WO2021167006A1 - Agent renforçant l'effet antitumoral contenant un composé dérivé d'uracile - Google Patents

Agent renforçant l'effet antitumoral contenant un composé dérivé d'uracile Download PDF

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WO2021167006A1
WO2021167006A1 PCT/JP2021/006128 JP2021006128W WO2021167006A1 WO 2021167006 A1 WO2021167006 A1 WO 2021167006A1 JP 2021006128 W JP2021006128 W JP 2021006128W WO 2021167006 A1 WO2021167006 A1 WO 2021167006A1
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dioxo
dihydropyrimidine
fluoro
deoxycytidine
cyclopentyloxy
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田中　望
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大鵬薬品工業株式会社
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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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A61K31/7072—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 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an antitumor effect enhancer and an antitumor agent using a uracil derivative compound having a deoxyuridine triphosphatase (dUTPase) inhibitory action.
  • dUTPase deoxyuridine triphosphatase
  • DNA methylation is known as one of the gene expression regulation mechanisms that suppress gene expression. Further, in tumors, suppression of expression of genes that originally suppress tumor growth is observed by advanced DNA methylation, and inhibition of DNA methylation is expected to be useful for tumor treatment.
  • DNA methyltransferase (DNMT) is a protein involved in DNA methylation, and its inhibition will suppress DNA methylation. Therefore, treatment of tumors with a DNA methyltransferase inhibitor (DNMTi) is expected.
  • DNA methyltransferase inhibitors include 5-fluoro-2'-deoxycytidine (FdCyd), 5-aza-2'-deoxycytidine (decitabine; 5-AZA-CdR), and zebularine as having a cytidine skeleton.
  • FdCyd 5-fluoro-2'-deoxycytidine
  • decitabine 5-aza-2'-deoxycytidine
  • 5-AZA-CdR 5-aza-2'-deoxycytidine
  • zebularine as having a cytidine skeleton.
  • Guadecitabine SGI-110
  • azacitidine Azacitidine
  • procaineamide, RG-108, SGI-1027 and the like are known as those having no cytidine skeleton (Non-Patent Document 1).
  • Non-Patent Document 2 hematopoietic tumors (acute myelogenous leukemia (AML), myelogenous dysplasia syndrome (MDS), multiple myelogenous tumors (MM), chronic myelogenous leukemia (CML), acute lymphocytic).
  • AML acute myelogenous leukemia
  • MDS myelogenous dysplasia syndrome
  • MM multiple myelogenous tumors
  • CML chronic myelogenous leukemia
  • ALL acute lymphocytic
  • Solid cancer breast cancer, lung cancer, colon cancer, liver cancer, pancreatic cancer, prostate cancer, esophageal cancer, head and neck cancer, renal cancer, skin cancer, bone / soft tumor, etc.
  • Non-Patent Document 3 some compounds have been clinically tested, and some have been approved as pharmaceuticals
  • Non-Patent Document 4 a DNA methyltransferase inhibitor having a cytidine skeleton is easily transformed into a uridine skeleton by the enzymatic activity of cytidine deaminase (CDA) and easily inactivates the DNA methyltransferase inhibitory activity. Therefore, when a DNA methyltransferase inhibitor having a cytidine skeleton is used in the treatment of tumors, it has been proposed to target cytidine deaminase as a further therapeutic target at the same time, and a combination of the DNA methyltransferase inhibitor and the cytidine deaminase inhibitor (CDAi) has been proposed.
  • cytidine deaminase inhibitors include tetrahydrouridine (THU), sedazuridine (CDZ), deoxy THU, ER-876437, and ER-876400 (Non-Patent Document 1).
  • TNU tetrahydrouridine
  • CDZ sedazuridine
  • deoxy THU ER-876437
  • ER-876400 Non-Patent Document 1
  • clinical trials such as a combination of decitabine and sedazlydin (ASTX727) and a combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine are being conducted.
  • Non-Patent Document 7 In clinical trials of azacitidine, nausea, vomiting, diarrhea, and hepatotoxicity were observed (Non-Patent Document 8), and in addition, 5-fluoro-2'-deoxycitidine was observed. In clinical trials using tetrahydrouridine in combination, colitis, malaise with elevations in liver enzymes, thrombocytopenia, and leukopenia were performed early from the start of the study.
  • Non-Patent Document 9 -Thrombocytopenia with gastrointestinal hepatotoxicities has been recognized as dose-limiting toxicity (Non-Patent Document 9), and such side effects are the exposure required for the clinical effect of DNA methyltransferase inhibitors. It has become a clinical issue, hindering its continuation.
  • (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propane -1-Sulfonamide (hereinafter also referred to as "Compound 1") or a pharmaceutically acceptable salt thereof, also called TAS-114, inhibits deoxyuridine triphosphatase and, as a result, is one of the nucleic acid antimetabolites. It is known as a compound that enhances the antitumor effect of one FU antitumor agent (Patent Document 1).
  • a uracil derivative compound having a deoxyuridine triphosphatase inhibitory activity and a DNA methyl transferase inhibitor can also be used in combination with a uracil derivative compound having a deoxyuridine triphosphatase inhibitory activity, a DNA methyl transferase inhibitor and citidine deaminase.
  • a uracil derivative compound having a deoxyuridine triphosphatase inhibitory activity a DNA methyl transferase inhibitor and citidine deaminase.
  • An object of the present invention is to provide a method for treating a tumor which exhibits a remarkably excellent antitumor effect and has few side effects.
  • compound 1 which is a uracil derivative having deoxyuridine triphosphatase inhibitory activity
  • 5-fluoro- which is a DNA methyl transferase inhibitor having a cytidine skeleton. It has been found that when used in combination with 2'-deoxycytidine and a cytidine deaminase inhibitor, the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor is enhanced, and at the same time, side effects are suppressed. The present invention has been completed.
  • the present invention provides the following inventions [1] to [6].
  • the instructions for use include (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-) for patients to whom it should be applied.
  • Dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor are administered in combination.
  • the kit formulation that is described.
  • the present invention also provides the following inventions [7] to [15].
  • [7] The agent according to any one of [1] to [6], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46:
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46:
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The agent according to [12], which is 1.5 to 15.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12:
  • the present invention also provides the following inventions [16] to [20].
  • [16] (R) -N- (1- (3- (cyclopentyloxy) phenyl) for the production of an effect enhancer of an antitumor agent in which 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are used in combination.
  • the present invention also provides the following inventions [21] to [29]. [21] The use according to any one of [16] to [20], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: Use according to [22], which is 7.5 to 75.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46:
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The use according to [26], which is 1.5 to 15.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The use according to [26], which is 0.11 to 1.1.
  • the present invention also provides the following inventions [30] to [39].
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: 7.5-75 according to [32] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
  • the citidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-).
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycitidine, and sedazlidine is 1: 0.046 to 0.
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: 1.5 to 15 of (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) according to [36].
  • the citidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-).
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycitidine, and sedazlidine is 1: 0.012 to 0.
  • the present invention also provides the following inventions [40] to [49].
  • (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) for use in the treatment of tumors A combination of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The combination according to [42], which is 7.5 to 75.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46:
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The combination according to [46], which is 1.5 to 15.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12:
  • the present invention also provides the following inventions [50] to [59].
  • [50] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy)
  • the combination according to [50] wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The combination according to [52], which is 7.5 to 75.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46:
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The combination according to [56], which is 1.5 to 15.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12:
  • the present invention also provides the following inventions [60] to [69].
  • [60] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy)
  • the cytidine deaminase inhibitor according to [60] wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46:
  • the cytidine deaminase inhibitor of [62] which is 7.5 to 75.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin is 1: 0.046 to 0. 46:
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12:
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin is 1: 0.012 to 0. 12:
  • the present invention also provides the following inventions [70] to [79].
  • [70] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) 5-Fluoro-2'-deoxycytidine for use in the treatment of tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine)
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: 5-fluoro-2'-deoxycytidine according to [72], which is 7.5 to 75.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The 5-fluoro-2'-deoxycytidine according to [72], which is 0.42 to 4.2.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine)
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12:
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazulidine is 1: 0.012 to 0. 12:
  • the present invention also provides the following inventions [80] to [84].
  • [80] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy)
  • Antitumor of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors including administering an effective amount of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject in need thereof. Effect enhancement method.
  • a method for treating tumors which is required for subjects, includes (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-). Effectiveness of 3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor A method comprising administering an amount.
  • the present invention also provides the following inventions [85] to [93]. [85] The method according to any one of [80] to [84], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The method according to [86], which is 7.5 to 75.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The method according to [86], which is 0.42 to 4.2.
  • the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine).
  • the molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The method according to [90], which is 1.5 to 15.
  • the cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-)
  • the molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The method according to [90], which is 0.11 to 1.1.
  • compound 1 is represented by the following formula.
  • Compound 1 or a pharmaceutically acceptable salt thereof is a known compound having excellent deoxyuridine triphosphatase inhibitory activity, and is, for example, according to the method described in Patent Document 1 (International Publication No. 2011/065541). Can be synthesized.
  • Examples of the pharmaceutically acceptable salt of Compound 1 include a base addition salt and an acid addition salt.
  • Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt and diethanolamine. Examples thereof include salts, triethanolamine salts, procaine salts, organic amine salts such as N, N'-dibenzylethylenediamine salts and the like.
  • acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; acetates, formates, maleates, fumarates, tartrates and citrates. , Organic acid salts such as ascorbate and trifluoroacetate; sulfonates such as methanesulfonate, ISEthionate, benzenesulfonate, p-toluenesulfonate and the like.
  • Compound 1 or a salt thereof may be amorphous or crystalline, and may be a single crystal form or a polymorphic mixture, and may be a pharmaceutically acceptable salt thereof of Compound 1 of the present invention or a salt thereof. Included. Crystals can be produced by crystallization by applying a known crystallization method.
  • Compound 1 or its pharmaceutically acceptable salt also includes its prodrug.
  • the prodrug is a compound that is converted into the compound of the present invention or a pharmaceutically acceptable salt thereof by a reaction with an enzyme, gastric acid, etc. under physiological conditions in the living body, that is, enzymatically undergoes oxidation, reduction, hydrolysis, etc.
  • 5-fluoro-2'-deoxycytidine (hereinafter, also referred to as "FdCyd") is an inhibitor of DNA methyltransferase represented by the following formula.
  • 5-Fluoro-2'-deoxycytidine is described in the literature (eg, Visser, Gerard WM, J Chem Soc, Perkin Trans 1: Organic and Bio-Organic Chemistry, 1972-1999; 1988 (9): 25). ) Can be obtained by the method described in.
  • 5-fluoro-2'-deoxycytidine also includes its pharmaceutically acceptable salt.
  • salts include base-added salts and acid-added salts.
  • base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt and diethanolamine.
  • Examples thereof include salts, triethanolamine salts, procaine salts, organic amine salts such as N, N'-dibenzylethylenediamine salts and the like.
  • acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; acetates, formates, maleates, fumarates, tartrates and citrates. , Organic acid salts such as ascorbate and trifluoroacetate; sulfonates such as methanesulfonate, ISEthionate, benzenesulfonate, p-toluenesulfonate and the like.
  • the cytidine deaminase inhibitor refers to an agent that inhibits the enzymatic activity of cytidine deaminase.
  • the cytidine deaminase inhibitor include tetrahydrouridine (hereinafter, also referred to as “THU”), sedazulysin (hereinafter, also referred to as “CDZ”), and deoxy THU.
  • TNU tetrahydrouridine
  • CDZ sedazulysin
  • deoxy THU deoxy Tetrahydrouridine
  • Tetrahydrouridine is obtained by the method described in the literature (eg, Hanze, AR, JAm Chem Soc. 1967; 89: 6720), and sedazulysin is obtained by the method described in US Pat. No. 8,268,800. be able to.
  • tetrahydrouridine and sedazuridine also include pharmaceutically acceptable salts thereof.
  • such salts include base-added salts and acid-added salts.
  • the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt and diethanolamine.
  • acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; acetates, formates, maleates, fumarates, tartrates and citrates. , Organic acid salts such as ascorbate and trifluoroacetate; sulfonates such as methanesulfonate, ISEthionate, benzenesulfonate, p-toluenesulfonate and the like.
  • Compound 1 can be used in combination with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors, and by further concomitant use, with respect to 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors. Enhances the antitumor effect of the combination.
  • compound 1 when compound 1 is further used in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, weight loss due to the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, etc. The occurrence of side effects is suppressed.
  • an antitumor effect enhancer in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor containing Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient is provided.
  • an antitumor agent comprising a combination of Compound 1 or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor in combination is provided. ..
  • the antitumor effect can be evaluated as, for example, a decrease in tumor volume, a stagnation in tumor growth, an extension of survival time, and the like.
  • the enhancement of the antitumor effect means to enhance the antitumor effect of another antitumor agent, and the effect enhancer of the antitumor effect exerts the enhancement of the antitumor effect of another antitumor agent.
  • the effect enhancer of the antitumor effect often accompanies the enhancement of side effects, but preferably the enhancement of side effects is mild, more preferably the enhancement of side effects is not accompanied, and more preferably. , With reduction of side effects.
  • the tumor to be treated by the medicament of the present invention is not particularly limited, and examples thereof include carcinomas, sarcomas, brain tumors, and hematopoietic tumors.
  • the cancer is not particularly limited, but head and neck cancer (oral cancer, pharyngeal cancer, laryngeal cancer, nasal cavity cancer, sinus cancer, salivary adenocarcinoma, thyroid cancer, etc.), gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, etc.) Liver cancer, biliary tract cancer (biliary sac / bile duct cancer, etc.), pancreatic cancer, colon cancer (colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesenteric cancer, etc.), breast cancer, reproductive organ cancer ( Examples include ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), urinary cancer (renal cancer, bladder cancer, prostate cancer, testicular tumor, etc.),
  • the sarcoma is not particularly limited, and examples thereof include bone tumors and soft tissue tumors.
  • the hematopoietic tumor is not particularly limited, and examples thereof include leukemia, malignant lymphoma, and multiple myeloma.
  • Leukemia is not particularly limited, and examples thereof include acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, myelodysplastic syndrome, and hairy cell leukemia.
  • the malignant lymphoma is not particularly limited, and examples thereof include Hodgkin lymphoma and non-Hodgkin lymphoma, and examples of the non-Hodgkin lymphoma include B cell-derived lymphoma, T / NK cell-derived lymphoma, and lymphoblastic lymphoma.
  • Brain tumors are not particularly limited, but include, for example, metastatic brain tumors (for example, brain tumors such as lung cancer, breast cancer, gastric cancer, colorectal cancer, bladder cancer, biliary tract cancer, and germinoma), hairy cell astrocytoma, Diffuse astrocytoma, oligoastrocytoma / oligoastrocytoma, osteogenic astrocytoma / oligoastrocytoma, oligoastrocytoma, gligodendroglioma, coat tumor, degeneration Sexual coat tumor, ganglion glioma, central neurocytoma, medullary blastoma, germinoma, central nervous system malignant lymphoma, meningeal tumor, nerve sheath tumor, GH-producing pituitary adenoma, PRL-producing pituitary adenoma , ACTH-producing pituitary adenomas, non-functional pituitary adenomas, cr
  • the tumor includes not only the primary tumor but also a tumor that has metastasized to other organs (liver, etc.). Further, even if the antitumor agent of the present invention is used for postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, it is performed in advance for surgical removal of the tumor. It may be preoperative adjuvant chemotherapy.
  • a pharmaceutical carrier may be added as necessary, depending on the prophylactic or therapeutic purpose.
  • Various administration forms can be adopted. Examples of the dosage form include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, and the like. Oral preparations and injection preparations are preferable. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • Pharmaceutical carriers include various general-purpose pharmaceutical carriers such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, etc. Examples thereof include pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.
  • the administration schedule of the drug of the present invention is appropriately selected within the range of exerting the effect of enhancing the antitumor effect, and each active ingredient is administered simultaneously or separately at intervals. When administered separately, either may be administered first.
  • the medicament of the present invention may be formulated by dividing each active ingredient into a plurality of dosage forms based on the administration form and administration schedule of each active ingredient, or may be formulated collectively in one dosage form.
  • each preparation may be manufactured and sold in a single package suitable for combined administration, or each preparation may be manufactured and sold in separate packages.
  • the administration or compounding ratio of compound 1 or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is not particularly limited as long as it exerts an effect of enhancing the antitumor effect.
  • compound 1 and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered, the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor while suppressing the onset of side effects.
  • the amount of 5-fluoro-2'-deoxycytidine may be 0.0001 to 10000 mol, preferably 0.001 per 1 mol of compound 1 or a pharmaceutically acceptable salt thereof.
  • the amount of the cytidine deaminase inhibitor may be 0.0001 to 10000 mol with respect to 1 mol of Compound 1 or a pharmaceutically acceptable salt thereof.
  • THU it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, further preferably 2.3 to 230 mol, particularly preferably 7.5 to 75 mol, and most preferably 18 to 54 mol. And it is sufficient.
  • CDZ it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, still more preferably 0.15 to 15 mol, particularly preferably 0.42 to 4.2 mol, and most preferably 0. It may be 56 to 1.7 mol.
  • 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection
  • 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered while suppressing the onset of side effects.
  • the amount of 5-fluoro-2'-deoxycytidine may be 0.0001 to 10000 mol with respect to 1 mol of compound 1 or a pharmaceutically acceptable salt thereof.
  • the amount of the cytidine deaminase inhibitor may be 0.0001 to 10000 mol with respect to 1 mol of Compound 1 or a pharmaceutically acceptable salt thereof.
  • THU it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, still more preferably 0.45 to 45 mol, particularly preferably 1.5 to 15 mol, most preferably 3.8 to It may be 11.4 mol.
  • CDZ it is preferably 0.001 to 1000 mol, more preferably 0.01 to 100 mol, further preferably 0.04 to 4 mol, particularly preferably 0.11 to 1.1 mol, and most preferably 0. It may be 17 to 0.51 mol.
  • the dose of each active ingredient can be appropriately selected depending on the usage, age of the patient, gender and other conditions, degree of disease and the like.
  • the daily dose of compound 1 or a pharmaceutically acceptable salt thereof per human is 0. It is 3 to 30,000 mg / m 2 / day.
  • 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is preferably 1 to 10000 mg / m 2 / day, and more preferably 3 to 3000 mg / m 2 /. It is a day, more preferably 10 to 1000 mg / m 2 / day, particularly preferably 60 to 600 mg / m 2 / day, and most preferably 90 to 270 mg / m 2 / day.
  • the dose of 5-fluoro-2'-deoxycytidine is 0.1-10000 mg / m 2 / day.
  • the cytidine deaminase inhibitor is 0.1 to 200,000 mg / m 2 / day.
  • THU it is preferably 2 to 20000 mg / m 2 / day, more preferably 18 to 18000 mg / m 2 / day, and further preferably. is a 150 ⁇ 15000mg / m 2 / day, particularly preferably at 500 ⁇ 5000mg / m 2 / day, most preferably 1200 ⁇ 3600mg / m 2 / day.
  • CDZ For CDZ, or preferably 1 ⁇ 10000mg / m 2 / day, more preferably 3 ⁇ 3000mg / m 2 / day, more preferably not more 10 ⁇ 1000mg / m 2 / day, particularly preferably 30 ⁇ 300 mg / M 2 / day, most preferably 40-120 mg / m 2 / day.
  • the daily dose of compound 1 or a pharmaceutically acceptable salt thereof per human is determined. It is 0.3 to 30,000 mg / m 2 / day. From the viewpoint of enhancing the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor , it is preferably 1 to 10000 mg / m 2 / day, and more preferably 3 to 3000 mg / m 2 /.
  • the dose of 5-fluoro-2'-deoxycytidine is 0.1-10000 mg / m 2 / day. From the viewpoint of exerting an antitumor effect and suppressing the onset of side effects , it is preferably 0.2 to 2000 mg / m 2 / day, more preferably 0.3 to 300 mg / m 2 / day, and even more preferably.
  • the dose of the cytidine deaminase inhibitor is 0.01 to 30,000 mg / m 2 / day.
  • the onset of side effects in the case of THU, preferably at 1 ⁇ 10000mg / m 2 / day, more preferably 5 ⁇ 5000mg / m 2 / day, more preferably Is 30 to 3000 mg / m 2 / day, particularly preferably 100 to 1000 mg / m 2 / day, and most preferably 250 to 750 mg / m 2 / day.
  • CDZ it is preferably 0.6 to 6000 mg / m 2 / day, more preferably 1 to 1000 mg / m 2 / day, still more preferably 3 to 300 mg / m 2 / day, and particularly preferably 8 It is -80 mg / m 2 / day, most preferably 12-36 mg / m 2 / day. This can be administered once a day or in several divided doses.
  • the present invention also presents compound 1 or a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof for cancer patients, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibition.
  • the present invention relates to a kit formulation containing instructions for administration in combination with the drug.
  • the "instruction manual” may be any one in which the above-mentioned dose is described, regardless of whether or not it is legally binding, but the one in which the above-mentioned dose is recommended is preferable.
  • package inserts, pamphlets and the like are exemplified.
  • the kit formulation including the instruction manual means that the instruction manual is printed and attached to the package of the kit formulation, but the instruction manual is enclosed with the antitumor agent in the package of the kit formulation. It may be a thing.
  • Example 1 in vitro test-1 The human hematopoietic tumor cell line MV-4-11 was suspended in medium, seeded in each well of a multi-well plate, and cultured in an incubator. The compound solution was added the day after the start of culturing, and the cells were further cultured for 3 days. The number of cells was measured using Celtitagro (manufactured by Promega) based on the protocol recommended by Promega.
  • the cell viability was calculated from the following formula, and the concentration of the compound (IC50 ( ⁇ M)) that inhibits cell viability by 50% was determined.
  • Cell viability (%) (T / C) x 100 T: Emission intensity of wells with compound added
  • C Emission intensity of wells without compound added
  • the rate of change of IC50 ( ⁇ M) depending on the presence or absence of combined use of compound 1 (10 ⁇ M) (combination effect by compound 1) was determined by the following formula, and the enhancing effect of compound 1 on FdCid + THU (THU: 10 ⁇ M). Asked.
  • Compound 1 enhanced the antitumor effect of FdCyd in the presence of THU by 10 times or more.
  • Example 2 in vivo test-1 The human hematopoietic tumor cell line MV-4-11 was transplanted into the right chest of BALB / cA Jcl-nu / nu mice. After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor are measured, the tumor volume (TV) is calculated by the following formula, and then mice are placed in each group so that the average TV in each group is even. The day when the allocation and grouping were carried out was set as Day 0.
  • the Control group was a 0.5% hypromellose (HPMC) aqueous solution
  • the FdCyd + THU administration group was 1 + 100 mg / kg / day FdCyd + THU
  • the Compound 1 administration group was 600 mg / kg / day Compound 1.
  • 1 + 100 + 600 mg / kg / day of FdCyd + THU + compound 1 was orally administered to Day 1-14 once a day every day.
  • the relative tumor volume (reactive tumor volume: RTV) and body weight change (BWC) with respect to Day 0 were obtained from the TV and body weight (BW) of each group by the following formula. And compared the changes over time of RTV and BWC in each group.
  • RTV (TV on evaluation date) / (TV on Day 0)
  • BWC (%) (BW at BW-Day 0 on the evaluation date) / (BW at Day 0) ⁇ 100
  • Compound 1 showed an extremely excellent effect of enhancing the antitumor effect of FdCyd + THU, while suppressing the weight loss caused by FdCid + THU.
  • Example 3 in vitro test-2 Various cell lines derived from human hematopoietic tumors shown in Table 1 below were suspended in a medium, seeded in each well of a multi-well plate, and cultured. The compound solution was added the day after the start of culturing, and the cells were further cultured for 3 days. The number of cells was measured using Celtitagro (manufactured by Promega) based on the protocol recommended by Promega.
  • compound 1 was found to have an enhancing effect on the antitumor effect of FdCyd in the presence of THU or CDZ in cell lines derived from various types of hematopoietic tumors. rice field. It is compared to the antitumor effect of compound 1 on other DNA methyltransferase inhibitors in the presence of THU or CDZ (eg, Decitabine, SGI-110, Azacitidine) and Cytarabine, which also has a cytidine skeleton. Remarkably strong. In addition, it exceeded the enhancing effect of Compound 1 on the antitumor effect of 5-FU and FdUrd.
  • the enhancing effect of FdCyd on the antitumor effect of FdCyd in the presence of THU or CDZ on hematopoietic tumors is specific as compared with other compounds having a pyrimidine skeleton, which is a surprising result.
  • Example 4 in vitro test-3 Various cell lines derived from human carcinoma, sarcoma and brain tumor shown in Table 2 below were suspended in a medium, seeded in each well of a multi-well plate, and cultured. The compound solution was added the day after the start of culturing, and the cells were further cultured for 3 days. The number of cells was measured using Celtitagro (manufactured by Promega) based on the protocol recommended by Promega. As for the rest, the combined effect of Compound 1 was determined in the same manner as in Example 3. The results are shown in FIGS. 8 to 17.
  • Compound 1 has an enhancing effect on the antitumor effect of FdCyd in the presence of THU or CDZ in cell lines derived from various types of carcinomas, sarcomas and brain tumors. Admitted. It exceeded the enhancing effect of Compound 1 on the antitumor effect of 5-FU and FdUrd. This is a surprising result. In the first place, the antitumor effect of a DNA methyltransferase inhibitor on carcinoma, sarcoma and brain tumor is considered to be limited regardless of the combined use of a cytidine deaminase inhibitor. In contrast, Compound 1 was found to have an enhancing effect on the antitumor effect of FdCyd in the presence of THU or CDZ. This is an even more surprising result.
  • Example 5 in vivo test-2 The human hematopoietic tumor cell line MV-4-11 was transplanted into the right chest of BALB / cA Jcl-nu / nu mice. After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor are measured, the tumor volume (TV) is calculated by the following formula, and then mice are placed in each group so that the average TV in each group is even. The day when the allocation and grouping were carried out was set as Day 0.

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Abstract

L'invention concerne une méthode de traitement d'une tumeur qui présente un effet antitumoral remarquable et peu d'effets secondaires.　Cet agent renforçant l'effet antitumoral de la 5-fluoro-2'-désoxycytidine et d'un inhibiteur de la cytidine désaminase contient, en tant que principe actif, du (R)-N-(1-(3-(cyclopentyloxy)phényl)éthyl)-3-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)méthoxy)propane-1-sulfonamide ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2021/006128 2020-02-18 2021-02-18 Agent renforçant l'effet antitumoral contenant un composé dérivé d'uracile WO2021167006A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011065541A1 (fr) * 2009-11-30 2011-06-03 大鵬薬品工業株式会社 Potentialisateur d'effet anticancéreux
WO2016175324A1 (fr) * 2015-04-30 2016-11-03 大鵬薬品工業株式会社 Agent permettant d'atténuer une réaction indésirable liée à un médicament antitumoral

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011065541A1 (fr) * 2009-11-30 2011-06-03 大鵬薬品工業株式会社 Potentialisateur d'effet anticancéreux
WO2016175324A1 (fr) * 2015-04-30 2016-11-03 大鵬薬品工業株式会社 Agent permettant d'atténuer une réaction indésirable liée à un médicament antitumoral

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUO DUOLI, MYRDAL PAUL B., KARLAGE KELLY L., O’CONNELL SEAN P., WISSINGER TRAVIS J., TABIBI S. ESMAIL, YALKOWSKY SAMUEL H.: "Stability of 5-Fluoro-2′-deoxycytidine and Tetrahydrouridine in Combination", AAPS PHARMSCITECH, vol. 11, no. 1, 1 March 2010 (2010-03-01), pages 247 - 252, XP055850108, DOI: 10.1208/s12249-010-9383-2 *

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