WO2005091711A2 - Nouveaux pyrimidones condenses - Google Patents

Nouveaux pyrimidones condenses Download PDF

Info

Publication number
WO2005091711A2
WO2005091711A2 PCT/IB2005/000736 IB2005000736W WO2005091711A2 WO 2005091711 A2 WO2005091711 A2 WO 2005091711A2 IB 2005000736 W IB2005000736 W IB 2005000736W WO 2005091711 A2 WO2005091711 A2 WO 2005091711A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidin
phenyl
pyrimido
methylthio
diamino
Prior art date
Application number
PCT/IB2005/000736
Other languages
English (en)
Other versions
WO2005091711A3 (fr
Inventor
Shiv Kumar Agarwal
Ravi Kumar Tadiparthi
Pawan Aggarwal
Savithri Shivkumar
Original Assignee
Orchid Chemicals & Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Orchid Chemicals & Pharmaceuticals Ltd filed Critical Orchid Chemicals & Pharmaceuticals Ltd
Publication of WO2005091711A2 publication Critical patent/WO2005091711A2/fr
Publication of WO2005091711A3 publication Critical patent/WO2005091711A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel condensed pyrimidones of the general formula (I), their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the present invention more particularly provides novel condensed pyrimidone derivatives of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel condensed pyrimidones of the formula (I) pharmaceutically acceptable salts, their derivatives, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
  • the novel condensed pyrimidones of the present invention are useful for the treatment of inflammation and immunological diseases.
  • the compounds of the present invention are useful for the treatment of inflammation and immunological diseases those mediated by cytokines such as TNF- ⁇ , IL-1, IL-6, IL-l ⁇ , IL-8 and cyclooxygenase such as COX-2 and COX-3.
  • the compounds of the present invention are also useful for the treatment of rheumatoid arthritis; osteoporosis; uveititis; acute and chronic myelogenous leukemia; atherosclerosis, cancer, pancreatic ⁇ cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease.
  • 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.
  • 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.
  • analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone
  • Macrophages are important mediators of both inflammation and providing the necessary "help" for T cell stimulation and proliferation.
  • macrophages make IL-1, IL-12 and TNF- ⁇ all of which are potent pro-inflammatory molecules and also provide help for T cells.
  • 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.
  • COX-2 cyclooxygenase-2
  • COX-3 cyclooxygenase-3
  • iNOS inducible nitric oxide synthase
  • phospho tyrosine kinases PTKs
  • 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.
  • TNF- ⁇ 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.
  • TNF- ⁇ also stimulates the synthesis of acute-phase proteins.
  • rheumatoid arthritis a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF- ⁇ mediates the cytokme cascade that leads to joint damage and destruction (Arend et al, Arthritis Rheum, 38, 151-60,1995).
  • TNF- ⁇ Food and Drug Administration
  • soluble TNF receptors etanercept
  • infliximab anti-TNF- ⁇ antibody
  • 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-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 ⁇ 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
  • T ⁇ F- ⁇ HIV-1, HIV- 2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSN-1, HSV-2), and herpes zoster viruses are also exacerbated by T ⁇ F- ⁇ .
  • CMV cytomegalovirus
  • influenza influenza
  • adenovirus the herpes viruses
  • herpes zoster viruses are also exacerbated by T ⁇ F- ⁇ .
  • inhibitors of T ⁇ F- ⁇ are potentially useful in the treatment of a wide variety of diseases.
  • Compounds that inhibit T ⁇ F- ⁇ have been described in several patents. Excessive production of IL-6 is implicated in several disease states; it is highly desirable to develop compounds that inhibit IL-6 secretion.
  • Compounds that inhibit IL-6 have been described in U.S. Pat. Nos. 6,004,813; 5,527,546 and 5,166,137.
  • the cytokine IL-l ⁇ also participates in the inflammatory response. It stimulates thymocyte proliferation, ftbroblast 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-l ⁇ is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-l ⁇ .
  • IL-1 is a more potent inducer of stromelysm than TNF- ⁇ . (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.
  • IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil in filtration into sites of inflammation or injury (e.g., ischemia) is mediated chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowl disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis.
  • IL-8 has also has ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminish neutrophil infiltration.
  • the derivatives may be useful in the treatment of inflammation and immunological diseases.
  • the compound of the present invention are useful for the treatment of inflammation and immunological diseases those mediated by cytokines such as TNF- ⁇ , IL-1, IL-6, IL-l ⁇ , IL-8 and cyclooxygenase such as COX-2 and COX-3.
  • the compound of the present invention are also useful for the treatment of rheumatoid arthritis; osteoporosis; uveititis; acute and chronic myelogenous leukemia; cancer; ischemic-induced cell damage; pancreatic ⁇ cell destruction; osteoarthritis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis.
  • the present invention relates to novel condensed pyrimidones of the formula (I) their derivatives, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions, wherein X represents O or S; Ar 1 and Ar may be same or different and independently represent substituted or unsubstituted aryl, five to seven membered heteroaryl or heterocyclylgroup; Ri and R 2 may be same or different and independently represent hydrogen, hydroxy, thiol, nitro, formyl, azido, cyano, halo or substituted or unsubstituted groups selected from alkyl, halo alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, arylsulfonyl, alkylsulfinyl, aryls
  • Suitable groups represented by Ar and Ar are selected from substituted or unsubstituted aryl such as phenyl, naphthyl and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl and the like, which may be substituted; heterocyclyl group such as pyrrolidinyl, thiazolidinyl, oxazolidinyl, mo holinyl, thiomorpholinyl, piperidinyl,
  • the groups represented by Ar and Ar may be substituted by one to four substituents selected from hydroxy, thiol, nitro, formyl, azido, cyano, halo or substituted or unsubstituted groups selected from alkyl, halo alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, arylsulfonyl, alkylsulfmyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives.
  • salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, per chlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Representative compounds according to the present invention include: 5,7-Diamino-3-(4-methylphenyl)-2-[4-(methylthio)phenyl]-pyrimido[4,5- ]pyrimidin-4(3H)-one;
  • R 2 represents amino and other symbols are as defined earlier which comprises condensing a compound of formula (la) o NC ⁇ (la) R3 ⁇ N ⁇ Ar 2 wherein R 3 represents SCH 3 or SO 2 CH 3 and all other symbols are as defined earlier with a compound of the formula (lb) NH ⁇ (lb) R1 NH 2 where Riis as defined above through the formation of an intermediate
  • reaction of compound of formula (la) with compound of formula (lb) may be carried out using solvents such as toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethylacetate, acetonitrile, dimethylformamide, DMAc, dimethylsulfoxide, ethanol, methanol, isopropyl alcohol, tert-butylalcohol etc., a mixture thereof or the like or by neat reactions.
  • the condensation reaction may be carried out under acidic condition using organic acids, or basic conditions viz.
  • reaction may be carried out by the use of phase transfer catalysts viz. triethylbenzylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like.
  • phase transfer catalysts viz. triethylbenzylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like.
  • the reaction is usually carried out under cooling to refluxing conditions.
  • the oxidizing agent may be selected from potassium peroxymonosulfate (Oxone), hydrogen peroxide, tert-butylperoxide, Jones reagent, per acid [e.g.
  • 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 [e.g. methanol, ethanol, etc.], a mixture thereof or the like.
  • the reaction temperature is usually carried out under cooling to refluxing conditions.
  • Anhydrous potassium carbonate (0.885g, 64mmol) was added to DMF (15ml) containing guanidine hydrochloride (0.61g, 64mmol) and 5-cyano-l- (3,4- dimethylphenyl)-4-methylthio-2-(4-methylthiophenyl)-l,6-dihydro-pyrimidin-6- one (2.5g, 64mmol) under stirring at room temperature.
  • the reaction mass was heated to 150°C for fourteen hours, poured onto ice-water mixture. The precipitate thus obtained was filtered, washed with water and dried.
  • Rat Carrageenan Paw Edema Test The carrageenan paw edema test is performed as described by Winter et al (Proc.Soc.Exp.Biol.Med, 111, 544, 1962). Male Wistar rats are selected and the body weights are equivalent within each group. The rats are fasted for eighteen hours with free access to water. The rats are dosed orally with the test compound suspended in vehicle containing 0.5% methylcellulose. The control rats are administered the vehicle alone. After an hour, the rats are injected with 0.1 ml of 1% Carrageenan solution in 0.9% saline into the sub-plantar surface of the right hind paw. Paw volume is measured using water plethysmograph before and after 3 hours of carrageenan injection.
  • Human Whole Blood Assay Human whole blood provides a protein and cell rich, milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as selective COX-2 inhibitors. Studies have shown that normal human blood does not contain COX-2 enzyme. This is correlating with the observation that COX-2 inhibitors have no effect on prostaglandin E 2 (PGE2) production in normal blood. These inhibitors are active only after incubation of human blood with lipopolysaccharide (LPS), which induces COX-2 production in the blood. Method Fresh blood is collected in tubes containing potassium EDTA by vein puncture from male volunteers. The subjects should have no apparent inflammatory conditions and not taken NSAIDs for at least 7 days prior to blood collection.
  • PGE2 prostaglandin E 2
  • Plasma samples are treated with aspirin in vitro (lO ⁇ g/ml, at time zero) to inactivate COX-1, and then with LPS (lO ⁇ g/ml) along with test agents or vehicle.
  • the blood is incubated for 24 h at 37 °C, after which the tubes are centrifuged, the plasma is separated and stored at -80 °C (J.Pharmacol.Exp.Ther, 271, 1705, 1994; Proc.Natl.Acad.Sci. USA., 96, 7563, 1999).
  • the plasma is assayed for PGE2 using Cayman ELISA kit as per the procedure outlined by the manufacturer (Cayman Chemicals, Ann Arbor, USA). Representative results of COX-2 inhibition are shown in Table II. Table II
  • Tumor Necrosis Factor Alpha This assay determines the effect of test compounds on the production of TNF alpha in human whole blood.
  • TNF-alpha assay is carried out as described by Armin hatzelmann and Christian Schudt (J Pharm Exp Ther 297, 261,2001). Compounds are tested for their ability to inhibit the activity of TNF alpha in human whole blood. The test compounds are pre-incubated for 15 minutes at 37° C and then stimulated with Lipopol ⁇ ysaccharide (Salmonella abortus equi, 1 ⁇ g/ml) for 4 h at 37 ° C in 5% CO 2 .
  • Lipopol ⁇ ysaccharide Salmonella abortus equi, 1 ⁇ g/ml
  • Thte levels of TNF alpha are estimated using Enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer (Cayman Chemical, Ann Arbor, USA). Representative results of TNF- ⁇ inhibition are shown in Table III. Tat>le III
  • Interleukin-6 IL-6
  • This assay determines the effect of test compounds on the production of IL-6 from human whole blood. Compounds are tested for their ability to downregulate the production of IL-6 in activated wliole blood. The test compounds are pre- incubated for 15 minutes at 37° C an . then stimulated with Lipopolysaccharide (Salmonella abortus equi, 1 ⁇ g/ml) fox 4 h at 37 ° C in 5% CO 2 . The levels of Interleukin-6 are estimated using Enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer. (Cayman Chemical, Ann Arbor, USA). Representative results of IL-6 inhibition are shown in Table IN. Table IV
  • TNF-alpha inhibitory activity is assessed by in-vzvo inhibition of serum TNF- alpha production in mice. This method is used to assess the inhibitory actions of compounds on TNF-alpha production in mouse (Griswold et al J Pharmacol Exp Ther 287,705,1998, Garcia et al, Histol Histopathol 5(1), 43, 1990, and Victor et al, Physiol Res 52,789,2003).
  • Male Swiss albino mice are selected and the body weights are equivalent within each group. The animals are fasted for eighteen hours with free access to water.
  • the control group receives only LPS and the drug treatment group receives LPS and test compound. At the start of the experiment, the drug is administered orally.
  • Adjuvant Arthritis Compounds are assayed for their activity on rat adjuvant induced arthritis according to Theisen-Popp et al., (Agents Actions, 42, 50-55,1994). Six to seven weeks old, Wistar rats are weighed, marked and assigned to groups [a negative control group in which arthritis is not induced (non-adjuvant control), a vehicle- treated arthritis control group, test substance treated arthritis group].
  • Adjuvant induced arthritis is induced by an injection of Mycobacterium butyricum (Difco) suspended in liquid paraffin into the sub-plantar region of the right hind paw (J.Pharmacol.Exp.Ther., 284, 714, 1998).
  • Body weight, contra-lateral paw volumes are measured at various days (0, 4, 14, 21) for all the groups.
  • the test compound or vehicle is administered orally beginning post injection of adjuvant and continued for 21 days.
  • body weight and paw volume of both right and left hind paw, spleen, and thymus weights are determined.
  • the radiographs of both hind paws are taken to assess the tibio-tarsal joint integrity. Hind limb below the stifle joint is removed and fixed in 1% formalin saline.
  • plasma samples are analysed for cytokines, interleukins and prostaglandins. The presence or absence of lesions in the stomach is also observed.
  • treatment' and "time') Analysis of Variance with repeated measures on "time” is applied to the % changes for body weight and foot volumes.
  • a post hoc Dunnett's test is conducted to compare the effect of treatments to vehicle.
  • a one-way Analysis of Variance is applied to the thymus and spleen weights followed by the Dunnett's test to compare the effect of treatments to vehicle.
  • Dose-response curves for % inhibition in foot volumes on days 4, 14 and 21 are fitted by a 4-parameter logistic function using a nonlinear Least Squares' regression.
  • ID 50 is defined as the dose corresponding to a 50% reduction from the vehicle and is derived by interpolation from the fitted 4- parameter equation.
  • the three cell lines, one-dose prescreen carried out which identifies a large proportion of the compounds that would be inactive in multi-dose 60 cell line screening.
  • the current assay utilizes a 384 well plate format and fluorescent staining technologies resulting in greater screening capacity for testing of synthetic samples.
  • the cell lines of the cancer-screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine.
  • cells are inoculated into 96 well microtiter plates in 100 ⁇ L. After cell inoculation, the microtiter plates are incubated at 37° C, 5 % CO 2 , 95 % air and 100 % relative humidity for 24 h prior to addition of experimental drugs.
  • the cells are plated a densities of 5000 cells/well (MCF7), 1000 cells/well (NCI-H460), and 7500 cells/well (SF-268) to allow for varying doubling time of the cell lines.
  • MCF7 cells/well
  • NCI-H460 7500 cells/well
  • SF-268 7500 cells/well
  • DMSO dimethyl sulfoxide
  • NSC 19893 (5-FU) and NSC 123127 (Adriamycin).
  • Endpoint Measurement After compound addition, plates are incubated at standard conditions for 48 hours, 10 ⁇ l/well Alamar Blue is added and the plates are incubated for an additional 4 hours. Fluorescence is measured using an excitation wavelength of 530 nm and an emission wavelength of 590 nm.
  • T/C Percent Test Cell Growth/Control (untreated) Cell Growth

Landscapes

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

Abstract

L'invention concerne de nouveaux pyrimidones condensés de formule (I), leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables les contenant. L'invention concerne en particulier des dérivés de pyrimidones condensés de formule (I).
PCT/IB2005/000736 2004-03-24 2005-03-22 Nouveaux pyrimidones condenses WO2005091711A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN270/CHE/2004 2004-03-24
IN270CH2004 2004-03-24

Publications (2)

Publication Number Publication Date
WO2005091711A2 true WO2005091711A2 (fr) 2005-10-06
WO2005091711A3 WO2005091711A3 (fr) 2006-03-09

Family

ID=35056602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/000736 WO2005091711A2 (fr) 2004-03-24 2005-03-22 Nouveaux pyrimidones condenses

Country Status (1)

Country Link
WO (1) WO2005091711A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005091711A2 (fr) * 2004-03-24 2005-10-06 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux pyrimidones condenses
WO2012011591A1 (fr) 2010-07-23 2012-01-26 武田薬品工業株式会社 Composé hétérocyclique fusionné et application associée
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005091711A2 (fr) * 2004-03-24 2005-10-06 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux pyrimidones condenses

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005091711A2 (fr) * 2004-03-24 2005-10-06 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux pyrimidones condenses

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005091711A2 (fr) * 2004-03-24 2005-10-06 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux pyrimidones condenses
WO2005091711A3 (fr) * 2004-03-24 2006-03-09 Orchid Chemicals & Pharm Ltd Nouveaux pyrimidones condenses
WO2012011591A1 (fr) 2010-07-23 2012-01-26 武田薬品工業株式会社 Composé hétérocyclique fusionné et application associée
US9023858B2 (en) 2010-07-23 2015-05-05 Takeda Pharmaceutical Company Limited Substituted pyrido[2,3-d]pyrimidines as delta-5-desaturase inhibitors
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives

Also Published As

Publication number Publication date
WO2005091711A3 (fr) 2006-03-09

Similar Documents

Publication Publication Date Title
JP5237115B2 (ja) 新規複素環類
US20030232813A1 (en) Novel amino substituted pyrimidinone derivatives
US7759350B2 (en) Pyrimidine carboxamides
CA2492342C (fr) Nouveaux derives bioactifs de la pyrimidine
JPH11512390A (ja) ピリミジンカルボキシレートおよび関連化合物ならびに炎症状態を処置するための方法
JP2002105081A (ja) 新規チオフェンニ環化合物
US7399760B2 (en) Pyrimidinedione derivatives
US20090163521A1 (en) Novel Pyrazolopyrimidinone Derivatives
WO2005091711A2 (fr) Nouveaux pyrimidones condenses
US7365069B2 (en) Pyrimidone derivatives
US20080207606A1 (en) Novel heterocycles
KR101595506B1 (ko) 신규한 헤테로사이클
WO2006129181A2 (fr) Nouveaux composes

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase