[go: up one dir, main page]

WO2019176985A1 - Agent antitumoral, potentialisateur d'effet antitumoral et kit antitumoral - Google Patents

Agent antitumoral, potentialisateur d'effet antitumoral et kit antitumoral Download PDF

Info

Publication number
WO2019176985A1
WO2019176985A1 PCT/JP2019/010170 JP2019010170W WO2019176985A1 WO 2019176985 A1 WO2019176985 A1 WO 2019176985A1 JP 2019010170 W JP2019010170 W JP 2019010170W WO 2019176985 A1 WO2019176985 A1 WO 2019176985A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
antitumor
salt
tumor
alkylating agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2019/010170
Other languages
English (en)
Japanese (ja)
Inventor
山田　孝之
和徳 佐伯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujifilm Corp
Original Assignee
Fujifilm Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujifilm Corp filed Critical Fujifilm Corp
Publication of WO2019176985A1 publication Critical patent/WO2019176985A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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 an antitumor agent, an antitumor effect enhancer, and an antitumor kit.
  • Compound A (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known to be useful as an antitumor agent (Patent Document 1). Compound A is also known to have strong antitumor activity even after oral administration to mice (Non-Patent Documents 1 and 2). Further, a salt of Compound A and a production method thereof are also known (Patent Documents 2 to 4).
  • antitumor drugs with enhanced antitumor effects by combining specific acylthiourea compounds with antitumor agents such as paclitaxel, gemcitabine, rapanitib, decafur, gimeracil, oteracil potassium, irinotecan) are known (Patent Document 5).
  • alkylating agents are known as representative agents of antitumor agents.
  • Representative alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, ranimustine, nimustine, temozolomide, and the like, which are used for the treatment of various malignant tumors.
  • high nephrotoxicity, hemorrhagic cystitis and resistant cancer are prone to be induced in clinical settings (Non-Patent Documents 3 to 5).
  • multi-drug combination therapy is performed to compensate for the difference in sensitivity of each anti-tumor agent to the tumor and enhance its efficacy, and various alkylating agents can be used in combination with various drugs. Approval or development of combination therapy for multiple tumors. However, even if the alkylating agent has an antitumor effect, the antitumor action enhancing effect is not always obtained by using it together with other drugs.
  • An object of the present invention is to provide an antitumor agent, an antitumor kit, and an antitumor effect potentiator that have an excellent antitumor effect as compared with gemcitabine, an alkylating agent, and a combination therapy thereof.
  • an antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
  • the alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor agent.
  • the tumor is bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, stomach cancer, bone Sarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant melanoma, chronic The antitumor agent according to (1) or (2), which is myeloid leukemia or multiple myeloma.
  • the antitumor agent according to any one of (1) to (3), wherein the tumor is breast cancer or pancreatic cancer.
  • An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
  • An antitumor kit comprising a preparation containing an alkylating agent and a preparation containing 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
  • An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
  • the alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor effect enhancer.
  • the alkylation is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Anti-tumor kit. (7-1) The alkylation is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor agent.
  • Effective therapeutic dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and combined treatment with alkylating agent
  • a therapeutic method for a tumor which comprises administering to a subject in combination with a therapeutically effective dose when used in the above.
  • Effective therapeutic dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination treatment, and combination treatment with alkylating agent
  • a method of treating a tumor comprising administering to a subject a therapeutically effective dose when used in a method simultaneously, separately, sequentially or at intervals.
  • the daily dose of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is 20 to 200 mg / m 2 (1 ) Or (2).
  • Compound A or a salt thereof exhibits a remarkable antitumor effect when used in combination with an alkylating agent. That is, the antitumor agent and antitumor kit of the present invention have an excellent tumor growth inhibitory effect as compared with gemcitabine alone, an alkylating agent alone, or a combination of gemcitabine and an alkylating agent.
  • the antitumor effect enhancer of the present invention can enhance the antitumor effect by co-administering in combination with an alkylating agent.
  • FIG. 1 is a graph showing the combined effect of Compound A and temozolomide on the cell viability of human pancreatic cancer-derived cell line SUIT-2.
  • the range represented by “to” includes values at both ends unless otherwise specified.
  • the “subject” is a mammal such as a human, a mouse, a monkey, a domestic animal or the like in need of the prevention or treatment, and preferably a human in need of the prevention or treatment.
  • Prevention means inhibition of onset, reduction of onset risk or delay of onset.
  • Treatment means improvement of a target disease or condition or suppression (maintenance or delay) of progression.
  • Treatment means prevention or treatment of various diseases.
  • Tuor means benign or malignant tumor.
  • Benign tumor means a tumor in which the tumor cells and their sequences are close to the normal cells from which they are derived and which are not invasive or metastatic.
  • Malignant tumor means a tumor that is different from the normal cells from which the morphology and sequence of the tumor cells are derived, and exhibits invasive or metastatic properties.
  • the present invention is an antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (Compound A) or a salt thereof.
  • the present invention is also an antitumor agent comprising a combination of an alkylating agent and Compound A or a salt thereof.
  • “combination” means a combination for using compounds in combination, and includes both forms in which different substances are used at the time of administration, and forms as a mixture (compound).
  • “combination” does not mean that the administration timing of the compound of the present invention and the alkylating agent is completely the same.
  • one administration schedule includes an embodiment in which the compound of the present invention and the alkylating agent are administered, the form in which these are administered simultaneously or separately means “combination”.
  • the alkylating agent may be administered after the compound of the invention has been administered first.
  • the compound of the present invention may be administered after the alkylating agent is administered first.
  • salt examples include pharmaceutically acceptable salts, and specific examples include mineral acid salts, organic carboxylate salts, and sulfonate salts.
  • Preferred salts include mineral acid salts and sulfonic acid salts.
  • Examples of mineral acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, and sulfate, and hydrochloride, hydroiodide, nitrate, and sulfate are preferable. Hydrochloride is more preferable.
  • Examples of organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and Examples include trifluoroacetate.
  • sulfonate examples include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate, and naphthalenesulfonate, and methanesulfonate is preferable.
  • the salt of Compound A may be an anhydride, hydrate or solvate.
  • the form may be an anhydride, hydrate or solvate.
  • the term “anhydride” as used herein refers to a case in which it is in a state that is neither a hydrate nor a solvate, unless otherwise specified. Originally, even if the substance does not form a hydrate or solvate, the salt of Compound A having no water of crystallization, water of hydration and an interactive solvent is included in the “anhydride” in the present invention. . An anhydride may be referred to as an “anhydrate”.
  • the number of hydrated water is not particularly limited, and may be a monohydrate, a dihydrate or the like.
  • solvates include methanol solvates, ethanol solvates, propanol solvates and 2-propanol solvates.
  • particularly preferable salts of the compound A are as follows.
  • compound A or a salt thereof may be used alone or in combination of two or more.
  • Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, Vol. 64, pages 7912-7920.
  • the salt of compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4.
  • the compound A or a salt thereof according to the present invention can be used as an antitumor agent or as an active ingredient of a pharmaceutical composition.
  • alkylating agent examples include cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine, ranimustine, bendamustine, busulfan, procarbazine, melphalan, thiotepa, and carbocon.
  • the alkylating agent of the present invention is preferably cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine, ranimustine, busulfan, procarbazine, melphalan or thiotepa, more preferably cyclophosphamide or temozolomide.
  • alkylating agents can be produced by known methods. Moreover, these alkylating agents can also be obtained by purchasing a commercial item.
  • cyclophosphamide is commercially available as Endoxan (registered trademark) from Shionogi & Co., Ltd.
  • Ifosfamide is commercially available as Ifomide (registered trademark) from Shionogi & Co., Ltd.
  • dacarbazine is commercially available as dacarbazine (registered trademark) from Kyowa Hakko Kirin Co., Ltd.
  • Temozolomide is commercially available from MSD Corporation as Temodal®.
  • Nimustine is commercially available from Daiichi Sankyo Co., Ltd. as Nidran (registered trademark).
  • Ranimustine is commercially available as Cymerin (registered trademark) from Nipro ES Pharma Co., Ltd.
  • Busulfan is commercially available from Otsuka Pharmaceutical Co., Ltd. as Busulfex (registered trademark) or from Ohara Pharmaceutical Co., Ltd. as Mablin (registered trademark).
  • Procarbazine is commercially available from Chugai Pharmaceutical Co., Ltd. as procarbazine hydrochloride.
  • Melphalan is commercially available as Alquelan (registered trademark) from Aspen Japan.
  • the alkylating agent may form a pharmaceutically acceptable salt (hereinafter sometimes referred to as “the salt”) with an acid or a base.
  • the alkylating agent of the present invention includes these pharmaceutically acceptable salts. Only one alkylating agent may be used, or two or more alkylating agents may be contained.
  • the alkylating agent may be a composition containing them in addition to the alkylating agent or a salt thereof.
  • the salt include pharmaceutically acceptable salts, and specific examples include salts that are generally known in basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And the salt.
  • alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
  • Compound A is an antitumor agent having an excellent DNA synthesis inhibitory action.
  • Compound A is used in combination with an alkylating agent, it is expected to have an action of enhancing the antitumor effect of the alkylating agent without showing a marked increase in toxicity.
  • An antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof; and An antitumor agent comprising-(2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof: Is provided.
  • the antitumor agent of the present invention is usually used for formulation, excipients, binders, lubricants, disintegrants, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents.
  • Additives such as agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
  • the antitumor agent of the present invention containing an alkylating agent and compound A or a salt thereof is an alkylating agent and compound A or a salt thereof, even if it is a one-part preparation containing an alkylating agent and compound A or a salt thereof. It may be a two-part preparation containing a salt. Preferably, it is a two-drug preparation in which the alkylating agent and Compound A or a salt thereof are separate preparations.
  • each formulation can be administered to the subject simultaneously, separately, sequentially, or at intervals.
  • the administration means of the composition containing the alkylating agent and the administration means of the composition containing Compound A may be the same or different (for example, oral administration and injection).
  • the administration route of the antitumor agent of the present invention includes intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository. Is mentioned.
  • parenteral administration is preferable.
  • intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and / or intrathecal injection can be mentioned.
  • Examples of the administration method include administration by syringe or infusion.
  • the dosage or compounding amount of the alkylating agent and compound A or a salt thereof contained in the antitumor agent of the present invention is not particularly limited as long as the antitumor effect is enhanced.
  • the amount of the compound A of the present invention to be used varies depending on the individual combination with the alkylating agent, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the alkylating agent, preferably about 0.001 to 1000 times (weight ratio).
  • the combination of Compound A and temozolomide is not particularly limited.
  • the dose of Compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg / day per adult. m 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dosage of temozolomide is 10 to 1000 mg / m 2 , preferably 20 to 200 mg / m 2 per day for an adult. More preferably, the dose is 50 to 150 mg / m 2, and the dose of the compound of the present invention is about 0.02 to 20 times (weight ratio), preferably about 0.53 to 3 times (weight ratio) of temozolomide. To be.
  • the dose of the compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg per day for an adult. / M 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dose of cyclophosphamide is 20 to 2000 mg / m 2 , preferably 30 to 1500 mg / m 2 , more preferably 50 to 1000 mg / m 2, and the dose of the compound of the present invention is about 0.01 to 10 times (weight ratio) of cyclophosphamide, preferably about 0.08. ⁇ 3 times (weight ratio).
  • the dose and frequency of administration of the alkylating agent may be, for example, 1 to 1000 mg / m per day by oral or parenteral (eg injection, infusion and administration to the rectal site) for adults. 2 can be administered in one to several divided doses. If the patient experiences excessive toxicity, a dose reduction is necessary. Dosage amount and regimen may be altered if one or more additional chemotherapeutic agents are used in addition to the combination therapy of the invention. The dosage regimen can be determined by the physician treating the particular patient.
  • 1 to 2000 mg / m 2 per day can be administered in 1 to several divided doses. However, it is not limited to these doses and administration methods.
  • the daily dose of Compound A or a salt thereof is 20 mg / m 2 or more, preferably 40 mg / m 2 or more, preferably 60 mg / m 2 or more, preferably 80 mg / m 2 or more.
  • the upper limit of the dose per day is 200 mg / m 2 , preferably 150 mg / m 2 , more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 .
  • the daily dose is more preferably 40 to 200 mg / m 2 , further preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2 , and even more preferably 80 to 120 mg / m 2 .
  • the daily dose is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , still more preferably 40 to 100 mg / m 2 , and more More preferably, it is 60 to 100 mg / m 2 .
  • a single dose may be 20 to 200 mg / m 2, and a course in which the drug is withdrawn in the 4th week after repeated administration once a week for 3 weeks may be repeated several times. it can.
  • the single dose is the same as the above-mentioned daily dose, preferably 40 to 200 mg / m 2 , more preferably 40 to 150 mg / m 2 , and still more preferably 80 ⁇ 150 mg / m 2 .
  • the dose per administration is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , and still more preferably 40 to 100 mg / m 2 .
  • dosage forms of the antitumor agent of the present invention include tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, suppositories, eye drops, nasal drops, ear drops Although an agent, a patch, an ointment, and an injection are mentioned, an injection is preferable.
  • Each of these dosage forms can be produced by conventional formulation methods known to those skilled in the art.
  • the antitumor agent of the present invention is preferably an antineoplastic agent and can be used as an anticancer agent.
  • Antitumor agents of the present invention include, for example, bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, Gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant black It can be used effectively for the treatment of various types of tumors including tumors, chronic myelogenous leukemias, multiple myeloma or other organ tumors.
  • prostate cancer osteosarcoma, germ cell tumor, malignant bone / soft tissue tumor, multiple myeloma, malignant lymphoma, breast cancer, lung cancer, uterine cancer, ovarian cancer, pancreatic cancer, malignant melanoma, neuroblastoma, retinoblast Tumor, thyroid cancer, stomach cancer, liver cancer, colon cancer or chronic myelogenous leukemia are preferred, and particularly effective for the treatment of pancreatic cancer or breast cancer.
  • the present invention also relates to an antitumor effect potentiator comprising Compound A or a salt thereof for enhancing the antitumor effect of an alkylating agent for cancer patients. That is, according to the present invention, An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof in combination with an alkylating agent is provided.
  • the antitumor effect potentiator of the present invention is usually an excipient, a binder, a lubricant, a disintegrant, a colorant, a flavoring agent, an emulsifier, a surfactant, a solubilizing agent, a suspension, Additives such as turbidity agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
  • the antitumor effect potentiator of the present invention can be administered to a subject simultaneously, separately or at intervals with the alkylating agent.
  • parenteral administration is preferable.
  • intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection
  • administration method include administration by syringe or infusion.
  • the dose or amount of compound A or a salt thereof contained in the antitumor effect potentiator of the present invention is not particularly limited as long as it exhibits a potentiating effect on the antitumor effect.
  • the amount of the compound A of the present invention to be used varies depending on the individual combination with the alkylating agent, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the alkylating agent, preferably about 0.001 to 1000 times (weight ratio).
  • 1 to 2000 mg / m 2 can be divided into 1 to several times per day. . However, it is not limited to these doses and administration methods.
  • the daily dose of Compound A or a salt thereof is 20 mg / m 2 or more, preferably 40 mg / m 2 or more, preferably 60 mg / m 2 or more, preferably 80 mg / m 2 or more.
  • the upper limit of the dose per day is 200 mg / m 2 , preferably 150 mg / m 2 , more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 .
  • the dose per day is more preferably 40 to 200 mg / m 2 , further preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2 , and still more preferably 80 to 120 mg. / M 2 .
  • the daily dose is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , still more preferably 40 to 100 mg / m 2 , and more More preferably, it is 60 to 100 mg / m 2 .
  • a single dose may be 20 to 200 mg / m 2, and a course in which the drug is withdrawn in the 4th week after repeated administration once a week for 3 weeks may be repeated several times. it can.
  • the single dose is the same as the above-mentioned daily dose, preferably 40 to 200 mg / m 2 , more preferably 40 to 150 mg / m 2 , and still more preferably 80 ⁇ 150 mg / m 2 .
  • the dose per administration is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , and still more preferably 40 to 100 mg / m 2 .
  • the antitumor effect enhancer of the present invention is preferably an antimalignant effect enhancer and can be used as an anticancer effect enhancer.
  • Antitumor effect potentiators of the present invention include bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, Gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant black It can be used effectively for the treatment of various types of tumors including tumors, chronic myelogenous leukemias, multiple myeloma or other organ tumors.
  • prostate cancer osteosarcoma, germ cell tumor, malignant bone / soft tissue tumor, multiple myeloma, malignant lymphoma, breast cancer, lung cancer, uterine cancer, ovarian cancer, pancreatic cancer, malignant melanoma, neuroblastoma, retinoblast Tumor, thyroid cancer, stomach cancer, liver cancer, colon cancer or chronic myelogenous leukemia are preferred, and particularly effective for the treatment of pancreatic cancer or breast cancer.
  • an antitumor kit comprising a preparation containing an alkylating agent and a preparation containing 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
  • the antitumor kit of the present invention is a kit comprising a combination of (a) an alkylating agent and (b) compound A or a salt thereof. Further, in the above kit, (a) the alkylating agent and (b) compound A or a salt thereof can be in various known preparation forms, and are accommodated in various commonly used containers according to the preparation form. Is done.
  • the alkylating agent and (b) compound A or a salt thereof may be stored in separate containers, or may be mixed and stored in the same container. It is preferable that (a) the alkylating agent and (b) compound A or a salt thereof are respectively contained in separate containers.
  • the present invention provides an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof, preferably for use in the treatment of tumors.
  • a method for use in the treatment of pancreatic cancer or breast cancer comprising the step of administering a therapeutically effective dose to a subject in need of such treatment (mammals including humans).
  • the present invention also provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and an alkylating agent.
  • a method for treating a tumor characterized by being administered to a subject in combination with a therapeutically effective dose when used in combination therapy.
  • the present invention provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and an alkylating agent.
  • a method of treating a tumor characterized in that a therapeutically effective dose when used in combination therapy is administered to a subject simultaneously, separately, sequentially or at intervals.
  • cytosine or a salt thereof can be used for the production of an antitumor agent in combination with an alkylating agent.
  • cytosine or a salt thereof can be used for an antitumor agent in combination with an alkylating agent.
  • D-arabinofuranosyl) cytosine or a salt thereof can be obtained.
  • Example 1 A methanesulfonate salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (Compound A) was synthesized by the method described in International Publication No. 2013/146833 pamphlet. did.
  • SUIT-2 cells a human pancreatic cancer cell line
  • 10% serum Cat. # 10437-028 manufactured by Thermo Fisher Scientific Inc.
  • RPMI-1640 10% serum (Cat. # 10437-028 manufactured by Thermo Fisher Scientific Inc.) medium RPMI-1640.
  • All cell cultures were performed in a CO 2 incubator (37 ° C, 5% CO 2 setting, steam saturation).
  • the solution was diluted with 10% serum medium to 15000 cells / well / 100 ⁇ L and seeded in a 96-well plate.
  • the culture supernatant of each well was discarded, washed twice with 150 ⁇ L of serum-free medium, and 100 ⁇ L of serum-free medium was added and cultured for 3 days.
  • Methanesulfonic acid salt of compound A and gemcitabine were dissolved in DMSO to prepare 100 mmol / L DMSO solutions, respectively.
  • a DMSO solution having a concentration 1000 times the final treatment concentration was sequentially diluted with DMSO.
  • Temozolomide was dissolved in a serum-free medium to prepare a Temozolomide solution of 1200 ⁇ mol / L.
  • a DMSO diluted solution of Compound A and Gemcitabine was diluted with a Temozolomide solution (1200 ⁇ mol / L) to prepare treatment solutions each having a concentration 6 times the final treatment concentration.
  • Compound A and Gemcitabine were used in combination with Temozolomide with a maximum concentration of 10 ⁇ mol / L and a common ratio of 1/3 and 9 concentrations.
  • 20 ⁇ L of Compound A or Gemcitabine diluted with Temozolomide solution (1200 ⁇ mol / L) was added to each well.
  • a group in which only a solvent without a drug was added to a well in which cells were seeded positive control group
  • the cells were cultured for 3 days, and the cell viability was evaluated using CellTiter Glo (registered trademark) Reagent (cat. # G7570 manufactured by PROMEGA Co.) using the intracellular ATP amount as an index.
  • the concentration IC50 value that inhibits cell viability by 50% was calculated using XLFit software Ver.3 (registered trademark) (manufactured by CTC).
  • the cell viability of each well was determined with the amount of luminescent signal in the negative control group as 0% cell viability and the amount of luminescent signal in the positive control group as 100% cell viability.
  • the average value and standard deviation of the cell viability of each treatment group were calculated, and Table 1 was created.
  • the IC50 value when gemcitabine and temozolomide calculated from Table 1 were used together was 10,000 nmol / L (nM) or more, and the IC50 value when compound A and temozolomide were used together was 279.2 nmol / L.
  • Compound A significantly enhanced the antitumor effect of temozolomide. The effect was thought to be greater than the existing drug gemcitabine. A more detailed description will be given later.
  • CI Combination Index
  • the administration cycle is repeated for cancer patients by intravenous injection of compound A and oral administration of temozolomide for 5 consecutive days and withdrawn for 16 days or more.
  • the dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of temozolomide is 20 to 200 mg / m 2 .
  • compound A is intravenously injected on day 1 and temozolomide is orally administered to cancer patients, and only temozolomide is orally administered from day 2 to day 5, Repeat the dosing cycle with a withdrawal of 16 days or more.
  • the dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of temozolomide is 20 to 200 mg / m 2 .
  • the dosing cycle of administering compound A and cyclophosphamide to the cancer patient by intravenous injection and withdrawing the drug for 20 days is repeated. Repeat this for 4 to 6 cools.
  • the dose per administration of Compound A is 8 to 135 mg / m 2
  • the dose of cyclophosphamide is 50 to 1000 mg / m 2 .
  • the effect of treatment can be determined according to the following criteria.
  • the evaluation object was confirmed by diagnostic imaging using magnetic resonance imaging (MRI), and judged according to the following criteria.
  • MRI magnetic resonance imaging
  • CR Complete Response
  • PR Partial Response
  • SD Stable Disease
  • Tumor size does not change
  • PD Progressive Disease
  • the present invention is useful as an antitumor agent and an antitumor kit exhibiting a remarkable antitumor effect, and an antitumor effect enhancer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention aborde le problème consistant à fournir un agent antitumoral et un kit antitumoral présentant un effet antitumoral supérieur par rapport à la gemcitabine, un agent alkylant et une polythérapie associée, et un potentialisateur d'effet antitumoral. L'invention concerne un agent antitumoral qui comprend un agent alkylant et la 1-(2-désoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine ou un sel de celle-ci.
PCT/JP2019/010170 2018-03-13 2019-03-13 Agent antitumoral, potentialisateur d'effet antitumoral et kit antitumoral Ceased WO2019176985A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018045431 2018-03-13
JP2018-045431 2018-03-13

Publications (1)

Publication Number Publication Date
WO2019176985A1 true WO2019176985A1 (fr) 2019-09-19

Family

ID=67906833

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/010170 Ceased WO2019176985A1 (fr) 2018-03-13 2019-03-13 Agent antitumoral, potentialisateur d'effet antitumoral et kit antitumoral

Country Status (2)

Country Link
TW (1) TW202002988A (fr)
WO (1) WO2019176985A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023008511A1 (fr) 2021-07-29 2023-02-02 富士フイルム株式会社 Composition pharmaceutique et agent antitumoral pour des tumeurs présentant au moins une fonction bap1 ou pbrm1 altérée

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013531069A (ja) * 2010-07-19 2013-08-01 バイパー サイエンシズ，インコーポレイティド ４−ヨード−３−ニトロベンズアミド及びイリノテカンを用いる転移性乳癌の治療方法
WO2018043530A1 (fr) * 2016-08-31 2018-03-08 富士フイルム株式会社 Agent antitumoral, activateur d'effet antitumoral et kit anti-tumoral

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013531069A (ja) * 2010-07-19 2013-08-01 バイパー サイエンシズ，インコーポレイティド ４−ヨード−３−ニトロベンズアミド及びイリノテカンを用いる転移性乳癌の治療方法
WO2018043530A1 (fr) * 2016-08-31 2018-03-08 富士フイルム株式会社 Agent antitumoral, activateur d'effet antitumoral et kit anti-tumoral

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AKAMATSU, HIROAKI: "Action mechanism of cancer pharmacotherapeutic agents, Cytotoxic antineoplastic agent, Platinum preparation, alkylating agent, and anticancer antibiotics", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 72, no. suppl. 2, 2014, pages 124 - 126 *
MIMA, S. ET AL.: "FF-10502, an Antimetabolite with Novel Activity on Dormant Cells, Is Superior to Gemcitabine for Targeting Pancreatic Cancer Cells", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 366, no. 1, July 2018 (2018-07-01), pages 125 - 135, XP55636878 *
MIURA, S. ET AL.: "The antitumor mechanism of 1-(2-deoxy-2-fluoro-4-thio- beta -D-arabinofuranosyl)cytosine: effects of its triphosphate on mammalian DNA polymerases", JAPANESE JOURNAL OF CANCER RESEARCH, vol. 92, no. 5, 2001, pages 562 - 567, XP055213494, doi:10.1111/j.1349-7006.2001.tb01130.x *
ZAJCHOWSKI, D. ET AL.: "Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio- beta -D-arabinofuranosyl)cytosine (4'-thio-FAC) in human pancreatic and ovarian xenograft models", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL MEETING, vol. 45, 2004, pages 714, XP055213460, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/content/64/7_Supplement/714.3> [retrieved on 20190423] *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023008511A1 (fr) 2021-07-29 2023-02-02 富士フイルム株式会社 Composition pharmaceutique et agent antitumoral pour des tumeurs présentant au moins une fonction bap1 ou pbrm1 altérée
KR20240028451A (ko) 2021-07-29 2024-03-05 후지필름 가부시키가이샤 Bap1 및 pbrm1 중 적어도 하나의 기능 저하를 갖는 종양에 대한 의약 조성물 및 항종양제

Also Published As

Publication number Publication date
TW202002988A (zh) 2020-01-16

Similar Documents

Publication Publication Date Title
WO2023190748A1 (fr) Composition pharmaceutique pour le traitement de tumeurs
KR20240130818A (ko) 혈액학적 장애를 치료하기 위한 화합물 및 조성물
US11369625B2 (en) Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit
JP7183371B2 (ja) 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット
WO2010086964A1 (fr) Thérapie de combinaison pour traitement d&#39;un cancer
EP3429582B1 (fr) Polythérapie pour traiter les maladies prolifératives
WO2019176985A1 (fr) Agent antitumoral, potentialisateur d&#39;effet antitumoral et kit antitumoral
EP4656193A1 (fr) Composition pharmaceutique pour le traitement de tumeurs
AU2020276392B2 (en) Combination therapy for proliferative conditions
US12036215B2 (en) Antitumor agent and method for tumor therapy
HK40038916A (en) Antitumor agent, antitumor effect potentiator and antitumor kit
KR20240159340A (ko) 폐섬유화 예방 또는 치료를 위한 펙시다티닙 및 닌테다닙의 병용 요법
HK40005976B (zh) 抗肿瘤剂、抗肿瘤效果增强剂及抗肿瘤用试剂盒
HK40005976A (en) Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19767895

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19767895

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP