WO2005092896A1 - Compose pour inhiber l'activite tyrosine kinase de la proteine ddr2 - Google Patents

Compose pour inhiber l'activite tyrosine kinase de la proteine ddr2 Download PDF

Info

Publication number
WO2005092896A1
WO2005092896A1 PCT/KR2005/000019 KR2005000019W WO2005092896A1 WO 2005092896 A1 WO2005092896 A1 WO 2005092896A1 KR 2005000019 W KR2005000019 W KR 2005000019W WO 2005092896 A1 WO2005092896 A1 WO 2005092896A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
amino
substituted
halogen
Prior art date
Application number
PCT/KR2005/000019
Other languages
English (en)
Inventor
Beom-Seok Yang
Kyung-Mi Yang
Hae-Jong Kim
In-Sung Park
Sung-Dae Park
Jang-Hyuk Lee
Hyuk-Man Kwon
Byoung-Young Woo
Original Assignee
Korea Institute Of Science And Technology
Jeil Pharmaceutical Co., 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 Korea Institute Of Science And Technology, Jeil Pharmaceutical Co., Ltd. filed Critical Korea Institute Of Science And Technology
Publication of WO2005092896A1 publication Critical patent/WO2005092896A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01F—MEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F15/00—Details of, or accessories for, apparatus of groups G01F1/00 - G01F13/00 insofar as such details or appliances are not adapted to particular types of such apparatus
    • G01F15/10—Preventing damage by freezing or excess pressure or insufficient pressure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01F—MEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F15/00—Details of, or accessories for, apparatus of groups G01F1/00 - G01F13/00 insofar as such details or appliances are not adapted to particular types of such apparatus
    • G01F15/14—Casings, e.g. of special material

Definitions

  • the present invention relates to a new furopyrimidine compound, their phamaceutically acceptable salt, and a tyrosine kinase activity inhibitor. Since the furopyrimidine compound of the present invention suppresses activity of DDR2 (Discoidin Domain Receptor 2) tyrosine kinase, it can be used for treatment of illnesses on which the DDR2 tyrosine kinase activity works such as liver cirrhosis, rheumatoid arthritis, cancer, or the like.
  • DDR2 Discoidin Domain Receptor 2
  • DDR Discoidin Domain Receptor
  • the DDR protein has been revealed to work to enhance development of fibroblast, hepatic stellate cell of liver tissue, a synovial fibroblast extracted from a patient with rheumatism, collagen synthesis by these cells, and generation of MMP-1 or MMP-2.
  • the tyrosine kinase activity of the DDR2 protein is known to be critical.
  • an object of the present invention is to furovide a new low- molecule compound for inhibiting DDR2 tyrosine kinase activity and a medical treatment caused by tyrosine kinase activity of DDR2 protein including the same, in order to treat a disease caused by tyrosine kinase activity of DDR2 protein represented by a tissue fibrosis, rheumatism and cancer.
  • the inventors of the present invention has invented a new low-molecule compound inhibiting activity by inhibiting ATP bonding to the active pocket of DDR2 tyrosine kinase, which can inhibit major morbid phenomenon appearing in diseases such as liver cirrhosis, rheumatism or cancer, and as such the inventors have completed the present invention by confirming that the new low-molecule compound can be utilized as an excellent treatment to those diseases.
  • a new furopyrimidine compound which inhibits tyrosine kinase activity of DDR2 protein, its precursor, their pharmaceutically acceptable salt and treatment of diseases related to tyrosine kinase activity of the DDR2 protein containing the same is furovided.
  • Figure 1 is a graph showing that a compound in accordance with the present invention inhibiting DDR2 kinase activity by an ATP competitive mechanism, and specifically, showing a result of a reaction rate which was obtained by changing an amount of ATP, the substrate, at various densities of the compound which was then reciprocally plotted;
  • Figure 2 is an electrophoresis photo showing an inhibiting activity of the compound of the present invention with respect to tyrosine phosphorylation of DDR2 protein induced by a first type collagen in hepatic stellate cell HSC T6;
  • Figure 3 is a graph showing viability of treated cell with the density of the chemical treatment;
  • Figure 4A is a graph showing that the compound in accordance with the present invention is treated in an HSC T6 cell cultivation solution and an amount of relative MMP-2
  • the furopyrimidine compound of the present invention has the effect of inhibiting activity of the DDR2 tyrosine kinase, so it can be used for treating illnesses related to the DDR2 tyrosine kinase activity.
  • the present invention furovides a furopyrimidine compound, which inhibits tyrosine kinase activity of DDR2 protein and is defined by Chemical Formula (1) incorporated with various derivatives in a furopyrimidine ring, its precursor and its pharmaceutically acceptable salt: [Chemical Formula 1]
  • Ri may be single-substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, C0 2 H, CONH 2 , CSNH 2 , amidine, C1-C4 alkyl group, C1-C4 halo alkyl group, C1-C7 alkoxy group, C1-C4 alkyl amino group, C1-C4 alkylthio group, C1-C4 alkyl amide group, C1-C4 acyl amino group, C1-C4 acyl oxy group, C1-C4 alkyl sulfone amide group, C1-C4 alkyl sulfonate group, imidic acid C1-C4 alkyl ester, thioimidic acid C1-C4 alkyl ester, hydroxy or amino, morpholine, acetate, acetamide, methan
  • R may be single-substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO 2 H, CONH 2 , CSNH 2 , amidine,
  • C1-C4 alkyl group C1-C4 haloalkyl group, C1-C7 alkoxy group, C1-C4 alkylamino group, C1-C4 alkylthio group, C1-C4 alkylamide group, C1-C4 acylamino group, C1-C4 acyloxy group, or C1-C4 alkylsufoneamide group.
  • the substituent R of the Chemical Formula 1 is a compound of Chemical Formula 5 for inhibiting tyrosine kinase activity of DDR2 protein
  • R" is a furopyrimidine compound defined by the following Chemical Formula 2, hydrogen, its precursor, and its pharmaceutically acceptable salt: [Chemical Formula 5] [Chemical Formula 2]
  • Ri and R 3 are independently identical or different and may be single- substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO 2 H, CONH 2 , CSNH 2 , amidine, C1-C4 alkyl group, C1-C4 halo alkyl group, C1-C7 alkoxy group, C1-C4 alkyl amino group, C1-C4 alkylthio group, C1-C4 alkyl amide group, C1-C4 acyl amino group, C1-C4 acyl oxy group, C1-C4 alkyl sulfoneamide group, C1-C4 alkyl sulfonate group, imidic acid C1-C4 alkyl ester, thioimidic acid
  • Ri may be single-substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO 2 H, CONH 2 , CSNH 2 , amidine, C1-C4 alkyl group, C1-C4 halo alkyl group, C1-C7 alkoxy group, C1-C4 alkyl amino group, C1-C4 alkylthio group, C1-C4 alkyl amide group, C1-C4 acyl amino group, C1-C4 acyl oxy group, C1-C4 alkyl sulfone amide group, C1-C4 alkyl sulfonate group, imidic acid C1-C4 alkyl ester, thioimidic acid C1-C4 alkyl ester, hydroxy or amino, morpholine, acetate, acetamide, methane
  • R may be single-substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO 2 H, CONH 2 , CSNH 2 , C1-C4 alkyl group, amidine, C1-C4 haloalkyl group, C1-C7 alkoxy group, C1-C4 alkylamino group, C1-C4 alkyl thio group, C1-C4 alkyl amide group, C1-C4 acylamino group, C1-C4 acyloxy group, or C1-
  • the substituent R of Chemical Formula 1 is a compound of Chemical Formula 6 for inhibiting tyrosine kinase activity of DDR2 protein
  • R" is a furopyrimidine compound represented by the following Chemical Formula 4, hydrogen, and its precursor, and its pharmaceutically acceptable salt: [Chemical Formula 6]
  • Ri and R 3 ' are independently identical or different, and may be single- substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO 2 H, CONH 2 , CSNH 2 , amidine, C1-C4 alkyl group, C1-C4 halo alkyl group, C1-C7 alkoxy group, C1-C4 alkyl amino group, C1-C4 alkylthio group, C1-C4 alkyl amide group, C1-C4 acyl amino group, C1-C4 acyl oxy group, C1-C4 alkyl sulfoneamide group, C1-C4 alkyl sulfonate group, imidic acid C1-C4 alkyl ester, thioimidic acid C1-C
  • R 2 indicates hydrogen, halogen, cyano, nitro, hydroxyl, amino, CO 2 H, CONH 2 , CSNH 2 , C1-C5 alkyl group, C1-C5 haloalkyl group, alkylester, phenyl group, halogen-substituted phenyl group, C1-C4 alkoxy group-substituted phenyl group, or C1-C4 haloalkoxy group-substituted phenyl group.
  • the compound represented by the Chemical Formulas 1 , 2, 3 and 4 can exist in a free base or in an acid-addition salt such as chloride, sulfuric acid, citric acid or fumaric acid.
  • the present invention furovides an intermediate of the furopyrimidine compounds shown in formulas 1 to 4 defined by the following Chemical Formulas XI and XII, which inhibit tyrosine kinase activity of DDR2 protein, and its precursor and its pharmaceutically acceptable salt: [Chemical Formula XI]
  • R' of Chemical Formula IV since the substituent R' of Chemical Formula IV must generate a functional group that can be substituted by a substituent defined by Chemical Formula 5, it is preferred that R' is hydrogen, halogen, cyano, nitro, hydroxy, amino, CO2H, COHN2, CSNH2, amidine, C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C7 alkoxy group, C1-C4 alkylamino group, C1-C4 alkylthio group, C1-C4 alkylamide group, C1-C4 acylamino group, C1-C4 acyloxy group or C1-C4 alkylsulfoneamide group.
  • R' is hydrogen, halogen, cyano, nitro, hydroxy, amino, CO2H, COHN2, CSNH2, amidine, C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C7 alkoxy group,
  • Formula 4 can be produced by the following Reaction Formula 1 by using a compound (IV) of the Chemical Formula IV, whose R' is -OCH 3, as a starting material:
  • R-i, R 3 and R 3 ' are independently identical or different to each other, and may be single-substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO 2 H, CONH 2 , CSNH 2 , amidine, C1-C4 alkyl group, C1-C4 halo alkyl group, C1-C7 alkoxy group, C1-C4 alkyl amino group, C1-C4 alkylthio group, C1-C4 alkyl amide group, C1-C4 acyl amino group, C1-C4 acyl oxy group, C1-C4 alkyl sulfoneamide group, C1-C4 alkyl sul
  • Reaction Formula 1 is one example for preparing the compound of Chemical Formula 2 and the compound of Chemical Formula 4, and the compounds can be produced by using compounds other than those illustrated (IV) in Reaction Formula 1 or without undergoing the process of producing the compound of VII' by adding isoamylnitrite and CCI 4 and then substituting -NH2 with -Cl to the compound VI', but rather, -OCH 3 of the compound VI' can be demethylated for the reaction to occur.
  • the compound (IV") of Chemical Formula IV having the same R' as R can be used to produce it.
  • the compound of Chemical Formula 1 can be produced by the following Reaction Formula 2: [Reaction Formula 2]
  • Reaction Formula 2 is one example for producing the compound of Chemical Formula 1 , and it can be produced by reacting the compound VI" with the compound XII by adding isoamylnitrite and CCI without substituting -NH 2 of the compound VI" with -Cl.
  • the compound of Chemical Formula 3 can be produced by the following reaction Formula 3:
  • Z is O, S or NH
  • Ri is single-substituted or independently double-substituted by hydrogen, halogen, cyano, nitro, hydroxy, amino, CO H, CONH 2 , CSNH 2 , amidine, C1-C4 alkyl group, C1-C4 halo alkyl group, C1-C7 alkoxy group, C1-C4 alkyl amino group, C1-C4 alkylthio group, C1-C4 alkyl amide group, C1-C4 acyl amino group, C1-C4 acyl oxy group, C1-C4 alkyl sulfoneamide group, C1-C4 alkyl sulfonate group, imidic acid C1-C4 alkyl ester, thioimidic acid C1-C4 alkyl ester, hydroxy or amino, morpholine, acetate, acetamide, methanesulfoneamide group
  • Formulas 1 , 2, 3 and 4 can be a compound of the numbers 5 ⁇ 132 of Table 6-1 as shown below.
  • the present invention also furovides a DDR2 tyrosine kinase activity inhibitor which contains a medically effective amount of one or more of the new furopyrimidine derivatives having an effect of inhibiting activity of DDR2 tyrosine kinase expressed by Chemical Formulas 1 , 2, 3, 4, XI, XII and its pharmaceutically acceptable salts as an effective ingredient.
  • the present invention as an effective ingredient, furovides for a remedial agent for treating diseases related to DDR2 tyrosine kinase activity such as liver cirrhosis or rheumatism that contains a medically effective amount of one or more of the new furopyrimidine derivatives and its pharmaceutically acceptable salts.
  • the pharmaceutical composition of the present invention can additionally include pharmaceutically acceptable carrier or excipient. As shown in Table 11 below, it was confirmed that the compounds of Chemical Formulas XI and XII, as well as the compounds of Chemical Formula 1 to 4, which are the end products, also exhibit excellent DDR2 tyrosine kinase inhibiting activity.
  • the pharmaceutical composition of the present invention can include the compounds of Chemical Formulas XI and/or XII as an effective ingredient.
  • the DDR2 protein is a receptor protein that exhibits tyrosine kinase activity and includes a tyrosine kinase activity portion at its c-end.
  • a protein that exhibits tyrosine kinase activity at the c-end portion (amino acid 441- 825), which is a portion exposed to cytoplasm and is over-expressive in an insect cell, can be obtained.
  • the inhibiting activity of the compound of the present invention with respect to the DDR2 protein having the tyrosine kinase activity was measured.
  • the tyrosine kinase activity of the tyrosine kinase activity portion of the DDR2 protein can be measured in various ways. For example, as a peptide substance, poly(D4Y)n attached with biotin furovided by Promega Co.
  • a histone H2B protein can be used to measure, or the degree/amount of self- phosphorylation in the tyrosine kinase activity portion of the DDR2 protein can be measured.
  • the degree of activity can be measured by marking the gamma position of the phosphate group of the ATP with a 2 P isotope and then detecting the amount of 32 P radioactivity of the peptide substance.
  • the density of each compound inhibiting 50 % of the DDR2 tyrosine kinase activity is defined by IC 50 value of each compound, which is as shown in Table 11.
  • IC 50 value of each compound which is as shown in Table 11.
  • the compounds expressed by Chemical Formulas VI and VII as well as Chemical Formulas 1 , 2 and 3 all have the IC 50 value below 500uM and an excellent tyrosine kinase inhibiting capability of DDR2 protein.
  • the compounds of the present invention are competitively joined with ATP, which is one of the DDR2 kinase substance, to exhibit the inhibiting effect.
  • the compound of the present invention can be used as a remedial agent of various illnesses related to the tyrosine kinase activity of the DDR2 protein.
  • increase in the tyrosine kinase activity of the DDR2 acceptor protein in hepatic stellate cells is related to the increase in number of cells. Based on this fact, various experimentations have been performed to verify the effect of inhibiting the growth and activity of the hepatic stellate cells when the compounds of the present invention are treated during the cultivation of the hepatic stellate cells, and the following results were obtained.
  • Figure 2 illustrates inhibiting of tyrosine phosphorylation of the DDR2 protein induced by a first type collagen in an HSC T6 cell, a hepatic stellate cell modem with an activated compound.
  • the compound (100 of Table 6) is processed in a density of 5uM to 20uM for 24 hours and a tyrosine phosphorylation degree of the DDR2 protein of the HSC T6 cell was measured by Western blotting using a phosphorylated tyrosine specific antibody, and its results are shown.
  • tyrosine phosphorylation of DDR2 protein induced by the first type collagen which is the active ligand of the DDR2 receptor, is dependently reduced by the density of the treatment.
  • Figure 3 shows that the compounds of the present invention selectively inhibits the growth of HSC T6 cell which is determined by the SRB assay for detecting cell growth inhibiting effect.
  • the representative compound (100) of Table 6 when the representative compound (100) of Table 6 is treated for 48 hours, the cell viability of HSC T6, which has been found to express the activated DDR2 tyrosine kinase, is shown to be reduced compared with rat2 fibroblast (- ⁇ -) or HT1080 cell (..o..).
  • the compounds of the present invention selectively work by specific inhibition of the DDR2 kinase activity.
  • liver cirrhosis it is known that the number of hepatic stellate cells is increased and become active at the same time in case of liver cirrhosis.
  • the active hepatic stellate cells increase generation of smooth muscle actin protein with an MMP-2 together with collagen. For this reason, inhibiting and eliminating the activity of the active hepatic stellate cells in liver cirrhosis is a major target to achieve a remedial effect.
  • the representative compound (100) of Table 6 was treated in HSC T6 cell, namely, in a model of the activated hepatic stellate cells, for 24 hours, and cell cultivation solution was used to measure an amount of generated MMP-2 using ELISA assay. Its results are as shown in Figure 4A. More particularly, the cell cultivation solution was condensed by 20 times before the protein was attached to 96 well Maxi-Sorp plate, then it was masked by using a 5% skim milk solution followed by reacting with an MMP-2 specific antibody before washing it.
  • the amount of the attached MMP-2 antibody was quantitatively measured through a general peroxidase color development reaction using peroxidase-attached secondary antibody. As shown in Figure 4A, generation of MMP-2 was inhibited in proportion to the compound treatment density.
  • the representative compound (100) of Table 6 of the present invention was processed in HSC T6 cells, namely, the active hepatic stellate cell model, for 24 hours, the cell was collected then was melted in a 1x lameli buffer solution before it was western-blotted by using the smooth muscle specific antibody to measure change in the amount of the smooth muscle actin protein according to the compound treatment. Its result is shown in Figure 4B. As shown in Figure 4B, generation of the smooth muscle actin protein was reduced in proportion to the compound treatment density.
  • the compounds of the present invention is found to induce apoptosis of active hepatic, stellate cells, confirming an excellent remedial effect with respect to liver cirrhosis.
  • the compound (Table 6, Number 100) of the present invention was treated to HSC T6 cell, namely, the hepatic stellate cell, for 24 hours, and a gene-segmentation phenomenon of the entire genome DNA was observed. Its results are as shown in Figure 5. As noted in Figure 5, when the compounds of the present invention were treated, the segmentation effect of DNA was largely observed at a high density of
  • the compounds of the present invention inhibit the growth and the activity of the hepatic stellate cells, which are the main causes of liver cirrhosis, reduce generation of the MMP-2, which is a feature of an active hepatic stellate cell and the smooth muscle actin protein, and induce apoptosis, thus furoviding an excellent treatment effect for liver cirrhosis.
  • the compound of the present invention inhibits accumulation of collagen in a liver tissue causing liver fibrosis which is the main cause of liver cirrhosis, thereby treating liver cirrhosis.
  • a liver cirrhosis animal model for bile duct suture was made by using a whistar rat aged 7 weeks, and the compound of the present invention (the number 100 of Table 6) of the present invention was injected intravenously by the amount of 10mg/kg, one time per day for two weeks through tail intravenous injections.
  • the compound of the present invention the number 100 of Table 6
  • the results were shown in Table 12, which also shows the measured value from the group that did not undergo the bile duct suture operation.
  • Hydroxy proline seldom exists in any other proteins in a human body and is amino acid constituting collagen. In the present invention, it is an index for directly indicating the amount of collagen in the liver tissue, and the amount of hydroxyl proline of the liver tissue was measured. As shown in Figure 12, the amount of hydroxy proline measured in the group in which the compound of the present invention was not injected after the bile duct suture operation was higher, by about 2.5 times, than that of the group which did not undergo the bile duct suture operation. This shows that collagen was considerably accumulated in the liver tissue due to the bile duct suture and the liver cirrhosis pathogenic effect had been developed.
  • the group in which the compound of the present invention was injected showed that there was an increase of the amount of the hydroxyl proline in the liver tissue, which is a considerable alleviation.
  • the compound of the present invention inhibits accumulation of collagen in the liver tissue as well as increase and activity of the hepatic stellate cell, so that it has an anti-fibrosis effect with respect to liver cirrhosis.
  • the excellent liver cirrhosis treatment effect of the compound of the present invention is shown again.
  • Figure 6 shows the comparing results of the liver tissues from the rats administered with the representative compound 100 (Table 6) of the present invention, the rats that were injected with only carriers, and the rats to which the bile duct suture operation was not performed, all of which were made into respective freeze dehydration sections, and then the sections were stained with Masson stain. The results confirm that the deposition of collagen was reduced because of the compound of the present invention. As shown in Figure 6, the liver tissue from the rat, into which the compound of the present invention was injected after the bile duct suture operation was performed, showed considerably reduced amount of collagen, which was dyed in blue color, when compared to that of the rat into which only the carrier was injected.
  • the compound of the present invention also has an excellent inhibiting effect for an arthritis pathogenic factor such as rheumatism.
  • arthritis pathogenic factor such as rheumatism
  • One cause of arthritis such as rheumatism is activation and excessive furoliferation of synovial cell of synovium.
  • the activated synovial cells excessively secrete MMP-1 proteins, thereby destroying collagen proteins constituting cartilage tissues to make the rheumatism serious.
  • the synovial cell is a type of fibrotic cells like the hepatic stellate cell
  • expression of DDR2 in the synovial cell is the cause of the disease.
  • the compound (100 of Table 6) of the present invention was processed in a synovial fibroblast extracted from a rheumatism patient for 48 hours according to each density, and then, the number of living cells was compared with the number of cells before the treatment with the compound was performed through the SRB assay to obtain a % cell viability rate as shown in Figure 7.
  • the cell viability of the synovial fibroblast is reduced in proportion to the density of the compound of the present invention.
  • the compound of the present invention which is an inhibiting material specific for the DDR2 kinase activity, inhibits the growth and the activity of the synovial fibroblast, which is the cause of the rheumatism, thereby having a remedial effect for rheumatism.
  • the compound of the present invention expresses inhibiting activity of the MMP-1 (matrix metalloproteinase-1) in the synovial fibroblast, it has a treatment activity of arthritis.
  • Figure 8 shows that a commonly- used Northern blotting was performed on the synovial fibroblast processed with the representative compound (100 of Table 6) of the present invention and an MMP-1 m-RNA was quantitatively measured. Moreover, it is also shown that MMP-1 expression in the synovial fibroblast was considerably inhibited by the compound of the present invention. This fact verifies that the compound of the present invention is usable as a treatment for rheumatism according to its inhibition of the kinase activity of the DDR2, and that the compound of the present invention can also be used as a treatment for a malignant tumor by inhibiting expression of the MMP-1 based on the fact that the activity of the MMP- 1 is critical for spread of various cancers.
  • Example 3 Preparation of alpha-bromoketone-based compound (compound 111) (1) 2-bromo-4'-chlorofuropiophenone (compound Hid) 50ml of acetic acid was added dropwiselyly to 16.86g of 4'- chlorofuropiophenone and was cooled at 0°C before 5.14ml (0.1 mol) of brome was slowly added dropwiselyly. The resultant mixture was stirred at a room temperature for two hours, to which 270ml of water was added, filtered, washed with a sufficient amount of water and then dried to obtain a white solid product of 24.13g of 2-bromo-4'-chlorofuropiophenone(llld).
  • the resultant mixture was cooled at a room temperature and water was added thereto, from which an organic layer was extracted with diethylether twice or three times.
  • the obtained organic layer was dried, condensed, and then, purified by column chromatography to obtain 27.6g of white solid product of 4'- phenoxyfuropiophenone.
  • a starting material IV was prepared by the following Reaction Formula 5: [Reaction Formula 5]
  • Example 4 Preparation of alpha-hvdroxyketone-based (compound V) compound (1)
  • Preparation of 4,4'-dichlorobenzoin (Vv) 120 ml of ethyl alcohol was added dropwisely to 14 g (0.1 mol) of chlorobenzaldehyde, to which 14.98 g (0.23 mol) solution obtained by dissolving potassium cyanide (KCN) in 10 ml of water was slowly added, and heated and refluxed for 12 hours.
  • KCN potassium cyanide
  • the resultant mixture was cooled at a room temperature and water was added thereto, which was then filtered, dried and then re- crystalized or purified by column chromatography to obtain a light yellow solid product of 4,4'-dichlorobenzoin (Vv).
  • Example 5 Preparation of 2-amino-3-furonitril-based compound (compound IV) (1) Preparation of 2-amino-3-cyano-5-(4-chlorophenyl)furan (IVa) 20 ml of dimethylformamide (DMF) was added dropwisely to the 11.67g (50 mmol) of 2-bromo-4'-chloroacetophenone(llla) obtained in Example 3 and 3.3 g (50 mmol) of malononitril (CH2((CN)2), which was then cooled at 0°C, and 15.5 ml (150 mmol) of diethylamine was slowly added thereto for about 30 minutes.
  • DMF dimethylformamide
  • Example 6 Preparation of 4-amino furopyrimidine-based compound 4- amino-6-(4-chlorophenyl)furof2,3,d]pyrimidine (Via) 20ml of formamide was applied dropwisely to the 4.37 g (20 mmol) of 2- amino-3-cyano-5-(4-chlorophenyl)furan (IVa) obtained in Example 5, which was heated and refluxed for 12 hours and then cooled at a room temperature. 100 ml of water was added thereto, and a generated solid was filtered, which was washed with water and n-hexane sufficiently, and then, dried.
  • Via 20ml of formamide was applied dropwisely to the 4.37 g (20 mmol) of 2- amino-3-cyano-5-(4-chlorophenyl)furan (IVa) obtained in Example 5, which was heated and refluxed for 12 hours and then cooled at a room temperature. 100 ml of water was added thereto, and a generated solid was filtered
  • Example 7 Preparation of 4-chloro furopyrimidine-based compound 4- chloro-6-(4-chlorophenyl)furor2,3,d1pyrimidine (Vila) 50ml of chloroform was applied dropwisely to the 7.37 g (30 mmol) of 4- amino-6-(4-chlorophenyl)-furo[2,3,d]pyrimidine (Via) obtained in Example 6, and 8.6 ml (65.1 mmol) of isoamilnitrite was added thereto, which was then heated and refluxed for 14 hours.
  • Example 8 Preparation of 4,5,6-substituted furopyrimidine-based compound A compound furopyrimidine-based compound of the present invention was prepared by using the compound VI or VII obtained in Example 6 or 7 as a starting material. [Reaction Formula 7]
  • Example 9 A compound "A", a precursor of the compounds of the present invention, can be prepared by using the thusly-obtained compound VIII, for example, by the following Reaction Formula 8: [Reaction Formula 8]
  • Example 9-1 Preparation of 4-chloro-5-methyl-6-(4-hvdroxyphenvD furor2,3,d1pyrimidine (VIII-2) 10 ml of dichloromethane was added to 1.268g (4.6 mmol) of 4-chloro-5- methyl-6-(4-methoxyphenyl)furo[2,3,d]pyrimidine (Vile) obtained in Example 7, cooled at -78°C, to which 13.85 ml of BBr 3 (1M in dichloromethane) was slowly applied dropwisely.
  • VIII-2 4-chloro-5-methyl-6-(4-hvdroxyphenvD furor2,3,d1pyrimidine
  • Example 9-3 Preparation of 4-(3-hydroxyanilino)-5-methyl-6-[4-(2- chloroethoxy)phenvnfuror2,3,d1pyrimidine (X') 2 ml of n-butylalcohol was applied to 79 mg (0.25 mmol) of 4-chloro-5- methyl-6-[4-(2-chloroethoxy)phenyl]furo[2,3,d]pyrimidine (IX-2) obtained in Example 9-2 and 53.5 mg (0.5 mmol) of 3-aminopenol, and heated and refluxed for 4 hours. After the solvent was removed, water was applied to the resulting mixture, and an organic layer was extracted with ethylacetate twice or three times.
  • Example 9-4 Preparation of 4-(3-hvdroxyanilino)-5-methyl-6- ⁇ 4-[2-(4- molphorvnyl)ethoxy]phenyl ⁇ furo[2,3,d]pyrimidine (A-1 ) A small amount of 0.07 ml (0.8 mmol) of molphorine was added to 19 mg of 4-(3-hydroxyanilino)-5-methyl-6-[4-(2-chloroethoxy)phenylfuro ⁇ 2,3,d ⁇ pyrimidine (X-2) obtained in Example 9-3 and 7 mg (0.046 mmol) of sodium iodide (Nal), and then, stirred at 90°C for 24 hours.
  • A-1 A small amount of 0.07 ml (0.8 mmol) of molphorine was added to 19 mg of 4-(3-hydroxyanilino)-5-methyl-6-[4-(2-chloroethoxy)phenylfuro ⁇ 2,3,d ⁇ pyrimidine (X-2) obtained in Example 9-3 and
  • a compound "B,” a precursor of the compounds of the present invention, can be prepared by using the thusly-obtained compound Vlll, for example, according to the following Reaction Formula 9. [Reaction Formula 9]
  • Example 10-1 Preparation of 4-chloro-5-methyl-6-r4-(methyl 2- acetoxy)phenvnfuro ⁇ 2,3,d pyrimidine (XV-1) 336.5 mg (2.2 mmol) of methyl 2-bromoacetophenon was added to a mixture of 260.68 mg (1 mmol) of 4-chloro-5-methyl-6-(4- hydroxyphenyl)furo[2,3,d]pyrimidine (VIII-2) obtained in Example 9-1 , 716.8 g (2.2 mmol) of cesium carbonate (Cs 2 CO 3 ) and 5 ml of dimethylformamide, and then stirred at 60°C for 2 hours.
  • Cs 2 CO 3 cesium carbonate
  • Compound XV-2 1 H NMR (400 MHz CDCI 3 ) ⁇ (ppm) 8.66 (s, 1 H),
  • Example 10-2 Preparation of 4-(3-hvdroxyanilino)-5-methol-6-[4-methyl 2-acetoxytohenvHfurof2,3,d]pyrimidine (XVI'-1) 2 ml of n-butylalcohol was applied to 83.18 mg (0.25 mmol) of 4-chloro-5- methyl-6-[4-(methyl 2-acetoxy)phenyl]furo[2,3,d]pyrimidine (XVI'-1) obtained in Example 10-1 and 53.5 mg (0.5 mmol) of 3-aminophenol, and heated and refluxed for 4 hours. After the solvent was removed, water was applied thereto, and an organic layer was extracted with ethylacetate twice or three times.
  • Example 10-3 Preparation of 4-(3-hvdroxyanilino)-5-(4-chlorophenyl)-6- [4-(carboxylicmethoxy)phenv ⁇ furo[2,3,d]pyrimidine (XV1 '-2) 0.5 ml of tetrahydrofuran (THF) was added dropwisely to 24 mg (0.047 mmol) of 4-(3-hydroxyanilino)-5-(4-chlorophenyl)-6-[4-(methyl 2- acetoxy)phenyl]furo[2,3,d]pyrimidine (XVI'-2) obtained in Example 10-2, to which 0.056 ml (0.056 mmol) of 0.1 N-UOH was slowly applied dropwisely at 0°C and then stirred for 1 hour at a room temperature.
  • THF tetrahydrofuran
  • Example 11 A compound XXIII, a precursor of the compounds of the present invention, can be prepared by using the thusly obtained compound VII, for example, according to the following Reaction Formula 10. [Reaction Formula 10]
  • Example 11-1 Preparation of 4-chloro-5-bromo-6-(4- methoxyphenyl)furo[2,3,d]pyrimidine (XVIII) 25 ml of carbontetrachloride was added to 380 mg (1.46 mmol) of 4- chloro-6-(4-methoxyphenyl)furo[2,3,d]pyrimidine (Vllb) obtained in Example 7, 359.23 mg (1.53 mmol) of N-bromosuccinimide and 47.5 mg (0.146 mmol) of ⁇ , ⁇ '-azobis (isobutylonitril), and stirred and refluxed for 12 hours.
  • Example 11-2 4-chloro-5-bromo-6-(4- hvdroxyphenyl)furor2,3,d1pyrimidine (Vlll-3) 4-chloro-5-bromo-6-(4-hydroxyphenyl)furo[2,3,d]pyrimidine (Vlll-3) was obtained by proceeding in the same manner as Example 9-1.
  • Table 7 shows analysis results of the thusly-obtained compound.
  • Example 11-3 Preparation of 4-(3-hydroxyanilino)-5-bromo-6- ⁇ 4-[3-(3- methylpiperidinyl)ethoxy]phenyl ⁇ furo[2,3,d]pyrimidine (A-12) 4-(3-hydroxyanilino)-5-bromo-6- ⁇ 4-[2-(3- methylpiperidinyl)ethoxy]phenyl ⁇ furo[2,3,d]pyrimidine (A-12) was obtained by sequentially performing Examples 9-2, 9-3 and 9-4. Tables 8-1 and 8-2 show analysis results of the thusly obtained compound. [Reaction Formula 11] ci
  • Example 12-1 Preparation of 4-chloro-5-bromomethyl-6-r4-(2- chloroethoxy)phenyl1furo(2,3,d)pyrimidine (IX-6)
  • Example 12-1 was performed in the same manner as Example 11-1 by using 4-chloro-5-methyl-6-[4-(2-chloroethoxy)phenyl]furo ⁇ 2,3,d ⁇ pyrimidine (IX-2) obtained in Example 9-1.
  • Example 12-2 Preparation of 4-chloro-5-methoxymethyl-6-r4-(2- chloroethoxy)phenv ⁇ furof2,3,dlpyrimidine (IX-7) 15 ml of methylalcohol was added to 160 mg (0.04 mmol) of 4-chloro-5- methyl-6-[4-(2-chloroethoxy)phenyl]furo[2,3,d]pyrimidine (IX-6) obtained in Example 9-1 , and stirred and refluxed for 6 hours.
  • Example 13 Preparation of 2,4,5,6-substituted furopyrimidine-based compound
  • Example 13-1 2-chloromethyl-4-chloro-5-methyl-6-(4- chlorophenyl)furo[2,3,d]pyrimidine (Xll-A) 2.32g (10 mmol) of 2-amino-3-cyano-5-(4-chlorophenyl)furan(IVd) obtained in Example 5 was diluted in 30 ml of dioxane, to which 0.69 ml (11 mmol) of chloroacetonitril was applied dropwisely.
  • the reaction solution was stirred while continuously generating a hydrochloric acid gas in the reaction solution at a room temperature for 6 hours, and then left as it is for 12 hours. 100 ml of water was applied to the reaction solution to generate a solid. The generated solid was filtered, sufficiently washed with water and n-hexane, and then, dried to obtain 544 g of white solid of 2-chloromethyl-4-amino-5-methyl-6- (4-chlorophenyl)furo[2,3,d]pyrimidine (Xl-A) (yield: 17%).
  • Example 13-2 2-chloromethyl-4-.3-hvdroxyanilino)-5-methyl-6-(4- chlorophenyl,furo[2,3,d1pyrimidine (141) 3 ml of n-butylalcohol was applied dropwisely to 163.8 mg (0.5 mmol) of 2-chloromethyl-4-chloro-5-methyl-6-(4-chlorophenyl)furo[2,3,d]pyrimidine (Xll-A) obtained in Example 13-1 and 109.13 mg (1 mmol) of 3-aminophenol, and heated and refluxed for 4 hours, from which the solvent was then removed.
  • Example 14 Measurement of inhibiting activity with respect to tyrosine kinase activity of DDr2 protein of the compounds of the present invention 2 ug of poly (D4Y)n (Promega, USA) or histone H2B protein at which biotin was attached as a peptide substrate was used to be reacted in a 20 ul of a mixture solution of Tris-HCl (pH 7.5), 5 mM of MgCI2 100 ng of activated DDR2 kinase enzyme protein (prepared according to the method disclosed in Korean Patent Application Nos. 2002-0067233 and 2003-0076967) for 10 to 30 minutes, to which a 30% phosphoric acid solution with 1/2 volume was applied to finish the reaction.
  • Tris-HCl pH 7.5
  • MgCI2 activated DDR2 kinase enzyme protein
  • DDR2 kinase activity portion In order to measure self-phosphorylation activity of a DDR2 kinase activity portion, it was reacted in a reaction solution excluding the peptide substrate in the above conditions, and the reactant underwent electrophoresis in 10% PAGE gel and then was stained using Kumagi dye to check existence of DDR2 kinase activity portion protein. Thereafter, the gel was dried and autoradiography was performed by using X-ray film to measure the self- phosphorylation degree of the DDR2 protein portion.
  • the compounds of the present invention can effectively inhibit the tyrosine kinase activity of DDR2 protein.
  • the present invention is expected to have a remedial treatment effect with respect to hepatocirrhosis, rheumatism and metastatic cancers caused by the tyrosine kinase activity of DDR2 protein.
  • the compound 100 in Table 6 was used as a representative compound of the compounds of the present invention, but as noted in Table 11 , the effect of the representative compound can be applied to the other compounds of the present invention.
  • a reaction speed was obtained according to the enzyme activity measurement method while changing the amount of ATP. More specifically, the substrate of each density of 0, 0.2 uM and 1.2 uM of the representative compound 100 (Table 6) and then reciprocally plotted (Lubert Stryer, 4 th revised version of biochemistry, Seoul foreign books, pp.202-205) which are generally known to check a change in a Y segment and x segment according to each density of the compounds.
  • Example 15 Measurement of Tyrosine Phosphorylation Inhibiting Activity of DDR2 Protein in HSC T6 Cell of Compounds of the Present Invention
  • Two hundred thousand HSC T6 cells (Prof. Fridman, Medical college of Mount Sini, N.Y. USA) were plated in each well of a 6-well cultivation dish, cultivated for 24 hours and processed at a 10 ug/ml density for 24 hours, or the compound (100 of Table 6) of the present invention dissolved in DMSO at a collagen 10 ug/ml density was processed according to each density (0, 5, 10 and 20 uM) for 24 hours, the cell was retrieved with a 1x lameli solution and fractured, and the cell fractured solution underwent the electrophoresis in 7% PAGE gel.
  • the developed protein of the gel was moved to a nitrocellulose paper, and western-blotted to an antibody which specially recognizes human DDR2. It was confirmed that its amount is not much different from that of DDR2 protein at a position of130,000 dalton molecular mass, and its position was checked.
  • the membrane was stripped, Western-blotted by using an antibody which specifically recognizes phosphorylated tyrosine, and it was verified that the tyrosine phosphorylation degree at a portion where the DDR2 is positioned is reduced according to a processing density of the representative compound 100 as shown in Figure 2.
  • Figure 2 It was confirmed that, like other studies reported by other researches, tyrosine phosphorlation of DDR2 was induced in the HSC T6 cell by the collagen treatment.
  • the tyrosine phosphorylation of DDR2 indicates the activity of DDR2 kinase. However, as shown in Figure 2, it was also confirmed that the tyrosine phosphorylation of the DDR2 protein according to the collagen was reduced by the treatment with the representative compound 100. Accordingly, it was confirmed that the compound of the present invention has the activity of inhibiting activation of DDR2 protein by collagen.
  • Example 16 Measurement of cell growth inhibition activity of the compounds of the present invention In order to measure the cell growth inhibition function of the compounds of the present invention, activity of a liver stellate cell HSC-T6, HT1080 and Rat2 cell was measured and compared. The cells were placed in the 96-well cultivation dish; 100 cells were placed in each well.
  • Absorbancy of the well of day 0 was set as 0%, absorbancy of the well left without the treêt of the compound for two days was set as 100%, and an absorbancy of 0 because there is no living cell in the well was set as -100%, and absorbancy at each density of each compound was calculated proportionally to indicate % of cell viability of respective compound-treated wells.
  • the cell was cultivated in 5% carbon dioxide and at a below 37°C, the HSC-T6 cell was cultivated in DMEM+10% FBS, and the remaining cells were cultivated in RPMI1640+10% FBS.
  • Figure 3 shows the results of the experimentation. As shown .
  • the compounds of the present invention exhibit relatively high growth inhibiting activity over hepatic stellate cell HSC-T6 (-•-) compared with other cells. Thus, it is confirmed that the compounds of the present invention exhibit the specific growth-inhibiting activity with the liver stellate-cell.
  • Example 17 Conformation of inducing apoptosis of the hepatic stellate cell of the compounds of the present invention
  • the compound (100 of Table 6) of the present invention dissolved in DMSO treated according to each density for the HSC T6 cell, and after 24 hours, an entire genome DNA was extracted according to a general method. The apoptosis was confirmed by measuring the degree of segmentation of DNA.
  • the extracted DNA was developed in a 1.2% agarose gel, dyed with EtBr, and the segmented DNA was observed under UV.
  • Figure 5 shows the results. As shown in Figure 5, many segmented DNAs are observed at a high processing density of the compounds of the present invention. Therefore, it is confirmed that the compounds of the present invention induces apoptosis of the HSC T6 cell.
  • Example 18 Confirmation of anti-fibrosis effect of the compounds of the present invention over liver cirrhosis
  • a bile duct of a whistar rat aged 7 weeks was sutured to induce a liver cirrhosis.
  • the compound (100 of Table 6) dissolved in DMSO at a density of 10mg/kg was injected to its tail vein every day for two weeks.
  • a rat to which only DMSO (carrier) was injected after suturing the bile duct was used, and as a normal reference group, a rat which got a placebo operation without suturing its bile duct was used.
  • collagen quantitative measurement of the liver tissue an amount of hydroxy furorin in the liver tissue was quantitatively measured using a general method. Table 12 shows the results.
  • liver cirrhosis was caused according to an increase in the number of hydroxy prolin, compared to the case where the bile duct was not sutured.
  • the case where the compound was processed shows that the increase of the hydroxy prolin is mitigated. Accordingly, it is considered that the compounds of the present invetinon have the anti-fibrous activity over the liver cirrhosis.
  • Example 19 Measurement of synovial fibroblase growth inhibiting activity of the compound of the present invention Synovial fibroblasts extracted from a rheumatism patient which has been cultivated from an animal cell cultivator at 37°C in a DMEM medium including 10% FBS while supplying 5% carbon dioxide were seeded in 24-well cultivation dish, 5000 synovial fibroblase per well, and cultivated for one more day.
  • the formalin-fixed cell was dyed in a sulferodamine B solution using a general method and the sulferodamine adsorbed in the cell was removed with 0.1 M Tris-HCl (pH 8.0), and its absorbancy was measured at the wavelength of 520 nM, to quantitatively measure the number of relative cells in each well.
  • Example 20 Measurement of effect on the MMP-1 mRNA of the compounds of the present invention Synovial fibroblasts taken from a rheumatism patient was cultivated in a dish with a diameter of 10cm with a DMEM medium including 10 % FBS under the condition of 5% CO 2 .
  • the compound of the present invention dissolved in the DMSO was treated at the density of 10 uM for 24 hours, or as a reference group, the compound was not treated and left as it is 24 hours, and then, the entire RNA of the cells in the cultivation dish were purified.
  • Triazol Reagent catalog No. 15596-026
  • RNA Isolation' method furovided when the GIBCO BRL Co. sells Triazol Reagent was taken for sepration.
  • the 10 ug of the entire purified RNA underwent electrophoresis in a formaldehyde-agarose gel, and mRNA was moved to a nitran membrane.
  • An MMP-1 probe marked with 32 P radioactive isotope was prepared by using a kit purchased from Beringer-lngelheim by using an MMP-1 c-DNA fragmentation.
  • the amount of mRNA of the MMP-1 was quantitatively measured through common northern blotting by using the prepared probe.
  • Figure 8 shows the results.
  • the compound of the present invention has the effect of reducing the amount of mRNA of the MMP-1.
  • the compound of the present invention has the remedial activity over the rheumatism caused by the incrase of the amount of MMP-1.
  • the new furopyrimidine compounds of the present invention have the excellent inhibiting activity over the tyrosine kinase activity of DDR2 protein, and thus it can be applied as a remedial agent of various illnesses caused by the tyrosine kinase activity of DDR2.
  • the compounds of the present invention can be advantageously used as a remedy for hepatocirrhosis, rheumatoid or cancer.

Abstract

L'invention concerne un composé furopyrimidine, son sel pharmaceutiquement acceptable et un inhibiteur d'activité tyrosine kinase. Le composé furopyrimidine, de formule 1, 2, 3 ou 4, ou son précurseur peuvent se présenter sous forme de base libre ou dans un sel d'addition acide. Inhibant l'activité tyrosine kinase de DDR2, ce composé furopyrimidine peut s'avérer utile dans le traitement de maladies causées par l'activité tyrosine kinase de DDR2 comme la cirrhose du foie, la polyarthrite rhumatoïde ou le cancer.
PCT/KR2005/000019 2004-03-12 2005-01-05 Compose pour inhiber l'activite tyrosine kinase de la proteine ddr2 WO2005092896A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2004-0016922 2004-03-12
KR1020040016922A KR20050091462A (ko) 2004-03-12 2004-03-12 푸로피리미딘 화합물 및 이를 포함하는 ｄｄｒ2 티로신키나아제 활성 저해제

Publications (1)

Publication Number Publication Date
WO2005092896A1 true WO2005092896A1 (fr) 2005-10-06

Family

ID=35056130

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2005/000019 WO2005092896A1 (fr) 2004-03-12 2005-01-05 Compose pour inhiber l'activite tyrosine kinase de la proteine ddr2

Country Status (2)

Country Link
KR (2) KR20050091462A (fr)
WO (1) WO2005092896A1 (fr)

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007079861A1 (fr) * 2005-12-21 2007-07-19 Bayer Healthcare Ag Nouveaux derives de furopyrimidines a substitution cyclique et leur utilisation pour traiter des maladies cardiovasculaires
WO2008001956A1 (fr) * 2006-06-29 2008-01-03 Eisai R & D Management Co., Ltd. Agent thérapeutique contre la fibrose hépatique
DE102007019691A1 (de) 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von acyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
DE102007019690A1 (de) 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von cyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
EP1992347A1 (fr) * 2007-05-18 2008-11-19 Cellzome Ag Traitement de cancer positif DDR1
DE102007027800A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte bicyclische Heteroaryl-Verbindungen und ihre Verwendung
DE102007027799A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte Furopyrimidine und ihre Verwendung
DE102007054786A1 (de) 2007-11-16 2009-05-20 Bayer Healthcare Ag Trisubstituierte Furopyrimidine und ihre Verwendung
JP2009520713A (ja) * 2005-12-21 2009-05-28 バイエル・ヘルスケア・アクチェンゲゼルシャフト 新規非環状置換フロピリミジン誘導体および心臓血管疾患を処置するためのその使用
US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US7994159B2 (en) 2003-03-10 2011-08-09 Eisai R&D Management Co., Ltd. c-Kit kinase inhibitor
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
US8138194B2 (en) 2008-04-30 2012-03-20 National Health Research Institutes Fused bicyclic pyrimidine compounds as aurora kinase inhibitors
US8212045B2 (en) 2007-09-21 2012-07-03 Array Biopharma, Inc. Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US8652472B2 (en) 2006-12-05 2014-02-18 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
WO2014032755A2 (fr) 2012-08-29 2014-03-06 Merck Patent Gmbh Inhibiteurs de ddr2 pour le traitement de l'arthrose
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US8916555B2 (en) 2012-03-16 2014-12-23 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
US8962655B2 (en) 2007-01-29 2015-02-24 Eisai R&D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006252B2 (en) 2008-09-26 2015-04-14 National Health Research Institutes Fused multicyclic compounds as protein kinase inhibitors
US9006256B2 (en) 2006-05-18 2015-04-14 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US9012458B2 (en) 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9334239B2 (en) 2012-12-21 2016-05-10 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9499856B2 (en) 2012-04-02 2016-11-22 The Board Institute, Inc. DDR2 mutations in squamous cell lung cancer
US9540351B2 (en) 2013-09-18 2017-01-10 Axikin Pharmaceuticals, Inc. Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
US9546163B2 (en) 2014-12-23 2017-01-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
WO2020207570A1 (fr) * 2019-04-09 2020-10-15 Rottapharm Biotech S.R.L. Phénazines servant d'inhibiteurs de récepteurs 2 à domaine discoïdine (ddr2)
RU2746423C2 (ru) * 2019-09-02 2021-04-13 Общество с ограниченной ответственностью "Научно-исследовательский институт ХимРар" (ООО "НИИ ХимРар") Ингибитор вируса гепатита В (ВГВ)
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
WO2021239643A1 (fr) 2020-05-25 2021-12-02 Chiesi Farmaceutici S.P.A. Dérivés de benzylamine en tant qu'inhibiteurs de ddr
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
EP4032896A1 (fr) * 2021-01-20 2022-07-27 Fundación del Sector Público Estatal Centro Nacional de Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thiazolopyrimidinones en tant qu'inhibiteurs de ddr1/2 et leurs utilisations thérapeutiques
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013151677A1 (fr) * 2012-04-02 2013-10-10 Broad Institute, Inc. Mutations touchant le gène ddr2 et cancer

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092603A1 (fr) * 2001-05-14 2002-11-21 Novartis Ag Oxazolopyrimidines et furopyrimidines et utilisation dans des agents pharmaceutiques contre les tumeurs
WO2003018589A1 (fr) * 2001-08-22 2003-03-06 Bayer Healthcare Ag Nouvelles 4-aminofuropyrimidines et leur utilisation
WO2003022852A2 (fr) * 2001-09-11 2003-03-20 Smithkline Beecham Corporation Composes chimiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092603A1 (fr) * 2001-05-14 2002-11-21 Novartis Ag Oxazolopyrimidines et furopyrimidines et utilisation dans des agents pharmaceutiques contre les tumeurs
WO2003018589A1 (fr) * 2001-08-22 2003-03-06 Bayer Healthcare Ag Nouvelles 4-aminofuropyrimidines et leur utilisation
WO2003022852A2 (fr) * 2001-09-11 2003-03-20 Smithkline Beecham Corporation Composes chimiques

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US8372981B2 (en) 2000-10-20 2013-02-12 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US7994159B2 (en) 2003-03-10 2011-08-09 Eisai R&D Management Co., Ltd. c-Kit kinase inhibitor
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
US9504746B2 (en) 2004-09-17 2016-11-29 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006240B2 (en) 2005-08-02 2015-04-14 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
TWI405764B (zh) * 2005-12-21 2013-08-21 拜耳智慧財產有限公司 新穎之經非環取代之呋喃并嘧啶衍生物及其用途
US8324222B2 (en) 2005-12-21 2012-12-04 Bayer Intellectual Property Gmbh Cyclically substituted furopyrimidine derivatives and use thereof
JP2009520713A (ja) * 2005-12-21 2009-05-28 バイエル・ヘルスケア・アクチェンゲゼルシャフト 新規非環状置換フロピリミジン誘導体および心臓血管疾患を処置するためのその使用
JP2009523711A (ja) * 2005-12-21 2009-06-25 バイエル・ヘルスケア・アクチェンゲゼルシャフト 新規環状置換フロピリミジン誘導体および心臓血管疾患を処置するためのその使用
WO2007079861A1 (fr) * 2005-12-21 2007-07-19 Bayer Healthcare Ag Nouveaux derives de furopyrimidines a substitution cyclique et leur utilisation pour traiter des maladies cardiovasculaires
US8183246B2 (en) 2005-12-21 2012-05-22 Bayer Intellectual Property Gmbh Acyclically substituted furopyrimidine derivatives and use thereof
US9006256B2 (en) 2006-05-18 2015-04-14 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
WO2008001956A1 (fr) * 2006-06-29 2008-01-03 Eisai R & D Management Co., Ltd. Agent thérapeutique contre la fibrose hépatique
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US8652472B2 (en) 2006-12-05 2014-02-18 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer
US8962655B2 (en) 2007-01-29 2015-02-24 Eisai R&D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
WO2008131858A2 (fr) * 2007-04-26 2008-11-06 Bayer Schering Pharma Aktiengesellschaft Utilisation de dérivés de furopyrimidine à substitution acyclique dans le traitement de l'hypertonie artérielle pulmonaire
WO2008131858A3 (fr) * 2007-04-26 2009-07-16 Bayer Schering Pharma Ag Utilisation de dérivés de furopyrimidine à substitution acyclique dans le traitement de l'hypertonie artérielle pulmonaire
WO2008131859A2 (fr) * 2007-04-26 2008-11-06 Bayer Schering Pharma Aktiengesellschaft Utilisation de dérivés de furopyrimidine à substitution cyclique dans le traitement de l'hypertonie artérielle pulmonaire
DE102007019690A1 (de) 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von cyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
WO2008131859A3 (fr) * 2007-04-26 2009-07-16 Bayer Schering Pharma Ag Utilisation de dérivés de furopyrimidine à substitution cyclique dans le traitement de l'hypertonie artérielle pulmonaire
DE102007019691A1 (de) 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von acyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
WO2008141796A1 (fr) * 2007-05-18 2008-11-27 Cellzome Ag Traitement d'un cancer ddr1-positif à l'aide d'imatinib
EP1992347A1 (fr) * 2007-05-18 2008-11-19 Cellzome Ag Traitement de cancer positif DDR1
DE102007027799A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte Furopyrimidine und ihre Verwendung
DE102007027800A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte bicyclische Heteroaryl-Verbindungen und ihre Verwendung
WO2008155016A1 (fr) * 2007-06-16 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Furopyrimidines substituées et leur utilisation
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9079890B2 (en) 2007-09-21 2015-07-14 Array Biopharma Inc. Intermediates for the preparation of pyridin-2-yl-amino-1,2,4-thiadiazole derivatives
US8212045B2 (en) 2007-09-21 2012-07-03 Array Biopharma, Inc. Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US8853409B2 (en) 2007-09-21 2014-10-07 Array Biopharma Inc. Pyridin-2yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
DE102007054786A1 (de) 2007-11-16 2009-05-20 Bayer Healthcare Ag Trisubstituierte Furopyrimidine und ihre Verwendung
US8138194B2 (en) 2008-04-30 2012-03-20 National Health Research Institutes Fused bicyclic pyrimidine compounds as aurora kinase inhibitors
US9006252B2 (en) 2008-09-26 2015-04-14 National Health Research Institutes Fused multicyclic compounds as protein kinase inhibitors
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9012458B2 (en) 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US9382237B2 (en) 2012-03-16 2016-07-05 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9365556B2 (en) 2012-03-16 2016-06-14 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9346792B2 (en) 2012-03-16 2016-05-24 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US8916555B2 (en) 2012-03-16 2014-12-23 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9499856B2 (en) 2012-04-02 2016-11-22 The Board Institute, Inc. DDR2 mutations in squamous cell lung cancer
US10385403B2 (en) 2012-04-02 2019-08-20 The Broad Institute, Inc. DDR2 mutations in squamous cell lung cancer
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
WO2014032755A2 (fr) 2012-08-29 2014-03-06 Merck Patent Gmbh Inhibiteurs de ddr2 pour le traitement de l'arthrose
US9334239B2 (en) 2012-12-21 2016-05-10 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US9540351B2 (en) 2013-09-18 2017-01-10 Axikin Pharmaceuticals, Inc. Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
US10407393B2 (en) 2014-08-28 2019-09-10 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11186547B2 (en) 2014-08-28 2021-11-30 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10513499B2 (en) 2014-08-29 2019-12-24 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US9546163B2 (en) 2014-12-23 2017-01-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9730914B2 (en) 2014-12-23 2017-08-15 Axikin Pharmaceuticals 3,5-diaminopyrazole kinase inhibitors
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
WO2020207611A1 (fr) * 2019-04-09 2020-10-15 Rottapharm Biotech S.R.L. Phénazines servant d'inhibiteurs de récepteurs 2 à domaine discoïdine (ddr2)
WO2020207570A1 (fr) * 2019-04-09 2020-10-15 Rottapharm Biotech S.R.L. Phénazines servant d'inhibiteurs de récepteurs 2 à domaine discoïdine (ddr2)
RU2746423C2 (ru) * 2019-09-02 2021-04-13 Общество с ограниченной ответственностью "Научно-исследовательский институт ХимРар" (ООО "НИИ ХимРар") Ингибитор вируса гепатита В (ВГВ)
WO2021239643A1 (fr) 2020-05-25 2021-12-02 Chiesi Farmaceutici S.P.A. Dérivés de benzylamine en tant qu'inhibiteurs de ddr
EP4032896A1 (fr) * 2021-01-20 2022-07-27 Fundación del Sector Público Estatal Centro Nacional de Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thiazolopyrimidinones en tant qu'inhibiteurs de ddr1/2 et leurs utilisations thérapeutiques
WO2022157166A1 (fr) * 2021-01-20 2022-07-28 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thiazolopyrimidones en tant qu'inhibiteurs de ddr1/2 et leurs utilisations thérapeutiques

Also Published As

Publication number Publication date
KR100883909B1 (ko) 2009-02-17
KR20070012648A (ko) 2007-01-26
KR20050091462A (ko) 2005-09-15

Similar Documents

Publication Publication Date Title
WO2005092896A1 (fr) Compose pour inhiber l'activite tyrosine kinase de la proteine ddr2
CN103450077B (zh) IRE-1α抑制剂
US5770603A (en) Quinazoline derivatives
US8592430B2 (en) Quinazolin-oxime derivatives as Hsp90 inhibitors
JP4845736B2 (ja) プロテインキナーゼ阻害剤
CN100381428C (zh) 喹唑啉酮类化合物及应用
CA2317589C (fr) Composes heteroaromatiques bicycliques agissant comme inhibiteurs de la tyrosine kinase
WO2006116733A2 (fr) Inhibiteurs des proteines kinases
CN1989131A (zh) 取代的噻吩衍生物用作抗癌药
CA2450934A1 (fr) Inhibiteurs pyrimidine de la phosphodiesterase (pde) 7
CN101948425A (zh) 作为糖皮质激素配体的化合物、包含它们的药物组合物、试剂盒及其制备方法
CN109721600A (zh) 一类含氮稠环化合物及其制备方法和用途
WO2021017996A1 (fr) Composé de phénylpipérazine quinazoline ou sel pharmaceutiquement acceptable de celui-ci, procédé de préparation correspondant et utilisation associée
EP2496230B1 (fr) Inhibiteurs de l'ire-1 alpha
JP4564713B2 (ja) 窒素性複素環式化合物、ならびに窒素性複素環式化合物およびその中間体を作製するための方法
EP0580753B1 (fr) Derives de pyrimidine permettant de stimuler l'activite antitumorale
WO2004080979A1 (fr) Nouveaux derives de 3-(2-amino-4-pyrimidinyl)-4-hydroxyphenyl cetone
WO2010064737A1 (fr) Composé hétérocyclique et son utilisation
WO2008149311A1 (fr) Utilisation de dérivés de la 3-oxo-2,3-dihydro-5h-thiazolo[3,2-a]pyrimidine ou de la 3-oxo-2,3-dihydro-5h-sélénazolo[3,2-a]pyrimidine ou de la 3-oxo-1,2,3-trihydro-5h-imidazolo[1,2-a]pyrimidine pour la préparation de compositions pharmaceutiques destinées au traitement du cancer
SK125299A3 (en) Novel carboxylic acid derivatives, their preparation and use in treating cancer
CN110229172B (zh) 一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用
CN115093419A (zh) 一种嘧啶酮类化合物及其制备方法和医药应用
CN101302204A (zh) 喹唑啉酮类化合物、包含该化合物的组合物及应用
CZ324199A3 (cs) Léčivo k zabránění růstu solidního tumoru u člověka a způsob jeho výroby

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1020067018588

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

WWP Wipo information: published in national office

Ref document number: 1020067018588

Country of ref document: KR

122 Ep: pct application non-entry in european phase
WWE Wipo information: entry into national phase

Ref document number: 2194/KOLNP/2007

Country of ref document: IN