WO2014050779A1 - Combinaison d'un inhibiteur de gsk3 et d'un anticorps anti-dr5 - Google Patents

Combinaison d'un inhibiteur de gsk3 et d'un anticorps anti-dr5 Download PDF

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WO2014050779A1
WO2014050779A1 PCT/JP2013/075616 JP2013075616W WO2014050779A1 WO 2014050779 A1 WO2014050779 A1 WO 2014050779A1 JP 2013075616 W JP2013075616 W JP 2013075616W WO 2014050779 A1 WO2014050779 A1 WO 2014050779A1
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cancer
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amino acid
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脇田　賢一
島崎　尚美
志保 岩崎
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第一三共株式会社
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95

Definitions

  • the present invention relates to a combined treatment for cancer comprising a combination of a glycogen synthase kinase 3 (GSK3) inhibitor and an anti-death receptor 5 (DR5) antibody.
  • GSK3 glycogen synthase kinase 3
  • DR5 anti-death receptor 5
  • GSK3 was found as a serine / threonine kinase that phosphorylates glycogen synthase (Non-patent Document 1), and it is currently known that there are two subtypes, ⁇ and ⁇ . Since GSK3 ⁇ gene-deficient mice are embryonic lethal (Non-Patent Document 2), their functions are important in cell survival, and Akt signals (Non-Patent Document 3) and Wnt signals that are closely related to cancer (Non-Patent Document 2) It has been reported that it plays a wide role in the important signal of Patent Document 4).
  • GSK3 ⁇ gene-deficient mice are not embryonic lethal (Non-Patent Document 5), and it has been reported that some functions relating to sugar metabolism are different from normal ones. However, it has been reported that the functions are basically mutually complemented, and stronger signal suppression is observed when both GSK ⁇ and ⁇ genes are deficient (Non-patent Document 6).
  • GSK3 has a wide variety of targets such as amyloid protein, presenilin, ⁇ -catenin, cyclin D1 (Non-patent Document 7), and is attracting attention as a therapeutic target in various diseases.
  • Non-Patent Document 4 In the cancer region, phosphorylation of ⁇ -catenin by GSK3 governs the degradation of ⁇ -catenin in the cell and consequently suppresses gene expression via the transcription factor Tcf, and thus is widely positioned as a suppressor of colorectal cancer. It has been accepted (Non-Patent Document 4). However, in recent years, antitumor activity due to GSK3 inhibition has been reported in leukemias such as MLL leukemia and CML (Non-Patent Documents 8 and 9), and clinical trials for acute leukemia using the GSK3 inhibitor LY2090314 are also underway.
  • Non-Patent Document 10 Non-Patent Document 10
  • maleimide derivatives Patent Document 1, Non-Patent Document 11
  • pyrimidine derivatives Patent Document 2, Non-Patent Document 12
  • pyrimidinones Derivatives (Patent Literature 3), pyridine derivatives (Patent Literature 4), azole derivatives (Non-Patent Literature 13), quinolone derivatives (Patent Literature 5, Non-Patent Literature 14) and the like have been reported.
  • Apoptosis is an essential phenomenon in the physiological process of keeping normal cell counts by eliminating unnecessary cells and damaged cells in vivo.
  • Non-patent Document 15 a ligand for a cell surface receptor involved in apoptosis induction typified by a death receptor and an antibody capable of binding to the receptor are expected to have a therapeutic effect on these diseases.
  • Death Receptor 5 which is a type of death receptor, is sometimes referred to as KILLER, TRICK2A, TRAIL-R2, TRICKB, or CD262, and a plurality of agonist antibodies that induce apoptosis in cells are known (Non-Patent Literature). 16 or 17, or Patent Documents 7 to 12).
  • Several antibodies are currently in the preclinical or clinical development stage as therapeutic candidates, and act as agonists specifically for cells expressing the receptor (cancer cells / immune disease-related cells).
  • Non-patent Document 18 the expression level of intracellular signal molecules such as caspase-8 and Bcl-2 involved in the apoptotic pathway.
  • Non-patent Document 19 the expression level of intracellular signal molecules such as caspase-8 and Bcl-2 involved in the apoptotic pathway.
  • Non-patent Document 20 the expression level of DR5 is increased by a GSK3 inhibitor, and the induction of apoptosis by TRAIL (TNF-RELATED APOTOSIS-INDUCING LIGAN), which is an endogenous ligand of DR5, is enhanced.
  • TRAIL TNF-RELATED APOTOSIS-INDUCING LIGAN
  • Non-patent Document 20 the therapeutic effect of the combined use of a GSK3 inhibitor and an anti-DR5 antibody has not been known, including which compound and antibody are suitable for combination.
  • the present invention is characterized in that a GSK3 inhibitor and an anti-DR5 antibody are administered in combination, and a GSK3 inhibitor and an anti-DR5 antibody are administered in combination.
  • a method for treating cancer is provided.
  • GSK3 inhibitor LY20903144 or a compound having a structure represented by the following general formula (1) or a salt thereof, and an anti-DR5 antibody are particularly excellent in combination.
  • the present invention was completed.
  • a medicament for treating cancer comprising a combination of a glycogen synthase kinase 3 (GSK3) inhibitor and an anti-death receptor 5 (DR5) antibody.
  • a glycogen synthase kinase 3 (GSK3) inhibitor and an anti-death receptor 5 (DR5) antibody are each contained as an active ingredient in different preparations, and are administered at the same time or at different times.
  • the medicament according to claim 1 wherein the glycogen synthase kinase 3 (GSK3) inhibitor and the anti-death receptor 5 (DR5) antibody are contained in a single preparation.
  • the medicament according to claim 1 which is a kit preparation comprising a glycogen synthase kinase 3 (GSK3) inhibitor and an anti-death receptor 5 (DR5) antibody.
  • GSK3 glycogen synthase kinase 3
  • DR5 anti-death receptor 5
  • a method for treating cancer comprising administering a glycogen synthase kinase 3 (GSK3) inhibitor and an anti-death receptor 5 (DR5) antibody in combination.
  • the glycogen synthase kinase 3 (GSK3) inhibitor is LY2090314 or the following general formula (1)
  • R 1 represents a carboxy group, a carbamoyl group or a cyano group
  • R 2 represents a methyl group or a hydrogen atom
  • R 3 represents a halogen atom
  • R 4 has a piperidinyl group which may have a substituent selected from the following group A, a pyridyl group which may have a substituent selected from the following group A, and a substituent selected from the following group A.
  • a cyclohexanyl group or a hydrogen atom which may be X 1 represents C—H, C—F or N
  • X 2 represents CH 2 , NH or S.
  • Group A C 1 -C 6 alkyl group, acetyl group, methylsulfonyl group, hydroxyl group optionally substituted with 1 to 3 halogen atoms, hydroxyl group or methoxy group.
  • Glycogen synthase kinase 3 (GSK3) inhibitor is LY2090314 or the following general formula (1)
  • R 1 represents a carboxy group, a carbamoyl group or a cyano group
  • R 2 represents a methyl group or a hydrogen atom
  • R 3 represents a halogen atom
  • R 4 has a piperidinyl group which may have a substituent selected from the following group A, a pyridyl group which may have a substituent selected from the following group A, and a substituent selected from the following group A.
  • a cyclohexanyl group or a hydrogen atom which may be X 1 represents C—H, C—F or N
  • X 2 represents CH 2 , NH or S.
  • Group A C 1 -C 6 alkyl group, acetyl group, methylsulfonyl group, hydroxyl group optionally substituted with 1 to 3 halogen atoms, hydroxyl group or methoxy group.
  • glycogen synthase kinase 3 (GSK3) inhibitor is LY2090314, one compound selected from the following group or a salt thereof.
  • An anti-death receptor 5 (DR5) antibody is shown in SEQ ID NO: 2 and a heavy chain sequence consisting of amino acid residues 1 to 449 or amino acids 1 to 448 of the amino acid sequence shown in SEQ ID NO: 1 [1] to [4], [6], [8], wherein the antibody comprises a light chain sequence consisting of amino acid residues 1 to 213 of the amino acid sequence.
  • DR5 anti-death receptor 5
  • An anti-death receptor 5 (DR5) antibody is represented by SEQ ID NO: 4 and a heavy chain sequence consisting of amino acid residues 1 to 452 or amino acid residues 1 to 451 of the amino acid sequence shown in SEQ ID NO: 3 [1] to [4], [6], or [8], which is an antibody having a light chain sequence consisting of amino acid residues 1 to 219 of the amino acid sequence.
  • the anti-death receptor 5 (DR5) antibody is represented by SEQ ID NO: 6 and a heavy chain sequence consisting of amino acid residues 1 to 452 or amino acids 1 to 451 of the amino acid sequence shown in SEQ ID NO: 5; [1] to [4], [6], or [8], wherein the antibody comprises a light chain sequence consisting of amino acid residues 1 to 215 of the amino acid sequence.
  • An anti-death receptor 5 (DR5) antibody is shown in SEQ ID NO: 2 and a heavy chain sequence consisting of amino acid residues 1 to 449 or amino acids 1 to 448 of the amino acid sequence shown in SEQ ID NO: 1
  • the therapeutic method according to any one of [5], [7], and [9], wherein the antibody is a light chain sequence consisting of amino acid residues 1 to 213 of the amino acid sequence.
  • An anti-death receptor 5 (DR5) antibody is represented by SEQ ID NO: 4 and a heavy chain sequence consisting of amino acid residues 1 to 452 or amino acids 1 to 451 of the amino acid sequence shown in SEQ ID NO: 3;
  • the therapeutic method according to any one of [5], [7], and [9], which is an antibody comprising a light chain sequence comprising amino acid residues 1 to 219 of the amino acid sequence.
  • An anti-death receptor 5 (DR5) antibody is represented by SEQ ID NO: 6 and a heavy chain sequence consisting of amino acid residues 1 to 452 or amino acid residues 1 to 451 of the amino acid sequence shown in SEQ ID NO: 5
  • the therapeutic method according to any one of [5], [7], and [9], which is an antibody comprising a light chain sequence consisting of amino acid residues 1 to 215 of the amino acid sequence.
  • Cancer is blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal tract Stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, endometrial cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi sarcoma
  • the medicament according to any one of [1] to [4], [6], [8], and [10] to [12], which are sarcoma, kidney cancer, bladder cancer, or testicular cancer.
  • Cancer is blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal tract Stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, endometrial cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi sarcoma
  • the method according to any one of [5], [7], [9], and [13] to [15], which are sarcoma, kidney cancer, bladder cancer, or testicular cancer.
  • the present invention is useful as a cancer treatment method and / or an anticancer agent.
  • Example compound (Compound) 18 and hB273 with respect to human acute lymphocytic leukemia cell line RS4; 11. It is the figure which showed the combined use effect (growth inhibitory activity and cell death (Caspase) induction activity) of Compound21 and hB273 with respect to human acute lymphocytic leukemia cell line RS4; 11. It is the figure which showed the combined use effect (growth inhibitory activity and cell death (Caspase) induction activity) of Compound36 and hB273 with respect to human acute lymphocytic leukemia cell line RS4; 11.
  • FIG. 4 is a graph showing in vitro combined effects (growth inhibitory activity and cell death inducing activity) of Compound 21 and hB273 against human myeloma cell line NCI-H929. It is the figure which showed the combined use effect (growth inhibitory activity and cell death (Caspase) induction activity) of Compound21 and hB273 with respect to human chronic myeloid leukemia cell line K562.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is LY2090314 100 mg / kg
  • the symbol black circle is LY2090314 100 mg / kg + hB273 3 mg / kg
  • the symbol white square is LY2090314 200 mg / kg
  • the symbol black square represents LY2090314 200 mg / kg + hB273 3 mg / kg.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hTRA8 10 mg / kg
  • the symbol white circle is LY2090314 100 mg / kg
  • the symbol black circle is LY2090314 100 mg / kg + hTRA8 10 mg / kg
  • the symbol white square is LY2090314 200 mg / kg
  • the symbol black square represents LY2090314 200 mg / kg + hTRA8 10 mg / kg. It is the figure which showed the combined effect in vivo of LY2090314 and Conatumumab with respect to human melanoma cell line A375.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is Conatumumab 3 mg / kg
  • the symbol white circle is LY2090314 100 mg / kg
  • the symbol black circle is LY2090314 100 mg / kg + Contumumab 3 mg / kg
  • the symbol white square is LY2090314 200 mg / kg
  • the symbol black square indicates LY2090314 200 mg / kg + Contumumab 3 mg / kg. It is the figure which showed the combined effect in vivo with Compound18 (upper figure), 21 (lower figure), and hB273 with respect to human melanoma cell line A375.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 18 7.5 mg / kg
  • the symbol black circle is Compound 18 7.5 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 18 15 mg / kg
  • symbol black square indicates Compound 18 15 mg / kg + hB273 3 mg / kg.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 21 3.5 mg / kg
  • the symbol black circle is Compound 21 3.5 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 21 7 mg / kg
  • symbol black square indicates Compound 21 7 mg / kg + hB273 3 mg / kg. It is the figure which showed the combined effect in vivo with Compound36 (upper figure), 27 (lower figure), and hB273 with respect to human melanoma cell line A375.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 36 3 mg / kg
  • the symbol black circle is Compound 36 3 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 36 6 mg / kg.
  • the symbol black square indicates Compound 36 6 mg / kg + hB273 3 mg / kg.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 27 2.5 mg / kg
  • the symbol black circle is Compound 27 2.5 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 27 5 mg / kg
  • symbol black square indicates Compound 27 5 mg / kg + hB273 3 mg / kg. It is the figure which showed the combined effect in vivo of Compound53 (upper figure) or 54 (lower figure), and hB273 with respect to human melanoma cell line A375.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 53 3 mg / kg
  • the symbol black circle is Compound 53 3 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 53 6 mg / kg.
  • Symbol black square indicates Compound 53 6 mg / kg + hB273 3 mg / kg.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 54 25 mg / kg
  • the symbol black circle is Compound 54 25 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 54 50 mg / kg.
  • Symbol black square indicates Compound 54 50 mg / kg + hB273 3 mg / kg. It is the figure which showed the combined effect in vivo of Compound21 (upper figure) or Compound18 (lower figure) and hB273 with respect to human acute lymphocytic leukemia cell line RS4; 11.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 21 2 mg / kg
  • the symbol black circle is Compound 21 2 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 21 4 mg / kg.
  • Symbol black square indicates Compound 21 4 mg / kg + hB273 3 mg / kg.
  • the symbol white triangle is the untreated control group
  • the symbol black triangle is hB273 3 mg / kg
  • the symbol white circle is Compound 18 7.5 mg / kg
  • the symbol black circle is Compound 18 7.5 mg / kg + hB273 3 mg / kg
  • the symbol white square is Compound 18 15 mg / kg
  • symbol black square indicates Compound 18 15 mg / kg + hB273 3 mg / kg.
  • tumor in the present invention, tumor, malignant tumor, cancer, malignant neoplasm, carcinoma, sarcoma, etc. may be collectively referred to as “tumor” or “cancer”.
  • GSK3 refers to GSK3 gene. It refers to the encoded protein. Unless otherwise specified, includes both isomers GSK ⁇ and GSK ⁇ .
  • the GSK3 protein includes a GSK3 protein encoded by a full-length GSK3 gene, a GSK3 protein encoded by a GSK3 gene mutant (including a deletion mutant, a substitution mutant, and an additional mutant).
  • GSK3 includes homologs derived from various animal species.
  • the GSK3 inhibitor refers to an inhibitor of GSK3 function as a kinase.
  • the inhibitory activity of GSK3 may be measured by a method known per se, for example, by the method described in Test Example 1 described later.
  • Examples of the GSK3 inhibitor include compounds described in Non-Patent Document 10, maleimide derivatives described in Patent Document 1 or Non-Patent Document 11, pyrimidine derivatives described in Patent Document 2 or Non-Patent Document 12, and Patent Document 3.
  • LY20903314 the above-mentioned general formula (the pyridine derivative described in Patent Document 4, the azole derivative described in Non-Patent Document 13, the quinolone derivative described in Patent Document 5 or Non-Patent Document 14, etc.)
  • Examples thereof include the compounds described in 1) or salts thereof, but are not particularly limited as long as they are compounds having an action of inhibiting GSK3.
  • LY2090314 is a compound described in Example 365 of WO03 / 076442, and can be synthesized with reference to this document.
  • the GSK3 inhibitor used in the present invention is preferably LY2090314 or a compound described in the above general formula (1) or a salt thereof, more preferably LY2090314 or a compound selected from the following group or a salt thereof. .
  • C 1 -C 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the “C 1 -C 6 alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • R 1 represents a carboxy group, a carbamoyl group or a cyano group.
  • R 2 represents a methyl group or a hydrogen atom.
  • R 3 represents a halogen atom, preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.
  • R 4 has a piperidinyl group optionally having a substituent selected from Group A, a pyridyl group optionally having a substituent selected from Group A, and a substituent selected from Group A.
  • An optionally substituted cyclohexanyl group or a hydrogen atom is shown.
  • the bonding position of the piperidinyl group and the pyridyl group is not particularly limited, but is preferably bonded at the 3rd or 4th position.
  • substituents substituted on the piperidinyl group pyridyl group and cyclohexanyl group
  • substitution on the nitrogen atom is preferred, and examples of the substituent include an acetyl group and a methyl group. Is particularly preferred.
  • substituent of the cyclohexanyl group a hydroxyl group is preferable.
  • X 1 represents C—H, C—F or N.
  • X 2 represents CH 2 , NH or S.
  • the compound represented by the general formula (1) in the present invention has a basic group such as an amino group, it can be converted into a pharmaceutically acceptable salt as desired.
  • salts include hydrohalates such as hydrochloride and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; methanesulfonate and trifluoromethanesulfone.
  • Lower alkane sulfonates such as acid salts and ethane sulfonates; aryl sulfonates such as benzene sulfonates and p-toluene sulfonates; formic acid, acetic acid, malic acid, fumarate, succinate, citric acid Organic acid salts such as acid salts, tartrate salts, oxalate salts, maleates; and amino acid salts such as ornithates, glutamates, aspartates; and the like. preferable.
  • the pharmaceutically acceptable salt include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt , Morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl -N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, organic amine salt such as tris (hydroxymethyl) aminomethane salt, and the like.
  • alkali metal salts such as sodium salt, potassium salt and lithium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • inorganic salts such as ammonium salt
  • the compound represented by the general formula (1) or a salt thereof in the present invention may exist as a free form or a solvate. It may exist as a hydrate by absorbing moisture in the air.
  • the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable.
  • a nitrogen atom is present in the compound represented by the general formula (1), it may be an N-oxide form, and these solvates and N-oxide forms are also included in the scope of the present invention. .
  • the compound represented by the general formula (1) in the present invention or a pharmacologically acceptable salt thereof can give stereoisomers depending on their structures.
  • the compound represented by the general formula (1) or a salt thereof in the present invention includes all of these stereoisomers and a mixture of these stereoisomers in an arbitrary ratio.
  • the definition of stereoisomers is as shown in 1996 IUPC, Pure and Applied Chemistry 68, 2193-2222.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof exists as a tautomeric organism, the tautomeric organism exists in a parallel state, or Any case where a certain form predominates is included within the scope of the present invention.
  • a tautomer refers to an isomer produced by shifting the proton of one atom of a molecule to another atom.
  • the compound represented by the general formula (1) in the present invention may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), carbon-14 ( 14 C), and the like. These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compound represented by general formula (1) are included within the scope of the present invention, whether radioactive or not.
  • a compound that is converted to compound (1) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. and converted to compound (1)
  • a “pharmaceutically acceptable prodrug compound” that is converted to compound (1) by hydrolysis or the like with gastric acid or the like is also encompassed in the present invention.
  • the prodrug when an amino group is present in the compound (1), a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the compound (1) has a hydroxyl group
  • a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated for example, the hydroxyl group is acetylated, palmitoyl.
  • a carboxy group is present in compound (I), a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylamino Methyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation, or methylamidated compounds, etc.).
  • the prodrug of the compound can be produced from the compound (1) by a known method.
  • Prodrugs of compounds include those that change to compound (1) under physiological conditions, as described in Hirokawa Shoten, 1990, “Pharmaceutical Development”, Volume 7, Molecular Design, pages 163-198. .
  • the compound represented by the general formula (1) can be produced by various production methods, and the production methods shown below are merely examples, and the present invention should not be construed as being limited thereto.
  • the substituent can be protected with an appropriate protecting group, and the kind of the protecting group is not particularly limited.
  • the raw material used here can be purchased as a commercial product, is a compound known in the literature, or can be synthesized with reference to Examples or Reference Examples.
  • [Production Method 1] When benzoic acid 2 having a nitro group is available or can be synthesized, it can be synthesized as follows. The preferred order of production steps after the latter half of the intermediate 6 varies depending on the compound.
  • the substituent R in the enamine 4 is an alkyl group such as methyl, ethyl, isopropyl, t-butyl, etc., and represents an ester group as COOR. Even if this ester group is replaced with a cyano group, it can be synthesized in the same manner.
  • Process 1 The nitration reaction from compound 1 to 2 is carried out under generally known nitration conditions (Albright, LF; Carr. RVC; Schmitt, RJ Eds. Nitration; ACS Symposium Series 623, 1996). Specifically, for a substrate that is likely to undergo nitration, it can be carried out using acetic acid, concentrated sulfuric acid or the like as a solvent and 1 mol to excess mol of potassium nitrate at room temperature.
  • nitration In the case of a substrate in which nitration is difficult to proceed, it can be carried out using concentrated sulfuric acid or acetic anhydride or trifluoroacetic anhydride as a solvent and using a large excess of nitric acid or fuming nitric acid under heating conditions. In some cases, nitration is performed only with fuming nitric acid without using a solvent. Further, as a nitro source, a salt such as diammonium cerium (IV) nitrate or an ester such as butyl nitrite may be used.
  • a salt such as diammonium cerium (IV) nitrate or an ester such as butyl nitrite may be used.
  • Process 2 The conversion from compound 2 to 3 is carried out by reacting 1 to excess moles of oxalyl chloride in the presence of a catalytic amount of N, N-dimethylformamide in a suitable solvent (dichloromethane, tetrahydrofuran, etc.) that does not adversely affect the reaction.
  • a catalytic amount of N, N-dimethylformamide in a suitable solvent (dichloromethane, tetrahydrofuran, etc.) that does not adversely affect the reaction.
  • a suitable solvent dichloromethane, tetrahydrofuran, etc.
  • the reaction time is 30 minutes to 24 hours
  • the reaction temperature is 0 ° C. to 80 ° C., and preferably 0 ° C. to room temperature.
  • Thionyl chloride can also be used as a reagent. In general, the residue obtained by distilling off the reagent and the solvent is directly used in the next step.
  • Process 3 Conversion from compound 3 to 5 is carried out by allowing 1 to several moles of acid chloride to act on 1 mole of the corresponding enamine in an appropriate solvent (toluene, tetrahydrofuran, acetonitrile, etc.) that does not adversely affect the reaction. it can.
  • a base such as triethylamine or diisopropylethylamine may be present in an amount of 1 mol to several mols.
  • the reaction temperature is in the range of 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature. However, when it is desired to proceed to the cyclization reaction, it may be heated to 50 ° C. to 100 ° C. in the presence of a base.
  • the reaction time is preferably about 30 minutes to 10 hours, more preferably about 30 minutes to 3 hours.
  • Process 4 The cyclization reaction from compound 5 to 6 is carried out using 1 mol to several mols of an appropriate base such as sodium hydride or potassium carbonate in an appropriate solvent (tetrahydrofuran, acetone, acetonitrile, etc.) that does not adversely influence the reaction. To do.
  • the reaction temperature can be 0 to 100 ° C.
  • sodium hydride is used, it is preferably 0 ° C to 40 ° C, and when potassium carbonate is used, it is preferably 60 ° C to 100 ° C.
  • the reaction time is preferably about 30 minutes to 10 hours, more preferably about 30 minutes to 3 hours.
  • Process 5 The reduction reaction from compound 6 to 7 is carried out in a suitable solvent (N, N-dimethylformamide, dichloroethane, etc.) that does not adversely affect the reaction using 10 to 100 wt% of palladium carbon catalyst with respect to the substrate. Is called.
  • a suitable solvent N, N-dimethylformamide, dichloroethane, etc.
  • the reaction time varies depending on the substrate and is several hours to several days.
  • the reaction temperature is preferably about 0 ° C to 40 ° C.
  • Reduction reactions from compounds 9 to 10 and 12 to 13 are performed in the same manner. Reduction can also be performed using other catalysts such as palladium hydroxide and platinum carbon catalyst, and metals such as iron and zinc under acidic conditions.
  • a salt such as sodium dithionite may also be used.
  • Step 6 The substitution reaction from compound 7 to compound 8 uses 1 mol to several mols of amine per 1 mol of the mother nucleus in an appropriate solvent (N, N-dimethylsulfoxide, N-methylpyrrolidone, etc.) that does not adversely affect the reaction. Implemented. In some cases, 1 mol to several mol of a base such as triethylamine is allowed to coexist.
  • the reaction temperature is preferably 40 ° C to 150 ° C, and more preferably 60 ° C to 100 ° C.
  • the reaction time is several hours to several days.
  • the reaction temperature is 80 ° C. to 120 ° C.
  • the reaction time is 12 hours to several days.
  • a method of heating at a reaction temperature of 160 ° C. for 1 hour is preferable.
  • it can also be synthesized by performing a coupling reaction using a metal catalyst such as palladium.
  • the reaction site is not a fluorine atom but a bromine atom or a chlorine atom.
  • 1,4-dioxane and toluene are particularly preferable, and 1 mol to several mols of amine or aromatic amine and 1 mol to several mols of cesium carbonate, sodium t-butoxide and the like as a base with respect to 1 mol of the mother nucleus, 0.01 to 0.1 mol of tris (dibenzylideneacetone) dipalladium as a palladium catalyst, and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene or 2,2′-bis ( Diphenylphosphino) -1,1′-binaphthyl and the like are used in an amount of 0.01 to 0.2 mol, the reaction temperature is 70 to 120 ° C., and the reaction time is 6 hours to several days. The same applies to compounds 10 to 11 and 13 to 14.
  • Step 7 Deesterification from compounds 6 to 9 is carried out under general alkaline conditions in the case of methyl esters, ethyl esters, and isopropyl esters.
  • a suitable solvent that is easily miscible with water such as alcohol
  • an aqueous solution of 1 mol to large excess of sodium hydroxide is used, preferably about 3 to 10 mol.
  • the reaction temperature is room temperature to 100 ° C, preferably 50 ° C to 80 ° C.
  • the reaction time is about several hours to 1 day.
  • sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like can be used.
  • a reaction under acidic conditions such as concentrated hydrochloric acid-acetic acid can also be selected.
  • reaction temperature is preferably 0 ° C. to room temperature, and the reaction time is preferably 1 hour to 1 day. The same applies to compounds 7 to 10 and 8 to 11.
  • the amidation step of compounds 9 to 12 is carried out by adding HOBt (1-hydroxyl) to a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide in an appropriate solvent (such as dichloromethane) that does not adversely influence the reaction. It can also be carried out by adding an acidic additive such as benztriazole), but preferably 1 to several moles of hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium and several bases such as triethylamine.
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • an appropriate solvent such as dichloromethane
  • the reaction temperature is about 0 ° C. to 40 ° C., and the reaction time is about several hours to several days.
  • it can be synthesized by a simple method such as adding acid water to the reaction system after adjusting acid chloride using oxalyl chloride or the like.
  • a solvent that does not adversely influence the reaction and is easily miscible with water is preferable.
  • the reaction temperature is about 0 ° C to 60 ° C.
  • the reaction time is 30 minutes to several days, preferably 30 minutes to several hours.
  • the reaction temperature is 60 to 100 ° C., and the reaction time is half to several days.
  • the steps from compound 10 to 13, 11 to 14 are also carried out in the same manner.
  • Step 9 Although the cyanation step of compounds 14 to 15 can be performed by the action of a dehydrating agent such as triphosgene or phosphorus pentachloride, Tetrahedron Letter, No. 1, et al. 21, pp 1813-1616, 1977, a method using trifluoroacetic anhydride is preferred.
  • a dehydrating agent such as triphosgene or phosphorus pentachloride, Tetrahedron Letter, No. 1, et al. 21, pp 1813-1616, 1977
  • a method using trifluoroacetic anhydride is preferred.
  • a solvent that does not adversely influence the reaction such as dichloroethane
  • 1 mol to excess mol of trifluoroacetic anhydride and 1 mol to excess mol of a base such as triethylamine are used.
  • the reaction can be carried out in pyridine as a solvent and base.
  • the reaction temperature is preferably 0 ° C. to 40 ° C., and the reaction time
  • Step 10 The step of introducing an N atom from compound 18 to 20 can be carried out by allowing 1 to several moles of p-methoxybenzylamine to act in a solvent that does not adversely influence the reaction (such as N, N-dimethylformamide). it can. It is preferable to select an amine that can be easily deprotected, such as p-methoxybenzylamine and allylamine.
  • the reaction temperature is 60 ° C to 200 ° C, preferably 80 ° C to 100 ° C.
  • the reaction time is several hours to several days.
  • Sodium azide can also be selected as another nitrogen source.
  • the process from compound 19 to 21 is similarly performed.
  • Step 11 The deprotection step of p-methoxybenzylamine from compound 21 to 11 is carried out by catalytic reduction using a palladium carbon catalyst in a hydrogen atmosphere or oxidation using DDQ or the like, as described in PROTECTIVE GROUPS in Organic Synthesis.
  • An automatic removal method can be used.
  • the reaction temperature is room temperature to 60 ° C., and the reaction time is several hours to half a day.
  • allylamine When allylamine is used, it can be carried out by using a method utilizing isomerization of an allyl group as described in PROTECTIVE GROUPS in Organic Synthesis.
  • a palladium carbon catalyst is used in an alcohol solution in an amount of 10 to 100 wt%, and methanesulfonic acid or trifluoroacetic acid is allowed to coexist in an amount of 1 to a large excess.
  • the reaction temperature is room temperature to 100 ° C, preferably 60 to 80 ° C.
  • the reaction time is several hours to 1 day. Subsequent conversion to carboxylic acid and substitution reaction are carried out in the same manner as in Step 6 and Step 7.
  • a compound in which the 9-position of the quinoline ring is a hydrogen atom can use the corresponding benzoic acid, but can be easily synthesized by the following method of reductively removing the halogen atom (in the scheme).
  • R represents an ester group, a carboxy group, a carbamoyl group, or a nitrile group
  • R 2 , R 3 , R 4 , X 1 , and X 2 are as defined above.
  • the reduction reaction from compound 22 to 23 is carried out using an appropriate solvent that does not adversely influence the reaction (such as tetrahydrofuran containing an antioxidant such as dichloroethane, methanol, ethanol, BHT, etc.).
  • an appropriate solvent such as tetrahydrofuran containing an antioxidant such as dichloroethane, methanol, ethanol, BHT, etc.
  • a mixed solvent of an aprotic solvent and an alcohol is used.
  • a catalyst such as palladium carbon is used in an amount of 10 to 100 wt%, preferably about 30 to 50 wt%, in a hydrogen atmosphere.
  • the reaction temperature is 0 to 40 ° C., preferably room temperature.
  • the reaction time is several hours to several days.
  • a naphthyridine-type compound can be synthesized from the brominated intermediate 25 as described below in the same manner as in the above-mentioned “Production Method 2”. Step 13
  • the bromination reaction from compound 24 to 25 is carried out by reacting 2 mol or more of a suitable base such as methyl lithium or normal butyl lithium in an appropriate solvent (such as tetrahydrofuran or diethyl ether) that does not adversely influence the reaction, and then bromine.
  • a suitable base such as methyl lithium or normal butyl lithium
  • an appropriate solvent such as tetrahydrofuran or diethyl ether
  • a source (1,2-dibromotetrachloroethane, phenyltrimethylammonium tribromide, etc.) is used in an amount of 1 mole to a large excess mole, preferably about several moles.
  • the reaction temperature is ⁇ 100 ° C. to room temperature, and the reaction time is 30 minutes to 6 hours.
  • Examples of the anti-DR5 antibody used in the present invention include hTRA8.
  • the production method of hTRA8 is described in WO01 / 083560.
  • the heavy chain sequence of hTRA8 consists of the 1st to 449th amino acid residues or the 1st to 448th amino acid residues of the amino acid sequence shown in SEQ ID NO: 1.
  • the light chain sequence of hTRA8 consists of amino acid residues 1 to 213 in the amino acid sequence shown in SEQ ID NO: 2.
  • amino acid sequence consisting of amino acid residues 1 to 118 of the amino acid sequence of SEQ ID NO: 1 described in the sequence listing corresponds to the heavy chain variable region of hTRA8, and 1 of the amino acid sequence of SEQ ID NO: 2 described in the sequence listing
  • amino acid sequence consisting of the ⁇ 107th amino acid residue corresponds to the light chain variable region of hTRA8.
  • Antibodies having these variable regions and any constant regions can also be used in the present invention.
  • HB273 may be mentioned as another anti-DR5 antibody used in the present invention.
  • the production method of hB273 is described in WO12 / 0577288.
  • the heavy chain sequence of hB273 consists of amino acid residues 1 to 452 or amino acid residues 1 to 451 of the amino acid sequence shown in SEQ ID NO: 3.
  • the light chain sequence of hB273 consists of amino acid residues 1 to 219 of the amino acid sequence shown in SEQ ID NO: 4.
  • the amino acid sequence consisting of amino acid residues 1 to 122 of the amino acid sequence of SEQ ID NO: 3 described in the sequence listing corresponds to the heavy chain variable region of hB273, and 1 of the amino acid sequence of SEQ ID NO: 4 described in the sequence listing.
  • the amino acid sequence consisting of the ⁇ 114th amino acid residue corresponds to the light chain variable region of hB273. Antibodies having these variable regions and any constant regions can also be used in the present invention.
  • Another anti-DR5 antibody used in the present invention can further include Conatumumab.
  • Contumumab is available from WHO Drug Information, Vol. 22, no. Based on the amino acid sequences of the light and heavy chains described in 2, 2008, p129-130, for example, it can be produced by the method described in WO12 / 0577288.
  • the heavy chain sequence of Conatumumab consists of amino acid residues 1 to 452 or amino acid residues 1 to 451 of the amino acid sequence shown in SEQ ID NO: 5.
  • the light chain sequence of Conatumumab consists of amino acid residues 1 to 215 of the amino acid sequence shown in SEQ ID NO: 6.
  • the amino acid sequence consisting of amino acid residues 1 to 122 of the amino acid sequence of SEQ ID NO: 5 described in the sequence listing corresponds to the heavy chain variable region of Conatumumab, and 1 of the amino acid sequence of SEQ ID NO: 6 described in the sequence listing.
  • the amino acid sequence consisting of the ⁇ 110th amino acid residues corresponds to the light chain variable region of Conatumumab.
  • Antibodies having these variable regions and any constant regions can also be used in the present invention.
  • Anti-DR5 antibodies that can be used in the present invention are not limited to the above three types of antibodies, and can be used in combination with GSK3 inhibitors as long as they have a function of inducing apoptosis in DR5-expressing cells. It is.
  • WO98 / 51793, WO2001 / 83560, WO2002 / 94880, WO2003 / 54216, WO2006 / 83971, WO2007 / 22157, WO11 / 039126 or WO11 / 1098520 describe anti-DR5 antibodies that induce apoptosis in DR5-expressing cells.
  • Anti-DR5 antibodies called Lexatumumab (HGS-ETR2), HGS-TR2J, Drozitamab (APOMAB), LBY135, and TAS266 can also be used in the present invention.
  • Drozitamab is available from WHO Drug Information, Vol. 25, no.
  • the heavy chain sequence of Drozitamab consists of amino acid residues 1 to 451 or amino acid residues 1 to 450 of the amino acid sequence shown in SEQ ID NO: 7.
  • the light chain sequence of Drozitumab consists of amino acid residues 1 to 213 in the amino acid sequence shown in SEQ ID NO: 8.
  • the amino acid sequence consisting of amino acid residues 1 to 121 of the amino acid sequence of SEQ ID NO: 7 described in the sequence listing corresponds to the heavy chain variable region of Drozitumab, and 1 of the amino acid sequence of SEQ ID NO: 8 described in the sequence listing.
  • the amino acid sequence consisting of the ⁇ 113th amino acid residue corresponds to the light chain variable region of Drozitamab. Antibodies having these variable regions and any constant regions can also be used in the present invention.
  • Lexatumumab is available from WHO Drug Information, Vol. 21, no. It can be produced based on the amino acid sequences of the light and heavy chains described in 1,2007, p69-70.
  • the heavy chain sequence of Lexatumumab consists of amino acid residues 1 to 451 or amino acids 1 to 450 of the amino acid sequence shown in SEQ ID NO: 9.
  • the light chain sequence of Lexatumumab consists of amino acid residues 1 to 214 in the amino acid sequence shown in SEQ ID NO: 10.
  • the amino acid sequence consisting of amino acid residues 1 to 121 of the amino acid sequence of SEQ ID NO: 9 described in the sequence listing corresponds to the heavy chain variable region of Lexatumumab, and is 1 of the amino acid sequence of SEQ ID NO: 10 described in the sequence listing.
  • the amino acid sequence consisting of the ⁇ 114th amino acid residue corresponds to the light chain variable region of Lexatumumab.
  • Antibodies having these variable regions and any constant regions can also be used in the present invention.
  • an antibody having the complementarity determining region (CDR) of any of the above antibodies can also be used in the present invention.
  • CDRs also called hypervariable domains
  • hypervariable domains are sites in the variable regions of antibody heavy and light chains that have particularly high primary structure variability, and are heavy and light chain polypeptide chains. In the primary structure of each, it is separated into three locations. These sites are close to each other on the three-dimensional structure and determine the specificity for the antigen to be bound. Therefore, for example, an antibody having a combination of 6 CDRs on the heavy and light chains of hTRA8 can be used in the present invention, and the same applies to other anti-DR5 antibodies such as hB273.
  • an appropriate host cell and an expression vector can be used in combination.
  • the heavy chain sequence gene and the light chain sequence gene can be inserted into the same expression vector, or can be inserted into separate expression vectors. is there.
  • eukaryotic cells animal cells, plant cells, and eukaryotic microorganisms can be used.
  • animal cells include (1) mammalian cells such as COS cells (Gluzman, Y. Cell (1981) 23, p.175-182, ATCC CRL-1650) which are monkey cells, mouse fibroblasts NIH3T3 (ATCC). No. CRL-1658), a Chinese hamster ovary cell (CHO cell, ATCC CCL-61) dihydrofolate reductase deficient strain (Urlauub, G.
  • an antibody can be obtained by introducing a desired antibody gene into these cells by transformation and culturing the transformed cells in vitro. In the above culture method, the yield of the antibody may be different, and it is possible to select an antibody-producing cell that can be easily produced as a pharmaceutical using the yield as an index.
  • the antibody of the present invention may be a functional fragment (antigen-binding fragment) of an antibody having an antigen-binding portion of an antibody or a modified product thereof.
  • a fragment of the antibody can be obtained by treating the antibody with a proteolytic enzyme such as papain or pepsin, or modifying the antibody gene by a genetic engineering technique and expressing it in an appropriate cultured cell.
  • a fragment that retains all or part of the functions of the full-length antibody molecule can be referred to as an antibody functional fragment.
  • Antibody functions generally include antigen-binding activity, activity that neutralizes antigen activity, activity that enhances antigen activity, antibody-dependent cytotoxic activity, complement-dependent cytotoxic activity, and complement-dependence Mention may be made of cellular cytotoxic activity.
  • the function retained by the functional fragment of the antibody in the present invention is a binding activity to DR5, preferably an activity inducing apoptosis in cells, and more preferably a cytotoxic activity through induction of apoptosis in cancer cells.
  • the antibody of the present invention may have antibody-dependent cytotoxic activity, complement-dependent cytotoxic activity and / or complement-dependent cytotoxic activity in addition to the activity of inducing apoptosis in cells. good.
  • antibody fragments include Fab, F (ab ′) 2, Fv, or single chain Fv (scFv), diabodies (diabodies), linear antibody in which Fvs of heavy and light chains are linked by an appropriate linker. And multispecific antibodies formed from antibody fragments.
  • Fab ′ which is a monovalent fragment of the variable region of an antibody obtained by treating F (ab ′) 2 under reducing conditions, is also included in the antibody fragment.
  • the “medicine administered in combination with a GSK3 inhibitor and an anti-DR5 antibody” is a drug that is assumed to be administered in combination with a GSK3 inhibitor and an anti-DR5 antibody.
  • “administered in combination” with a GSK3 inhibitor and an anti-DR5 antibody means that the administration subject takes the GSK3 inhibitor and the anti-DR5 antibody into the body for a certain period of time.
  • a formulation containing a GSK3 inhibitor and an anti-DR5 antibody in a single formulation may be administered, or each may be formulated separately and administered separately.
  • the timing of administration is not particularly limited, and may be administered at the same time, and may be administered at different times or on different days.
  • the GSK3 inhibitor and the anti-DR5 antibody are administered at different times or days, the order of administration is not particularly limited. Usually, since each formulation is administered according to each administration method, the administration may be the same number of times or may be different times.
  • the administration method (administration route) of each formulation may be the same, and may be administered by different administration methods (administration route).
  • the GSK3 inhibitor and the anti-DR5 antibody do not need to be present in the body at the same time, and may be present in the body during a certain period of time (for example, one month, preferably one week, more preferably several days, even more preferably one day).
  • the other active ingredient may disappear from the body at any time of administration.
  • Examples of the administration form of the medicament of the present invention include, for example, 1) administration of a single preparation containing a GSK3 inhibitor and an anti-DR5 antibody, 2) obtained by separately formulating a GSK3 inhibitor and an anti-DR5 antibody 2 Simultaneous administration of the same formulation by the same route of administration, 3) Administration of the two formulations obtained by separately formulating the GSK3 inhibitor and the anti-DR5 antibody at different time intervals by the same route of administration, 4) Inhibition of GSK3 Of two preparations obtained by separately formulating an agent and an anti-DR5 antibody by different administration routes, and 5) different two preparations obtained by separately formulating a GSK3 inhibitor and an anti-DR5 antibody Examples include administration with a time difference in the administration route.
  • kits containing them when two different preparations are used, a kit containing them can be used.
  • the medicament according to the present invention contains a GSK3 inhibitor and / or an anti-DR5 antibody and a pharmaceutically acceptable carrier, and is used as various injections such as intravenous injection, intramuscular injection, subcutaneous injection, orally administered or transdermally. It can be administered by various methods such as skin administration.
  • a pharmaceutically acceptable carrier is a pharmaceutically acceptable material involved in transporting a compound of the present invention or a composition comprising a compound of the present invention from one organ or organ to another. (For example, excipient, diluent, additive, solvent, etc.).
  • an appropriate preparation for example, an oral preparation or an injection
  • oral preparations include tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions, and oily or aqueous suspensions.
  • oral administration it may be in the free form or in the salt form.
  • Aqueous preparations can be prepared by forming an acid adduct with a pharmaceutically acceptable acid or by forming an alkali metal salt such as sodium.
  • stabilizers, preservatives or solubilizers can be used in the preparation.
  • a solution that may contain these adjuvants and the like may be stored in a container and then prepared as a solid preparation by lyophilization or the like.
  • the single dose may be stored in one container, and the multiple doses may be stored in one container.
  • solid preparations include tablets, powders, granules, capsules, pills, and lozenges. These solid preparations may contain pharmaceutically acceptable additives together with the compound of the present invention.
  • the additive include fillers, extenders, binders, disintegrants, dissolution accelerators, wetting agents, and lubricants, which are selected and mixed as necessary. And can be formulated.
  • liquid preparations include solutions, syrups, elixirs, emulsions, and suspensions.
  • the additive include a suspending agent or an emulsifier, and these can be selected and mixed as necessary to prepare a formulation.
  • the present invention can be used for cancer treatment of mammals, particularly humans.
  • the dosage and administration interval of the medicament of the present invention can be appropriately selected according to the judgment of a doctor depending on the location of the disease, the height, weight, sex or medical history of the patient.
  • the dosage range is from about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg per day for one active ingredient.
  • Body weight to about 100 mg / kg body weight.
  • it is preferably administered once a day or divided into 2 to 4 times and repeated at appropriate intervals.
  • the daily amount may exceed the above amount depending on the judgment of the doctor.
  • the pharmaceutical composition containing the anti-DR5 antibody used in the present invention has pH, osmotic pressure, viscosity, transparency, color, isotonicity, sterility, stability, dissolution rate, sustained release rate, absorption rate, and penetration rate.
  • Substances for formulation may include, but are not limited to: amino acids such as glycine, alanine, glutamine, asparagine, arginine or lysine, antibacterial agents, ascorbic acid, sodium sulfate or sodium bisulfite Antioxidants, phosphoric acid, citric acid, boric acid buffer, sodium bicarbonate, buffer such as tris-hydrochloric acid (Tris-Hcl) solution, filler such as mannitol and glycine, chelate such as ethylenediaminetetraacetic acid (EDTA) Agents, caffeine, polyvinylpyrrolidine, complexing agents such as ⁇ -cyclodextrin and hydroxypropyl- ⁇ -
  • the addition amount of the substance for these preparations is preferably 0.01 to 100 times, particularly 0.1 to 10 times the weight of the anti-DR5 antibody.
  • the composition of a suitable pharmaceutical composition in the preparation can be appropriately determined by those skilled in the art depending on the disease to be applied, the route of administration and the like.
  • Excipients and carriers in the pharmaceutical composition may be liquid or solid. Appropriate excipients and carriers may be water for injection, physiological saline, artificial cerebrospinal fluid and other substances commonly used for parenteral administration. Neutral physiological saline or physiological saline containing serum albumin can also be used as a carrier.
  • the pharmaceutical composition may include Tris buffer at pH 7.0-8.5, acetate buffer at pH 4.0-5.5, citrate buffer at pH 3.0-6.2. These buffers may also contain sorbitol and other compounds.
  • the type of cancer to be treated is not particularly limited as long as it is a cancer that is confirmed to be sensitive to a combination treatment of a GSK3 inhibitor and an anti-DR5 antibody.
  • Head and neck cancer esophageal cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate
  • Examples include cancer, neuroendocrine tumors, melanoma, breast cancer, endometrial cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi sarcoma, myoma, kidney cancer, bladder cancer or testicular cancer.
  • MLL mixed-lineage leukemia
  • the cell growth inhibitory activity can be examined using a growth inhibition test method commonly used by those skilled in the art.
  • Cell growth inhibitory activity can be performed, for example, by comparing the extent of cell (eg, tumor cell) growth in the presence or absence of the test agent.
  • the degree of proliferation can be examined using, for example, a test system that measures live cells. Examples of the method for measuring living cells include [ 3 H] -thymidine incorporation test, BrdU method, MTT assay and the like.
  • Cell apoptosis assay methods include confirmation of chromosomal DNA ladders by electrophoresis, detection of chromosome fragmentation by TUNEL staining, changes in phosphatidylserine distribution in cell membranes by labeled Annexin V, and expression levels of various caspases associated with apoptosis Or an activity measurement can be mentioned.
  • various kits for detecting apoptosis including the above methods are widely available on the market, and by using these kits, apoptosis due to a combination of a GSK3 inhibitor and an anti-DR5 antibody can be detected.
  • the antitumor activity in vivo can be examined using an antitumor test method usually used by those skilled in the art. For example, after transplanting various tumor cells into mice, rats, etc., and confirming the engraftment of the transplanted cells, GSK3 inhibitor and DR5 antibody are administered by a suitable administration method, and no drug is administered several days to several weeks later.
  • the in vivo antitumor activity of the present invention can be confirmed by comparing tumor growth in the group and tumor growth in the compound administration group.
  • the medicament according to the present invention may be used in combination with other antitumor agents.
  • antitumor antibiotics for example, antitumor antibiotics, antitumor plant components, BRM (biological response regulator), hormones, vitamins, antitumor antibodies, molecular targeted drugs, alkylating agents, antimetabolites and other antitumor agents Etc.
  • BRM biological response regulator
  • hormones for example, antitumor antibiotics, antitumor plant components, BRM (biological response regulator), hormones, vitamins, antitumor antibodies, molecular targeted drugs, alkylating agents, antimetabolites and other antitumor agents Etc.
  • examples of the alkylating agent include an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl, an aziridine alkylating agent such as carbocone or thiotepa, dibromomannitol or dibromodarsi Epoxide alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride, nitrosourea alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate, temozolomide or dacarbazine .
  • an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl
  • an aziridine alkylating agent such as carbocone or thiotepa
  • dibromomannitol or dibromodarsi Epoxide alkylating agents such as Toll, carmustine, lomustine
  • antimetabolites for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.
  • purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine
  • pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine
  • antifolate inhibitors such as methotrexate or trimethrexate.
  • Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A Examples include 3 or actinomycin D.
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pir
  • antineoplastic plant component examples include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.
  • BRM examples include tumor necrosis factor or indomethacin.
  • hormones include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinyl estradiol, chlormadinone, or medroxyprogesterone.
  • vitamins examples include vitamin C and vitamin A.
  • Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib.
  • antitumor agents include, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.
  • the present invention includes a method for preventing and / or treating cancer characterized by administering the compound of the present invention or a salt thereof.
  • reaction mixture was diluted with chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by flash silica gel column chromatography (1% methanol / chloroform ⁇ 2%) to obtain the title compound (3.8 g) as an oil.
  • the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the solid (40 mg, 0.08 mmol) obtained above was dissolved in tetrahydrofuran (0.5 ml) -ethanol (0.5 ml), 1M aqueous sodium hydroxide solution (0.29 ml) was added, and the mixture was heated at 60 ° C. for 8 hours. Stir.
  • reaction mixture was allowed to cool, 1M hydrochloric acid (0.3 ml) was added under ice-cooling, and the mixture was partitioned between ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (25 mg) as a solid.
  • the catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure.
  • the extract was washed successively with water (40 ml ⁇ 3) and saturated brine (40 ml), and dried over anhydrous sodium sulfate.
  • the obtained residue was solidified with a mixed solvent of ethyl acetate and n-hexane to obtain the title compound (25 mg) as a solid.
  • reaction mixture was diluted with methylene chloride, washed with 1M aqueous sodium hydroxide solution and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Methanol was added to the residue, and the insoluble material was collected by filtration and dried to obtain the title compound (3.54 g) as a solid.
  • Example 16 (1R) -8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7-fluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2 -A] quinoline-4-carboxamide (Process 1) (1R) -8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-9-chloro-7-fluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2-a] quinoline-4-carboxamide
  • the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, the residue was partitioned between chloroform and saturated aqueous sodium bicarbonate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (149 mg) as a solid. It was.
  • Example 17 8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7,9-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2 -A] quinoline-4-carboxylic acid (Process 1) (1-Hydroxy-5,5-dimethylpyrrolidin-2-yl) acetate isopropyl ester
  • the reaction mixture was stirred at room temperature for 2 hours, poured into a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate.
  • the aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in acetone (100 ml), potassium carbonate (6.6 g) was added, and the mixture was heated to reflux for 18 hours. Under ice cooling, the solution was made weakly acidic with 1M hydrochloric acid and extracted with ethyl acetate.
  • Step 6 8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7,9-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2 -A] quinoline-4-carboxylic acid
  • Example 18 The compound obtained in Example 18 (1.19 g, 2.8 mmol) was dissolved in methylene chloride (50 ml), ammonium chloride (3.0 g, 57 mmol), triethylamine (12 ml), hexafluorophosphoric acid (benzotriazole- 1-yloxy) tripyrrolidinophosphonium (1.6 g) was added and stirred for 2 hours.
  • the reaction mixture was diluted with methylene chloride, washed with 1M aqueous sodium hydroxide solution and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with dichloromethane, and 10% aqueous citric acid was added.
  • Example 23 8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7,9-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2 -A] quinoline-4-carbonitrile (Process 1) (1-Hydroxy-5,5-dimethylpyrrolidin-2-yl) acetonitrile
  • Methanesulfonyl chloride was added to a solution of (1-hydroxy-5,5-dimethylpyrrolidin-2-yl) acetonitrile (3.48 g, 22.6 mmol) and triethylamine (12.6 ml, 902 mmol) in methylene chloride (40 ml) under ice-cooling. (2.1 ml, 27.1 mmol) was added. The reaction mixture was heated to reflux for 1 hour and allowed to return to room temperature. The reaction mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and the mixture was extracted with ethyl acetate.
  • Step 6 8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7,9-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2 -A] quinoline-4-carbonitrile
  • Example 25 8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7-fluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2-a ] Quinoline-4-carboxylic acid (Process 1) (1-Hydroxy-5,5-dimethylpyrrolidin-2-yl) acetic acid tert-butyl ester
  • the amorphous was dissolved in a mixed solvent of 1,2-dichloroethane (15 mL) and ethanol (15 mL), 10% palladium carbon (AD, wet, 550 mg) was added, and the mixture was stirred at room temperature for 13 hours in a hydrogen atmosphere.
  • Aqueous ammonia was added to the reaction solution, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Ethanol (10 mL) was added to the obtained residue, heated to 95 ° C., and aqueous ammonia was added until the insoluble material was dissolved. As it was heated, ammonia was gradually vaporized to precipitate a solid.
  • Example 30 8-[(1-Acetylpiperidin-4-yl) amino] -6-amino-7-fluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2-a ] Quinoline-4-carboxamide (Process 1) 6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2-a] quinoline-4-carboxamide
  • 6-amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2-a] quinoline-4-carboxamide 200 mg, 1- (4-Aminopiperidin-1-yl) ethanone (250 mg, 1.76 mmol) was added to a dimethyl sulfoxide solution (5 ml) of 0.59 mmol) and stirred at 100 ° C. overnight. Water was added, the mixture was extracted with chloroform containing 10% methanol, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Trifluoroacetic anhydride (0.145 mL) was added to a dichloromethane solution (20 mL) of the compound obtained in Step 3 of Example 30 (223 mg, 0.519 mmol) and triethylamine (0.579 mL, 4.15 mmol) in an ice bath. , 1.04 mmol) was added and stirred. After 30 minutes, trifluoroacetic anhydride (0.145 mL, 1.04 mmol) and triethylamine (0.290 mL, 2.07 mmol) were further added, and the mixture was stirred for 30 minutes.
  • Example 32 Using the compound obtained in Example 32, the title compound was obtained as a solid in the same manner as in Example 33.
  • Example 40 4-Amino-3-fluoro-9,9-dimethyl-5-oxo-2- (pyridin-3-ylamino) -5,7,8,9-tetrahydropyrrolo [1,2-a] [1,8] Naphthyridine-6-carboxylic acid (Process 1) 2-Chloro-3-fluoro-4- (4-methoxybenzylamino) -9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo [1,2-a] [1,8] Naphthyridine-6-carboxylic acid tert-butyl ester
  • Trifluoroacetic acid (3 ml) was added to a solution of the above intermediate in methylene chloride (3 ml) and stirred for 7 hours.
  • the solvent was distilled off under reduced pressure, toluene was added to the residue, and the solvent was distilled off again.
  • 4M Hydrochloric acid / dioxane was added to the residue, the solvent was evaporated again, and the residue was solidified with dioxane-methanol to obtain the title compound (554 mg) as a solid.
  • Example 41 2-[(1-Acetylpiperidin-4-yl) amino] -4-amino-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo [1,2-a ] [1,8] Naphthyridine-6-carboxamide (Process 1) 4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo [1,2-a] [1,8] naphthyridine-6-carboxamide
  • Example 43 4-Amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl) amino] -5-oxo-5,7,8,9-tetrahydropyrrolo [1,2-a ] -1,8-naphthyridine-6-carbonitrile (Process 1) 4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo [1,2-a] -1,8-naphthyridine-6-carbonitrile
  • Ethyl 3-ethoxy-3-iminopropionate hydrochloride (10.0 g, 51.1 mmol) was added to an ethanol solution of 1,2-diamino-2-methylpropane (4.96 g, 56.2 mmol) at room temperature. Stir for 1 hour. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate (100 ml) and tetrahydrofuran (150 ml) were added, and a tetrahydrofuran solution (50 ml) of N- (benzyloxycarbonyloxy) -succinimide (5.95 g, 23.9 mmol) was added dropwise at room temperature. For 2 hours.
  • 6-amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo [1,2-a] quinoline-4-carboxylic acid ethyl ester 1- (4-aminopiperidin-1-yl) ethanone (528 mg, 3.71 mmol) was added to a dimethyl sulfoxide solution (3 ml) of 230 mg), and the mixture was stirred at 130 ° C. overnight. Water was added, the mixture was extracted with chloroform containing 10% methanol, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Acetic acid (148 ⁇ l, 2.58 mmol) was added to make the solution acidic, and then the solution was made basic by adding aqueous ammonia, extracted with chloroform containing 10% methanol, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol system) to obtain the title compound (110 mg) as a solid.
  • 1,2-Diamino-2-methylpropane (3.93 ml, 37.9 mmol) was added to an ethanol solution (130 ml) of ethyl 2-cyanoethaneimidate hydrochloride (5.12 g, 34.5 mmol) at room temperature. Stir for hours. After the solvent was distilled off, tetrahydrofuran (300 ml), saturated aqueous sodium hydrogen carbonate (150 ml) and ditert-butyl dicarbonate (8.27 g, 37.9 mmol) were added and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate and washed with saturated brine.
  • Triethylamine (436 ⁇ l, 3.13 mmol) was added and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Potassium carbonate (520 mg, 3.76 mmol) was added to an acetone solution (30 ml) of the residue (1.49 g), and the mixture was stirred at room temperature for 3 hours. Water was added, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added, and the precipitated solid was collected by filtration.
  • Example 50 4-Amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl) amino] -5-oxo-5,7,8,9-tetrahydroimidazo [1,2-a ] [1,8] Naphthyridine-6-carboxamide (Process 1) 2-Chloro-3-fluoro-4-[(4-methoxybenzyl) amino] -9,9-dimethyl-5-oxo-8,9-dihydro-5H-imidazo [1,2-a] [1,8 ] Naphthyridine-6,7-dicarboxylic acid 7-benzyl ester 6-ethyl ester
  • Step 1 of Example 35 To the compound obtained in Step 1 of Example 35 (5 g, 17.3 mmol) were added thionyl chloride (8 ml) and N, N-dimethylformamide (3 drops), and the mixture was stirred at 70 ° C. for 2 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, the solvent was distilled off again under reduced pressure, and the residue was dissolved in tetrahydrofuran (50 ml). A solution of the compound obtained in Step 1 of Example 45 (6.1 g, 19 mmol) in tetrahydrofuran (10 ml) was added, sodium hydrogen carbonate (1.5 g) was added, and the mixture was stirred at 50 ° C. for 8 hours. Stir for 10 hours.
  • thionyl chloride 8 ml
  • N, N-dimethylformamide 3 drops
  • the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over magnesium sulfate.
  • Acetonitrile (30 ml) and p-methoxybenzylamine (4.7 ml) were added to the oil (6.85 g), and the mixture was stirred at 50 ° C. for 2 hours. Further, p-methoxybenzylamine (1 ml) was added and stirred at the same temperature for 2 hours.
  • the mixture was diluted with chloroform containing 10% methanol and washed with 1M aqueous sodium hydroxide solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, ethyl acetate was added, and the precipitated solid was collected by filtration. Trifluoroacetic acid (149 ⁇ l, 2.02 mmol) was added to a methylene chloride suspension (2 ml) of the obtained solid (75 mg), and the mixture was stirred at room temperature for 4 hours. After running off the solvent, aqueous ammonia was added to make it basic, and the precipitate was collected by filtration to obtain the title compound (45 mg) as a solid.
  • the obtained residue was diluted with methanol, 4N hydrochloric acid-dioxane solution was added, and the mixture was stirred. After evaporating the solvent under reduced pressure, isopropanol and ethyl acetate were added to the resulting residue and solidified to obtain the desired product (150 mg) as a solid.
  • Example 17 Using the compound obtained in Step 5 of Example 17 and 1- (4-aminopiperidin-1-yl) -2-methylpropan-2-ol, the title compound was obtained as a solid in the same manner as in Example 17. It was.
  • the substrate peptide is phosphorylated by the kinase activity of GSK3. Since the substrate phosphorylated by the kinase changes to minus (negative) by the amount of the phosphate group compared to the non-phosphorylated substrate, this change is separated by the principle of electrophoresis (Mobility Shift Assay method) The degree of phosphorylation was then quantified.
  • GST-GSK3 protein GSK3 ⁇ , Carnabio
  • a GSK3 ⁇ enzyme solution containing the GST-GSK3 protein and 100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mM DTT, 10 mM MgCl 2 was prepared. Dispensing into well plate (Corning).
  • test compound was dissolved in DMSO, and a dilution series was prepared using DMSO. This compound solution was added to the dispensed GSK3 enzyme solution, mixed, and then preincubated for 30 minutes at room temperature.
  • a substrate solution 100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mM DTT, 10 mM MgCl 2 , ATP (final concentration 20 ⁇ M), FL -Peptide 15 (caliper life science) was added and mixed, and then allowed to stand at 28 ° C for 1.5 hours to allow the enzyme reaction to proceed.
  • reaction stop solution 100 mM HEPES (pH 7.4), 0.015% Brij-35, 40 mM EDTA, 0.1% Coating Reagent 3 (caliper life science) was applied to each well.
  • the phosphorylated substrate and the non-phosphorylated substrate were separated using caliper life science EZ Reader II, and the ratio of phosphorylation of the substrate peptide (Conversion) and the inhibitory activity (Inhibition) were measured. By fitting the measured value to the sigmoid curve, the concentration at which the compound exhibited 50% inhibition was calculated as the IC 50 value of GSK3 ⁇ enzyme inhibitory activity.
  • the IC 50 value of each Example compound was 20 nM or less.
  • Example Compound Human acute lymphocytic leukemia cell line RS4; 11 (ATCC, USA) was seeded in a 96-well plate at 2 ⁇ 10 4 cells / well and cultured overnight.
  • a cell group was prepared by adding a secondary antibody solution (concentration: 10 ⁇ g / mL) and a secondary antibody for cross-linking (goat anti-human IgG antibody, MP Biomedicals, LLC, Cat #: 55071, final concentration: 20 ⁇ g / mL) to each well. Cultured for days.
  • FIGS. 3-1 to 3-6 The results are shown in FIGS. 3-1 to 3-6 and FIGS. 4-1 to 4-6.
  • LY2090314 was administered twice and anti-DR5 antibody was administered only once on the first day.
  • the major axis (mm) and minor axis (mm) of the tumor were measured with electronic digital calipers over time, and the tumor growth inhibition rate (GI%) on the date of determination (one week after administration) according to the following calculation formula (4) evaluated.
  • GI (%) (1-A / B) ⁇ 100 (4)
  • the anti-DR5 antibody and its dose used in this study were hB273 (3 mg / kg), hTRA8 (10 mg / kg) and Conatumumab (3 mg / kg).
  • the administration is performed only once on the first day, and the major axis (mm) and minor axis (mm) of the tumor are measured with electronic digital calipers over time, and the tumor on the determination date (one week after administration) according to the following calculation formula (4)
  • the growth inhibition rate (GI%) was evaluated.
  • GI (%) (1-A / B) ⁇ 100 (4)
  • the administration is performed only once on the first day, and the major axis (mm) and minor axis (mm) of the tumor are measured with electronic digital calipers over time, and the tumor on the determination date (one week after administration) according to the following calculation formula (4)
  • the growth inhibition rate (GI%) was evaluated.
  • GI (%) (1-A / B) ⁇ 100 (4)

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Abstract

L'invention concerne une thérapie combinée destinée au cancer, qui comprend une combinaison d'un inhibiteur de GSK3 et d'un anticorps anti-DR5. On décrit un produit pharmaceutique et une thérapie combinée, dont chacun comprend une combinaison de divers anticorps anti-DR5 et d'un inhibiteur de GSK3, tel que LY2090314, un composé représenté par la formule générale (1) ou un sel du composé. (Dans la formule, R1, R2, R3, R4, X1 et X2 sont tels que définis dans la description.)
PCT/JP2013/075616 2012-09-25 2013-09-24 Combinaison d'un inhibiteur de gsk3 et d'un anticorps anti-dr5 WO2014050779A1 (fr)

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US10041047B2 (en) 2013-03-14 2018-08-07 Massachusetts Institute Of Technology Compositions and methods for epithelial stem cell expansion and culture
JP2019194236A (ja) * 2014-09-17 2019-11-07 セルジーン シーエーアール エルエルシー Ｍｋ２阻害剤およびその使用
US10501552B2 (en) 2015-01-26 2019-12-10 Macrogenics, Inc. Multivalent molecules comprising DR5-binding domains
US10568883B2 (en) 2014-09-03 2020-02-25 Massachusetts Institute Of Technology Compositions, systems, and methods for generating inner ear hair cells for treatment of hearing loss
WO2020069187A1 (fr) * 2018-09-28 2020-04-02 The Children's Medical Center Corporation Polythérapie pour le traitement de la leucémie aiguë myéloïde
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille
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JP7375072B2 (ja) 2014-09-17 2023-11-07 ブリストル－マイヤーズ スクイブ カンパニー Ｍｋ２阻害剤およびその使用
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US11021687B2 (en) 2016-01-08 2021-06-01 The Brigham And Women's Hospital, Inc. Production of differentiated enteroendocrine cells and insulin producing cells
US11160868B2 (en) 2016-03-02 2021-11-02 Frequency Therapeutics, Inc. Thermoreversible compositions for administration of therapeutic agents
US11260130B2 (en) 2016-03-02 2022-03-01 Frequency Therapeutics, Inc. Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: IV
US11033546B2 (en) 2016-03-02 2021-06-15 Frequency Therapeutics, Inc. Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: I
US11066419B2 (en) 2016-12-30 2021-07-20 Frequency Therapeutics, Inc. 1H-pyrrole-2,5-dione compounds and methods of using same
US11162071B2 (en) 2018-08-17 2021-11-02 Frequency Therapeutics, Inc. Compositions and methods for generating hair cells by upregulating JAG-1
US11617745B2 (en) 2018-08-17 2023-04-04 Frequency Therapeutics, Inc. Compositions and methods for generating hair cells by downregulating FOXO
WO2020069187A1 (fr) * 2018-09-28 2020-04-02 The Children's Medical Center Corporation Polythérapie pour le traitement de la leucémie aiguë myéloïde
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille

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