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WO2010038428A1 - Agent alternatif à l'agent taxane anticancéreux - Google Patents

Agent alternatif à l'agent taxane anticancéreux Download PDF

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Publication number
WO2010038428A1
WO2010038428A1 PCT/JP2009/004992 JP2009004992W WO2010038428A1 WO 2010038428 A1 WO2010038428 A1 WO 2010038428A1 JP 2009004992 W JP2009004992 W JP 2009004992W WO 2010038428 A1 WO2010038428 A1 WO 2010038428A1
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WO
WIPO (PCT)
Prior art keywords
difluorophenyl
anticancer agent
taxane anticancer
salt
administration
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PCT/JP2009/004992
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English (en)
Japanese (ja)
Inventor
松本裕
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武田薬品工業株式会社
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Publication of WO2010038428A1 publication Critical patent/WO2010038428A1/fr

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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
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a replacement drug for a taxane anticancer agent.
  • Paclitaxel a taxane anticancer agent
  • paclitaxel has to be administered by infusion over several hours with standard therapy, and it has significant side effects such as leukopenia, neutropenia, peripheral neuropathy, and nausea and vomiting, which can be very burdensome to patients. large. For this reason, it is necessary to take a drug holiday for at least 3 weeks.
  • the present invention provides a replacement agent for a taxane anticancer agent that can extend the drug withdrawal period of the taxane anticancer agent while maintaining the therapeutic effect of a taxane anticancer agent such as paclitaxel.
  • the issue is to provide.
  • the present inventors have demonstrated that by using p38 MAPK (p38 mitogen-activated protein kinase) inhibitor, the drug withdrawal period can be extended while maintaining the cancer therapeutic effect of paclitaxel. I found it. Furthermore, the present inventors have found that p38 MAPK inhibitors are useful for the prevention or treatment of non-small cell lung cancer. Furthermore, the present inventors have found that there is an anchorage-independent cancer growth-specific inhibitory effect, which is promoted by the combined use with paclitaxel. The present invention has been completed based on these findings. That is, the present invention provides the following [1] to [17] and the like.
  • a taxane anticancer agent is not administered during the period of 2 to 8 months. Replacement drug for taxane anticancer drugs.
  • the p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino
  • the medicament according to [1] above, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
  • [4] A method of enhancing the anticancer action of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with the taxane anticancer agent.
  • [5] A method for reducing side effects of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent.
  • the p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-
  • the taxane anticancer agent is paclitaxel or a salt thereof.
  • a method for treating cancer comprising a single administration of a taxane anticancer agent to a patient; Administration of the taxane anticancer agent followed by two or more administrations of the p38 MAPK inhibitor to the patient over a period of 2 to 8 months.
  • the p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-
  • the taxane anticancer agent is paclitaxel or a salt thereof.
  • a medicament for preventing or treating non-small cell lung cancer comprising a p38 MAPK inhibitor.
  • the p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-
  • An anchorage-independent cancer growth-specific inhibitor containing a p38 MAPK inhibitor is [(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
  • [13a] The anchorage-independent cancer growth-specific inhibitor according to [13] above, further comprising a taxane anticancer agent.
  • [13b] (A) administering a taxane anticancer agent and a p38 MAPK inhibitor to a cancer cell over 3-7 days; and (B) and then administering a p38 MAPK inhibitor to the cancer cell for a week or more and not administering a taxane anticancer agent to the cancer cell, Specific suppression of anchorage-independent cancer growth.
  • the p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino
  • the drug suspension period of the taxane anticancer agent can be extended while maintaining the therapeutic effect of the taxane anticancer agent.
  • an anchorage independent cancer growth specific inhibitor is provided.
  • the present invention also provides a medicament for preventing or treating non-small cell lung cancer.
  • FIG. 1A is a graph showing the inhibitory effect of Compound 1 on the growth of A549 cell colonies, ie, anchorage-independent growth.
  • FIG. 1B is a phase contrast micrograph showing the inhibitory action of Compound 1 on the growth of A549 cell colonies, ie, anchorage-independent growth.
  • FIG. 2 is a graph showing changes in tumor volume of mice.
  • FIG. 3 is a graph showing mouse body weight fluctuations.
  • FIG. 4A is a graph showing tumor weight of mice.
  • FIG. 4B is a graph showing the white blood cell count.
  • FIG. 5A is a graph showing changes in tumor volume in mice.
  • FIG. 5B is a graph showing the weight fluctuation of the mouse.
  • the replacement agent for the taxane anticancer agent of the present invention contains a p38 MAPK inhibitor.
  • the p38 MAPK inhibitor used in the present invention include the following compounds or salts thereof.
  • SB203580 Ishizuka et al., J. Immunol. 167 (4): 2298-304 (2001), Calbiochem
  • SB202190 Karahashi et al., Biochim. Biophys. Acta 1502 (2): 207-23 (2000) ) (Calbiochem), SB220025 (Calbiochem), EO-1428 (Leo Pharm), SB239063 (Legos et al., 2001, Brain Res.
  • p38 MAPK inhibitors used in the present invention include inhibitors of p38 MAPK gene expression.
  • examples of the “salt” include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt) or an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the replacement agent for the taxane anticancer agent of the present invention can enhance the anticancer effect and / or reduce the side effects of the taxane anticancer agent for patients having a history of administration of the taxane anticancer agent. Therefore, it is administered more than once over a period of 2-8 months. During the period of 2 to 8 months, the taxane anticancer agent is not administered to the patient.
  • taxane anticancer agent includes paclitaxel: ANX-513, BMS-181339, DHP-107, DHP-208, DTS-301, NSC-125973, Nova- 12005, OAS-PAC-100, SDP-013, MPI-5018 (Trademarks: Taxol, Anzatax, Zenaxol, Genexol, Genexol-PM, Nanotaxel (Nanotax) OncoGel, Paclical, Pacligel, Paxceed, Paxene, Xorane, Taxane (Yewtaxan), Genetaxyl, ABI-007 (Nanoparticle albumin-bound paclitaxel) (Trademark: Abraxan / Abraxane), CT-2 (Polyglutamate paclitaxel)) (trademark: Opaxio, PG-TXL, Geotax), docetaxel: ANX-514, NSC-628503, RP-56976, SDP
  • taxane anticancer agents include shock, anaphylaxis-like symptoms, bone marrow suppression such as leukopenia or neutropenia, peripheral neuropathy, nausea and vomiting, paralysis, interstitial pneumonia, lung fiber Disease, acute respiratory distress syndrome, myocardial infarction, congestive heart failure, cardiac conduction disorder, pulmonary embolism, thrombophlebitis, stroke, pulmonary edema, hearing loss, tinnitus, gastrointestinal necrosis, intestinal perforation, gastrointestinal bleeding, gastrointestinal ulcer, Severe enteritis, intestinal obstruction, intestinal palsy, liver dysfunction, jaundice, pancreatitis, acute renal failure, mucocutaneous ocular syndrome (Stevens-Johnson syndrome), toxic epiderma, intestinal obstruction, intestinal palsy, liver dysfunction, jaundice, pancreatitis, acute renal failure, mucocutaneous ocular syndrome (Stevens-Johnson syndrome), toxic epiderma, intestinal obstruction, intestinal palsy, liver dysfunction, jaundice, pancreatitis, acute
  • the replacement drug of the present invention is used for patients having a history of administration of taxane anticancer agents. That is, the patient is usually a patient suffering from cancer to which a taxane anticancer is applied. Examples of such cancer include ovarian cancer, non-small cell lung cancer, breast cancer, stomach cancer, head and neck cancer, prostate cancer, and endometrial cancer. Since the replacement drug of the present invention contains a p38 MAPK inhibitor, the replacement drug of the present invention is based on the fact that the present inventors have newly found that the p38 MAPK inhibitor has an anchorage-independent cancer growth-specific suppressing effect. Is suitably applied to patients suffering from cancer that can exhibit anchorage-independent growth.
  • the replacement drug of the present invention is a patient suffering from non-small cell lung cancer. It is preferably applied to.
  • the replacement drug of the present invention is administered after the administration of the taxane anticancer agent.
  • a set of one administration of a xanthine anticancer agent and two or more administrations of the replacement agent of the present invention is repeated and administered.
  • the administration of the replacement drug of the present invention is preferably started within 0 to 28 days (more preferably within 0 to 1 day) after the administration of the taxane anticancer agent.
  • the replacement drug of the present invention is administered at least once more (total of 2 or more times).
  • the replacement agent of the present invention is preferably administered 1 to 4 times a day (more preferably 2 times a day).
  • the dose of the replacement drug of the present invention varies depending on the administration subject, administration route, and the like. For example, when administered orally to an adult (60 kg), the active ingredient is about 5 to about 20 mg / day, preferably about 10 mg / day.
  • Such administration of the replacement agent of the present invention is continued for a period of 2 to 8 months (preferably a period of 3 to 6 months).
  • the starting point of the period is the first administration of the replacement drug of the present invention after the administration of the taxane anticancer agent.
  • the end point of the period is the last administration of the replacement drug of the present invention before the next administration.
  • the end point of the period is the last administration of the replacement drug of the present invention to the patient. That is, as described above, during the “period”, the taxane anticancer agent is not administered to the patient.
  • the form in which the p38 MAPK inhibitor is administered during the administration period of the taxane anticancer agent is also within the scope of the present invention.
  • a method for treating cancer comprising administering the taxane anticancer agent to the patient two or more times over a period of 2 to 8 months following administration of the taxane anticancer agent is also an aspect of the present invention.
  • examples of the p38 MAPK inhibitor include those described above. Of these, compound 1 or a salt thereof, and compound 2 or a salt thereof are preferable. Of these, compound 1 and compound 2 are particularly preferable.
  • the administration method (administration regimen) of the p38 MAPK inhibitor may be performed according to the administration of the replacement drug of the present invention described in the present specification.
  • Examples of cancer to be treated by this method include ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, and endometrial cancer. “Method of treating cancer” also includes “method of suppressing cancer metastasis”.
  • the dosage form of the replacement drug of the present invention is not particularly limited, and is a pharmaceutical composition in which a p38 MAPK inhibitor is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se, such as a tablet (sugar-coated tablet, film (Including coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, orally disintegrating films, solutions, injections, suppositories, sustained-release preparations, patches, etc. Good.
  • a preparation can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.).
  • it is suitably administered as an oral preparation as a tablet, granule, capsule or the like.
  • Examples of pharmacologically acceptable carriers that may be used in the production of the pharmaceutical composition of the present invention include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials.
  • the additives include binders, disintegrants, water-soluble polymers, basic inorganic salts; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid preparations. Further, if necessary, additives such as ordinary preservatives, antioxidants, colorants, sweeteners, sour agents, foaming agents, and fragrances can be used.
  • Examples of the “excipient” include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.
  • Examples of the “lubricant” include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
  • Examples of the “binder” include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropylcellulose, and the like.
  • Examples of the “disintegrant” include (1) crospovidone, (2) disintegrants called super disintegrants such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Pharmaceutical), (3) carboxymethyl Examples include starch sodium (eg, Matsutani Chemical Co., Ltd.), (4) low-substituted hydroxypropylcellulose (eg, Shin-Etsu Chemical Co., Ltd.), (5) corn starch and the like.
  • the “crospovidone” has a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including those called polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer.
  • water-soluble polymer examples include ethanol-soluble water-soluble polymers [for example, cellulose derivatives such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, etc.], ethanol-insoluble water-soluble polymers Molecules [for example, hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC), cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum, etc.] and the like.
  • HPMC hydroxypropylmethylcellulose
  • basic inorganic salt examples include basic inorganic salts of sodium, potassium, magnesium and / or calcium. Preferred is a basic inorganic salt of magnesium and / or calcium.
  • a basic inorganic salt of magnesium More preferred is a basic inorganic salt of magnesium.
  • the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like.
  • Examples of the basic inorganic salt of potassium include potassium carbonate and potassium hydrogen carbonate.
  • Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 ( OH) 16 ⁇ CO 3 ⁇ 4H 2 O] and alumina / magnesium hydroxide, preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like.
  • Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • dissolution aid examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • the “suspending agent” examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • examples of the “isotonic agent” include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the “buffering agent” include buffer solutions of phosphate, acetate, carbonate, citrate, and the like.
  • Examples of the “soothing agent” include benzyl alcohol.
  • Examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the “antioxidant” include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • Examples of the “colorant” include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments, bengara and the like.
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
  • sweetening agent examples include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.
  • fuming agent examples include sodium bicarbonate.
  • fragment may be a synthetic product or a natural product, and examples thereof include lemon, lime, orange, menthol, and strawberry.
  • the p38 MAPK inhibitor in the replacement drug of the present invention may be used in combination with another drug (concomitant drug) in addition to the taxane anticancer agent.
  • concomitant drugs include hormone therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors).
  • hormone therapeutic agent examples include phosfestol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, Mepaltricin, raloxifene, olmeloxifen, levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydroch
  • chemotherapeutic agent examples include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, altretamine, ambmustine, dibrospdium hydrochloride, fotemustine, predonimustine, pumitepa, ribomustine, temosofredomestre , Trophosphamide, Dinostatin styramer,
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enositabine, cytarabine, cytarabine okphosphat, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, garocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritroxime, idoxyuridine, mitoxifridin , And ambamustine.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, garocitabine, emiteful, etc.
  • aminopterin
  • anticancer antibiotic examples include anthracycline anticancer drugs (daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, Examples include bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like.
  • plant-derived anticancer agent examples include vinca alkaloid anticancer drugs (vinblastine sulfate, vincristine sulfate, vindesine sulfate), etoposide, etoposide phosphate, teniposide, vinorelbine, DJ-927, TZT-1027, and the like.
  • immunotherapeutic agent examples include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, coryne Examples include bacterial parvum, levamisole, polysaccharide K, and procodazole.
  • the “cell growth factor” in the “drug that inhibits the action of cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000.
  • the following peptides include factors that exert their actions at low concentrations by binding to receptors.
  • EGF epidermal growth factor
  • IGF insulin receptor 1
  • IGF-2 insulin receptor 2
  • FGF fibroblast growth factor
  • Other cell growth factors eg, CSF (colony stimulating factor), EPO (erythropoietin), IL- 2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF ( Hepatocyte growth factor), VEGF (vascular endothelial growth factor) and the like.
  • CSF colony stimulating factor
  • EPO erythropoietin
  • IL- 2 interleukin-2
  • NGF nerve growth factor
  • PDGF platelet-derived growth factor
  • TGF ⁇ transforming growth factor ⁇
  • HGF Hepatocyte growth factor
  • VEGF vascular endothelial growth factor
  • the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically includes an EGF receptor, a haregulin receptor (HER2). Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2.
  • Examples of the “drug that inhibits the action of cell growth factor” include trastuzumab (trade name Herceptin (anti-HER2 antibody)), gefitinib (EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor); Iressa (Trademark)), ZD1839 or cetuximab (EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor)), imatinib mesylate (c-met, c-kit, abl inhibitor; Gleevec (trademark)) Etc.
  • trastuzumab trade name Herceptin (anti-HER2 antibody)
  • gefitinib EGFR-TKI (epidermal growth
  • drugs that block the action of multiple cell growth factors with a single drug and drugs that block intracellular information emitted by cell growth factors.
  • the form of the combination of the replacement drug of the present invention and such a combination drug is not particularly limited, and such a combination drug may be formulated in the replacement drug of the present invention together with the p38 MAPK inhibitor.
  • the administration mode of the combination of the p38 MAPK inhibitor and the concomitant drug in the replacement drug of the present invention is not particularly limited, as long as the p38 MAPK inhibitor and the concomitant drug are combined at the time of administration. More specifically as such a dosage form, for example, (1) Administration of the replacement drug of the present invention as a single preparation obtained by simultaneously formulating a p38 MAPK inhibitor and a concomitant drug, (2) Co-administration of two preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug by the same administration route, (3) Administration of two types of preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug with a time difference in the same administration route, (4) Simultaneous administration of two preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug through different administration routes, (5) Two types of preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug are administered
  • the concomitant drug and the replacement drug of the present invention may be administered at the same time, but after the administration of the concomitant drug, the replacement drug of the present invention may be administered, or after the administration of the replacement drug of the present invention, A drug may be administered.
  • the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when administering a concomitant drug first, within 0 minute to 28 days after administration of the concomitant drug, preferably Examples include a method of administering the replacement drug of the present invention within 0 minute to 1 day, more preferably within 0 minute to 2 hours.
  • the concomitant drug is administered within 0 minutes to 1 day, preferably within 0 minute to 12 hours, more preferably within 0 minute to 6 hours after the replacement drug of the present invention is administered.
  • the method of administering is mentioned.
  • the replacement drug of the present invention is used for enhancing the anticancer action and / or reducing side effects of the taxane anticancer drug.
  • These can enhance the anticancer effect of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent, and The p38 MAPK inhibitor is used in combination with a taxane anticancer agent, thereby reducing side effects of the taxane anticancer agent in the administration of the taxane anticancer agent to a patient.
  • a medicament containing Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent is also an embodiment of the present invention.
  • Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent are mixed according to a method known per se, and one pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule)) , Solutions, injections, suppositories, sustained-release agents, etc.) may be formulated and used together, or each may be formulated separately and administered to the same subject simultaneously or with a time difference.
  • a medicament containing compound 1 or compound 2 or a salt thereof and a taxane anticancer agent is compound 1 or compound 2.
  • it may be a kit having a preparation (B) containing a preparation (A) containing those salts and a taxane anticancer agent.
  • the administration form of Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent is not particularly limited, and Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent are combined at the time of administration. Just do it.
  • a dosage form for example, (1) Administration of a single preparation obtained by simultaneously preparing Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent, (3) Administration of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent with a time difference in the same administration route, (4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent, (5) Administration of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent at different administration routes (for example, Compound 1 or Compound 2 or a salt thereof ⁇ administration in the order of taxane anti
  • the taxane anticancer agent and Compound 1 or Compound 2 or a salt thereof may be administered at the same time.
  • Compound 1 or Compound 2 or a salt thereof may be administered, or after administration of Compound 1 or Compound 2 or a salt thereof, a taxane anticancer agent may be administered.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when a taxane anticancer agent is administered first, it is 0 after the taxane anticancer agent is administered.
  • Examples include a method of administering Compound 1 or Compound 2 or a salt thereof within minutes to 28 days, preferably 0 minutes to 1 day, more preferably 0 minutes to 2 hours.
  • Compound 1 or Compound 2 or a salt thereof is administered first, 0 minutes to 1 day, preferably 0 minutes to 12 hours, more preferably 0 after administration of Compound 1 or Compound 2 or a salt thereof.
  • Examples include a method of administering a taxane anticancer agent within minutes to 6 hours.
  • the daily dose of the taxane anticancer agent varies depending on the administration subject, administration route, symptom and the like.
  • the daily dose of the taxane anticancer agent varies depending on the administration subject, administration route, symptom and the like.
  • paclitaxel trademark: Taxol
  • 135 to 250 mg / m 2 body surface area is usually infused intravenously once every 3 weeks (24 hours )
  • intravenous infusion (1 hour) with a body surface area of 80 to 100 mg / m 2 may be administered once a week.
  • docetaxel (trademark: Taxotere)
  • a patient adult, body weight of about 60 kg
  • intravenous infusion 60 minutes
  • intravenous infusion 60 minutes
  • the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents.
  • the combination agent of the present invention has low toxicity.
  • Compound 1 or Compound 2 or a salt thereof or (and) the above taxane anticancer agent is mixed with a pharmacologically acceptable carrier according to a known method.
  • Pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc. Can be safely administered orally or parenterally (eg, topical, rectal, intravenous, etc.).
  • the concomitant drug of the present invention may be further used in combination with other drugs (concomitant drugs). Examples of such concomitant drugs include those exemplified for the above-described replacement drug of the present invention.
  • the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
  • the compounding ratio of Compound 1 or Compound 2 or a salt thereof and the taxane anticancer agent in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. Two or more taxane anticancer agents may be used in combination at an appropriate ratio.
  • the dose of the taxane anticancer agent can be appropriately selected based on the clinically used dose.
  • the content ratio of Compound 1 or Compound 2 or a salt thereof and the taxane anticancer agent can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, etc.
  • the taxane anticancer agent may be used in an amount of 0.0001 to 0.1 parts by weight, preferably 0.002 to 0.01 parts by weight, based on 1 part by weight of Compound 2 or a salt thereof.
  • the content of Compound 1 or Compound 2 or a salt thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 99.9% by weight with respect to the whole preparation The range is preferably from about 0.1 to about 90% by weight.
  • the content of the taxane anticancer agent in the concomitant drug of the present invention varies depending on the form of the preparation. For example, it is usually in the range of about 0.01 to about 99.9% by weight relative to the whole preparation, Is in the range of about 0.1 to about 90.0% by weight.
  • the content of an additive such as a carrier in the concomitant drug of the present invention varies depending on the form of the preparation. For example, it is usually in the range of about 0.01 to about 99.9% by weight relative to the whole preparation, The range is from about 0.1 to about 90% by weight.
  • compound 1 or compound 2 or a salt thereof and a taxane anticancer agent are formulated separately.
  • an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
  • the anchorage-independent cancer growth-specific inhibitor of the present invention contains a p38 MAPK inhibitor.
  • the p38 MAPK inhibitor include those described above. Of these, compound 1 or a salt thereof, and compound 2 or a salt thereof are preferable. Of these, compound 1 and compound 2 are particularly preferable.
  • the dosage form and production method of the anchorage-independent cancer growth-specific inhibitor of the present invention are in accordance with the above-described replacement drug of the present invention.
  • the dose of the anchorage-independent cancer growth-specific inhibitor of the present invention varies depending on the administration subject, administration route, and the like, but when administered orally to an adult (60 kg), for example, about 5 to About 20 mg / day, preferably about 10 mg / day.
  • the p38 MAPK inhibitor in the anchorage-independent cancer growth-specific inhibitor of the present invention may be used in combination with other drugs.
  • concomitant drugs include taxane anticancer agents and hormonal therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors). It is done.
  • concomitant drug examples include those similar to the concomitant drug that can be used in combination with the p38 MAPK inhibitor in the above replacement drug.
  • preferable concomitant drugs include taxane anticancer agents and gemcitabine (trademark: Gemzar).
  • the administration mode of the combination of the p38 MAPK inhibitor and the concomitant drug in the anchorage-independent cancer growth specific inhibitor of the present invention is not particularly limited, and it is sufficient that the p38 MAPK inhibitor and the concomitant drug are combined at the time of administration. . More specifically, such a dosage form conforms to the dosage form of a combination of a p38 MAPK inhibitor and a concomitant drug in the replacement drug of the present invention.
  • the p38 MAPK inhibitor enhances and / or maintains the anchorage-independent cancer growth-specific inhibitory action and the taxane-based anticancer agent anchorage-independent cancer growth-specific inhibitory action, respectively. can do.
  • the medicament for preventing or treating non-small cell lung cancer of the present invention contains a p38 MAPK inhibitor.
  • the p38 MAPK inhibitor include those described above. Of these, compound 1 or a salt thereof, and compound 2 or a salt thereof are preferable. Of these, compound 1 and compound 2 are particularly preferable.
  • the pharmaceutical dosage form and production method for the prevention or treatment of non-small cell lung cancer of the present invention are in accordance with the above-mentioned replacement drug of the present invention.
  • the dose of the pharmaceutical agent for preventing or treating non-small cell lung cancer of the present invention varies depending on the administration subject, administration route, etc., but for example, when administered orally to an adult (60 kg), about 5 to about 20 mg / day, preferably about 10 mg / day.
  • the p38 MAPK inhibitor in the medicament for preventing or treating non-small cell lung cancer of the present invention may be used in combination with other drugs.
  • concomitant drugs include taxane anticancer agents and hormonal therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors). It is done.
  • concomitant drug examples include those similar to the concomitant drug that can be used in combination with the p38 MAPK inhibitor in the above replacement drug.
  • preferable concomitant drugs include taxane anticancer agents and gemcitabine (trademark: Gemzar).
  • the administration mode of the combination of the p38 MAPK inhibitor and the concomitant drug in the medicament for the prevention or treatment of non-small cell lung cancer of the present invention is not particularly limited as long as the p38 MAPK inhibitor and the concomitant drug are combined at the time of administration. Good. More specifically, such a dosage form conforms to the dosage form of a combination of a p38 MAPK inhibitor and a concomitant drug in the replacement drug of the present invention.
  • Reference Examples 1 and 2 As a p38 MAPK inhibitor, 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one (compound 1), and 6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide (Compound 2) was synthesized. Synthesis examples of compounds 1 and 2 are shown in Reference Examples 1 and 2.
  • reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated under reduced pressure.
  • the residue was dissolved in ethyl acetate, 4N hydrogen chloride-ethyl acetate solution (9 mL) and diethyl ether (45 mL) were added, and the mixture was stirred as it was for 5 hr.
  • the precipitated solid was collected by filtration, washed with diethyl ether and dried to give the title compound (4.5 g, 74%) as a white powder.
  • Test example 1 DMEM: F12 medium containing gel of DMEM: F12 medium (Invitrogen) containing 0.8 ml 0.7% agar (agar) in 12 well-plate (well plate) and 0.6 ml 0.35% agar And put the gel. In addition, 10,000 A549 NSCLC cells (ATCC CCL-185) were seeded in the gel containing 0.35% agar. The next day, together with 5 ⁇ M Compound 1 (solvent: DMSO) or an equal amount of DMSO, paclitaxel (Calbiochem # 580555) (solvent: DMSO) was developed to a total concentration of 10 points from 0 nM, 0.25 nM to 64 nM as shown in FIG. And added.
  • FIG. 1A results are shown in FIG. 1A.
  • treatment with Compound 1 alone inhibited nearly 90% of colony formation, and confirmed a specific inhibitory effect on anchorage-independent growth unique to malignant tumors.
  • the combined use of Compound 1 and paclitaxel was able to reduce the concentration of paclitaxel required for anchorage-independent growth inhibition.
  • Test example 2 Mice subcutaneously transplanted with 5000000 A549 cells per animal 13 days later, administration of Compound 1 was started as follows, and the test was conducted for 20 days.
  • Solvent 0.5 w / v% methylcellulose 400 solution (Wako)
  • 100 mg / kg body weight Compound 1 once / day, po (oral administration)
  • single agent administration 100 mg / kg body weight Compound 1 (Once / day, po) and 30 mg / kg body weight
  • Paclitaxel Billristol-Myers 100 mg / 16.7 ml injection) (Day 1 and Day 4 (once each), ip (Intraperitoneal administration)), paclitaxel (on day 1 and day 4 (once each), ip), single agent administration, paclitaxel (once every 3 days, ip) Single agent administration.
  • the tumor diameter was measured almost every two days, and the tumor volume and the body weight of the mouse were measured (FIGS. 2 and 3). On day 21, all mice were dissected and the tumor, liver, spleen mass, blood red blood cell, white blood cell, and platelet count were measured (FIG. 4A (tumor weight), FIG. 4B (white blood cell count)). As is apparent from FIG. 2, 3 weeks after the start of administration, tumors in the group administered with 30 mg / kg body weight paclitaxel only on Day 1 (Day 1) and Day 4 (Day 4) were 58 tumors in the control group.
  • the tumors in the group receiving 30 mg / kg paclitaxel on Day 1 and Day 4 and daily Compound 1 were up to 14.3% of the control group tumors, while remaining reduced to .9% Reduced.
  • weight loss a significant side effect of paclitaxel, was suppressed by administration of Compound 1.
  • FIGS. 4A and 4B the decrease in white blood cell count, which is a significant side effect of paclitaxel, was suppressed by administration of Compound 1.
  • Test example 3 Mice subcutaneously transplanted with 5000000 A549 cells per animal 7 days later (Day 7), administration of Compound 2 was started as follows, and the test was conducted for 21 days.
  • Solvent 0.5 w / v% methylcellulose 400 solution (Wako Pure Chemical Industries)
  • 100 mg / kg body weight Compound 2 once / day, po
  • 30 mg / kg body weight Paclitaxel Bristol Myers 100 mg / 16.7 ml injection solution (Day 1 and Day 4 (once each time), ip (intraperitoneal administration)
  • 100 mg / kg body weight Compound 2 once / day, p.o.
  • 30 mg / kg body weight paclitaxel Bristol-Myers 100 mg / 16.7 ml injection
  • the tumor diameter was measured approximately every 3 days, and the tumor volume and mouse body weight were measured (FIGS. 5A and 5B).
  • FIG. 5A 3 weeks after the start of administration, the tumor of the group administered with 30 mg / kg body weight paclitaxel only on the first day and the fourth day was reduced to 26.1% of the tumor of the control group.
  • Tumors in the group receiving 30 mg / kg body weight paclitaxel on day 1 and day 4 and compound 2 daily were -0.6% of the control group tumors. It was reduced to.
  • weight loss which is a significant side effect of paclitaxel, was suppressed by administration of Compound 2.
  • Formulation Example (1) Compound 1 10.0 g (2) Lactose 70.0g (3) Corn starch 50.0g (4) 7.0g of soluble starch (5) Magnesium stearate 3.0 g Compound 1 (10.0 g) and magnesium stearate (3.0 g) are granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), then dried and mixed with 70.0 g of lactose and 50.0 g of corn starch (lactose, Corn starch, soluble starch and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.

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Abstract

L'invention concerne un agent alternatif à l'agent taxane anticancéreux tel que le paclitaxel, qui permet d'étendre la période de suppression de l'agent taxane anticancéreux tout en maintenant l'effet thérapeutique de cet agent taxane anticancéreux. L'agent alternatif comprend un inhibiteur de p38MAPK. L'agent alternatif est administré à un patient qui possède un historique d'administration de l'agent taxane anticancéreux au moins par deux fois sur une période comprise entre deux et huit mois dans le but de potentialiser une activité anticancéreuse de l'agent taxane anticancéreux et/ou de réduire les effets secondaires de l'agent taxane anticancéreux. Pendant la période comprise entre deux et huit mois, l'agent taxane anticancéreux n'est pas administré au patient.
PCT/JP2009/004992 2008-09-30 2009-09-29 Agent alternatif à l'agent taxane anticancéreux WO2010038428A1 (fr)

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US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

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Publication number Priority date Publication date Assignee Title
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4

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