WO2020246807A2 - Composition pharmaceutique pour le traitement du cancer, contenant un composé naphtoquinone - Google Patents

Composition pharmaceutique pour le traitement du cancer, contenant un composé naphtoquinone Download PDF

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WO2020246807A2
WO2020246807A2 PCT/KR2020/007223 KR2020007223W WO2020246807A2 WO 2020246807 A2 WO2020246807 A2 WO 2020246807A2 KR 2020007223 W KR2020007223 W KR 2020007223W WO 2020246807 A2 WO2020246807 A2 WO 2020246807A2
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alkyl
heterocyclyl
aryl
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alkyloxy
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WO2020246807A3 (fr
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이휘성
이은주
고인석
윤민혁
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주식회사 엘마이토테라퓨틱스
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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
    • A61K31/41—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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic 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
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/435—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
    • A61K31/44—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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/535—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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition for treating cancer comprising a naphthoquinone compound.
  • Immune anticancer drugs are treatments that help immune cells kill cancer cells by increasing the body's immune response.
  • immune homeostasis is building various defense systems for the purpose of protecting the human body from inside or outside. Proper balance of these immune systems is very important for maintaining good health, and this is called immune homeostasis.
  • Immune action to maintain immune homeostasis can be divided into immune response (immunity), which promotes immunity, and immune tolerance (tolerance), which suppresses excessive increase in immune response. Imbalances in immune homeostasis can be caused by various causes inside and outside the body. When the immune response is stronger than the immune tolerance, that is, when immune cells are excessively activated, inflammatory diseases or autoimmune diseases may occur. Conversely, if the immune tolerance is stronger than the immune response, that is, if the immune system does not function properly, it leads to infectious diseases or diseases such as cancer.
  • immune anticancer drugs are a breakthrough treatment that increases the immune system of our body so that activated immune cells attack cancer cells.
  • Immuno-anticancer drugs attack cancer cells by using the body's immune cells, so there are few side effects, and because of the memory capacity of the immune system, it has the advantage of expecting a continuous therapeutic effect.
  • immune anticancer drugs are a breakthrough treatment that increases the patient's own immunity so that immune cells remove cancer cells, the proportion of patients showing therapeutic effects by this method is not yet high, so various attempts have been made to increase the treatment success rate.
  • Cancer cells as well-known through the Warburg Effect, convert glucose to pyruvate, that is, rapidly generate main energy through glycolysis, and promote their own proliferation, metastasis, and survival. Synthetic intermediates of polymeric materials are obtained, and in this process, a large amount of lactate is produced.
  • NAD + nicotinamide adenine dinucleotide
  • GAPDH glycosyde 3-phosphate dehydrogenase
  • the method of obtaining NAD + in the cytoplasm is through the action of lactate dehydrogenase (LDH), which reduces pyruvate to lactate.
  • LDH acts as a side effect of oxidizing to NAD + by using NADH as a substrate in the process of producing lactate, and the resulting NAD + is used as a substrate of GAPDH, and the corresponding action in cancer cells continues.
  • TBE tumor microenvironment
  • the object of the present invention is to reduce the intra/external lactate concentration by reacting with the NQO1 enzyme in the cell to smoothly supply NAD + to reduce the action of cancer cells to reduce pyruvate to lactate.
  • Another object of the present invention is to use a compound that reacts with NQO1 enzyme in a cell to produce NAD + , or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, tautomer or prodrug thereof.
  • NAD + a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, tautomer or prodrug thereof.
  • the inventors of the present invention invented that a naphthoquinone compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof, reacts with the NQO1 enzyme in the cell to produce NAD + , which is excessively increased during the metabolic process of cancer cells. It was found that the activity of immune cells can be increased by inhibiting the production of excess lactate by the process, thereby reducing the amount of lactate discharged into the tumor microenvironment, and as a result, the activated immune cells can eliminate cancer cells. Completed. Therefore, means for solving the technical problem of the present invention described above are as follows.
  • a pharmaceutical composition for cancer treatment comprising a compound represented by Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, tautomer or prodrug thereof:
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur atoms, and at least two of X 1 , X 2 , X 3 and X 4 are nitrogen, oxygen and sulfur Although it is a hetero atom selected from atoms, X 1 and X 4 cannot be nitrogen atoms at the same time,
  • R 1 is one or more selected from the group consisting of hydrogen, alkyl, alkyloxy, C 6-10 aryl, heteroaryl, halo, nitro, hydroxy, cyano, and -NR 5 R 6 ;
  • R 2 is absent or is selected from the group consisting of hydrogen, oxygen, alkyl, C 1-6 alkyloxy, C 6-10 aryl and heterocyclyl, and the alkyl may be substituted with C 6-10 aryl, wherein Heterocyclyl may be substituted with -C(O)R 8 ;
  • R 3 is absent, hydrogen, oxygen, halo, alkyl, C 1-6 alkyloxy, C 6-10 aryl, heterocyclyl, -SO 2 NR 7 R 12, -NR 9 R 10 and -C(O )R 11 is selected from the group consisting of, and when the alkyl is substituted, the substituents are halo, alkyloxy, C 6-10 aryl, C 6-10 aryloxy, heterocyclyl, -C(O)R 8 , R 12 C(O)O- and -NR 13 R 14 is selected from the group consisting of, and the heterocyclyl may be substituted with -C(O)R 8 ;
  • R 4 is absent or is selected from the group consisting of hydrogen, oxygen, alkyl, alkyloxy, C 6-10 aryl, C 6-10 aryloxy, heterocyclyl and -C(O)R 15 , wherein the alkyl is When substituted, the substituent is selected from the group consisting of halo, C 6-10 aryl, heterocyclyl and -C(O)R 8 , and the heterocyclyl may be substituted with -C(O)R 8 ;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, and -C(O)R 7 , or a heterocyclyl containing at least one nitrogen atom in the ring when R 5 and R 6 are bonded to each other Can be;
  • R 7 and R 12 may each be alkyl, or R 7 and R 12 may be bonded to each other to form a heterocyclyl containing at least one nitrogen atom in the ring;
  • R 11 is heterocyclyl or -NR 13 R 14 ;
  • R 15 is alkyl, alkyloxy, C 6-10 aryloxy, heterocyclyl or -NR 13 R 14 ;
  • R 9 , R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, unsubstituted or halo substituted C 6-10 aryl, and -C(O)R 8 , or R 9 and R 10 may be bonded to each other or R 13 and R 14 may be bonded to each other to form a heterocyclyl including at least one nitrogen atom in each ring;
  • R 8 is alkyloxy
  • Each of the alkyl is a straight or branched alkyl having 1-10 carbon atoms, or a cyclic alkyl having 3-7 carbon atoms
  • the heterocyclyl is a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
  • heteroaryl is a 5 to 10 membered aromatic ring group having at least one hetero atom selected from N, O and S in the ring, and the aryl or heteroaryl When this is substituted, the substituent is each selected at least one from the group consisting of halo, alkyl, halo-substituted alkyl and alkyloxy;
  • R 2 and R 4 are not alkyl, aryl or heterocyclyl, wherein R 2 is alkyl, aryl or For heterocyclyl R 4 is not -C(O)R 15 ;
  • R 2 and R 4 are oxygen or alkyloxy.
  • a pharmaceutical composition for cancer treatment comprising a naphthoquinone compound, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, tautomer or prodrug thereof.
  • Naphthoquinone compounds or their pharmaceutically acceptable salts, hydrates, solvates, enantiomers, diastereomers, tautomers, or prodrugs facilitate the supply of NAD+ through reaction with the NQO1 enzyme, thereby allowing cancer cells to control NAD+. Since the method of obtaining, reducing the action of reducing pyruvate to lactate, reduces the intracellular/external lactate concentration, the pharmaceutical composition for cancer treatment according to the present invention weakens immune tolerance caused by excessive lactate in the tumor microenvironment.
  • 11 to 15 show the measured values of lactate concentration in and outside macrophages for compounds 6, 16, 17, 22 and 27 ( Figures, respectively, from left to right, Untreatment, LPS, LPS+1 ⁇ M compound, LPS+5 ⁇ M Compound, LPS+10 ⁇ M compound).
  • Figure 16 shows the acidity change due to the accumulation of extracellular lactate in macrophages for compounds 6 and 27.
  • 17 is a result of measuring the anticancer effect of compounds 6 and 27 when the tumor size reaches an average volume of 200 mm 3 in colon cancer-induced mice.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • hydrate refers to the form of a compound that does not impair its properties and properties.
  • the "pharmaceutically acceptable salt” is, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., or tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, fluoroacetic acid, glucose Acid addition salts formed by addition of organic acids such as conic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.
  • tartaric acid formic acid, citric acid, acetic acid, trichloroacetic acid, fluoroacetic
  • examples of pharmaceutically acceptable salts of carboxylic acids include metal salts or alkaline earth metal salts formed of lithium, sodium, potassium, calcium, magnesium, etc., lysine, arginine, guanidine, etc. And organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine.
  • the compounds of formula 1 according to the present invention can be converted to their salts by conventional methods.
  • hydrate refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • the solvent for the solvate may be any solvent that is volatile, non-toxic and/or suitable for administration to humans.
  • prodrug refers to a substance convertible in vivo to the compound of formula 1 according to the present invention.
  • Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, while they can obtain physiological activity by oral administration, the parent drug may not.
  • Prodrugs may also have improved solubility in pharmaceutical formulations compared to the parent drug. For example, in prodrugs, water solubility is detrimental to mobility, but once in a cell where water solubility is beneficial, esters that facilitate passage through cell membranes are hydrolyzed to carboxylic acids, which are active by metabolism. It may be in the form of a drug").
  • Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is linked to an acid group that is metabolized to reveal the active site.
  • tautomer is a type of structural isomer that has the same chemical formula or molecular formula but differs in the way the constituent atoms are connected. For example, the structure is reciprocated between both isomers, such as a keto-enol structure. Means to change.
  • enantiomer or "diastereoisomer” is an isomer that has the same chemical formula or molecular formula, but arises as the spatial arrangement of atoms in a molecule is different. Refers to an isomer that does not bear, and also means a stereoisomer that is not an enantiomeric relationship. All of these isomers and mixtures thereof are also included within the scope of the present invention.
  • alkyl refers to an aliphatic hydrocarbon group and includes both “saturated alkyl” and “unsaturated alkyl” having at least one double or triple bond site, and includes straight, branched and cyclic alkyl.
  • alkyl refers to an aliphatic hydrocarbon group, which includes both “saturated alkyl” and “unsaturated alkyl” having at least one double or triple bond site, and straight or branched alkyl having 1-10 carbon atoms and It contains cyclic alkyl of 3-7 carbon atoms.
  • aryl refers to an aromatic ring group having 6-10 carbon atoms
  • heterocyclyl is a 3-7 membered heterocycle having at least one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring Represents a group
  • heteroaryl refers to a 5- to 10-membered heteroaromatic ring group having at least one hetero atom selected from nitrogen (N), oxygen (O) and sulfur (S) in the ring.
  • the compound of Formula 1 may be a compound in which X 1 and X 4 are carbon atoms, and X 2 and X 3 are nitrogen atoms.
  • R 2 in Formula 1 is absent, alkyl, alkyloxy or C 6-10 aryl
  • R 3 is absent, hydrogen, alkyl or C 6-10 aryl
  • R 4 is absent, It is oxygen, alkyl or alkyloxy, but one of R 2 and R 4 is not alkyl or aryl, and when the alkyl or aryl is substituted, the substituents are as defined above.
  • the compound of Formula 1 may be a compound in which X 1 and X 3 are carbon atoms, and X 2 and X 4 are nitrogen atoms.
  • R 2 in Formula 1 is absent or is alkyl
  • R 3 is selected from the group consisting of halo, alkyl, alkyloxy, C 6-10 aryl and heterocyclyl
  • R 4 is absent or hydrogen
  • It may be selected from the group consisting of alkyl, C 6-10 aryl, C 6-10 aryloxy, heterocyclyl and -C(O)R 15 .
  • R 15 and alkyl, aryl, and heterocyclyl are substituted, the substituents are as defined above.
  • the compound of Formula 1 may be a compound in which X 1 and X 3 are carbon atoms, X 2 is a nitrogen atom, and X 4 is a sulfur atom.
  • R 2 and R 4 in Formula 1 do not exist, R 3 is alkyl or C 6-10 aryl, and when the alkyl and aryl are substituted, the substituents are as defined above.
  • the compound of Formula 1 may be a compound in which X 1 and X 3 are carbon atoms, one of X 2 and X 4 is a nitrogen atom, and the other is an oxygen atom.
  • R 2 in Formula 1 is absent
  • R 3 is oxygen, alkyl or C 6-10 aryl
  • R 4 is absent, hydrogen or alkyl, and when the alkyl and aryl are substituted, the substituent is Same as previously defined.
  • the compound of Formula 1 may be a compound in which all of X 2 , X 3 and X 4 are nitrogen atoms.
  • R 2 in Formula 1 is absent, alkyl or heterocyclyl
  • R 3 is absent, or alkyl, C 6-10 aryl, heterocyclyl, -SO 2 R 7 , -NR 9 R 10
  • it is selected from the group consisting of -C(O)R 11 , R 4 may not be present, or may be selected from the group consisting of alkyl, heterocyclyl and -C(O)R 15 .
  • R 7 , R 9 , R 10 , R 11 and R 15 and the alkyl, aryl and heterocyclyl are substituted, the substituents are as defined above.
  • the compound of Formula 1 may be a compound in which X 2 and X 3 are carbon atoms, and X 1 and X 4 are nitrogen atoms.
  • R 2 in Formula 1 is C 6-10 aryl, R 3 and R 4 do not exist, and when the aryl is substituted, the substituents are as defined above.
  • the halo may be any one of fluoro, chloro, bromo, and iodo
  • aryl is preferably phenyl
  • heteroaryl is preferably a hetero atom selected from N, O and S in the ring.
  • a 5- to 10-membered heteroaromatic ring group having one or more examples thereof include pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, and the like, It is not limited thereto.
  • the heterocyclyl is a 3 to 7 membered heteroaliphatic cyclic group having at least one hetero atom selected from N, O and S in the ring, examples of which include aziridinyl, azetidinyl, pyrrolidinyl, piperidine Neil, piperazinyl, morpholinyl, and the like, but are not limited thereto.
  • the naphthoquinone compound of Formula 1 or a pharmaceutically acceptable salt thereof facilitates the supply of NAD + through a reaction with the NQO1 enzyme, thereby lactate pyruvate, which is a method of obtaining NAD + by cancer cells.
  • the pharmaceutical composition for cancer treatment according to the present invention weakens the immune tolerance caused by excessive lactate in the tumor microenvironment, and enhances the immune function. Since the activity of immune cells is increased through the action, and as a result, activated immune cells can remove cancer cells, it can be used as a cancer therapeutic agent, especially as an immune anti-cancer agent, through administration alone or in combination with other immune anti-cancer agents.
  • the cancer may be selected from the group consisting of colorectal cancer, pancreatic cancer, breast cancer, lung cancer, and melanoma, but by facilitating the supply of NAD + through activity against the NQO1 enzyme, cancer cells convert pyruvate into lactate. It reduces the intracellular/external lactate concentration by lowering the reducing action, thereby weakening the immune tolerance caused by excessive lactate in the tumor microenvironment, and increasing the activity of immune cells through the action of enhancing the immune function. Any carcinoma is possible, as long as the activated immune cells remove the cancer cells so that they can exhibit cancer treatment effects.
  • the pharmaceutical composition for cancer treatment according to the present invention may be a compound of Formula 1 as an active ingredient, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer,
  • known drugs used for the prevention or treatment of each disease, known additives commonly used in the present invention, etc. may be additionally included, and other known treatments for the treatment of these diseases It can also be used in combination with.
  • the compound for which the NQO1 enzyme activity is to be measured was dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with DMSO to prepare a concentration of 250 ⁇ M.
  • As the enzyme reaction solution 50 ⁇ L of a 1.54 mM cytochrome C solution was added to 900 ⁇ L of a 50 mM Tris-HCl (pH 7.5) solution containing 0.14% BSA, and a synthetic sample solution having a concentration of 250 ⁇ M was added.
  • the absorbance change was measured for 10 minutes at a wavelength of 550 nm.
  • a change in absorbance was observed for 10 minutes at a wavelength of 550 nm using a 1 mL cuvette.
  • the absorbance value was obtained by observing the increase in absorbance as cytochrome C is reduced for 10 minutes at 550 nm, and the activity for NQO1 is the amount of reduced cytochrome C (nmol reduced cytochrome C/min/ ⁇ g NQO1 protein ).
  • BSA bovine serum albumin
  • Tris-HC Tris(hydroxymethyl)aminomethane hydrochloride (buffer)
  • NQO1 activity compound 5 ⁇ M, nmol reduced cytochrome C/min/ ⁇ g NQO1 protein
  • compound NQO1 2ng compound 5 ⁇ M
  • compound 5 ⁇ M One 180 3 3066 5 2602 6 7706
  • NQO1 activity compound 0.2 ⁇ M, nmol reduced cytochrome C/min/ ⁇ g NQO1 protein
  • compound NQO1 2ng compound 0.2 ⁇ M 2 3531 6 3782 7 2246 8 3768 9 2474 10 3455 11 2839 12 2981 13 2137 16 4441 17 5843 18 4232 19 4303 20 568 21 1426 22 6978 23 456 24 4336 25 1676 27 2269
  • BMDMs Primary bone marrow-derived macrophages isolated from C57BL/6 mice in DMEM medium containing M-CSF (Macrophage colony-stimulating factor; R&D Systems, 416-ML) for 3 to 5 days During incubation.
  • Mouse bone marrow-derived macrophages were collected and analyzed with Abcam's NAD/NADH Assay Kit (ab65348) to measure the degree of NAD + production and the NAD + /NADH ratio. All assays were performed according to the manufacturer's product manual.
  • BMDMs Primary bone marrow-derived macrophages isolated from C57BL/6 mice in DMEM medium containing M-CSF (Macrophage colony-stimulating factor; R&D Systems, 416-ML) for 3 to 5 days During incubation.
  • Mouse bone marrow-derived macrophages were collected and analyzed with Abcam's NAD/NADH Assay Kit (ab65348) to measure the degree of NAD + production and the NAD + /NADH ratio. All assays were performed according to the manufacturer's product manual.
  • a lactate assay kit (Abcam ab65331) was used to measure the lactate concentration outside and within the cells, and all analyzes were performed according to the manufacturer's product manual.
  • Primary bone marrow-derived macrophages (BMDMs) were isolated from C57BL/6 mice, using DMEM medium containing M-CSF (Macrophage colony-stimulating factor; R&D Systems, 416-ML) 3 Incubated for ⁇ 5 days.
  • Mouse bone marrow-derived macrophages were activated with 100 ng/mL LPS in DMEM medium containing 25 FBS, and then the solution portion and cells were separated, respectively, and lactate dehydrogenase was inactivated at -80°C. After mixing the reaction solution and the sample, lactate was measured with a microplate reader (OD450 nm).
  • 11 to 15 show the measured values of lactate concentration in and outside macrophages for compounds 6, 16, 17, 22, and 27 (Fig. Compound, LPS+10 ⁇ M compound).
  • BMDMs Primary bone marrow-derived macrophages isolated from C57BL/6 mice in DMEM medium containing M-CSF (Macrophage colony-stimulating factor; R&D Systems, 416-ML) for 3 to 5 days During incubation.
  • Mouse bone marrow-derived macrophages were measured using Seahorse XF24 Extracellular Flux Analyzer.
  • Figure 16 shows the acidity change due to the accumulation of extracellular lactate in macrophages for compounds 6 and 27.
  • Cancer xenograft mouse model was performed using 4 to 6 week old female nude mice (Central Lab. Animal, Korea) using JM Yuk et.al., Autophagy, 6(1):46-60 (2010) It was prepared according to the method described in. Specifically, HCT116 cells (colorectal carcinoma cell line) suspended to be 1x106 in 0.1 ml of cell medium were injected subcutaneously into mice, and the tumor volume was measured and observed for 7-10 days. Treatment was started when the tumor size reached an average volume of 200 mm 3 and 600 mm 3 , respectively. Tumor volume was using a caliper skin (skin calipers) measured every 3 days, the tumor length (tumor length) ⁇ tumor area 2 (tumor width 2) calculated as 0.5 ⁇ shown in mm 3. All experimental animals were managed in a pathogen-free environment.
  • FIG. 17 shows that after xenografting HCT116 cells into female nude mice, after waiting between 7 and 10 days, mice whose tumor size reached an average of 200 mm 3 were selected, and then compound 6 and compound 27 were respectively added to them on 3 days. This is the result of measuring the volume of the tumor once intraperitoneally (ip, intraperitoneal) for 30 days and each administration.
  • tumor size began to decrease compared to the control group (PBS) from day 6 after administration, and from day 24 in compound 6, tumor size was significantly reduced compared to the control group.
  • FIG. 18 shows that after xenografting HCT116 cells into female nude mice, after waiting between 17 and 21 days, mice whose tumor size reached an average of 600 mm 3 were selected, and then compound 6 and compound 27 were respectively added to them on 3 days. This is the result of measuring the volume of the tumor once intraperitoneally (ip, intraperitoneal) for 24 days and each administration.
  • tumor size began to decrease compared to the control group from the 18th day after administration, and in Compound 6, tumor size significantly decreased compared to the control group from day 21.
  • mice Six-week-old male nude mice (Charles river laboratories, Japan) were used as an orthotopic xenograft tumor model, and all experimental animals were managed in a pathogen-free environment. Specifically, after intravenous injection ( iv , Intravenous) of Bioware Brite A549-Red-Fluc Lung carcinoma cells (Perkinelmer, US) suspended to be 5x10 6 in 0.2 ml of D-PBS (Sigmaaldrich, US) into mice , Observed while measuring ROI (Regions of interest) of the chest for 14 days. Mice with a total flux [p/s (photons/seconds)] reaching 1.0E+06 or more that settled on lung cancer cells were selected as a tumor model, and were evenly distributed to 3 mice by group according to ROI.
  • iv Intravenous
  • D-PBS Sigmaaldrich, US
  • Compound 6 (100 mg/kg) was dispersed in a mixture of DMSO, PEG400 and DW 5:75:20 (v/v%) and administered orally ( po , per os) once a day for 28 days.
  • IVIS Lumina III instrument Perkinelmer, US, Camera: IS1748N7319, Andor, iKON
  • Living Imaging4.5.5 software were used to measure the degree of luminescence of the subject, and through this, the ROI of the chest was measured. I did.
  • the tumor model was first inhaled anesthesia with TerrellTM Isoflurane (Piramal, India), and anesthesia was maintained in the same manner while measuring the degree of luminescence.
  • Luciferin was thawed immediately before administration, administered intraperitoneally at an administration concentration of 150 mg/kg (10 mL/kg), and the degree of luminescence of the test subject 20 minutes after administration was automatically determined by the Radiance unit (P/sec/cm2/sr) according to the luminescence level. Measurement was performed by setting the measurement time in the mode. The measured ROI values were compared with Total Flux [p/s], and the results are shown in Table 4.

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Abstract

La présente invention concerne une composition pharmaceutique pour le traitement du cancer, contenant un composé naphtoquinone ou un sel pharmaceutiquement acceptable, un hydrate, un solvate, un énantiomère, un diastéréoisomère, un tautomère ou un promédicament de celui-ci, la composition augmentant le rapport de NAD+ et de NAD+/NADH par l'intermédiaire d'une activité par rapport à NQO1 in vivo, supprimant la production de lactate produite par glycolyse, qui est excessivement augmenté pendant le traitement métabolique des cellules cancéreuses, de manière à réduire la quantité de lactate devant être libérée dans un microenvironnement tumoral, ce qui améliore l'activité des cellules immunitaires et, par conséquent, permet aux cellules immunitaires activées d'éliminer les cellules cancéreuses, et ainsi la présente invention peut être utilisée dans le traitement du cancer.
PCT/KR2020/007223 2019-06-04 2020-06-03 Composition pharmaceutique pour le traitement du cancer, contenant un composé naphtoquinone WO2020246807A2 (fr)

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