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WO2006129181A2 - Nouveaux composes - Google Patents

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Publication number
WO2006129181A2
WO2006129181A2 PCT/IB2006/001448 IB2006001448W WO2006129181A2 WO 2006129181 A2 WO2006129181 A2 WO 2006129181A2 IB 2006001448 W IB2006001448 W IB 2006001448W WO 2006129181 A2 WO2006129181 A2 WO 2006129181A2
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WO
WIPO (PCT)
Prior art keywords
methylthio
oxo
carboximidamide
dihydropyrimidine
methyl
Prior art date
Application number
PCT/IB2006/001448
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English (en)
Other versions
WO2006129181A3 (fr
Inventor
Ravikumar Tadiparthi
Pawan Aggarwal
Gaddam Om Reddy
Venkatesan Parameswaran
Sriram Rajagopal
Sankaranarayanan Raghuveeraswaminathan
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Orchid Research Laboratories Limited
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Publication date
Application filed by Orchid Research Laboratories Limited filed Critical Orchid Research Laboratories Limited
Publication of WO2006129181A2 publication Critical patent/WO2006129181A2/fr
Publication of WO2006129181A3 publication Critical patent/WO2006129181A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • novel compounds of the present invention are useful for the treatment of inflammation and immunological diseases.
  • the compounds of the present invention are useful for the treatment of inflammation and immunological diseases those mediated by cytokines such as TNF- ⁇ , IL-I, IL-6, IL-l ⁇ , 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 ⁇ 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.
  • ARDS adult respiratory distress syndrome
  • psoriasis Crohn's
  • 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.
  • macrophages make IL-I, IL-12 and TNF- ⁇ , all of which are potent pro-inflammatory molecules and also provide help for T cells.
  • cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells.
  • enzymes such as cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3)
  • iNOS inducible nitric oxide synthase
  • Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN ⁇ ). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
  • PTKs phosphotyrosine kinases
  • 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-I, 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-I 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- ⁇ ) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF- ⁇ is a polypeptide hormone released by activated macrophages and other cells.
  • TNF- ⁇ 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).
  • TNF- ⁇ 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- ⁇ 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.
  • TNF- ⁇ mediates the cytokine cascade that leads to joint damage and destruction (Arend et al, Arthritis Rheum, 38, 151-60, 1995).
  • Inhibitors of TNF- ⁇ including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21, 75-87, 1999) and anti-TNF- ⁇ antibody (infliximab) (Luong et al, 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- ⁇ 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- ⁇ and/or IL-I 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 ⁇ 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.
  • ARDS adult respiratory distress syndrome
  • TNF- ⁇ HIV-I, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-I, HSV-2), and herpes zoster are also exacerbated by TNF- ⁇ .
  • CMV cytomegalovirus
  • HSV-I, HSV-2 herpes viruses
  • herpes zoster herpes zoster
  • the cytokine IL- l ⁇ 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- l ⁇ 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-I ⁇ is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-I ⁇ .
  • IL-I is a more potent inducer of stromelysin than TNF- ⁇ . (Firestein, Am. J. Pathol. 140, 1309, 1992). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed.
  • IL-8 chemokines
  • adhesion molecules e.g., IL-8
  • IL-8 chemokines
  • adhesion molecules e.g., IL-8
  • both IL-I and TNF- ⁇ induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints.
  • 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 reperfusion injury, thrombosis and glomerulonephritis.
  • IL-8 has also has ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to, diminish neutrophil infiltration.
  • Cyclooxygenase enzyme exists in three isoforms, namely, COX-I, COX-2 and COX-3.
  • COX-I enzyme is essential and primarily responsible for the regulation of gastric fluids whereas C0X-2 enzyme is present at the basal levels and is reported to have a major role in the prostaglandin synthesis for inflammatory response.
  • C0X-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
  • C0X-2 enzyme inflammation and its related disorders can be treated.
  • C0X-3 possesses glycosylation-dependent cyclooxygenase activity.
  • Comparison of canine COX-3 activity with murine COX-I 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.
  • analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone
  • inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
  • R 2 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);
  • R 3 is an alkyl, haloalkyl, polyhaloalkyl, haloalkenyl, polyhaloalkenyl, alkenyl, alkynyl, haloalkynyl, polyhaloalkynyl, alkoxyalkyl, dialkoxyalkyl, haloalkoxyalkyl, oxoalkyl, trimethylsilylalkynyl, cyanoalkyl or aryl group;
  • Rs is a hydrogen, halo, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkoxyalkyl, alkoxyimino, al
  • R 5 is a single bond or — (CH 2 ) m --, -NH-, etc., m is an integer of 0 to 4;
  • Y is Yj-B-Y 2 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; Rio and Rn together form oxo group;
  • R 2 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;
  • R 3 is alkyl substituted with carboxy or esterified carboxy.
  • Hf is an example of these compounds.
  • R 2 represents hydrogen, optionally substituted alkyl, or alkoxy, alkylthio, dialkylamino or aryl
  • R3 represents alkyl or aryl
  • R 4 represents hydrogen, halogen or alkyl
  • R 1 is H, alkyl, alkenyl, dialkylaminoalkyl, or aralkyl
  • R 2 is H, alkyl, aryl, or halogen
  • R 3 is alkyl, alkenyl, cycloalkyl, aralkyl, aralkenyl, or aryl
  • R 4 is alkyl, alkenyl, cycloalkyl, aralkyl, aryl, etc.
  • US Patent 5,470,975 discloses dihydropyrimidine derivatives of formula (Ilk) 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.
  • formula (Ilk) osteoarthritis
  • rheumatoid spondylitis gouty arthritis
  • inflammatory bowel disease e.gouty arthritis
  • ARDS adult respiratory distress syndrome
  • psoriasis psoriasis
  • Crohn's disease psoriasis
  • the present invention relates to novel compounds of the formula (I)
  • 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 1 and R 3 may be same or different and independently represent hydrogen, SR 5 , S(O) P R 6
  • R 2 and R 4 may be same or different and independently represent hydrogen, hydroxyl, halogen, nitro, cyano, azido, amino, alkyl, haloalkyl, alkoxy, monoalkylamino, dialkylamino, acyl, acylamino, alkoxycarbonyl
  • SR 5 , S(O) P R 6 alkoxyalkyl groups or -COR 7 or carboxylic acid or its derivatives
  • the derivatives may be useful in the treatment of inflammation and immunological diseases.
  • the compounds of the present invention are useful for the treatment of immunological diseases those mediated by cytokines such as TNF- ⁇ , IL-I, IL-6, IL-I ⁇ , 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 ⁇ -cell destruction; NHCSNHCOOC 2 H 5 , -NHCONH-aryl, -NHCSNH-aryl, -NHCONH-heteroaryl, - NHCSNH-heteroaryl, acyl, -CONH 2 , -CSNH 2 , -CSNHCOOC 2 H 5 .
  • 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.
  • Suitable ring systems represented by A and B are selected from phenyl, naphthyl, pyridyl, thienyl, pyrimidinyl, and the like.
  • R represents hydrogen, hydroxy 1, amino, linear or branched (Ci-C 4 ) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloroniethyl, dichloroethyl and the like.
  • Suitable groups represented by R 1 and R 3 are selected from hydrogen, SR 5 , or S(O) P R 6 .
  • Suitable groups represented by R 2 and R 4 are selected from hydrogen, hydroxyl, halogen atoms such as fluorine, chlorine, bromine, iodine; hydroxyl, nitro, cyano, azido, amino, linear or branched (Ci-C 4 ) 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 (Cj-C ⁇ ) alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; monoalkylamino groups such as NHCH 3 , NHC 2 H5, NHCsH 7, and the like; dialkylamino groups such as N(CHs) 2 , NCHs(C
  • Suitable groups represented by R 5 are selected from hydrogen, linear or branched (Q-C ⁇ ) 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 -CH 2 Cl, -CH 2 CH 2 Cl and the like; alkylester groups such as -CH 2 OCOC 2 H 5 , - CH 2 OCOC 3 H 7 and the like.
  • Suitable groups represented by R 7 are selected from hydrogen, hydroxyl, amino, halogen atoms such as fluorine, chlorine, bromine, iodine; linear or branched (Q-C 4 ) 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 (Q-C 4 ) 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 NHCH 3 , NHC 2 H 5 , NHC 3 H 7, NHC 6 Hi 3 , and the like
  • X represents oxygen or sulfur.
  • Suitable groups represented by Z are selected from -NR', -S(Q) q ;
  • 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, ⁇ -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;
  • reaction of the compound of formula (Ia) 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.
  • solvents like toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acet
  • 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, tricaprylylrnethylammonium 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
  • any of the groups Z or Y or R 1 or R 3 represent an amino functional group] to novel pyrimidones of the formula (I) wherein any of the groups Z or Y represent - NHCONH 2 , -NHCSNH 2 , -NHCONH-aryl, -NHCONH-heteroaryl, NHCSNHCOOC 2 H5 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.
  • any of the groups R 1 or R 3 represent SR 5 , wherein R 5 represents hydrogen alkyl or aryl and wherein Z represents S(O) q R, 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 1 or R 3 represent S(O) p R 6 , wherein p represents 1 or 2, and R 6 represents alkyl or aryl; and wherein Z represents S(O) q R, 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.
  • Oxone potassium peroxymonosulfate
  • hydrogen peroxide e.g peracetic acid, perbenzoic acid, m- chloroperbenzoic acid etc
  • chromic acid chromic acid
  • potassium permanganate chromic acid
  • alkali metal periodates e.g sodium periodate, etc
  • magnesium mono peroxypthalate osmium tetroxide/N-methylmorpholine-N
  • 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.
  • a solvent which does not adversely influence the reaction
  • the reaction is usually carried out under cooling to reflux conditions.
  • a process for the preparation of novel pyrimidones of the formula (I), wherein either of R 1 or R 3 represent S(O) P R 6 , wherein R 6 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 1 or R 3 represents hydrogen] with chlorosulfonic acid and ammonia
  • 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.
  • 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 0 C to reflux temperature for period in the range of 2 to 24 hours.
  • 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.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • Organic bases such as diethanolamine, ⁇ -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.
  • 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.
  • 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, hydroxynaphtho
  • 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.
  • 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 hydro lysing the pure diastereomeric amides.
  • 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.
  • 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.
  • 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 0 C.
  • Example 3 Synthesis of iV-methyl-l-(3,4-dimethylphenyl)-4-(methylthio)-2-[4-(inethylthio) phenyl]-6-oxo-l,6-dihydropyrimidine-5-carboximidamide.
  • Methylamine solution (30ml, 40% aqueous solution) was added to 5-cyano-l- (4-isopropyl ⁇ henyl)-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.
  • 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.
  • 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.
  • COX-I 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)
  • this assay the potential of the test compound to inhibit the production of prostaglandin either by COX-I 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 COXl/COX-2 in the presence or absence of the test compound.
  • the reaction was carried out at 37 0 C and after 2 minutes it was stopped by adding IM HCl.
  • the intermediate product PGH2 was converted to a stable prostanoid product PGF2 ⁇ by SnC12 reduction.
  • the amount of PGF2 ⁇ 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.
  • TNF- a Tumor Necrosis Factor Alpha
  • PBMC Peripheral Blood Mononuclear Cells
  • test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37° C and then stimulated with
  • Lipopolysaccharide (Escherichia col ⁇ . B4; 1 ⁇ g/ml) for 18 hours at 37 ° C in 5% CO 2 .
  • TNF ⁇ TNF ⁇ in the cell culture medium
  • 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- ⁇ inhibition are shown in Table II.
  • PBMC peripheral blood mononuclear cells
  • BD Bio Science BD Vacutainer CPTTM Cell preparation tube
  • the test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37° C and then stimulated with Lipopolysaccharide ⁇ Escherichia coli: B4; 1 ⁇ g/ml) for 18 h at 37 ° C in 5% CO 2 .
  • 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.
  • 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.
  • 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 (O'day) and continued for 21 days (pretreatment group).
  • the test compound or the vehicle was administered starting from day 14 th to 21 st .
  • the body weight and paw volume of both the right and left hind paw were taken.
  • Spleen, and thymus weights were determined.
  • 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.
  • the serum samples were analysed for inflammatory mediators. The presence or absence of lesions in the stomach was also observed.
  • 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 500 ⁇ g of Lipopo Iy saccharide ⁇ Escherichia coli, LPS: B4 from Sigma) in phosphate buffer saline solution into the intraperitoneal cavity of the mice.
  • 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- ⁇ levels using commercially available mouse TNF- ⁇ ELISA kit (Amersham Biosciences) and an assay was performed as per the manufacturer instruction. Representative results of TNF- ⁇ inhibition are shown in Table IV.
  • Anti-cancer screen
  • Experimental drugs are screened for anti-cancer activity in three cell lines for their GI 50 , TGI and LCs 0 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 DL for 24h at 37 0 C, 5% CO2, 95% air and 100% relative humidity.
  • 5000 HCTl 16 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 (T 0 ).
  • mice 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 DM) 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 0 C. Serial dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 DL of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100 DM 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.
  • GI5 0 is the concentration required to decrease % growth by 50%; TGI is the concentration required to decrease % growth by 100% and LC5 0 is the concentration required to decrease % growth by 150%. Representative results of growth are shown in Table V.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur de nouveaux composés de formule générale (I), sur leurs dérivés, leurs analogues, leurs formes tautomères, leurs stéréoisomères, leurs polymorphes et leurs sels acceptables d'un point de vue pharmaceutique et leurs compositions. La présente invention porte, notamment, sur de nouvelles pyrimidones de formule générale (I).
PCT/IB2006/001448 2005-06-03 2006-06-02 Nouveaux composes WO2006129181A2 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084938A2 (fr) * 2002-04-10 2003-10-16 Orchid Chemicals & Pharmaceuticals Limited Nouveaux derives de pyrimidone
WO2005026148A1 (fr) * 2003-09-08 2005-03-24 Takeda San Diego, Inc. Inhibiteurs de la dipeptidylpeptidase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084938A2 (fr) * 2002-04-10 2003-10-16 Orchid Chemicals & Pharmaceuticals Limited Nouveaux derives de pyrimidone
WO2005026148A1 (fr) * 2003-09-08 2005-03-24 Takeda San Diego, Inc. Inhibiteurs de la dipeptidylpeptidase

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