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WO2025033367A1 - Polythérapie pour agent antitumoral - Google Patents

Polythérapie pour agent antitumoral Download PDF

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WO2025033367A1
WO2025033367A1 PCT/JP2024/027809 JP2024027809W WO2025033367A1 WO 2025033367 A1 WO2025033367 A1 WO 2025033367A1 JP 2024027809 W JP2024027809 W JP 2024027809W WO 2025033367 A1 WO2025033367 A1 WO 2025033367A1
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methyl
carboxamide
formula
piperidin
antitumor
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PCT/JP2024/027809
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Japanese (ja)
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太一 上嶋
友亮 佐貫
朋則 山口
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湧永製薬株式会社
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • 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 antitumor drug combination therapy using pyridone carboxylic acid derivatives.
  • Certain pyridone carboxylic acid derivatives are known to have antitumor and anticancer activity. For example, it has been reported that pyridone carboxylic acid derivatives having a 2-thiazolyl group have antitumor activity (Patent Document 1, Patent Document 2).
  • Patent Document 1 1,4-dihydro-7-(3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid described in Patent Document 1 has been confirmed to have excellent antitumor effects in vitro and in vivo against human cancer cells (Non-Patent Documents 1, 2), and it has also been reported that in a phase III trial, when used in combination with cytarabine, it showed a significant therapeutic effect against relapsed/refractory acute myeloid leukemia in patients 60 years of age or older, compared to the placebo group (Non-Patent Document 3).
  • pyridone carboxylic acid compounds having a substituted azetidinyl group at the 7-position have excellent antitumor activity and are useful as antitumor agents (Patent Document 3).
  • Patent Document 3 5-methyl-7- ⁇ 3-[(oxan-2-ylmethyl)carbamoyl]azetidin-1-yl ⁇ -4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid has excellent proliferation inhibitory activity against acute myeloid leukemia (AML) cells, non-small cell lung cancer, prostate cancer cells, etc.
  • AML acute myeloid leukemia
  • Patent No. 5079612 International Publication No. 2011/056566 International Publication No. 2018/174266
  • the present invention relates to providing an antitumor drug combination therapy that uses pyridone carboxylic acid derivatives and has a high antitumor effect.
  • the inventors conducted extensive research to further enhance the antitumor effect of 5-methyl-7- ⁇ 3-[(oxan-2-ylmethyl)carbamoyl]azetidin-1-yl ⁇ -4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and discovered that a superior antitumor effect can be achieved by combining the compound with a specific antitumor agent.
  • an antitumor agent comprising, as an active ingredient, a compound represented by the following formula (1) or a salt thereof, which is administered in combination with another antitumor agent, wherein the other antitumor agent is selected from the group consisting of cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazolidin-2-yl)methyl, 1-methyl-2-( ...
  • An antitumor effect enhancer of another antitumor agent comprising a compound represented by the following formula (1) or a salt thereof as an active ingredient , wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazole-4-yl)-1H-pyrazole-4-yl
  • antitumor agents include 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17
  • octadecane-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid, or one or more thereof.
  • octadecane-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid, or one or more selected from the group consisting of octadecane-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid.
  • octatriacarter 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid or a salt thereof.
  • An anticancer therapy comprising administering to a patient a therapeutically effective amount of a compound represented by the following formula (1) or a salt thereof and another antitumor agent, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazole-4-yl)methyl, 1-methyl-2-( ...
  • a method for enhancing the antitumor effect of another antitumor agent comprising administering to a patient a therapeutically effective amount of a compound represented by the following formula (1) or a salt thereof, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazole- 4-
  • the antitumor agent of the present invention makes it possible to carry out cancer treatment that has a high antitumor effect while suppressing the onset of side effects, thereby resulting in long-term survival of patients.
  • the compound represented by formula (1) of the present invention is a pyridone carboxylic acid derivative named 5-methyl-7- ⁇ 3-[(oxan-2-ylmethyl)carbamoyl]azetidin-1-yl ⁇ -4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Patent Document 3, Compound 078), which has excellent proliferation inhibitory effect against various tumor cells such as acute myeloid leukemia (AML) cells, non-small cell lung cancer, and prostate cancer, and is particularly effective against acute myeloid leukemia (AML) cells, and is useful as a therapeutic agent for acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • AML acute myeloid
  • the compounds represented by formula (1) include stereoisomers of 5-methyl-7-(3- ⁇ [(2R)-oxan-2-ylmethyl]carbamoyl ⁇ azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (referred to as "(R)-WAC-224"), in which the steric configuration of the oxan-2-ylmethyl group is the R configuration, and 5-methyl-7-(3- ⁇ [(2S)-oxan-2-ylmethyl]carbamoyl ⁇ azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, in which the steric configuration of the oxan-2-ylmethyl group is the S configuration.
  • the compound represented by formula (1) can be produced, for example, according to the method described in Patent Document 3.
  • the compound represented by formula (1) can form a base addition salt.
  • This salt also includes a chelate salt with a boron compound.
  • base addition salts include (A) salts with alkali metals such as sodium and potassium, (B) salts with alkaline earth metals such as calcium and magnesium, (C) ammonium salts, (D) trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, 2-aminoethane-1-ol, N-methylaminoethanol, N,N-dimethylaminoethanol, 1,1,3,3-tetramethylethanol, and (E) tetramethylethanol.
  • salts include salts with nitrogen-containing organic bases such as methylguanidine, diethanolamine, triethanolamine, dicyclohexylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, glucamine, N-methylglucamine, and 1-carbamimidamido-N,N-dimethylmethanimidamide, and salts with basic amino acids such as (E) arginine, lysine, and ornithine.
  • boron compounds include boron halides such as boron fluoride, and lower acyloxyborons such as acetoxyboron.
  • the compounds of the present invention or salts thereof can exist not only in unsolvated form, but also as hydrates or solvates.
  • the compounds of the present invention or salts thereof include all crystal forms and hydrates or solvates thereof.
  • the other antitumor agent means a drug (also called a "concomitant drug") having an antitumor effect different from the compound represented by the above formula (1)
  • examples of the other antitumor agent include cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide (GSK126), 6-bromo-3-(1-methyl-1H-pyrazole-4 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide (AZD7762
  • octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid (AZD5991).
  • a compound may form a salt with a pharma- ceutically acceptable acid or base, so long as it is used as an antitumor agent.
  • Tables 1-1 to 1-2 below The substance information regarding such drugs is shown in Tables 1-1 to 1-2 below, and all of them are commercially available as medicines or reagents.
  • cytarabine is a DNA polymerase inhibitor
  • venetoclax is a BCL-2 (B-cell/CLL lymphoma-2) inhibitor
  • azacitidine is a DNA methyltransferase inhibitor
  • gilteritinib is an FLT3 (FMS-like tyrosine kinase 3) inhibitor
  • virabresib is a BRD (bromodomain-containing protein) 2,3,4 inhibitor
  • vorinostat is an HDAC (histone deacetylase) inhibitor
  • GSK126 is an EZH2 (Enhancer of zeste homolog 2) inhibitor
  • MK-8776, AZD7762, and ravusertib are CHK1 (Checkpoint kinase 1) inhibitors
  • dabrafenib and vemurafenib are BRAF (B-Raf) V600E inhibitors
  • olaparib is a PARP (Poly (ADP-ribose) polymerases) 1,2 inhibitor
  • adavosertib is a Wee1 inhibitor
  • alisertib is an Aurora Kinase A inhibitor
  • decitabine is a DNA demethylating agent
  • midostaurin is a multikinase inhibitor
  • AZD5991 is an MCL1 (Myeloid cell leukemia 1) inhibitor.
  • the compound represented by formula (1) exerts a significantly stronger cell proliferation inhibitory effect (cytotoxic activity) when administered in combination with another antitumor agent than when administered alone.
  • the cell proliferation inhibitory effect is a synergistic effect with a combination index (CI) of 0.9 or less in an evaluation of the combined effect calculated by the isobologram method (Cancer Chemother Pharmacol 31:259-264, 1993). Therefore, the combined administration of the compound represented by formula (1) or a salt thereof with another antitumor agent of the present invention is useful as an excellent anticancer therapy, and the compound represented by formula (1) or a salt thereof is useful as an antitumor agent combined with the other antitumor agent in anticancer therapy. Also, the compound represented by formula (1) or a salt thereof is useful as an antitumor effect enhancer for enhancing the antitumor effect of the other antitumor agent in anticancer therapy.
  • Cancers that can be treated or prevented by the antitumor agent of the present invention are not particularly limited, and examples thereof include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphatic malignancies. More specific examples thereof include neuroblastoma, intestinal cancer, such as rectal cancer, colon cancer, familial polyposis coli cancer and hereditary nonpolyposis, colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, malignant adenoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, head and neck cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, bladder cancer, malignant melanoma, brain tumors, such as glioblastoma, astrocytoma, meningi
  • the antitumor agent of the present invention is suitable for treating or preventing leukemia, colon cancer, kidney cancer, ovarian cancer, breast cancer, bladder cancer, malignant melanoma, lung cancer, fibrosarcoma, etc., and is particularly suitable for treating or preventing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), particularly acute myeloid leukemia (AML) resistant to treatment with venetoclax and myelodysplastic syndrome (MDS) resistant to treatment with venetoclax.
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • AML Acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • antitumor agents to be used together with the compound represented by formula (1) or a salt thereof include, for example, 1) when the purpose is to treat or prevent acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), it is preferable to use one or more selected from cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, decitabine, midostaurin, and AZD5991; 2) when the purpose is to treat or prevent colorectal cancer, it is preferable to use one or more selected from dabrafenib, vemurafenib, adavosertib, alisertib, and vorinostat; 3) when the purpose is to treat or prevent ovarian cancer, it is preferable to use one or more selected from GSK126, ravusertib, MK-8776, and olaparib; and 4) when the purpose is to treat or prevent ovarian cancer,
  • the antitumor agent of the present invention may be a combination drug in which the compound represented by formula (1) or a salt thereof and another antitumor agent are each formulated in an effective amount in a single dosage form at an appropriate mixing ratio (single-dose form), or may be a single drug formulation containing effective amounts of each of the above components so that they can be used simultaneously or separately with an interval between them (multiple-dose form).
  • the dosage form of the above preparation is not particularly limited and can be appropriately selected depending on the purpose of treatment. Specific examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc.
  • the compound represented by formula (1) or a salt thereof and the other antitumor agent may be administered in different dosage forms or in the same dosage form.
  • the formulations containing the compound represented by formula (1) or its salt and/or other antitumor agents of the present invention can be prepared by a commonly known method using a pharmacologically acceptable carrier.
  • a pharmacologically acceptable carrier include various types commonly used in ordinary pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavorings, odorants, etc.
  • excipients include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof.
  • lubricants include purified talc, stearates, borax, polyethylene glycol, and mixtures thereof.
  • binders include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, and mixtures thereof.
  • disintegrants include dry starch, sodium alginate, powdered agar, powdered laminaran, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and mixtures thereof.
  • diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof.
  • stabilizers include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and mixtures thereof.
  • isotonicity agents include sodium chloride, boric acid, glucose, glycerin, and mixtures thereof.
  • pH adjusters and buffers include sodium citrate, citric acid, sodium acetate, sodium phosphate, and mixtures thereof.
  • soothing agents include procaine hydrochloride, lidocaine hydrochloride, and mixtures thereof.
  • the amounts of the compound represented by formula (1) or a salt thereof and other antitumor agents in the above-mentioned preparation can be appropriately determined, but generally, the compound represented by formula (1) or a salt thereof in the preparation is present in an amount, calculated as the amount of the compound represented by formula (1), of 0.1 to 4000 mg/m 2 (body surface area), preferably 1 to 1000 mg/m 2 (body surface area), more preferably 10 to 400 mg/m 2 (body surface area) per day.
  • the dose of other antitumor agents is appropriately set within the range permitted for each drug.
  • the dose is 0.1 to 4000 mg/m 2 (body surface area), preferably 1 to 1000 mg/m 2 (body surface area), more preferably 10 to 400 mg/m 2 (body surface area), for azacitidine, the dose is 0.1 to 4000 mg/m 2 (body surface area), preferably 1 to 1000 mg/m 2 (body surface area), more preferably 10 to 400 mg/m 2 (body surface area), for venetoclax, the dose is 0.1 to 4000 mg, preferably 1 to 2000 mg, more preferably 10 to 800 mg per day.
  • the agent containing the compound represented by formula (1) or its salt formulated as described above and the other antitumor agent can be packaged separately, and each pharmaceutical preparation can be taken out of its respective package at the time of administration. Also, each pharmaceutical preparation can be packaged in a form suitable for combined administration each time.
  • the dosage of the antitumor agent of the present invention is not particularly limited as long as the compound represented by formula (1) or a salt thereof and the other antitumor agent can exert a synergistic antitumor effect to effectively treat cancer, and is appropriately set depending on the patient's age, type of cancer, stage of disease, presence or absence of metastasis, treatment history, presence or absence of other drugs, etc., but the compound represented by formula (1) or a salt thereof is administered in an amount equivalent to the compound represented by formula (1) per day of 0.1 to 4000 mg/m 2 (body surface area), preferably 1 to 1000 mg/m 2 (body surface area), more preferably 10 to 400 mg/m 2 (body surface area).
  • the dose of other antitumor agents is appropriately set within the range permitted for each drug.
  • the dose is 0.1 to 4000 mg/m 2 (body surface area), preferably 1 to 1000 mg/m 2 (body surface area), more preferably 10 to 400 mg/m 2 (body surface area), for azacitidine, the dose is 0.1 to 4000 mg/m 2 (body surface area), preferably 1 to 1000 mg/m 2 (body surface area), more preferably 10 to 400 mg/m 2 (body surface area), for venetoclax, the dose is 0.1 to 4000 mg, preferably 1 to 2000 mg, more preferably 10 to 800 mg per day.
  • each individual preparation may be administered simultaneously or at intervals.
  • HEL92.1.7 and MOLM13 were cultured in RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS) (GIBCO Co., Ltd.), TF-1 in RPMI-1640 medium containing 10% fetal bovine serum and 2 ng/mL recombinant human GM-CSF (BioLegend Co., Ltd.), KG-1 and HL-60 in IMDM medium containing 20% FBS (Fujifilm Wako Pure Chemical Industries, Ltd.), and MV4-11 in IMDM medium containing 10% FBS to prepare cell suspensions.
  • RPMI-1640 medium Fejifilm Wako Pure Chemical Industries, Ltd.
  • FBS fetal bovine serum
  • TF-1 in RPMI-1640 medium containing 10% fetal bovine serum and 2 ng/mL recombinant human GM-CSF
  • BioLegend Co., Ltd. BioLegend Co., Ltd.
  • each tumor cell line (other than AML cell line) UM-UC-3, a bladder cancer cell line, 786-O, a kidney cancer cell line, SK-OV-3, an ovarian cancer cell line, A375, SK-MEL5, and SK-MEL28, which are malignant melanoma cell lines, RKO and HCT116, MDA-MB-462, MDA-MB-436, and MDA-MB-468, which are breast cancer cell lines, NCI-H460, which is a lung cancer cell line, and HT1080, which is a fibrosarcoma cell line, were used (Table 3 below).
  • UM-UC-3, A375, SK-MEL5, SK-MEL28, RKO, MDA-MB-436, MDA-MB-468, and HT1080 were cultured in 10% FBS-containing DMEM medium (Fujifilm Wako Pure Chemical Industries, Ltd.), 786-O and NCI-H460 in 10% FBS-containing RPMI-1640 medium, and SK-OV-3 and HCT116 in 10% FBS-containing McCoy's 5a medium (ThermoFisher Scientific, Inc.), and cell suspensions were prepared.
  • AML human-derived acute myeloid leukemia
  • the EC50 for venetoclax was measured using RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS) (GIBCO) for HEL92.1.7 and MOLM13, RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum and 2 ng/mL recombinant human GM-CSF (BioLegend) for TF-1, IMDM medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 20% FBS for KG-1 and HL- 60 , and IMDM medium containing 10% FBS for MV4-11.
  • Concomitant medications cytarabine (Fujifilm Wako Pure Chemical Industries, Ltd.), venetoclax (Combi-Blocks, Inc.), azacitidine (Fujifilm Wako Pure Chemical Industries, Ltd.), gilteritinib (Medchemexpress, Inc.), decitabine (Angened, Inc.), midostaurin (BLD
  • the following drugs were purchased and used: AZD5991 (MCE), virabresib (Chemexpress), vorinostat (Abcam), AZD7762 (Funakoshi), ravusertib (Funakoshi), MK-8776 (Cosmo Bio), dabrafenib (Selleck), vemurafenib (ChemieTek), olaparib (Selleck), adavosertib (ChemieTek), alisertib (adooq bio), and vorinostat (Abcam).
  • Example 1 Evaluation of tumor cell proliferation inhibitory effect by drug combinations
  • Cell suspensions were seeded into 96-well plates at 25,000 to 50,000 cells/well for AML cells including venetoclax-resistant strains, and at 4,000 to 5,000 cells/well for other cells.
  • Drug solutions adjusted to the concentrations shown in (1) to (5) below were added to the cell culture medium.
  • the maximum concentrations of each compound alone and in combination were 40 ⁇ mol/L for (R)-WAC-224, 200 ⁇ mol/L for cytarabine, 40 ⁇ mol/L for venetoclax, 200 ⁇ mol/L for azacitidine, 0.08 ⁇ mol/L for gilteritinib, 160 ⁇ mol/L for decitabine, 2 ⁇ mol/L for midostaurin, 16 ⁇ mol/L for AZD5991, 16 ⁇ mol/L for virabresib, 1.6 ⁇ mol/L for vorinostat, and
  • the compound solutions used were 1 ⁇ mol/L for AZD7762, 6.5 ⁇ mol/L for rabuseritib, 13 ⁇ mol/L for SCH900776, 3.2 ⁇ mol/L for dabrafenib, 11 ⁇ mol/L for vemurafenib, 50 ⁇ mol/L for olaparib, 16 ⁇ mol/L for adavoserti
  • the combined effect was evaluated according to the following CI value grading: A CI value of ⁇ 0.9 indicates a synergistic effect, and a lower value indicates a stronger synergistic effect.
  • the CI value for SK-MEL5 was 0.29, indicating that the combined effect against malignant melanoma was a strong synergistic effect; the CI value for RKO was 0.43, indicating that the combined effect against colorectal cancer was a synergistic effect; and the CI value for SK-MEL28 was 0.77, indicating that the combined effect against malignant melanoma was a mild synergistic effect.
  • the CI value for MDA-MB-462 was 0.61, indicating that the combined effect against ovarian cancer was a synergistic effect, and the CI value for SK-OV-3 was 0.77, indicating that the combined effect against breast cancer was a mild synergistic effect.
  • the CI values for HT1080 and MDA-MB-436 were 0.55 and 0.62, respectively, indicating that the combined effect against fibrosarcoma and breast cancer was a synergistic effect
  • the CI values for HCT116 and NCI-H460 were 0.71 and 0.75, respectively, indicating that the combined effect against colorectal cancer and lung cancer was a mild synergistic effect.
  • the CI values for HT1080, MDA-MB-468, and NCI-H460 were 0.33, 0.57, and 0.68, respectively, indicating that the combined effect against fibrosarcoma, breast cancer, and lung cancer was a synergistic effect, and the CI value for HCT116 was 0.81, indicating that the combined effect against colorectal cancer was a mild synergistic effect.

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Abstract

L'invention concerne une polythérapie pour un agent antitumoral qui présente un effet antitumoral élevé à l'aide d'un dérivé d'acide carboxylique de pyridone.　Un agent antitumoral est caractérisé en ce qu'il est administré en combinaison avec d'autres agents antitumoraux, et comprend, en tant que principe actif, un composé représenté par la formule (1) (dans la formule, la ligne ondulée représente la configuration stérique qui est la configuration R ou la configuration S) ou un sel de celui-ci, les autres agents antitumoraux étant un ou plusieurs types choisis parmi la cytarabine, le vénétoclax, l'azacitidine, le giltéritinib, le birabrésib, le vorinostat, GSK126, MK-8776, AZD7762, rabusertib, le dabrafénib, le vémurafénib, l'olaparib, l'adavosertib, l'alisertib, la décitabine, la midostaurine et AZD5991.
PCT/JP2024/027809 2023-08-04 2024-08-02 Polythérapie pour agent antitumoral WO2025033367A1 (fr)

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