WO2000059541A1 - Agents prophylactiques ou therapeutiques contre le cancer et leur procede de criblage - Google Patents

Agents prophylactiques ou therapeutiques contre le cancer et leur procede de criblage Download PDF

Info

Publication number
WO2000059541A1
WO2000059541A1 PCT/JP2000/001302 JP0001302W WO0059541A1 WO 2000059541 A1 WO2000059541 A1 WO 2000059541A1 JP 0001302 W JP0001302 W JP 0001302W WO 0059541 A1 WO0059541 A1 WO 0059541A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
undifferentiated
cells
screening method
Prior art date
Application number
PCT/JP2000/001302
Other languages
English (en)
Japanese (ja)
Inventor
Yasuhisa Fukui
Sayoko Ihara
Satoshi Nagata
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Publication of WO2000059541A1 publication Critical patent/WO2000059541A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to an agent for preventing or treating cancer based on a novel effect and a method for screening the same.
  • non-invasive cancer which has a low metastatic potential and can be easily removed by surgical operation
  • invasive cancer with high metastatic potential which is difficult to treat surgically
  • a p38 inhibitor inhibits the conversion of differentiated cancer cells into undifferentiated cancer cells, while differentiating undifferentiated cancer cells. It was discovered that p38 inhibitors are effective as prophylactic or therapeutic agents for cancer, especially undifferentiated cancer. Further, the present inventors have developed a screening method using such a mechanism as an index based on the differentiation state of cancerous cells, particularly the differentiation state of p38 tyrosine phosphorylated cancer cells. It has been discovered that the resulting compound is effective as a prophylactic or therapeutic agent for cancer, and that it can convert undifferentiated cancer cells into differentiated cancer cells by inhibiting p38. The present invention has been completed.
  • the present invention provides (1) a cancer preventive or therapeutic agent containing P 38 inhibitor, (2) a preventive or therapeutic agent for undifferentiated carcinoma containing p38 inhibitor, (3) Not A prophylactic or therapeutic agent for a cancer containing a p38 inhibitor characterized by converting a differentiated cancer into a differentiated cancer, and (4) a p38 inhibitor characterized by inhibiting the development of an undifferentiated cancer.
  • a prophylactic or therapeutic agent for cancer comprising a compound obtained by using the screening method of (5) or (6) as an active ingredient, and (11) inhibiting the development of undifferentiated cancer.
  • a prophylactic or therapeutic agent for cancer containing a compound obtained by using the screening method of (5) or (6) as an active ingredient, and (12) undifferentiated cancer cells are differentiated cancer cells. This is a method of inhibiting p38 when converting to cells.
  • the p38 inhibitor of the present invention is not particularly limited as long as it has a p38 inhibitory action.
  • a 5-membered ring is used.
  • Including teloaryl the following general formula
  • A represents a nitrogen atom or a CH group
  • B represents a nitrogen atom or a CH group
  • X represents a nitrogen atom, an oxygen atom, a sulfur atom, a carbon atom, a CH group or an NH group
  • Y represents a nitrogen atom
  • R 1 represents an alkyl group
  • R 2 represents a hydrogen atom, an alkyl group which may have a substituent, an alkylthio group, an alkylsulfinyl group, an aryl group or a substituent which may have a substituent
  • R 3 represents a hydrogen atom, an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent
  • R 4 represents a hydrogen atom, an alkoxy group, substituted showing also an amino group.
  • the form of R 2 and R 3 are fused ring May be.
  • halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom Or an iodine atom, preferably a fluorine atom.
  • alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butynole, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-pentyl Ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1
  • a linear or branched alkyl group having 1 to 6 carbon atoms such as 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl; From 4 to 4 linear or branched alkyl groups.
  • cycloalkyl group refers to an optionally condensed 3- to 10-membered ring such as cyclopropyl, cyclopentinole, cyclopentinole, cyclohexinole, cycloheptyl, nonorebornyl, and adamantyl
  • a saturated cyclic hydrocarbon group can be mentioned, and a 5- to 10-membered saturated cyclic hydrocarbon group is preferred.
  • alkylthio group refers to a group in which the above “alkyl group” is bonded to a sulfur atom.
  • thio, 2,3-dimethylbutylthio, 2-ethylbutylthio It represents a linear or branched alkylthio group having 1 to
  • alkylsulfinyl group refers to a group in which the above “anolealkyl group” is bonded to a sulfier group, such as methylsulfinyl, ethinolesulfiel, n-propinolesnorfeienole, isopropynole Sulfinyl, n-butynoresulfinyl, Isobutylsulfiel, s-butylsulfinyl, tert-butylsulfiel, n-pentylsulfenyl, isopentylsulfinyl, 2-methylbutylsulfininole, neopentinoles refininole, 1-ethinolepropinoles nofinini Nore, n-hexinolesulfininole, isohexylsulfinyl, 4-methinolepentylsul
  • alkoxy group means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, tert-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexoxy, 4-ethoxy Methynorpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethyl It may be a linear or branched alkoxy group having 1 to 6 carbon atoms such as butoxy or 2,3-dimethylbutoxy, and is preferably a methoxy group, an ethoxy group or a tert-butoxy group.
  • the “aryl group” includes, for example, an aromatic hydrocarbon group having 5 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl, and anthracenyl, and is preferably a phenyl group.
  • the screening method of the present invention which is a screening method using the differentiation state of cancerous cells as an index
  • a method described in the literature eg, J. Biol. Chem. 27, 16089 (1997), etc.
  • HCC2998 or MKN45 which is a differentiated cancer cell line
  • Cre_Adenovirus Cre recombinase Denouinores
  • the screening method of the present invention is performed by comparing the differentiation state of cells obtained by culturing a cancer cell line expressing active PI3 kinase in the presence or absence of a test compound in the presence of Cre-Adenovirus.
  • the screening method of the present invention can be carried out by using NUGC4, an undifferentiated cancer cell line, by comparing the differentiation state of cells cultured in the presence or absence of a test compound.
  • the present inventors have shown for the first time that the cell line NUGC4 that can be used in the present invention has enhanced p38 tyrosine phosphorylation.
  • the cell line NUGC4 used in the present invention is available from the Medical Cell Resource Center attached to the Tohoku University Institute of Aging and Medicine, under the number TKG0049, and the cell line MKN45 is number JCRB0254, under the Human Science Foundation Available from the Science Research Resource Bank.
  • the means for judging the differentiation state means judging a differentiated cell and an undifferentiated cell.
  • a means for judging is used in the screening method.
  • compositions of the present invention include oral administration with tablets, capsules, granules, powders or syrups, and parenteral administration with injections or suppositories.
  • excipients e.g., lactose, sucrose, dextrose, saccharides such as mannitol, sorbitol; corn starch, non-starch starch, starch derivatives such as alpha starch, dextrin; Cell mouth-Derivatives; Gum arabic; Dextran; Organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminium; calcium hydrogen phosphate Phosphate such as calcium carbonate such as calcium carbonate; sulfate such as calcium sulfate.
  • Lubricants eg, stearic acid metal salts such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silica; waxes such as bi-gum, gay; boric acid; adipic acid; sodium sulfate Sulphate such as sodium; dalicol; fumaric acid; sodium benzoate; DL leucine; sodium fatty acid salt; lauryl sulphate such as sodium lauryl sulphate, magnesium lauryl sulphate; And silicic acids; and the above-mentioned starch derivatives.
  • Binders eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same as the above-mentioned excipients
  • disintegrants eg, Low-substituted hydroxypitol mouth pinoresenorelose, canolebox
  • the amount used depends on the symptoms, age, administration method, etc.
  • the lower limit is 0.1 Ol mgZkg (preferably 0.1 mgZkg) per day for adults per day.
  • As an upper limit it is desirable to administer 5 OmgZkg (preferably 1 OmgZkg) once or in several divided doses according to the symptoms.
  • the lower limit is 0.0 lmgZkg (preferably 0.01 mg / kg) and the upper limit is 1 Omg kg (preferably 5 mgZkg) per day for adults. It is desirable to administer the drug once or several times depending on the symptoms.
  • HCC2998 In the absence of Compound A, HCC2998 is converted to undifferentiated form along with the expression of active PI3 kinase (upper panel), whereas in the presence of Compound A, conversion to undifferentiated form is inhibited (Lower row).
  • Lacz indicates a cell line that does not express active PI3
  • Cre indicates a cell line that expresses active PI3.
  • MKN45 is converted to undifferentiated form along with the expression of active PI3 kinase (upper row), whereas in the presence of Compound A, conversion to undifferentiated form is inhibited. Harm (lower).
  • Lacz indicates a cell line that does not express active PI3
  • Cre indicates a cell line that expresses active PI3.
  • the HCC2998 / BD110 cells were cultured in RPMI1640 (10% calf serum added) to 1X10 5 cells 3cm petri dish, after 1 day at mo i. 50 infecting Cre-Adenovirus. At this time, a morphological change is observed between the case where the test compound is present and the case where the test compound is not present.
  • Compounds that prevent the transition to the undifferentiated form are selected as preventive or therapeutic agents for cancer.
  • MKN45 / BD110 cells are cultured in RPMI 1640 (10% calf serum added) on 5 1 ⁇ 10 3 cm dishes, and infected with Cre-Adenovirus at mo i. 50 one day later. At this time, a morphological change is observed between the presence and absence of the test compound.
  • Compounds that inhibit the transition to undifferentiated form are selected as preventive or therapeutic agents for cancer.
  • NUGC4 a 1X10 to five 3cm petri dishes in RPMI 1640 (10% calf serum added), test compound was added, and the mixture was cultured for 10 B.
  • the compounds that allow the cells to adhere to the organ wall and shift to a differentiated cancer cell-like morphology are selected as cancer preventive or therapeutic agents.
  • NUGC4 was cultured in RPMI1640 (10% calf serum added) on 5 1 ⁇ 10 3 cm dishes, and cultured for 10 days after adding the p38 inhibitor. The cells become attached to the organ wall and adopt a differentiated cancer cell-like morphology.
  • the MKN45 / BD110 cells are cultured in RPMI 1640 (10% calf serum added) on 5 1 ⁇ 10 3 cm dishes, and infected with Cre-Adenovirus one day later at moi 50. At this time, the morphological changes in the presence and absence of the p38 inhibitor are observed. Addition of the p38 inhibitor blocks the transition to the undifferentiated form.
  • NUGC4 was cultured in RPMI1640 (containing 10% calf serum) in 5 1 ⁇ 10 3 cm dishes, and cultured for 10 days after adding Compound A. The cells began to adhere to the organ wall and took on a differentiated cancer cell-like morphology.
  • HCC2998 / BD110 cells are cultured in RPMI1640 (10% calf serum added) on 5 1 ⁇ 10 3cm dishes, and infected with Cre-Adenovirus at mo i. 50 one day later. At this time, a morphological change is observed between the compound A and the compound A. Addition of compound A prevented the transition to the undifferentiated form.
  • RPMI1640 10% calf serum added
  • MKN45 / BD110 cells are cultivated in RPMI 1640 (10% calf serum added) on 5 1 ⁇ 10 3 cm dishes, and infected with Cre-Adenovirus at moi 50 one day later. At this time, a morphological change is observed between the case where compound A is present and the case where compound A is not present. Addition of compound A prevented the transition to the undifferentiated form. [Figure 3]
  • Total proteins (50 micrograms) of the undifferentiated cancer cell lines NUGC4, ⁇ 0 ⁇ and other differentiated gastric cancer cell lines SCH and SH10-TC were electrophoresed on a 10% polyacrylamide gel and subjected to Western blotting. After blocking with buffer containing 3% skimmed milk (isotonic Tris buffer containing 1% tween20), the activated P 38 using Chiro forest oxide p38 antibody in the same solution, also using p38 antibody It detected t undifferentiated cell lines specifically activate the p38 and p38 Te is seen.
  • a mixture of Compound A in a digestible oil compound such as soybean oil, cottonseed oil or olive oil, is prepared and injected into gelatin with a positive displacement pump to give soft capsules containing 100 mg of active ingredient. After washing, dry.
  • a digestible oil compound such as soybean oil, cottonseed oil or olive oil
  • the composition containing the p38 inhibitor of the present invention can convert undifferentiated cancer cells into differentiated cancer cells or convert differentiated cancer cells into undifferentiated cells by inhibiting p38. Inhibiting this can prevent and treat cancer.
  • the method for screening a compound using the differentiation state of cancerous cells as an indicator of the present invention is useful as a method for screening a drug for preventing or treating cancer.
  • the method for screening a compound using the indicator of the differentiation state of cancerous cells having enhanced p38 tyrosine phosphorylation as an indicator according to the present invention is useful as a method for screening a drug for preventing or treating cancer.
  • compounds obtained by these screening methods are useful as preventive or therapeutic agents for cancer.
  • the p38 inhibition method of the present invention is useful as a method for converting undifferentiated cancer cells to differentiated cancer cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux agents thérapeutiques contre le cancer et un procédé servant à les préparer. Elle concerne des agents prophylactiques ou thérapeutiques contre le cancer contenant des inhibiteurs de p38, ainsi qu'un procédé servant à cribler un composé et basé sur l'état de différenciation des cellules cancéreuses.
PCT/JP2000/001302 1999-03-30 2000-03-03 Agents prophylactiques ou therapeutiques contre le cancer et leur procede de criblage WO2000059541A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11089803A JP2000281588A (ja) 1999-03-30 1999-03-30 ガンの予防又は治療薬及びそのスクリーニング方法
JP11/89803 1999-03-30

Publications (1)

Publication Number Publication Date
WO2000059541A1 true WO2000059541A1 (fr) 2000-10-12

Family

ID=13980887

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/001302 WO2000059541A1 (fr) 1999-03-30 2000-03-03 Agents prophylactiques ou therapeutiques contre le cancer et leur procede de criblage

Country Status (2)

Country Link
JP (1) JP2000281588A (fr)
WO (1) WO2000059541A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047266A1 (fr) * 2003-11-14 2005-05-26 Lorus Therapeutics Inc. Imidazoles d'aryle et leur utilisation comme agents anticancereux
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
US7884120B2 (en) 2002-08-19 2011-02-08 Lorus Therapeutics Inc. 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents
US8148392B2 (en) 2005-05-25 2012-04-03 Lorus Therapeutics Inc. 2-indolyl imidazo [4,5-d] phenanthroline derivatives and their use in the treatment of cancer
US9309247B2 (en) 2013-03-20 2016-04-12 Lorus Therapeutics Inc. 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer
US11104957B2 (en) 2013-10-04 2021-08-31 Aptose Biosciences, Inc. Compositions and methods for treating cancers
US11149047B2 (en) 2017-10-30 2021-10-19 Aptose Biosciences, Inc. Aryl imidazoles for treatment of cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027098A1 (fr) * 1996-12-18 1998-06-25 Vertex Pharmaceuticals Incorporated AZOTE SUBSTITUEE CONTENANT DES HETEROCYCLES INHIBITEURS DE PROTEINE KINASE p38
WO1998052937A2 (fr) * 1997-05-22 1998-11-26 G.D. Searle And Co. PYRAZOLES 3(5)-HETEROARYL SUBSTITUEES UTILISEES COMME INHIBITEURS DE KINASE p38
WO1999000357A1 (fr) * 1997-06-27 1999-01-07 Vertex Pharmaceuticals Incorporated INHIBITEURS DE p38
WO1999010325A1 (fr) * 1997-08-06 1999-03-04 Glaxo Group Limited Derives de benzylidene-1,3-dihydro-indol-2-one utilises comme inhibiteurs des tyrosine-recepteur-kinases, notamment des raf-kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027098A1 (fr) * 1996-12-18 1998-06-25 Vertex Pharmaceuticals Incorporated AZOTE SUBSTITUEE CONTENANT DES HETEROCYCLES INHIBITEURS DE PROTEINE KINASE p38
WO1998052937A2 (fr) * 1997-05-22 1998-11-26 G.D. Searle And Co. PYRAZOLES 3(5)-HETEROARYL SUBSTITUEES UTILISEES COMME INHIBITEURS DE KINASE p38
WO1999000357A1 (fr) * 1997-06-27 1999-01-07 Vertex Pharmaceuticals Incorporated INHIBITEURS DE p38
WO1999010325A1 (fr) * 1997-08-06 1999-03-04 Glaxo Group Limited Derives de benzylidene-1,3-dihydro-indol-2-one utilises comme inhibiteurs des tyrosine-recepteur-kinases, notamment des raf-kinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SIMON C. et al., "Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion", Cancer Res., March 1998, Vol. 58, No. 6, pages 1135-1139. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
US8987305B2 (en) 2002-08-19 2015-03-24 Aptose Biosciences Inc. 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents
US7884120B2 (en) 2002-08-19 2011-02-08 Lorus Therapeutics Inc. 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents
US8394815B2 (en) 2002-08-19 2013-03-12 Lorus Therapeutics Inc. 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents
JP2007511504A (ja) * 2003-11-14 2007-05-10 ローラス セラピューティクス インコーポレーテッド アリールイミダゾールおよびその抗癌剤としての使用
AU2004289539B2 (en) * 2003-11-14 2011-11-24 Lorus Therapeutics Inc. Aryl imidazoles and their use as anti-cancer agents
AU2004289539C1 (en) * 2003-11-14 2012-06-07 Lorus Therapeutics Inc. Aryl imidazoles and their use as anti-cancer agents
US8969372B2 (en) 2003-11-14 2015-03-03 Aptose Boisciences Inc. Aryl imidazoles and their use as anti-cancer agents
WO2005047266A1 (fr) * 2003-11-14 2005-05-26 Lorus Therapeutics Inc. Imidazoles d'aryle et leur utilisation comme agents anticancereux
US10080739B2 (en) 2003-11-14 2018-09-25 Aptose Biosciences Inc. Aryl imidazoles and their use as anti-cancer agents
US8148392B2 (en) 2005-05-25 2012-04-03 Lorus Therapeutics Inc. 2-indolyl imidazo [4,5-d] phenanthroline derivatives and their use in the treatment of cancer
US9309247B2 (en) 2013-03-20 2016-04-12 Lorus Therapeutics Inc. 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer
US11104957B2 (en) 2013-10-04 2021-08-31 Aptose Biosciences, Inc. Compositions and methods for treating cancers
US11149047B2 (en) 2017-10-30 2021-10-19 Aptose Biosciences, Inc. Aryl imidazoles for treatment of cancer

Also Published As

Publication number Publication date
JP2000281588A (ja) 2000-10-10

Similar Documents

Publication Publication Date Title
EP4194451A1 (fr) Inhibiteur du facteur b du complément et composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée
JP4542783B2 (ja) スルホンアミド含有複素環化合物及び血管新生抑制剤とを組み合わせてなる抗腫瘍剤
US20170260188A1 (en) Tricyclic Compounds as Inhibitors of Immunosuppression Mediated By Tryptophan Metabolization
CA2404152C (fr) Inhibition de l'activite de l'enzyme cyclooxygenase-2
US6069150A (en) Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents
WO2000059541A1 (fr) Agents prophylactiques ou therapeutiques contre le cancer et leur procede de criblage
AU2004202912A1 (en) Pyrazole compounds and uses thereof
WO2005089068A2 (fr) Compositions pharmaceutiques comprenant des derives de quinazolinecarboxamide anti-inflammatoires
JP2006290810A (ja) 糖代謝促進剤並びに肥満及び糖尿病治療薬のスクリーニング方法
JP2000355549A (ja) ガンの予防又は治療薬及びそのスクリーニング方法
US20230167120A1 (en) Aryl-fused isoselenazole compound containing tetrazine substituent, synthesis method therefor, and use thereof
CN112961159B (zh) 氨基嘧啶并吡唑/吡咯类衍生物及其制备方法和用途
US8288399B2 (en) Medicine containing pyrimidine derivative
JP2011509982A (ja) 上皮起源からのガン転移を防ぎ又は処置する為のアミノペプチダーゼインヒビター又はアザインドール化合物の使用
CN114469950A (zh) 白屈菜碱在制备flt3-itd突变的急性髓系白血病治疗药物中的应用
CN113893250A (zh) Gsk126在制备抗骨肉瘤的药物中的应用
US20070191400A1 (en) Pharmaceutical compositions comprising anti-inflammatory quinazolinecarboxamide derivatives
KR102142112B1 (ko) 골 질환 예방 또는 치료용 화합물 및 이의 용도
CN106995368B (zh) 一种非atp竞争性fgfr1抑制剂及其应用
CN111265526B (zh) 一种治疗胃癌的药物及其制备方法
JPH10511673A (ja) スクラレオリドを用いる細胞過度増殖を特徴とする病気の処置法
CN110963906B (zh) 针对Fyn-CD147信号通路靶点的抗肿瘤化合物及其制备方法和应用
CZ2002178A3 (cs) Terapeutické a profylaktické látky pro nádorová onemocnění
CN118319913A (zh) 用于治疗红细胞增多症的组合物和方法
CN117205188A (zh) 维生素k4在制备治疗黑色素瘤的药物中的应用

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA US

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)