WO2000059541A1 - Preventives or remedies for cancer and method for screening the same - Google Patents

Preventives or remedies for cancer and method for screening the same Download PDF

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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
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Prior art keywords
cancer
compound
undifferentiated
cells
screening method
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PCT/JP2000/001302
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French (fr)
Japanese (ja)
Inventor
Yasuhisa Fukui
Sayoko Ihara
Satoshi Nagata
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Sankyo Company, Limited
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Publication of WO2000059541A1 publication Critical patent/WO2000059541A1/en

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    • 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.

Abstract

[Object]: to provide novel remedies for cancer and a process for producing the remedies. [Means for Solution]: preventives or remedies for cancer containing p38 inhibitors and a method for screening a compound with the use of the differentiation state of cancer cells.

Description

明 細 書  Specification
[発明の名称]  [Title of Invention]
ガンの予防又は治療薬及びそのスクリーニング方法 Cancer preventive or remedy and screening method thereof
[技術分野]  [Technical field]
本発明は、 新規作用に基づくガンの予防又は治療薬及びそのスク リーニング方法 に関する。  The present invention relates to an agent for preventing or treating cancer based on a novel effect and a method for screening the same.
[背景技術]  [Background technology]
ガンにおいて、 転移の可能性が少なく、 外科的な手術により容易に除去可能であ る非浸潤性ガンと、 外科的な治療が困難である転移可能性の高い浸潤性ガンが臨床 病理学的に知られており、これら 2種のガンの性質はガン細胞の分化状態を反映し、 非浸潤性ガンでは分化型の細胞種、 浸潤性ガンにおいては未分化型の細胞種である と考えられている。  In cancer, non-invasive cancer, which has a low metastatic potential and can be easily removed by surgical operation, and invasive cancer with high metastatic potential, which is difficult to treat surgically, has a clinicopathological It is known that the characteristics of these two types of cancer reflect the differentiation state of cancer cells, and it is considered that non-invasive cancer is a differentiated cell type and invasive cancer is an undifferentiated cell type. I have.
しかし、 浸'驛性ガンに対する治療法は、 その転移能の高さにより完全な外科的な 除去が不可能であるため、 他の療法に頼るほかなく、 完全な治癒を期待することが できなかった。  However, the treatment of invasive cancer cannot be completely surgically removed due to its high metastatic potential, so it cannot rely on other therapies and cannot be expected to be completely cured. Was.
浸潤性ガンを外科的な治療可能な非浸潤性ガンへと転換するような薬剤、 及び、 ガン細胞が浸潤性ガンに変換されることを阻害するような薬剤は、 かかる臨床上の 治療の困難性を予防又は解決することができると考えられ、 いまだかって存在しな いこのような薬剤の開発が非常に待ち望まれていた。  Agents that convert invasive cancers into non-invasive, surgically treatable cancers and that inhibit the conversion of cancer cells to invasive cancers are difficult to treat in such clinical settings. Therefore, the development of such a drug, which does not exist yet, has been very much anticipated.
[発明の開示]  [Disclosure of the Invention]
本発明者らは、 上記課題を解決するために鋭意研究を重ねた結果、 p38 阻害剤が 分化型ガン細胞の未分化型ガン細胞への変換を阻害し、 一方、 未分化型ガン細胞を 分化型ガン細胞へと変換することを発見し、 p38 阻害剤がガン、 特に未分化型ガン の予防又は治療剤として有効であることを見いだした。 更に本発明者らは、 かかる 機作を用いてガン化細胞の分化状態、 特に p38チロシンリン酸化されたガン細胞の 分化状態を指標としたスクリ一ニング方法を開発すると共に、 スクリ一ニングによ り得られる化合物がガンの予防又は治療剤として有効であることを発見し、併せて、 p38 を阻害することにより未分化型ガン細胞を分化型ガン細胞に変換し得ること見 いだして本発明を完成するに至った。 The present inventors have conducted intensive studies to solve the above problems, and as a result, 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.
即ち、 本発明は、 （1) P38阻害剤を含有するガンの予防又は治療薬であり、 （2) p38 阻害剤を含有する未分化型ガンの予防又は治療薬であり、（3)未分化型ガンを分化型 ガンに変換することを特徴とする p38阻害剤を含有するガンの予防又は治療薬であ り、（4)未分化型ガンの発生を阻害することを特徴とする p38阻害剤を含有するガン の予防又は治療薬であり、 （5) (a)ガン化細胞を被検化合物の存在又は非存在下培養 する手段及び（b)—定時間経過後の分化状態を判定する手段からなるスクリ一ニン グ方法であり、 （6) (al) p38チロシンリン酸化が亢進したガン化細胞を被検化合物 の存在又は非存在下培養する手段及び（b)—定時間経過後の分化状態を判定する手 段からなるスクリ一二ング方法であり、（7) (5)乃至（6)のスクリ一ニング方法を用い て得られる化合物であり、 （8) (5)乃至（6)のスクリーニング方法により得られる化 合物を有効成分として含有するガンの予防又は治療薬であり、 （9) (5)乃至（6)のス クリ一二ング方法を用いて得られる化合物を有効成分として含有する未分化型ガン の予防又治療薬であり、 （10)未分化型ガンを分化型ガンに変換することを特徴とす る、 （5)乃至（6)のスク リーニング方法を用いて得られる化合物を有効成分として含 有するガンの予防薬又は治療薬であり、 (11)未分化型ガンの発生を阻害することを 特徴とする、 （5)乃至（6)のスクリ一ニング方法を用いて得られる化合物を有効成分 として含有するガンの予防又は治療薬であり、 （12)未分化型ガン細胞を分化型ガン 細胞に変換する際 p38を阻害する方法である。 That is, 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. (5) (a) means for culturing cancerous cells in the presence or absence of a test compound and (b) —determining the differentiation state after a lapse of a fixed time (6) (al) means for culturing cancerous cells with enhanced p38 tyrosine phosphorylation in the presence or absence of a test compound, and (b)- This is a screening method comprising means for determining the differentiation state, and the screening method of (7) (5) or (6) (8) a prophylactic or therapeutic agent for cancer, comprising as an active ingredient a compound obtained by the screening method of (5) to (6); It is a prophylactic or therapeutic agent for undifferentiated cancer containing a compound obtained by using the screening method of 6) as an active ingredient, and (10) is characterized by converting undifferentiated cancer to differentiated 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.
本発明の p38阻害剤は、 p38阻害作用を持つものであれば特に限定はないが、 例 えば、 Expert Opin. Ther. Patents, I, 729 (1997)に挙げられているように 5員環へ テロアリールを含むものして、 以下の一般式
Figure imgf000005_0001
The p38 inhibitor of the present invention is not particularly limited as long as it has a p38 inhibitory action. For example, as described in Expert Opin. Ther. Patents, I, 729 (1997), a 5-membered ring is used. Including teloaryl, the following general formula
Figure imgf000005_0001
(式中、 Aは窒素原子又は CH基を示し、 Bは窒素原子又は CH基を示し、 Xは窒素原 子、 酸素原子、 硫黄原子、 炭素原子、 CH基又は NH基を示し、 Yは窒素原子、 酸素原 子、 硫黄原子、 炭素原子、 CH基又は NH基を示し、 Zは窒素原子、 酸素原子、 硫黄原 子、 炭素原子、 CH基又は NH基を示し、 R1はアルキル基、 アルコキシ基又はハロゲ ン原子を示し、 R2は水素原子、 置換基を有しても良いアルキル基、 アルキルチオ基、 アルキルスルフィニル基、 置換基を有しても良いァリ一ル基又は置換基を有しても よいピペリジノ基を示し、 R3は水素原子、 置換基を有しても良いアルキル基又は置 換基を有しても良いシクロアルキル基を示し、 R4は水素原子、 アルコキシ基、 置換 基を有しても良いアミノ基を示す。 又、 R2 と R3は縮合して環を形成してもよい。） で表される化合物又はその薬理上許容される塩であり、 より好適には以下の化合物 A乃至 T (Where 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, and Y represents a nitrogen atom. Represents an atom, oxygen atom, sulfur atom, carbon atom, CH group or NH group, Z represents a nitrogen atom, oxygen atom, sulfur atom, carbon atom, CH group or NH group, and R 1 represents an alkyl group, alkoxy 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. in addition, the form of R 2 and R 3 are fused ring May be.) With a compound represented by or a pharmacologically acceptable salt thereof, more preferably the following compounds A to T
Figure imgf000006_0001
Figure imgf000006_0001
化合物 A 化合物 B 化合物 C
Figure imgf000006_0002
化合物 D 化合物 ECompound A Compound B Compound C
Figure imgf000006_0002
Compound D Compound E
Figure imgf000006_0003
Figure imgf000006_0003
化合物 G 化合物 H 化合物 I
Figure imgf000006_0004
Compound G Compound H Compound I
Figure imgf000006_0004
化合物 J 化合物 化合物し Compound J Compound Compound
Figure imgf000007_0001
Figure imgf000007_0001
化合物 M 化合物 N  Compound M Compound N
Figure imgf000007_0002
Figure imgf000007_0002
化合物 0 化合物？  Compound 0 Compound?
Figure imgf000007_0003
Figure imgf000007_0003
化合物 Q 化合物 R  Compound Q Compound R
Figure imgf000007_0004
化合物 s 化合物 T
Figure imgf000007_0004
Compound s Compound T
又はその薬理上許容される塩を挙げることができる。 Or a pharmacologically acceptable salt thereof.
上記において 「ハロゲン原子」 とは、 例えば、 フッ素原子、 塩素原子、 臭素原子 又はヨウ素原子のことをいい、 好適には、 フッ素原子である。 In the above, “halogen atom” means, for example, a fluorine atom, a chlorine atom, a bromine atom Or an iodine atom, preferably a fluorine atom.
上記において 「アルキル基」 とは、 例えば、 メチル、 ェチル、 n—プロピル、 ィ ソプロピル、 n—ブチノレ、 イソブチル、 s—ブチル、 tert—ブチル、 n—ペンチル、 イソペンチル、 2—メチルブチル、 ネオペンチル、 1—ェチルプロピル、 n—へキ シル、 イソへキシル、 4ーメチルペンチル、 3—メチルペンチル、 2—メチルペン チル、 1—メチルペンチル、 3， 3—ジメチルブチル、 2 , 2—ジメチルブチル、 1 , 1ージメチルブチル、 1， 2—ジメチルブチル、 1， 3—ジメチルブチル、 2 , 3—ジメチルブチル、 2—ェチルブチルのような炭素数 1乃至 6個の直鎖又は分枝 鎖アルキル基を示し、 好適には炭素数 1乃至 4個の直鎖又は分枝鎖アルキル基であ る。  In the above, the “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.
上記において 「シクロアルキル基」 とは、 例えば、 シクロプロピル、 シクロプチ ノレ、 シクロペンチノレ、 シク ロへキシノレ、 シクロへプチル、 ノノレボルニル、 ァダマン チルのような縮環していてもよい 3乃至 1 0員飽和環状炭化水素基を挙げることが でき、 好適には 5乃至 1 0員飽和環状炭化水素基である。  In the above, the “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.
上記において 「アルキルチオ基」 とは前記 「アルキル基」 が硫黄原子に結合した 基をいい、 例えば、 メチルチオ、 ェチルチオ、 n—プロピルチオ、 イソプロピルチ ォ、 n—ブチノレチォ、 イソブチノレチォ、 s—ブチノレチォ、 tert—ブチノレチォ、 n― ペンチノレチォ、 イソペンチノレチォ、 2—メチノレブチルチオ、 ネオペンチノレチォ、 1 ーェチノレプロピノレチォ、 n—へキシノレチォ、 イ ソへキシノレチォ、 4ーメチノレペンチ ルチオ、 3—メチルペンチルチオ、 2—メチルペンチルチオ、 1—メチルペンチル チォ、 3， 3 —ジメチルブチルチオ、 2 , 2—ジメチルブチルチオ、 1 , 1—ジメ チルブチルチオ、 1， 2 —ジメチルブチルチオ、 1， 3 —ジメチルブチルチオ、 2， 3 —ジメチルブチルチオ、 2—ェチルブチルチオのような炭素数 1乃至 6個の直鎖 又は分枝鎖アルキルチオ基を示し、 好適には炭素数 1乃至 4個の直鎖又は分枝鎖ァ ルキルチオ基である。  In the above, the “alkylthio group” refers to a group in which the above “alkyl group” is bonded to a sulfur atom. , N-pentinorethio, isopentinorethio, 2-methinolebutylthio, neopentinolethio, 1-ethinolepropinorethio, n-hexinorethio, isohexinorethio, 4-methinolepentiothio, 3-methylpentylthio , 2-Methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutyl Like thio, 2,3-dimethylbutylthio, 2-ethylbutylthio It represents a linear or branched alkylthio group having 1 to 6 carbon atoms, preferably a straight-chain or branched Kusaria alkylthio group having 1 to 4 carbon atoms.
上記において 「アルキルスルフィニル基」 とは上記 「ァノレキル基」 がスルフイエ ル基に結合した基をいい、 例えば、 メチルスルフィニル、 ェチノレスルフィエル、 n —プロピノレスノレフイエノレ、 イ ソプロピノレスルフィニル、 n—ブチノレスルフィニル、 イソブチルスルフィエル、 s—ブチルスルフィニル、 tert—ブチルスルフィエル、 n—ペンチルスルフィエル、 イソペンチルスルフィニル、 2—メチルブチルスルフ ィニノレ、 ネオペンチノレスノレフィニノレ、 1—ェチノレプロピノレスノレフィニノレ、 n—へキ シノレスルフィ二ノレ、 ィソへキシルスルフィニル、 4—メチノレペンチルスルフィ二ノレ、 3 —メチルペンチルスルフィニル、 2 _メチルペンチルスルフィニル、 1 _メチル ペンチルスルフィニル、 3 , 3 —ジメチルブチルスルフィニル、 2， 2—ジメチル ブチルスルフィ二ノレ、 1， 1ージメチノレブチルスノレフィエル、 1 , 2—ジメチノレブ チノレスノレフィニ > ^レ、 1， 3—ジメチノレブチノレスノレフイエ レ、 2 , 3—ジメチノレブチ ルスルフィニル、 2—ェチルブチルスルフィニルのような炭素数 1乃至 6個の直鎖 又は分枝鎖アルキルスルフィニル基を示し、 好適には炭素数 1乃至 4個の直鎖又は 分枝鎖アルキルスルフィエル基である。 In the above, the “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-methinolepentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3,3-dimethyl Butylsulfinyl, 2,2-dimethylbutylsulfinole, 1,1-dimethinolebutylsnorefiel, 1,2-dimethinoleb chinoresnorefini> ^ le, 1,3-dimethinolebutinoresphenol, 2,, 3-dimethynolebutyrsulfinyl, 2-ethylbutylsulfur It represents a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms such as Iniru, preferably a straight or branched chain alkyl sulfide El group of 1 to 4 carbon atoms.
上記において 「アルコキシ基」 とは、 例えば、 メ トキシ、 エトキシ、 プロポキシ、 イソプロポキシ、 ブトキシ、 イソブトキシ、 s —ブトキシ、 tert—ブトキシ、 ペン トキシ、 イソペントキシ、 2—メチルブトキシ、 ネオペントキシ、 へキシルォキシ、 4ーメチノレペントキシ、 3—メチルペントキシ、 2—メチルペントキシ、 3， 3— ジメチルブトキシ、 2 , 2—ジメチルブトキシ、 1， 1—ジメチルブトキシ、 1， 2—ジメチルブトキシ、 1 , 3 —ジメチルブトキシ又は 2 , 3—ジメチルブトキシ のよ うな炭素数 1乃至 6個の直鎖又は分枝鎖アルコキシ基であり得、 好適には、 メ トキシ基、 ェトキシ基又は tert—ブトキシ基である。  In the above, the “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.
上記において 「ァリール基」 とは、 例えば、 フエニル、 インデニル、 ナフチル、 フエナンスレニル、 アントラセニルのような炭素数 5乃至 1 4個の芳香族炭化水素 基を挙げることができ、 好適にはフエニル基である。  In the above, 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.
本発明のスクリ一二ング方法であるガン化細胞の分化状態を指標としたスクリ一 ニング方法においては、 例えば、 文献記載の方法 （例えば、 J. Biol. Chem. 27, 16089 (1997)等）に準じ、 分化型ガン細胞株である HCC2998 又は MKN45 を Cre recombinase デノウイノレス （以下、 「Cre_Adenovirus」 と ヽう。) ¾E下、 活性型 PI3 キナ一ゼを発現し得るよ う に調製した細胞株 HCC2998/BD110 又は MKN45/BD110を用いて行うことができる。 驚くべきことに、 Cre - Adenovirus存在下 で活性型 PI3キナーゼを発現するガン細胞株は、 p38チロシンリン酸化が亢進し、 分化型から未分化型へと変化する。本発明のスクリ一二ング方法は、 Cre - Adenovirus 存在下で活性型 PI3キナーゼを発現するガン細胞株を被検化合物の存在下又は非存 在下培養した細胞の分化状態の比較によって行われる。 In the screening method of the present invention, which is a screening method using the differentiation state of cancerous cells as an index, for example, a method described in the literature (eg, J. Biol. Chem. 27, 16089 (1997), etc.) HCC2998 or MKN45, which is a differentiated cancer cell line, was prepared in accordance with the above procedure under the condition of Cre recombinase Denouinores (hereinafter referred to as “Cre_Adenovirus”). It can be performed using BD110 or MKN45 / BD110. Surprisingly, in the presence of Cre-Adenovirus In cancer cell lines that express active PI3 kinase, p38 tyrosine phosphorylation is enhanced, and the cell line changes from differentiated to undifferentiated. 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.
さらに、 本発明のスクリーニング方法は、 未分化型ガン細胞株である NUGC4を用 いても、 被検化合物の存在下又は非存在下培養した細胞の分化状態の比較によって 行うことができる。  Furthermore, 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.
本発明に用いられ得る細胞株 NUGC4は、 本発明者らによって初めて p38チロシン リン酸化が亢進していることが明らかにされた。  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.
なお、 本発明に用いられる細胞株 NUGC4は、 番号 TKG0049として、 東北大学加齢 医学研究所附属医用細胞資源センターより入手可能であり、 細胞株 MKN45は、 番号 JCRB0254として、財団法人ヒューマンサイエンス振興財団ヒューマンサイエンス研 究資源バンクより入手可能である。  In addition, 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.
本発明のスクリーニング方法において、 分化状態を判定する手段とは、 分化型細 胞と未分化型細胞とを判定することをいい、 そのような判定する手段であってスク リーニング方法に用いられるものであれば特に限定されないが、 好適には、 分化型 細胞と未分化型細胞を形態の違いにより判定する手段であり、 より好適には、 細胞 を形態により器壁に付着する形態を取る細胞と器壁に付着せず浮遊する細胞とに区 分し、 前者を分化型細胞、 後者を未分化型細胞と判定する手段である。  In the screening method of the present invention, the means for judging the differentiation state means judging a differentiated cell and an undifferentiated cell. Such a means for judging is used in the screening method. There is no particular limitation so long as it is a means for judging a differentiated cell and an undifferentiated cell based on a difference in morphology. It is a means to classify cells into cells that do not adhere to the wall and float, and determine the former as differentiated cells and the latter as undifferentiated cells.
本発明の組成物の形態としては、 例えば、 錠剤、 カプセル剤、 顆粒剤、 散剤若し くはシロップ剤等による経口投与又は注射剤若しくは座剤等による非経口投与を挙 げることができ、 これらの製剤は、 賦形剤 （例えば、 乳糖、 白糖、 葡萄糖、 マンニ トール、 ソルビトールのような糖誘導体； トウモロコシデンプン、 ノ レイショデン プン、 α澱粉、 デキストリ ンのような澱粉誘導体；結晶セルロースのようなセル口 —ス誘導体； アラビアゴム ；デキストラン；プルランのような有機系賦形剤：及び 、 軽質無水珪酸、 合成珪酸アルミニウム、 珪酸カルシウム、 メタ珪酸アルミン酸マ グネシゥムのような珪酸塩誘導体；燐酸水素カルシウムのような燐酸塩；炭酸カル シゥムのような炭酸塩；硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げる ことができる。）、 滑沢剤 （例えば、 ステアリン酸、 ステアリン酸カルシウム、 ステ ァリン酸マグネシウムのようなステアリン酸金属塩； タルク ； コロイ ドシリカ ； ビ 一ガム、 ゲイ蠟のようなワックス類；硼酸； アジピン酸；硫酸ナトリ ウムのような 硫酸塩； ダリコール； フマル酸；安息香酸ナトリ ウム ； D Lロイシン ；脂肪酸ナト リ ウム塩； ラウリル硫酸ナトリ ウム、 ラウリル硫酸マグネシゥムのようなラウリル 硫酸塩； 無水珪酸、 珪酸水和物のような珪酸類 ；及び、 上記澱粉誘導体を挙げるこ とができる。）、 結合剤 （例えば、 ヒ ドロキシプロピルセルロース、 ヒ ドロキシプロ ピルメチルセルロース、 ポリ ビニルピロ リ ドン、 マクロゴール、 及び、 前記賦形剤 と同様の化合物を挙げることができる。）、 崩壊剤 （例えば、 低置換度ヒ ドロキシプ 口ピノレセノレロース、 カノレボキシメチノレセノレロース、 カノレボキシメチノレセノレロース力 ルシゥム、 内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘 導体； カルボキシメチルスターチ、 カルボキシメチルスターチナトリ ウム、 架橋ポ リ ビエルピロリ ドンのような化学修飾されたデンプン ·セルロース類を挙げること ができる。）、 安定剤 （メチルパラベン、 プロピルパラベンのようなパラォキシ安息 香酸エステル類； クロロブタノ一ル、 ベンジルアルコール、 フエニルェチルアルコ —ルのようなアルコール類；塩化ベンザルコニゥム ； フエノール、 クレゾールのよ うなフエノ一ル類； チメ口サール； デヒ ドロ酢酸；及び、 ソルビン酸を挙げること ができる。）、 矯味矯臭剤 （例えば、 通常使用される、 甘味料、 酸味料、 香料等を挙 げることができる。）、 希釈剤等の添加剤を用いて周知の方法で製造される。 Examples of the form of the composition of the present invention include oral administration with tablets, capsules, granules, powders or syrups, and parenteral administration with injections or suppositories. These preparations may contain 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. Include machine-based excipients be able to. ), 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) And disintegrants (eg, , Low-substituted hydroxypitol mouth pinoresenorelose, canoleboxy methinoresenorelose, canoleboxy methinoresenolerose, lucidum, cellulose derivatives such as sodium carboxymethylcellulose internally crosslinked; carboxymethyl starch, carboxymethyl starch sodium And chemically modified starch and cellulose such as crosslinked polypyrrolidone), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. It is manufactured by known methods using additives such as flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents.
その使用量は症状、 年齢、 投与方法等により異なるが、 例えば、 経口投与の場合 には、 成人に対して 1 日あたり、 下限として 0. O l mgZk g (好ましくは 0. l mgZk g)、 上限として、 5 OmgZk g (好ましくは 1 OmgZk g) を 1回 又は数回に分けて、 症状に応じて投与することが望ましい。 静脈内投与の場合には 、 成人に対して 1 日あたり、 下限として 0. 0 0 lmgZk g (好ましくは 0. 0 1 mg/k g), 上限として、 1 Omg k g (好ましくは 5mgZk g) を 1回又 は数回に分けて、 症状に応じて投与することが望ましい。  The amount used depends on the symptoms, age, administration method, etc.For example, in the case of oral administration, 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. In the case of intravenous administration, 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.
[図面の簡単な説明]  [Brief description of drawings]
[図 1 ] 培養前の NUGC4の未分化状態が、 化合物 Aの非存在下では変化しない （左側） のに 対し、 化合物 Aの存在下では分化型へと変換されている （右側； 10日培養後） こと を示す。 [Figure 1 ] The undifferentiated state of NUGC4 before culture does not change in the absence of Compound A (left), while it is converted to a differentiated form in the presence of Compound A (right; after 10 days of culture). Show.
[図 2 ]  [Figure 2 ]
化合物 Aの非存在下では、 活性型 PI3キナーゼの発現に伴なつて HCC2998が未分化 型へと変換される （上段） のに対し、 化合物 Aの存在下では、 未分化型への変換が 阻害される（下段）ことを示す。 図中、 Laczとは活性型 PI3を発現していない細胞株 を表し、 Creとは活性型 PI3を発現している細胞株を表す。 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). In the figure, Lacz indicates a cell line that does not express active PI3, and Cre indicates a cell line that expresses active PI3.
[図 3]  [Figure 3]
化合物 Aの非存在下では、 活性型 PI3キナーゼの発現に伴なつて MKN45が未分化型 へと変換される （上段） のに対し、 化合物 Aの存在下では、 未分化型への変換が阻 害される（下段）ことを示す。 図中、 Laczとは活性型 PI3を発現していない細胞株を 表し、 Creとは活性型 PI3を発現している細胞株を表す。 In the absence of Compound A, 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). In the figure, Lacz indicates a cell line that does not express active PI3, and Cre indicates a cell line that expresses active PI3.
[発明を実施するための最良の形態]  [Best Mode for Carrying Out the Invention]
以下に実施例を挙げて本発明をさらに詳細に説明する。  Hereinafter, the present invention will be described in more detail with reference to Examples.
[実施例]  [Example]
[実施例 1 ] HCC2998/BD110を用いたガン治療薬の探索  [Example 1] Search for cancer drug using HCC2998 / BD110
HCC2998/BD110細胞を 1X105個 3cmシャーレに RPMI1640 (10 % calf serum添加）中で 培養し、 1 日後 m. o. i . 50にて Cre-Adenovirusを感染させる。 この時被検化合物を 存在させたものと存在させないものでの形態変化を観察する。 未分化型への移行を 阻止する化合物をガンの予防又は治療薬として選別する。 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.
[実施例 2 ] MKN45/BD110を用いたガン治療薬の探索  [Example 2] Search for cancer therapeutics using MKN45 / BD110
MKN45/BD110細胞を 1X105個 3cmシャーレに RPMI 1640 (10 % calf serum添加）中で培 養し、 1日後 m. o. i . 50にて Cre-Adenovirusを感染させる。 この時被検化合物を存 在させたものと存在させないものでの形態変化を観察する。 未分化型への移行を阻 止する化合物をガンの予防又は治療薬として選別する。 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.
[実施例 3] NUGC4を用いたガン治療薬の探索  [Example 3] Search for cancer therapeutic drug using NUGC4
NUGC4を 1X105個 3cmシャーレに RPMI 1640 (10 % calf serum添加）中で、 被検化合物 を添加後 1 0 B間培養した。 細胞が器壁に接着するようになり、 分化型癌細胞様の 形態へと移行させる化合物をガンの予防又は治療薬として選別する。 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.
[実施例 4] p38阻害剤による未分化型ガン細胞の分化型細胞への転換  [Example 4] Conversion of undifferentiated cancer cells to differentiated cells by p38 inhibitor
NUGC4を 1X105個 3cmシャーレに RPMI1640 (10 % calf serum添加）中で培養し、 p38 阻害剤を添加後 1 0日間培養した。 細胞が器壁に接着するようになり、 分化型癌細 胞様の形態をとる。 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.
[実施例 5] p38阻害剤による分化型ガン細胞の未分化型細胞への転換阻害  [Example 5] Inhibition of conversion of differentiated cancer cells to undifferentiated cells by p38 inhibitor
MKN45/BD110細胞を 1X105個 3cmシャーレに RPMI 1640 (10 % calf serum添加）中で培 養し、 1 日後 m. o. i. 50にて Cre-Adenovirusを感染させる。 この時 p38阻害剤を存在 させたものと存在させないものでの形態変化を観察する。 p38阻害剤を加えたもの は未分化型への移行が阻止される。 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.
[実施例 6] 化合物 Aによる未分化型ガン細胞の分化型細胞への転換  [Example 6] Conversion of undifferentiated cancer cells to differentiated cells by compound A
NUGC4を 1X105個 3cmシャーレに RPMI1640 (10 % calf serum添加）中で培養し、 化合 物 Aを添加後 1 0日間培養した。 細胞が器壁に接着するようになり、 分化型癌細胞 様の形態をとつた。 [図 1] 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. [Figure 1]
[実施例 7] 化合物 Aによる分化型ガン細胞の未分化型細胞への転換阻害  [Example 7] Inhibition of conversion of differentiated cancer cells into undifferentiated cells by compound A
HCC2998/BD110細胞を 1X105個 3cmシャーレに RPMI1640 (10 % calf serum添加）中で 培養し、 1 日後 m. o. i . 50にて Cre - Adenovirusを感染させる。 この時化合物 Aを存在 させたものと存在させないものでの形態変化を観察する。 化合物 Aを加えたものは 未分化型への移行が阻止された。 [図 2] 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. [Figure 2]
[実施例 8] 化合物 Aによる分化型ガン細胞の未分化型細胞への転換阻害  [Example 8] Inhibition of conversion of differentiated cancer cells into undifferentiated cells by compound A
MKN45/BD110細胞を 1X105個 3cmシャーレに RPMI 1640 (10 % calf serum添加）中で培 養し、 1日後 m. o. i. 50にて Cre - Adenovirusを感染させる。 この時化合物 Aを存在さ せたものと存在させないものでの形態変化を観察する。 化合物 Aを加えたものは未 分化型への移行が阻止された。 [図 3] 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]
[実施例 9] ガンの予防又は治療薬の探索  [Example 9] Search for a drug for preventing or treating cancer
スクリーニングする化合物（l tng/ml程度、 MeOH: DMSO=7 : 3溶液） を 2 μ 1ずつ 96穴 プレートにあらかじめ分取しておく。 HCC2998/BD110細胞をプレ一トよりはがし、 PBSで洗浄後、 RPMI1640倍地懸濁液中で m. o. i.30にて Cre-Adenovirusを 1時間感染 させる。 この感染細胞を 1 0%血清を含む RPMI1640倍地で 10,000cells/mlになるよ うに希釈後、 0.2mlずつ 96穴プレートにまく。 1日後、 形態を観察し、 未分化型へ の移行を阻止する化合物をガンの予防薬又は治療薬として選別する。 Aliquot 2 μl of the compound to be screened (about lng / ml, MeOH: DMSO = 7: 3 solution) into a 96-well plate in advance. Remove HCC2998 / BD110 cells from the plate, After washing with PBS, Cre-Adenovirus is infected for 1 hour with moi30 in RPMI1640 medium suspension. Dilute the infected cells to 10,000 cells / ml in RPMI1640 medium containing 10% serum, and spread 0.2 ml each on a 96-well plate. One day later, the morphology is observed, and compounds that prevent the transition to an undifferentiated form are selected as cancer preventive or therapeutic agents.
[参考例] NUGC4細胞における p38チロシンリン酸化の亢進  [Reference Example] Enhanced phosphorylation of p38 tyrosine in NUGC4 cells
未分化ガン細胞株 NUGC4、 ΚΑΤ0ΠΙ及びその他の分化型胃癌細胞株 SCH、 SH10- TCの 総タンパク質 （50 micro gram) を 1 0%ポリアクリルアミ ドゲルに電気泳動し、 ウェスタンブロ ッテイングを行った。 3 %スキムミルクを含む緩衝液 （ 1 % tween20を含む等張トリス緩衝液） でブロッキングを行った後、 同じ溶液中でチロ シンリン酸化 p38抗体を用いて活性化 P38を、 また、 p38抗体を用いて p38を検出した t 未分化細胞株特異的に p38の活性化が見られる。 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.
[製剤例]  [Formulation example]
[製剤例 1] (カプセル剤）  [Formulation Example 1] (Capsule)
消化性油状化合物、 例えば、 大豆油、 綿実油又はオリーブ油中に入れた、 化合物 Aの混合物を調整し、 正置換ポンプでゼラチン中に注入して、 l O Omgの活性成 分を含有するソフトカプセルを得、 洗浄後、 乾燥する。  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.
[製剤例 2] (錠剤）  [Formulation Example 2] (Tablet)
常法に従って、 1 0 0m gの化合物A、 0. 2m gのコロイド性二酸化珪素、 5 m gのステアリン酸マグネシウム、 2 7 5 m gの微結晶性セルロース、 l l mgの デンプン及び 9 8. 8mgのラク トースを用いて製造する。  Following routine, 100 mg of compound A, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, ll mg of starch and 98.8 mg of lactose Manufactured using toast.
尚、 所望により、 剤皮を塗布する。  In addition, if necessary, a coating is applied.
[製剤例 3] (注射剤）  [Formulation Example 3] (Injection)
1. 5重量％の化合物 Bを、 1 0容量％のプロピレングリコール中で撹拌し、 次 いで、 注射用水で一定容量にした後、 滅菌して製造する。  1. Prepare 5% by weight of Compound B by stirring in 10% by volume of propylene glycol, then make up to volume with water for injection, and sterilize.
[製剤例 4] (懸濁剤）  [Formulation Example 4] (Suspension)
精製水 5m l中に、 1 0 Omgの微粉化した化合物 A、 l O Omgのナトリウム カルボキシメチルセルロース、 5 m gの安息香酸ナトリ ウム、 1. O gのソルビト ール溶液 （日本薬局方） 及び 0. 0 2 5m lのバニリンを含有するように製造する。 [産業上の利用の可能性] In 5 ml of purified water, 10 Omg of micronized compound A, lO Omg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1. Og of sorbitol solution (Japanese Pharmacopoeia) and 0. Produced to contain 0 25 ml of vanillin. [Possibility of industrial use]
本発明の p38阻害剤を含有する組成物は、 p38を阻害することによって、 未分化 型ガン細胞を分化型ガン細胞へと変換すること、 或いは、 分化型ガン細胞が未分化 型へと変化することを阻害することによって、 ガンの予防及び治療することが可能 である。 本発明のガン化細胞の分化状態を指標とした化合物のスクリ一二ング方法 は、 ガンの予防又は治療薬のスク リーニング方法として有用である。 また、 本発明 の p38チロシンリン酸化が亢進したガン化細胞の分化状態を指標とした化合物のス クリ一ニング方法はガンの予防又は治療薬のスクリ一ニング方法として有用である。 加えて、 これらスクリ一ニング方法によって得られる化合物はガンの予防又は治療 薬として有用である。 さらに、 本発明の p38阻害の方法は、 未分化型ガン細胞を分 化型ガン細胞に変換する方法として有用である。  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. In addition, 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. In addition, compounds obtained by these screening methods are useful as preventive or therapeutic agents for cancer. Furthermore, the p38 inhibition method of the present invention is useful as a method for converting undifferentiated cancer cells to differentiated cancer cells.

Claims

請 求 の 範 囲 The scope of the claims
1 . p38阻害剤を含有するガンの予防又は治療薬。  1. A prophylactic or therapeutic agent for cancer containing a p38 inhibitor.
2 . p38阻害剤を含有する未分化型ガンの予防又は治療薬。 2. A prophylactic or therapeutic agent for undifferentiated cancer containing a p38 inhibitor.
3 .未分化型ガンを分化型ガンに変換することを特徴とする p38 阻害剤を含有する ガンの予防又は治療薬。 3. An agent for preventing or treating cancer, comprising a p38 inhibitor, which converts undifferentiated cancer into differentiated cancer.
4.未分化型ガンの発生を阻害することを特徴とする p38阻害剤を含有するガンの予 防又は治療薬。 4. An agent for preventing or treating cancer, comprising a p38 inhibitor, which inhibits the development of undifferentiated cancer.
5 .以下の手段（a)乃至（b)からなるスクリ一ニング方法。 5. A screening method comprising the following means (a) and (b).
(a)ガン化細胞を被検化合物の存在又は非存在下培養する手段  (A) means for culturing cancerous cells in the presence or absence of a test compound
(b)—定時間経過後の分化状態を判定する手段  (b) —Means for judging the differentiation state after a fixed time has elapsed
6 . 以下の手段（al)乃至（b)からなるスクリ一二ング方法。 6. A screening method comprising the following means (al) to (b).
(al) p38チロシンリン酸化が亢進したガン化細胞を被検化合物の存在又は非存在下 培養する手段  (al) means for culturing cancerous cells with enhanced p38 tyrosine phosphorylation in the presence or absence of a test compound
(b)一定時間経過後の分化状態を判定する手段  (b) Means for judging differentiation state after a certain period of time
7 .請求項 5乃至 6記載のスクリ一二ング方法により得られる化合物。 7. A compound obtained by the screening method according to claim 5 or 6.
8.請求項 5乃至 6記載のスクリーニング方法により得られる化合物を有効成分とし て含有するガンの予防又は治療薬。 8. A prophylactic or therapeutic drug for cancer comprising a compound obtained by the screening method according to claim 5 or 6 as an active ingredient.
9 .請求項 5乃至 6記載のスクリ一ユング方法により得られる化合物を有効成分と して含有する未分化型ガンの予防又は治療薬。 9. An agent for preventing or treating undifferentiated cancer, comprising as an active ingredient a compound obtained by the screening method according to claim 5 or 6.
1 0 .未分化型ガンを分化型ガンに変換することを特徴とする、請求項 5乃至 6記載 のスクリ一二ング方法により得られる化合物を有効成分として含有するガンの予防 又は治療薬。 10. A prophylactic or therapeutic agent for cancer, comprising as an active ingredient a compound obtained by the screening method according to claims 5 or 6, characterized in that undifferentiated cancer is converted into differentiated cancer.
1 1 .未分化型ガンの発生を阻害することを特徴とする、請求項 5乃至 6記載のスク リ一二ング方法により得られる化合物を有効成分として含有するガンの予防又は治 療薬。 11. A prophylactic or therapeutic drug for cancer, comprising as an active ingredient a compound obtained by the screening method according to claims 5 or 6, characterized by inhibiting the development of undifferentiated cancer.
1 2 .未分化型ガン細胞を分化型ガン細胞に変換する際 p38を阻害する方法。 12. A method of inhibiting p38 when converting undifferentiated cancer cells to differentiated cancer cells.
PCT/JP2000/001302 1999-03-30 2000-03-03 Preventives or remedies for cancer and method for screening the same WO2000059541A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047266A1 (en) * 2003-11-14 2005-05-26 Lorus Therapeutics Inc. Aryl imidazoles and their use as anti-cancer agents
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 (en) * 1996-12-18 1998-06-25 Vertex Pharmaceuticals Incorporated SUBSTITUTED NITROGEN CONTAINING HETEROCYCLES AS INHIBITORS OF p38 PROTEIN KINASE
WO1998052937A2 (en) * 1997-05-22 1998-11-26 G.D. Searle And Co. 4-aryl-3(5)-heteroaryl substituted pyrazoles as p38 kinase
WO1999000357A1 (en) * 1997-06-27 1999-01-07 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
WO1999010325A1 (en) * 1997-08-06 1999-03-04 Glaxo Group Limited Benzylidene-1,3-dihydro-indol-2-one derivatives as receptor tyrosine kinase inhibitors, particularly of raf kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998027098A1 (en) * 1996-12-18 1998-06-25 Vertex Pharmaceuticals Incorporated SUBSTITUTED NITROGEN CONTAINING HETEROCYCLES AS INHIBITORS OF p38 PROTEIN KINASE
WO1998052937A2 (en) * 1997-05-22 1998-11-26 G.D. Searle And Co. 4-aryl-3(5)-heteroaryl substituted pyrazoles as p38 kinase
WO1999000357A1 (en) * 1997-06-27 1999-01-07 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
WO1999010325A1 (en) * 1997-08-06 1999-03-04 Glaxo Group Limited Benzylidene-1,3-dihydro-indol-2-one derivatives as receptor tyrosine kinase inhibitors, particularly of 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 (en) * 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 Arylimidazoles and their use as anticancer agents
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 (en) * 2003-11-14 2005-05-26 Lorus Therapeutics Inc. Aryl imidazoles and their use as anti-cancer agents
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

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