WO2023286823A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2023286823A1
WO2023286823A1 PCT/JP2022/027652 JP2022027652W WO2023286823A1 WO 2023286823 A1 WO2023286823 A1 WO 2023286823A1 JP 2022027652 W JP2022027652 W JP 2022027652W WO 2023286823 A1 WO2023286823 A1 WO 2023286823A1
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inhibitor
serotonin
phenyl
pentan
amine
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PCT/JP2022/027652
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English (en)
Japanese (ja)
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隼人 疋田
徹郎 竹原
賢二 福本
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国立大学法人大阪大学
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Publication of WO2023286823A1 publication Critical patent/WO2023286823A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/436—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 oxygen as a ring hetero atom, e.g. rapamycin
    • 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 pharmaceutical compositions containing LAT1 inhibitors and mTOR inhibitors or serotonin inhibitors.
  • Amino acid transporters are membrane transport proteins that supply cells with the amino acids necessary for many biological reactions. Amino acid transporters are classified based on substrate selectivity. L-type amino acid transporter 1 (LAT1) is expressed at low levels in physiological conditions, but is highly expressed in proliferative cells such as cancers and fetuses. have suggested the importance of LAT1 in cancer biology (Non-Patent Document 1).
  • LAT1 L-type amino acid transporter 1
  • LAT1 inhibitors are assumed to be target diseases for LAT1-expressing tumors including pancreatic cancer, inhibit the uptake of essential amino acids into cancer cells to suppress the growth of cancer cells, side effects that specifically act on cancer cells is expected as a novel anticancer agent with reduced
  • a competitive inhibitor of LAT1 O-[(5-amino-2-phenylbenzoxazol-7-yl)methyl]-3,5-dichloro-L-tyrosine dihydrochloride (Patent Document 1) is biliary tract cancer As a therapeutic agent, and 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine (Patent Document 2), a non-competitive inhibitor of LAT1, as a therapeutic agent for pancreatic cancer, are currently in clinical trials. is.
  • As a competitive inhibitor of LAT1 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (Non-Patent Document 1, etc.) has long been known.
  • serotonin inhibitors various serotonin receptor inhibitors such as serotonin 1 receptor and serotonin 3 receptor, serotonin reuptake inhibitors, etc. are known. It acts on the synaptic serotonin transporter that releases it to inhibit the reuptake of serotonin, and is widely used as an antidepressant.
  • Inhibition of serotonin uptake by the serotonin reuptake inhibitor fluoxetine suppresses Kras-induced formation of pancreatic ductal metaplasia (ADM) and tumor-stromal reaction in vitro/in vivo, leading to the carcinogenic progression of pancreatic ductal adenocarcinoma (PDAC). is known to suppress (Non-Patent Document 2).
  • mTOR mamallian target of rapamycin
  • angiogenesis suppresses tumor growth
  • an antineoplastic agent composition such as a pharmaceutical composition for treating pancreatic cancer containing a LAT1 inhibitor and other drugs such as an mTOR inhibitor
  • Pancreatic cancer is one of the malignant tumors that has been on the rise in recent years. .10-12).
  • a combination of forfirinox and nab-paclitaxel and gemcitabine for unresectable advanced pancreatic cancer has appeared as a new chemotherapy, prolonging life prognosis, but the average survival period still does not exceed 1 year (Conroy T et al. , Eur. J. Cancer, 2016 Apr; 57: 10-12; Von Hoff DD et al., N. Engl. J. Med., 2013 Oct 31; 369(18): 1691-1703) . Therefore, there is a demand for a novel therapeutic agent for pancreatic cancer with a higher therapeutic effect.
  • An object of the present invention is to provide a pharmaceutical composition containing a LAT1 inhibitor and having a higher therapeutic effect as a therapeutic drug for pancreatic cancer.
  • the present invention relates to the following (1) to (50).
  • 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or pharmaceutically acceptable thereof A pharmaceutical composition containing a salt and an mTOR inhibitor or a serotonin inhibitor.
  • 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[ The pharmaceutical composition according to (1) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
  • 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or pharmaceutically acceptable thereof A therapeutic agent for pancreatic cancer containing a salt and an mTOR inhibitor or a serotonin inhibitor for simultaneous or separated administration thereof.
  • 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[ The therapeutic agent for pancreatic cancer according to (8) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
  • the serotonin inhibitor is fluoxetine or sertraline.
  • 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[ 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[4-(trifluoromethyl)phenoxy]pentan-1-amine according to (14) above, which is 2.2.1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
  • kits comprising a first component containing an acceptable salt and (b) a second component containing an mTOR inhibitor or a serotonin inhibitor.
  • 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[ The kit according to (27) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
  • kits comprising (a) a first component containing a LAT1 inhibitor and (b) a second component containing a serotonin inhibitor. (49) Use of a LAT1 inhibitor and a serotonin inhibitor for the manufacture of a therapeutic agent for pancreatic cancer. (50) A method for treating pancreatic cancer, which comprises administering a LAT1 inhibitor and a serotonin inhibitor simultaneously or separately with an interval.
  • a pharmaceutical composition or the like containing a LAT1 inhibitor such as heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof and an mTOR inhibitor or a serotonin inhibitor is provided.
  • FIG. 1 is a graph showing the growth inhibitory effect of compound (1)/fluoxetine combination on various pancreatic cancer cell lines.
  • the vertical axis represents the ratio of the WST assay measured value before the addition of the test compound to 1, and the horizontal axis represents the time [h (hour)] after the addition of the test compound.
  • Fluoxetine also represents fluoxetine. * indicates that there was a significant difference (p ⁇ 0.01 student's T-test) compared to compound (1) alone and fluoxetine alone, and error bars indicate standard errors.
  • FIG. 2-1 is a graph showing the growth inhibitory effect of compound (1)/fluoxetine combination on various pancreatic cancer cell lines. The vertical axis represents the confluency (%) of the target cells, and the horizontal axis represents the time (days) after addition of the test compound.
  • FIG. 2-2 is a bar graph of the confluency at 48 hours in FIG. 2-1. The vertical axis represents the confluency (%) of target cells. Also, FL represents fluoxetine. * indicates that there was a significant difference (p ⁇ 0.01 student's T-test) compared to compound (1) alone and fluoxetine alone, and error bars indicate standard errors.
  • FIG. 3 is a graph showing the effect of combined use of compound (1)/fluoxetine on caspase 3/7 activity of various pancreatic cancer cell lines. The vertical axis represents absorbance. Fluoxetine also represents fluoxetine.
  • FIG. 4 is a graph showing the effect of compound (1)/fluoxetine combination on apoptosis of MIA PaCa-2 cells. The vertical axis represents the percentage of early atopotic cells. Fluoxetine also represents fluoxetine. * indicates that there was a significant difference (p ⁇ 0.01 student's T-test) compared to compound (1) alone and fluoxetine alone, and error bars indicate standard errors.
  • FIG. 4 is a graph showing the effect of compound (1)/fluoxetine combination on apoptosis of MIA PaCa-2 cells. The vertical axis represents the percentage of early atopotic cells. Fluoxetine also represents fluoxetine. * indicates that there was a significant difference (p ⁇ 0.01 student's T-test) compared to compound (1) alone and fluoxetine alone, and error bars indicate standard errors.
  • FIG. 4 is a graph showing the effect of compound (1)/fluoxetine combination on apoptosis of MIA PaCa-2 cells. The vertical axis represents the percentage of early atopotic cells. Fluoxetine also represents
  • FIG. 5 is a graph showing the effect of oral administration of compound (1)/fluoxetine combination to a mouse xenograft model.
  • the vertical axis of the left graph represents tumor volume
  • the vertical axis of the right graph represents tumor weight
  • the horizontal axis of the left graph represents the number of days after administration of the test compound (administration day is Day 1).
  • Fluoxetine represents fluoxetine
  • control represents a control group. * indicates that there was a significant difference (p ⁇ 0.05 student's T-test) compared to the control group. Error bars indicate standard error.
  • FIG. 6-1 is a graph showing the growth inhibitory effect of compound (1)/fluoxetine or sertraline combination on MIA PaCa-2 cells.
  • FIG. 6-2 is a bar graph of the confluency at 48 hours in FIG. 6-1.
  • the vertical axis represents the confluency (%) of MIA PaCa-2 cells.
  • FL represents fluoxetine and Sert represents sertraline. * indicates that there was a significant difference (p ⁇ 0.01 student's T-test) compared to compound (1) alone, and error bars indicate standard errors.
  • FIG. 7 is a graph showing growth inhibitory effects of compound (1)/rapamycin combination on various pancreatic cancer cell lines.
  • the vertical axis represents the ratio of the WST assay measured value before the addition of the test compound to 1, and the horizontal axis represents the time [h (hour)] after the addition of the test compound. Rapa also represents rapamycin. * indicates that there was a significant difference (p ⁇ 0.01 student's T-test) compared to compound (1) alone and rapamycin alone, and error bars indicate standard errors.
  • FIG. 8 is a graph showing growth inhibitory effects of compound (1)/everolimus combination on various pancreatic cancer cell lines.
  • the vertical axis represents the ratio of the WST assay measured value before the addition of the test compound to 1, and the horizontal axis represents the time [h (hour)] after the addition of the test compound.
  • eve represents everolimus.
  • the left side of FIG. 9 is a graph showing the growth inhibitory effect of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (hereinafter referred to as BCH)/everolimus combination on MIA PaCa-2 cells.
  • BCH 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid
  • the vertical axis represents the confluency (%) of the target cells, and the horizontal axis represents the time (hours) after addition of the test compound.
  • the right side of FIG. 9 is a bar graph of the confluency at 72 hours in the left side graph of FIG. The vertical axis represents the confluency (%) of target cells.
  • the left side of FIG. 10 is a graph showing the growth inhibitory effect of BCH/fluoxetine combination on MIA PaCa-2 cells.
  • the vertical axis represents the confluency (%) of the target cells, and the horizontal axis represents the time (hours) after addition of the test compound.
  • the right side of FIG. 10 is a bar graph of the confluency at 72 hours in the left side graph of FIG.
  • the vertical axis represents the confluency (%) of target cells.
  • FL represents fluoxetine.
  • the left side of FIG. 11 is a graph showing the growth inhibitory effect of BCH/sertraline combination on MIA PaCa-2 cells.
  • the vertical axis represents the confluency (%) of the target cells, and the horizontal axis represents the time (hours) after addition of the test compound.
  • the right side of FIG. 11 is a bar graph of the confluency at 72 hours in the left side graph of FIG.
  • the vertical axis represents the confluency (%) of target cells.
  • Sert represents sertraline. ** and *** indicate that there was a significant difference between the two subjects (p ⁇ 0.01 and p ⁇ 0.0001 student's T-test, respectively). Error bars indicate standard error.
  • Pharmaceutically acceptable salts of compound (L) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (L) include inorganic acid salts such as hydrochloride, sulfate, hydrobromide, nitrate and phosphate, acetate, mesylate and succinate. , maleate, fumarate, citrate, and tartrate.
  • Examples of pharmaceutically acceptable metal salts include alkali metal salts such as sodium and potassium salts, magnesium salts, calcium salts, and the like.
  • alkaline earth metal salts such as salts, aluminum salts, zinc salts, etc.
  • pharmaceutically acceptable ammonium salts include salts such as ammonium salts, tetramethylammonium salts
  • Examples of organic amine addition salts include addition salts of morpholine and piperidine, and pharmaceutically acceptable amino acid addition salts include addition salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like.
  • the method for producing compound (L) is known and is not particularly limited. /066574 or the like or a method based thereon.
  • the target compound in each production method can be isolated and purified by purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography.
  • BCH is a compound that has been known for a long time and can be obtained as a commercial product from each company.
  • compound (L) may have stereoisomers, it is used for the production of the pharmaceutical composition, therapeutic agent for pancreatic cancer, pharmaceutical composition for treating pancreatic cancer, kit, kit for treating pancreatic cancer, and therapeutic agent for pancreatic cancer of the present invention. and pancreatic cancer treatment methods can use all possible isomers and mixtures thereof, including these, and the compound (L) of the present invention includes all possible isomers and Mixtures thereof are included.
  • compound (L) when it is desired to obtain a salt of compound (L), when compound (L) is obtained in the form of a salt, it may be purified as it is. It may be dissolved or suspended, and isolated and purified by adding acid or base.
  • Compound (L) and its pharmaceutically acceptable salts may also exist in the form of adducts with water or various solvents. , a pharmaceutical composition for treating pancreatic cancer, a kit, a kit for treating pancreatic cancer, a therapeutic agent for pancreatic cancer, and a method for treating pancreatic cancer, and the compound (L) of the present invention or a pharmaceutically acceptable contained in the salt
  • mTOR inhibitors include agents that directly or indirectly target mTOR or reduce or inhibit the activity/function of mTOR, such as those that bind to mTOR (mammalian target of rapamycin) and inhibit cell proliferation signals. Any of them may be used, but examples include rapamycin, everolimus, temsirolimus, etc., with rapamycin or everolimus being preferred. These may be used alone or in combination.
  • the serotonin inhibitor may be any one as long as it antagonizes each serotonin receptor, inhibits or blocks serotonin reuptake, etc., but serotonin reuptake inhibitors, especially selective serotonin reuptake inhibitors, are preferred. , for example, fluvoxamine, paroxetine, sertraline, escitalopram, milnacipran, fluoxetine, citalopram and the like, preferably fluoxetine or sertraline. These may be used alone or in combination.
  • mTOR inhibitors and serotonin inhibitors may each exist in the form of pharmaceutically acceptable salts or adducts thereof with water or various solvents, and these salts or adducts are also present in the present invention. It can be used for the production of pharmaceutical compositions, therapeutic agents for pancreatic cancer, pharmaceutical compositions for treating pancreatic cancer, kits, kits for treating pancreatic cancer, therapeutic agents for pancreatic cancer, and methods for treating pancreatic cancer.
  • Examples of the pharmaceutically acceptable salt include the salts exemplified as the pharmaceutically acceptable salts of the compound (L).
  • the pharmaceutical composition and kit of the present invention can be used, for example, for treatment of cancer such as pancreatic cancer.
  • a LAT1 inhibitor such as a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor may be used as a single drug (combination drug) or in multiple forms, as long as they are formulated to contain their respective active ingredients. However, combinations of two or more formulations are preferred. These preparations are preferably used in the form of tablets, injections, and the like. When used or administered as a combination of multiple formulations, they may be used or administered simultaneously or separately at intervals.
  • the time may be adjusted according to the characteristics of the combined formulation (time of onset of action, peak of onset of action, etc.), and the interval and the order of use or administration are not particularly limited. is used or administered at intervals of, for example, 5 minutes to 1 month, preferably 5 minutes to 1 week, more preferably 5 minutes to 72 hours, even more preferably 30 minutes to 30 hours.
  • preparations contain, in addition to active ingredients, pharmaceutically acceptable diluents, excipients, disintegrants, lubricants, binders, surfactants, water, physiological saline, vegetable oil solubilizers, etc. It can be prepared by a conventional method using a tonicity agent, a preservative, an antioxidant and the like as appropriate.
  • excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, surfactants such as fatty acid esters, plasticizers such as glycerin, etc. etc. may be used in accordance with conventional methods.
  • water, physiological saline, vegetable oils such as soybean oil, various solvents, solubilizers, tonicity agents, preservatives, antioxidants and the like may be used in a conventional manner.
  • each Dosage and administration frequency vary depending on dosage form, patient age, body weight, symptoms, etc.
  • the LAT1 inhibitor is compound (1) or a pharmaceutically acceptable salt thereof, usually per day, compound (1) or A pharmaceutically acceptable salt thereof and an mTOR agent or serotonin inhibitor are preferably administered at the following dosages, respectively.
  • Compound (1) or a pharmaceutically acceptable salt thereof and an mTOR agent or serotonin inhibitor are administered, for example, at 0.01 to 1000 mg and 0.001 mg per adult, respectively. ⁇ 1000 mg or 0.01-1000 mg, preferably . 0.05 to 500 mg and 0.005 to 500 mg or 0.05 to 500 mg, more preferably 0.1 to 200 mg and 0.01 to 200 mg or 0.1 to 200 mg, usually once or several times a day , administered simultaneously or separately at intervals.
  • Compound (1) or a pharmaceutically acceptable salt thereof and an mTOR agent or serotonin inhibitor are added, for example, in an amount of 0.001 to 1000 mg and 0 mg per adult, respectively. .0001-1000 mg or 0.001-1000 mg, preferably .0001-1000 mg. 0.005 to 500 mg and 0.0005 to 500 mg or 0.005 to 500 mg, more preferably 0.01 to 200 mg and 0.001 to 200 mg or 0.01 to 200 mg, usually once or several times a day , administered simultaneously or separately at intervals.
  • the LAT1 inhibitor is BCH or a pharmaceutically acceptable salt thereof
  • BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor are usually administered at the following doses per day: preferably.
  • BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or serotonin inhibitor are administered, for example, at 0.001-10 g and 0.001-1000 mg per adult, respectively 0.01 to 1000 mg, preferably . 0.005 to 5 g and 0.005 to 500 mg or 0.05 to 500 mg, more preferably 0.01 to 2 g and 0.01 to 200 mg or 0.1 to 200 mg, usually once or several times a day , administered simultaneously or separately at intervals.
  • BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor are added, for example, to 0.0001 to 10 g and 0.0001 to 0.0001 g per adult, respectively. 1000 mg or 0.001-1000 mg, preferably . 0.0005 to 5 g and 0.0005 to 500 mg or 0.005 to 500 mg, more preferably 0.001 to 2 g and 0.001 to 200 mg or 0.01 to 200 mg, usually once or several times a day , administered simultaneously or separately at intervals.
  • each dose and The frequency of administration varies depending on the dosage form, patient age, body weight, symptoms, etc., but when using or administering a combination of the above multiple formulations, it is preferable to prepare and use or administer a single formulation at each dose. .
  • a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor for example, when the LAT1 inhibitor is compound (1) or a pharmaceutically acceptable salt thereof , mTOR agent or serotonin inhibitor in the range of 0.001 to 10000% by weight with respect to compound (1) or a pharmaceutically acceptable salt thereof. More specifically, for example, 0.01 to 100% by weight of rapamycin, 0.001 to 100% by weight of everolimus, 1 to 10000% by weight of fluoxetine, and sertraline relative to compound (1) or a pharmaceutically acceptable salt thereof Each is combined in the range of 1 to 10,000% by weight.
  • the mTOR agent or serotonin inhibitor is combined in the range of 0.00001 to 100% by weight with respect to BCH or a pharmaceutically acceptable salt thereof. More specifically, for example, 0.0001 to 1% by weight of rapamycin, 0.00001 to 1% by weight of everolimus, 0.01 to 100% by weight of fluoxetine, and 0% by weight of sertraline relative to BCH or a pharmaceutically acceptable salt thereof. Each is combined in the range of 0.01 to 100% by weight.
  • a first component containing a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof for example, (a) a first component containing a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof, and (b) an mTOR agent or
  • the second component containing a serotonin inhibitor is separately formulated as described above, prepared as a kit, and using this kit, each component is administered at the same time or at intervals to the same subject. It can also be administered by route or by a different route.
  • the kit is not particularly limited in material, shape, etc., as long as it is a container that does not cause denaturation of the components of the contents due to external temperature or light, elution of chemical components from the container, etc. during storage, for example.
  • a container e.g. vial, bag, etc.
  • contents, the first component and the second component can be administered via separate routes (e.g., tubes, etc.) or the same route. What has is used.
  • kits such as tablets and injections.
  • the method for treating pancreatic cancer of the present invention includes the above-described pharmaceutical composition, therapeutic agent for pancreatic cancer, pharmaceutical composition for treating pancreatic cancer, compound (1) or BCH used in the kit or kit for treating pancreatic cancer, or a pharmaceutical composition thereof. It can be carried out in the same manner as in the method of using or administering a LAT1 inhibitor such as a salt acceptable to , and an mTOR agent or a serotonin inhibitor. That is, a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor are formulated to contain the respective active ingredients, for example, as a single agent or multiple , preferably by administering two or more formulations in combination. When multiple formulations are administered in combination, the formulations can be administered simultaneously or separately at intervals and can be administered using a kit as described above.
  • Cell lines used MIA PaCa-2 cells, mPKC-1 cells and PANC-1 cells
  • Medium Dulbecco's Modified Eagle Medium (DMEM) (high glucose) + 10% fetal calf serum (FCS) + ampicillin
  • Test compounds DMSO (control), compound (1) (5 ⁇ M), fluoxetine (5 ⁇ M or 10 ⁇ M), compound (1) (5 ⁇ M) + fluoxetine (5 ⁇ M or 10 ⁇ M)
  • Test Example 1 48 hours after the addition of the test solution, the 96-well plate was centrifuged at 13,500 rpm for 1 minute to collect the supernatant. Next, the collected supernatant was divided into 96-well plates for reuse, and 25 ⁇ L was added dropwise, and the same amount (25 ⁇ L) of Caspase 3/7 assay solution [Caspase-Glo 3/7 (registered trademark) Assay (Promega # G8090-8093)] was injected with a continuous pipettor and covered with aluminum foil.
  • Caspase 3/7 assay solution [Caspase-Glo 3/7 (registered trademark) Assay (Promega # G8090-8093)] was injected with a continuous pipettor and covered with aluminum foil.
  • Cell line used MIA PaCa-2 cells
  • Test compounds DMSO (control), compound (1) (5 ⁇ M), fluoxetine (5 ⁇ M), compound (1) (5 ⁇ M) + fluoxetine (5 ⁇ M)
  • Cell lines used MIA PaCa-2 cells, mPKC-1 cells, BxPC-3 cells and PANC-1 cells
  • Test compounds DMSO (control), compound (1) (2. 5 ⁇ M or 5 ⁇ M), rapamycin (50 nM or 100 nM), compound (1) (2.5 ⁇ M or 5 ⁇ M) + rapamycin (50 nM or 100 nM)
  • Cell line used MIA PaCa-2 cells
  • Example 2 tablet (everolimus) 1) Everolimus 1g 2) Lactose 79g 3) Corn starch 15 g 4) 44 g of carboxymethylcellulose calcium 5) Magnesium stearate 1 g 1000 tablets total 140 g The entire amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, vacuum dried, and granulated. 14 g of 4) and 1 g of 5) are mixed with the obtained sieved powder and tableted with a tableting machine. 1000 tablets containing 1 mg everolimus per tablet are thus obtained.
  • Example 3 tablet (fluoxetine) 1) Fluoxetine 30 g 2) Lactose 50g 3) Corn starch 15 g 4) 44 g of carboxymethylcellulose calcium 5) Magnesium stearate 1 g 1000 tablets total 140 g The entire amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, vacuum dried, and granulated. 14 g of 4) and 1 g of 5) are mixed with the obtained sieved powder and tableted with a tableting machine. 1000 tablets containing 30 mg of fluoxetine per tablet are thus obtained.
  • Example 4 Tablet (compound (1) and fluoxetine) 1) Compound (1) 30 g 2) Fluoxetine 30 g 3) Lactose 50g 4) Corn starch 15 g 5) Carboxymethyl cellulose calcium 44 g 6) Magnesium stearate 1 g 1000 tablets total 170 g The entire amount of 1), 2), 3) and 4) and 30 g of 5) are kneaded with water, dried in vacuum, and then granulated. 14 g of 5) and 1 g of 6) are mixed with the obtained sieved powder and tableted with a tableting machine. Thus, 1000 tablets containing 30 mg of compound (1) and 30 mg of fluoxetine per tablet are obtained.
  • Example 5 Injection (compound (1)) 1) Compound (1) 1 g 2) Refined soybean oil 100g 3) Purified egg yolk lecithin 12 g 4) 25 g of glycerin for injection 5) Distilled water for injection 860 mL 1000 mL Dissolve 1) in 2) and add 3) and 4). The resulting mixture is kneaded and emulsified to 1000 mL with distilled water for injection. After aseptic filtration of the resulting dispersion using a 0.2 ⁇ m disposable membrane filter, 2 mL of the resulting dispersion is aseptically filled into glass vials to obtain injections (containing 2 mg of compound (1) per vial). .
  • Example 6 Injection (rapamycin) 1) Rapamycin 0.02 g 2) Refined soybean oil 101.98 g 3) Purified egg yolk lecithin 12 g 4) 25 g of glycerin for injection 5) Distilled water for injection 860 mL 1000 mL Dissolve 1) in 2) and add 3) and 4). The resulting mixture is kneaded and emulsified to 1000 mL with distilled water for injection. After sterile filtration of the resulting dispersion using a 0.2 ⁇ m disposable membrane filter, 2 mL of the suspension is aseptically filled into glass vials to obtain injections (each vial contains 0.04 mg of rapamycin).
  • Example 7 Injection (Sertraline) 1) Sertraline 1 g 2) Refined soybean oil 100g 3) Purified egg yolk lecithin 12 g 4) 25 g of glycerin for injection 5) Distilled water for injection 860 mL 1000 mL Dissolve 1) in 2) and add 3) and 4). The resulting mixture is kneaded and emulsified to 1000 mL with distilled water for injection. After aseptic filtration of the resulting dispersion using a 0.2 ⁇ m disposable membrane filter, 2 mL of each is aseptically filled into a glass vial to obtain an injection (containing 2 mg of sertraline per vial).
  • Example 8 Injection (compound (1) and rapamycin) 1) Compound (1) 0.98 g 2) Rapamycin 0.02 g 3) Refined soybean oil 100g 3) Purified egg yolk lecithin 12 g 4) 25 g of glycerin for injection 5) Distilled water for injection 860 mL 1000mL Dissolve 1) and 2) in 3) and add 4) and 5). The resulting mixture is kneaded and emulsified to 1000 mL with distilled water for injection. After aseptic filtration of the resulting dispersion using a 0.2 ⁇ m disposable membrane filter, 2 mL of each glass vial was aseptically filled to give an injection (1.96 mg of compound (1) and 0.96 mg of rapamycin per vial). 04 mg).
  • Example 9 Capsule (compound (1)) 1) Compound (1) 30 mg 2) Micronized cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60mg 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Example 10 Capsules (Everolimus) 1) Everolimus 1 mg 2) Micronized cellulose 20 mg 3) Lactose 38 mg 4) Magnesium stearate 1 mg Total 60mg 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Example 11 capsule (fluoxetine) 1) Fluoxetine 30 mg 2) Micronized cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60mg 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Example 12 Capsule (compound (1) and fluoxetine) 1) Compound (1) 30 mg 2) Fluoxetine 30 mg 3) Micronized cellulose 10 mg 4) Lactose 19 mg 5) Magnesium stearate 1 mg Total 90mg 1), 2), 3), 4) and 5) are mixed and filled into gelatin capsules.
  • Example 13 Injectables (BCH and rapamycin) 1) 9.98 g of BCH 2) Rapamycin 0.02 g 3) Refined soybean oil 100g 3) Purified egg yolk lecithin 12 g 4) 25 g of glycerin for injection 5) Distilled water for injection 851 mL 1000 mL Dissolve 1) and 2) in 3) and add 4) and 5). The resulting mixture is kneaded and emulsified to 1000 mL with distilled water for injection. After sterile filtration of the resulting dispersion using a 0.2 ⁇ m disposable membrane filter, 2 mL of each glass vial was aseptically filled into an injection (each vial containing 19.96 mg of BCH and 0.04 mg of rapamycin). ).
  • Example 14 Injection (BCH and sertraline) 1) 9 g of BCH 2) Sertraline 1 g 3) Refined soybean oil 100g 3) Purified egg yolk lecithin 12 g 4) 25 g of glycerin for injection 5) Distilled water for injection 851 mL 1000mL Dissolve 1) and 2) in 3) and add 4) and 5).
  • the resulting mixture is kneaded and emulsified to 1000 mL with distilled water for injection.
  • 2 mL of the suspension is aseptically filled into a glass vial to obtain an injection (containing 18 mg of BCH and 2 mg of sertraline per vial).
  • a pharmaceutical composition or the like containing a LAT1 inhibitor such as heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof and an mTOR inhibitor or a serotonin inhibitor is provided.

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Abstract

La présente invention concerne une composition pharmaceutique qui contient : un inhibiteur de LAT1, tel que la 5-phényl-5-[4-(trifluorométhyl)phénoxy]pentan-1-amine ou un acide 2-aminobicyclo[2.2.1]heptane-2-carboxylique, ou un sel de qualité pharmaceutique de celui-ci ; et un inhibiteur de mTOR ou un inhibiteur de la sérotonine.
PCT/JP2022/027652 2021-07-15 2022-07-14 Composition pharmaceutique WO2023286823A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014112646A1 (fr) * 2013-01-21 2014-07-24 国立大学法人大阪大学 Composé de phénoxyalkylamine
WO2015173970A1 (fr) * 2014-05-15 2015-11-19 ジェイファーマ株式会社 Composition d'agent anti-tumeur maligne

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014112646A1 (fr) * 2013-01-21 2014-07-24 国立大学法人大阪大学 Composé de phénoxyalkylamine
WO2015173970A1 (fr) * 2014-05-15 2015-11-19 ジェイファーマ株式会社 Composition d'agent anti-tumeur maligne

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHUN SUNG KIM, SEON-HO CHO,HONG SUNG CHUN,SOOK-YOUNG LEE, HITOSHI ENDOU,YOSHIKATSU KANAI , DO KYUNG KIM: "BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells", BIOL. PHARM. BULL, vol. 31, no. 6, 30 June 2008 (2008-06-30), pages 1096 - 10100, XP055634843, DOI: 10.1248/bpb.31.1096 *
SAPONARA ENRICA, VISENTIN MICHELE, BASCHIERI FRANCESCO, SELEZNIK GITTA, MARTINELLI PAOLA, ESPOSITO IRENE, BUSCHMANN JOHANNA, CHEN : "Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas : Serotonin promotes ADM formation", THE JOURNAL OF PATHOLOGY, LONGMAN, HOBOKEN, USA, vol. 246, no. 3, 1 November 2018 (2018-11-01), Hoboken, USA, pages 352 - 365, XP055875155, ISSN: 0022-3417, DOI: 10.1002/path.5147 *

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