-2-[4-(methylthio)phenyl]-^ oxo-1,6-dihydropyrimidine-5-carboximidamide;
9. l-(4-Chlorophenyl)-N-methyl-4-(methylthio)-2-[4-(methylthio)phen dihydropyrimidine-5-carboximidamide;

10. N-Methyl-4-(methylthio)-l-[4-(methylthio)phenyl]-6-oxo-2-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidine-5-carboximidamide;
11. N-Methyl-4-(methylthio)-1 -[4-(methylthio)phenyl]-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboximidamide;
12. l-(4-Fluorophenyl)-N-methyl-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide;
13. 2-(4-Fluorophenyl)-N-methyl-4-(methylthio)-l-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide;

14. 2-(4-Methoxyphenyl)-N-methyl-4-(methylthio)-l-[4-(methylthio)phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide;
15. 1 -(4-Methoxyphenyl)-N-methyl-4-(methylamino)-6-oxo-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboximidamide;
16. 1 -(4-Ethylphenyl)-N-methyl-4-(methylamino)-6-oxo-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboximidamide;
17. 1 -(3,4-Dimethylphenyl)-N-methyl-4-(methylamino)-6-oxo-2-pyridin-4-yl-1,6-dihydropyrimidine-5-carboximidamide;
18. N-(2-Hydroxyethyl)-4-[(2-hydroxyethyl)amino]-6-oxo-l-(3,4-dimethylphenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboximidamide;

19. 1 -(4-Chlorophenyl)-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl-1,6-dihydropyrimidine-5-carboximidamide;
20. N-(2-Hydroxyethyl)-2-[4-(dimethylamino)phenyl]-4-(methylthio)-6-oxo-1-(3,4-dimethylphenyl)-l,6-dihydropyrimidine-5-carboximidamide;
21. N-Methyl-1 - [4-(methylthio)phenyl] -4-(methylthio)-2- [4-(methylthio)phenyl] -6-oxo-1,6-dihydropyrimidine-5-carboximidamide;
22. 2-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-1 -phenyl-1,6-dihydropyrimidine-5-carboximidamide;
23. 2-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-l-(4-methylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
24. 2-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-1 -(3,4-dimethylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
25. 2-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-l-(4-fluorophenyl)-1,6-dihydropyrimidine-5-carboximidamide;
26. 1 -[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboximidamide;

27. l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-(4-methylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
28. l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-(3,4-dimethylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
29. l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-(4-isopropylphenyl)-1,6-dihydropyrimidine-5-carboximidamide;
30. l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-pyridin-3-yl-l,6-dihydropyrimidine-5-carboximidamide;
31. l-[4-(Aminosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-y^ l,6-dihydropyrimidine-5-carboximidamide;

32. l-[4-(Hydrazinosulfonyl)phenyl]-N-methyl-4-(methylthio)-6-oxo-2-pyridin-4-yl-1,6-dihydropyrimidine-5-carboximidamide;
33. l-[4-(Hydrazinosulfonyl)phenyl]-n-methyl-4-(methylamino)-6-oxo-2-pyridin-4-yl-1,6-dihydropyrimidine-5-carboximidamide;
34. 1 -(4-Methoxyphenyl)-N-methyl-4-( 1 -methylhydrazino)-6-oxo-2-pyridin-4-yl-1,6-dihydropyrimidine-5-carboximidamide and
35. 2-(4-Mehtylthiophenyl)-N-methyl-4-( 1 -methylhydrazino)-1 -(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboximidamide.
4. A pharmaceutical composition, which comprises a compound of formula (I)

as defined in the claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
5. A pharmaceutical composition as claimed in the claim 4, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension.
6. Use of a compound of formula (I) as claimed in the claim 1, for the prophylaxis or treatment of inflammation, rheumatoid arthritis, osteoporosis, uveititis, acute and chronic myelogenous leukemia, atherosclerosis, cancer, pancreatic (3 cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome (ARDS) and asthma.

7. Use of a compound as claimed in the claim 6 for inhibiting production of cytokines as selected from TNF-a, IL-1, IL-6, IL-8 and IL-12.


Documents:

0682-che-2005-abstract.pdf

0682-che-2005-claims.pdf

0682-che-2005-correspondnece-others.pdf

0682-che-2005-description(complete).pdf

0682-che-2005-description(provisional).pdf

0682-che-2005-form 1.pdf

0682-che-2005-form 26.pdf

0682-che-2005-form 5.pdf

0682-che-2005-form 6.pdf

0682-che-2005-others.pdf

682-CHE-2005 CORRESPONDENCE OTHERS 19-10-2010.pdf

682-CHE-2005 AMANDED CLAIMS 02-02-2010.pdf

682-CHE-2005 CORRESPONDENCE-OTHERS 02-02-2010.pdf

682-CHE-2005 EXAMINATION REPORT REPLY RECIEVED 26-08-2009.pdf

682-CHE-2005 FORM-2 26-08-2009.pdf

682-CHE-2005 PCT 26-08-2009.pdf

abs-682-che-2005.jpg

abs-682.jpg


Patent Number 239399
Indian Patent Application Number 682/CHE/2005
PG Journal Number 13/2010
Publication Date 26-Mar-2010
Grant Date 17-Mar-2010
Date of Filing 03-Jun-2005
Name of Patentee ORCHID RESEARCH LABORATORIES LTD
Applicant Address ORCHID TOWER 131 VALLURVAR KOTTAM HIGH ROAD NUNGAMBAKKAM CHENNAI 600 037
Inventors:
# Inventor's Name Inventor's Address
1 PAWAN AGGARWAL ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
2 RAVIKUMAR TADIPARTHI ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
3 GADDAM OM REDDY ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
4 VENKATESAN PARAMESWARAN ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119, TAMILNADU, INDIA
PCT International Classification Number A61K 31/505
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA