WO2023286823A1 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- inhibitor
- serotonin
- phenyl
- pentan
- amine
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 44
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 192
- 239000003112 inhibitor Substances 0.000 claims abstract description 133
- 229940076279 serotonin Drugs 0.000 claims abstract description 96
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- MPUVBVXDFRDIPT-UHFFFAOYSA-N 2-Amino-2-norbornanecarboxylic acid Chemical compound C1CC2C(N)(C(O)=O)CC1C2 MPUVBVXDFRDIPT-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229940124302 mTOR inhibitor Drugs 0.000 claims abstract description 67
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims abstract description 67
- HXBRLPHQEGOBJT-UHFFFAOYSA-N 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine Chemical compound C=1C=CC=CC=1C(CCCCN)OC1=CC=C(C(F)(F)F)C=C1 HXBRLPHQEGOBJT-UHFFFAOYSA-N 0.000 claims abstract description 41
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- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 36
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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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
- A61K31/435—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- 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
The present invention provides a pharmaceutical composition which contains: an LAT1 inhibitor, such as 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or a 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof; and an mTOR inhibitor or a serotonin inhibitor.
Description
本発明は、ＬＡＴ１阻害剤とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有する医薬組成物等に関する。
The present invention relates to pharmaceutical compositions containing LAT1 inhibitors and mTOR inhibitors or serotonin inhibitors.
腫瘍細胞では、その急速な増殖、上昇した細胞内代謝を保障するために糖やアミノ酸の細胞への取り込みが亢進している。これは、それらの栄養素の細胞への取り込みを担当するトランスポーターの機能活性および発現量の上昇により実現される。
In tumor cells, the uptake of sugars and amino acids into cells is accelerated in order to ensure their rapid proliferation and increased intracellular metabolism. This is achieved through increased functional activity and expression of transporters responsible for the uptake of these nutrients into cells.
アミノ酸トランスポーターは、多くの生体反応に必要なアミノ酸を細胞に供給する膜輸送蛋白質である。アミノ酸トランスポーターは、基質選択性に基づいて分類され、Ｌ型アミノ酸トランスポーター１（ＬＡＴ１）は、生理状態での発現量は低い一方で、癌や胎児等の増殖性細胞で高発現であることから、癌生物学におけるＬＡＴ１の重要性が示唆されている（非特許文献１）。従って、ＬＡＴ１の阻害剤は、膵癌を含むＬＡＴ１高発現腫瘍が対象疾患として想定され、癌細胞への必須アミノ酸取り込みを阻害して癌細胞の増殖を抑制する、癌細胞に特異的に作用する副作用の軽減された新規抗癌剤として期待されている。例えば、ＬＡＴ１の競合阻害剤であるＯ－［（５－アミノ－２－フェニルベンゾオキサゾール－７－イル）メチル］－３，５－ジクロロ－Ｌ－チロシン２塩酸塩（特許文献１）が胆道癌治療薬として、およびＬＡＴ１の非競合阻害剤である５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン（特許文献２）が膵癌治療薬として、それぞれ現在臨床治験中である。また、ＬＡＴ１の競合阻害剤としては、２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸（非特許文献１等）が古くから知られている。
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). Therefore, 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 For example, 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.
一方、セロトニン阻害剤としては、セロトニン１受容体、セロトニン３受容体等の各種セロトニン受容体阻害剤およびセロトニン再取り込み阻害剤等が知られており、これらのうちセロトニン再取り込み阻害剤は、セロトニンを放出するシナプスのセロトニントランスポーターに作用してセロトニンの再取り込みを阻害し、抗うつ薬等として広く使用されている。セロトニン再取り込み阻害剤であるフルオキセチンによるセロトニン取り込み阻害は、ｉｎ ｖｉｔｒｏ／ｉｎ ｖｉｖｏにおいてＫｒａｓ誘導性の膵管上皮化生（ＡＤＭ）形成や腫瘍間質反応を抑制し、膵管腺癌（ＰＤＡＣ）の発癌進展を抑制することが知られている（非特許文献２）。
On the other hand, as 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).
また、ｍＴＯＲ（ｍａｍｍａｌｌｉａｎ Ｔａｒｇｅｔ Ｏｆ Ｒａｐａｍｙｃｉｎ）阻害剤は、主にＧ１期からＳ期の間で細胞周期を停止させることで、免疫抑制作用や腫瘍細胞の増殖を抑制すると考えられており、血管新生を阻害することによっても腫瘍の増殖を抑制する（日腎会誌、２０１３、第５５巻、第２号、ｐ．１１２－１１８）。例えば、ｍＴＯＲ阻害剤であるエベロリムスの膵管腺癌に対する効果が、論じられている（非特許文献３）。また、ＬＡＴ１阻害剤とｍＴＯＲ阻害剤等の他の薬剤とを含む、膵がん治療用医薬組成物等の抗悪性腫瘍剤組成物が開示されている（特許文献３）。
In addition, mTOR (mammallian target of rapamycin) inhibitors are thought to inhibit the growth of tumor cells and immunosuppressive effects by arresting the cell cycle mainly between the G1 and S phases, thus inhibiting angiogenesis. Inhibition also suppresses tumor growth (Journal of Nichirenkai, 2013, Vol. 55, No. 2, pp. 112-118). For example, the effect of everolimus, an mTOR inhibitor, on pancreatic ductal adenocarcinoma has been discussed (Non-Patent Document 3). Also disclosed is 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 (Patent Document 3).
膵癌は、近年増加傾向にある悪性腫瘍の一つであり、悪性腫瘍の中でも予後不良で５年生存率は６％に過ぎない（Ｃｏｎｒｏｙ Ｔら、Ｅｕｒ．Ｊ．Ｃａｎｃｅｒ、２０１６ Ａｐｒ；５７：ｐ．１０－１２）。近年、新規の化学療法として切除不能進行膵癌に対するフォルフィリノックスやｎａｂ－パクリタキセルとゲムシタビンとの併用が登場し、生命予後の延長を認めるが、依然として平均生存期間は１年を超えない（Ｃｏｎｒｏｙ Ｔら、Ｅｕｒ．Ｊ．Ｃａｎｃｅｒ、２０１６ Ａｐｒ；５７：ｐ．１０－１２；Ｖｏｎ Ｈｏｆｆ Ｄ．Ｄ．ら、Ｎ．Ｅｎｇｌ．Ｊ．Ｍｅｄ．、２０１３ Ｏｃｔ ３１；３６９（１８）：ｐ．１６９１－１７０３）。従って、より治療効果の高い新規膵癌治療薬が望まれている。
Pancreatic cancer is one of the malignant tumors that has been on the rise in recent years. .10-12). In recent years, 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.
本発明は、ＬＡＴ１阻害剤を含有する、膵癌治療薬等としてより治療効果の高い医薬組成物等を提供することを目的とする。
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.
本発明は、以下の（１）～（５０）に関する。
The present invention relates to the following (1) to (50).
（１） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有する医薬組成物。
（２） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（１）記載の医薬組成物。
（３） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（１）または（２）記載の医薬組成物。
（４） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（３）記載の医薬組成物。
（５） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（１）または（２）記載の医薬組成物。
（６） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（５）記載の医薬組成物。
（７） 医薬組成物が膵癌治療用医薬組成物である、上記（１）～（６）のいずれかに記載の医薬組成物。
（８） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有し、それらを同時にまたは時間を置いて別々に投与するための膵癌治療剤。
（９） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（８）記載の膵癌治療剤。
（１０） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（８）または（９）記載の膵癌治療剤。
（１１） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（１０）記載の膵癌治療剤。
（１２） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（８）または（９）記載の膵癌治療剤。
（１３） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（１２）記載の膵癌治療剤。
（１４） ｍＴＯＲ阻害剤またはセロトニン阻害剤と同時にまたは時間を置いて別々に投与する膵癌治療における使用のための５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１５） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（１４）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１６） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（１４）または（１５）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１７） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（１６）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１８） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（１４）または（１５）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１９） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（１８）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（２０） ｍＴＯＲ阻害剤またはセロトニン阻害剤と同時にまたは時間を置いて別々に投与するための、５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩を有効成分として含有する医薬組成物。
（２１） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（２０）記載の医薬組成物。
（２２） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（２０）または（２１）記載の医薬組成物。
（２３） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（２２）記載の医薬組成物。
（２４） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（２０）または（２１）記載の医薬組成物。
（２５） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（２４）記載の医薬組成物。
（２６） 医薬組成物が、膵癌治療用医薬組成物である、上記（２０）～（２５）のいずれかに記載の医薬組成物。
（２７） （ａ）５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩を含有する第１成分と（ｂ）ｍＴＯＲ阻害剤またはセロトニン阻害剤を含有する第２成分とを有することを特徴とするキット。
（２８） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（２７）記載のキット。
（２９） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（２７）または（２８）記載のキット。
（３０） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（２９）記載のキット。
（３１） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（２７）または（２８）記載のキット。
（３２） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（３１）記載のキット。
（３３） キットが膵癌治療用キットである上記（２７）～（３２）のいずれかに記載のキット。
（３４） 膵癌治療剤の製造のための５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤との使用。
（３５） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（３４）記載の使用。
（３６） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（３４）または（３５）記載の使用。
（３７） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（３６）記載の使用。
（３８） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（３４）または（３５）記載の使用。
（３９） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（３８）記載の使用。
（４０） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを同時にまたは時間を置いて別々に投与することを特徴とする、膵癌の治療方法。
（４１） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（４０）記載の治療方法。
（４２） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（４０）または（４１）記載の治療方法。
（４３） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（４２）記載の治療方法。
（４４） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（４０）または（４１）記載の治療方法。
（４５） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（４４）記載の治療方法。
（４６） ＬＡＴ１阻害剤とセロトニン阻害剤とを含有する医薬組成物。
（４７） ＬＡＴ１阻害剤とセロトニン阻害剤とを含有し、それらを同時にまたは時間を置いて別々に投与するための膵癌治療剤。
（４８） （ａ）ＬＡＴ１阻害剤を含有する第１成分と（ｂ）セロトニン阻害剤を含有する第２成分とを有することを特徴とするキット。
（４９） 膵癌治療剤の製造のためのＬＡＴ１阻害剤とセロトニン阻害剤との使用。
（５０） ＬＡＴ１阻害剤とセロトニン阻害剤とを同時にまたは時間を置いて別々に投与することを特徴とする、膵癌の治療方法。 (1) 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.
(2) 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.
(3) The pharmaceutical composition according to (1) or (2) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(4) The pharmaceutical composition according to (3) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(5) The pharmaceutical composition according to (1) or (2) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(6) The pharmaceutical composition according to (5) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(7) The pharmaceutical composition according to any one of (1) to (6) above, which is a pharmaceutical composition for treating pancreatic cancer.
(8) 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.
(9) 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.
(10) The therapeutic agent for pancreatic cancer according to (8) or (9) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(11) The therapeutic agent for pancreatic cancer according to (10) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(12) The therapeutic agent for pancreatic cancer according to (8) or (9) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(13) The therapeutic agent for pancreatic cancer according to (12) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(14) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(15) 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.
(16) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2 according to (14) or (15) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor - aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(17) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(18) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2 according to (14) or (15) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor - aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(19) The 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(20) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo for administration simultaneously or separately with mTOR inhibitors or serotonin inhibitors [2.2.1] A pharmaceutical composition containing heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
(21) 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 (20) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
(22) The pharmaceutical composition according to (20) or (21) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(23) The pharmaceutical composition according to (22) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(24) The pharmaceutical composition according to (20) or (21) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(25) The pharmaceutical composition according to (24) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(26) The pharmaceutical composition according to any one of (20) to (25) above, which is a pharmaceutical composition for treating pancreatic cancer.
(27) (a) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or its pharmaceutically A kit comprising a first component containing an acceptable salt and (b) a second component containing an mTOR inhibitor or a serotonin inhibitor.
(28) 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.
(29) The kit according to (27) or (28) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(30) The kit according to (29) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(31) The kit according to (27) or (28) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(32) The kit according to (31) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(33) The kit according to any one of (27) to (32) above, which is a pancreatic cancer treatment kit.
(34) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid for the manufacture of therapeutic agent for pancreatic cancer or use of a pharmaceutically acceptable salt thereof with an mTOR inhibitor or a serotonin inhibitor.
(35) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[ The use according to (34) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
(36) The use according to (34) or (35) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(37) The use according to (36) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(38) The use according to (34) or (35) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(39) The use according to (38) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(40) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or its pharmaceutically acceptable A method of treating pancreatic cancer, which comprises administering a salt and an mTOR inhibitor or a serotonin inhibitor simultaneously or separately at intervals.
(41) 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 method according to (40) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
(42) The therapeutic method described in (40) or (41) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(43) The therapeutic method according to (42) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(44) The therapeutic method according to (40) or (41) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(45) The therapeutic method according to (44) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(46) A pharmaceutical composition containing a LAT1 inhibitor and a serotonin inhibitor.
(47) A therapeutic agent for pancreatic cancer containing a LAT1 inhibitor and a serotonin inhibitor, which are administered simultaneously or separately at intervals.
(48) A kit 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.
（２） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（１）記載の医薬組成物。
（３） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（１）または（２）記載の医薬組成物。
（４） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（３）記載の医薬組成物。
（５） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（１）または（２）記載の医薬組成物。
（６） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（５）記載の医薬組成物。
（７） 医薬組成物が膵癌治療用医薬組成物である、上記（１）～（６）のいずれかに記載の医薬組成物。
（８） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有し、それらを同時にまたは時間を置いて別々に投与するための膵癌治療剤。
（９） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（８）記載の膵癌治療剤。
（１０） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（８）または（９）記載の膵癌治療剤。
（１１） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（１０）記載の膵癌治療剤。
（１２） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（８）または（９）記載の膵癌治療剤。
（１３） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（１２）記載の膵癌治療剤。
（１４） ｍＴＯＲ阻害剤またはセロトニン阻害剤と同時にまたは時間を置いて別々に投与する膵癌治療における使用のための５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１５） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（１４）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１６） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（１４）または（１５）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１７） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（１６）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１８） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（１４）または（１５）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（１９） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（１８）記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。
（２０） ｍＴＯＲ阻害剤またはセロトニン阻害剤と同時にまたは時間を置いて別々に投与するための、５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩を有効成分として含有する医薬組成物。
（２１） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（２０）記載の医薬組成物。
（２２） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（２０）または（２１）記載の医薬組成物。
（２３） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（２２）記載の医薬組成物。
（２４） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（２０）または（２１）記載の医薬組成物。
（２５） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（２４）記載の医薬組成物。
（２６） 医薬組成物が、膵癌治療用医薬組成物である、上記（２０）～（２５）のいずれかに記載の医薬組成物。
（２７） （ａ）５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩を含有する第１成分と（ｂ）ｍＴＯＲ阻害剤またはセロトニン阻害剤を含有する第２成分とを有することを特徴とするキット。
（２８） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（２７）記載のキット。
（２９） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（２７）または（２８）記載のキット。
（３０） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（２９）記載のキット。
（３１） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（２７）または（２８）記載のキット。
（３２） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（３１）記載のキット。
（３３） キットが膵癌治療用キットである上記（２７）～（３２）のいずれかに記載のキット。
（３４） 膵癌治療剤の製造のための５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤との使用。
（３５） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（３４）記載の使用。
（３６） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（３４）または（３５）記載の使用。
（３７） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（３６）記載の使用。
（３８） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（３４）または（３５）記載の使用。
（３９） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（３８）記載の使用。
（４０） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを同時にまたは時間を置いて別々に投与することを特徴とする、膵癌の治療方法。
（４１） ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、上記（４０）記載の治療方法。
（４２） ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、上記（４０）または（４１）記載の治療方法。
（４３） ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、上記（４２）記載の治療方法。
（４４） ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、上記（４０）または（４１）記載の治療方法。
（４５） セロトニン阻害剤がフルオキセチンまたはセルトラリンである、上記（４４）記載の治療方法。
（４６） ＬＡＴ１阻害剤とセロトニン阻害剤とを含有する医薬組成物。
（４７） ＬＡＴ１阻害剤とセロトニン阻害剤とを含有し、それらを同時にまたは時間を置いて別々に投与するための膵癌治療剤。
（４８） （ａ）ＬＡＴ１阻害剤を含有する第１成分と（ｂ）セロトニン阻害剤を含有する第２成分とを有することを特徴とするキット。
（４９） 膵癌治療剤の製造のためのＬＡＴ１阻害剤とセロトニン阻害剤との使用。
（５０） ＬＡＴ１阻害剤とセロトニン阻害剤とを同時にまたは時間を置いて別々に投与することを特徴とする、膵癌の治療方法。 (1) 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.
(2) 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.
(3) The pharmaceutical composition according to (1) or (2) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(4) The pharmaceutical composition according to (3) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(5) The pharmaceutical composition according to (1) or (2) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(6) The pharmaceutical composition according to (5) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(7) The pharmaceutical composition according to any one of (1) to (6) above, which is a pharmaceutical composition for treating pancreatic cancer.
(8) 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.
(9) 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.
(10) The therapeutic agent for pancreatic cancer according to (8) or (9) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(11) The therapeutic agent for pancreatic cancer according to (10) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(12) The therapeutic agent for pancreatic cancer according to (8) or (9) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(13) The therapeutic agent for pancreatic cancer according to (12) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(14) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(15) 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.
(16) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2 according to (14) or (15) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor - aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(17) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(18) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2 according to (14) or (15) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor - aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(19) The 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
(20) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo for administration simultaneously or separately with mTOR inhibitors or serotonin inhibitors [2.2.1] A pharmaceutical composition containing heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
(21) 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 (20) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
(22) The pharmaceutical composition according to (20) or (21) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(23) The pharmaceutical composition according to (22) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(24) The pharmaceutical composition according to (20) or (21) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(25) The pharmaceutical composition according to (24) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(26) The pharmaceutical composition according to any one of (20) to (25) above, which is a pharmaceutical composition for treating pancreatic cancer.
(27) (a) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or its pharmaceutically A kit comprising a first component containing an acceptable salt and (b) a second component containing an mTOR inhibitor or a serotonin inhibitor.
(28) 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.
(29) The kit according to (27) or (28) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(30) The kit according to (29) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(31) The kit according to (27) or (28) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(32) The kit according to (31) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(33) The kit according to any one of (27) to (32) above, which is a pancreatic cancer treatment kit.
(34) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid for the manufacture of therapeutic agent for pancreatic cancer or use of a pharmaceutically acceptable salt thereof with an mTOR inhibitor or a serotonin inhibitor.
(35) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[ The use according to (34) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
(36) The use according to (34) or (35) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(37) The use according to (36) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(38) The use according to (34) or (35) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(39) The use according to (38) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(40) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or its pharmaceutically acceptable A method of treating pancreatic cancer, which comprises administering a salt and an mTOR inhibitor or a serotonin inhibitor simultaneously or separately at intervals.
(41) 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 method according to (40) above, which is 4-(trifluoromethyl)phenoxy]pentan-1-amine.
(42) The therapeutic method described in (40) or (41) above, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
(43) The therapeutic method according to (42) above, wherein the mTOR inhibitor is rapamycin or everolimus.
(44) The therapeutic method according to (40) or (41) above, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
(45) The therapeutic method according to (44) above, wherein the serotonin inhibitor is fluoxetine or sertraline.
(46) A pharmaceutical composition containing a LAT1 inhibitor and a serotonin inhibitor.
(47) A therapeutic agent for pancreatic cancer containing a LAT1 inhibitor and a serotonin inhibitor, which are administered simultaneously or separately at intervals.
(48) A kit 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.
本発明により、膵癌治療剤等としてより治療効果の高いことが期待できる、５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有する医薬組成物等が提供される。
According to the present invention, 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] 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.
ＬＡＴ１阻害剤としては、ＬＡＴ１および／またはＬＡＴ１遺伝子を阻害し、ＬＡＴ１の活性／機能を低減若しくは阻害する薬剤であれば、ＬＡＴ１の競合阻害剤、非競合阻害剤等を含め、いずれでもよいが、５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン（以下、化合物（１）という）、２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸（以下、ＢＣＨという）、Ｏ－［（５－アミノ－２－フェニルベンゾオキサゾール－７－イル）メチル］－３，５－ジクロロ－Ｌ－チロシン（以下、化合物（２）という）（以下、これらをまとめて化合物（Ｌ）という）またはそれらの薬学的に許容される塩等があげられ、化合物（１）若しくはＢＣＨまたはそれらの薬学的に許容される塩がより好ましく、化合物（１）またはその薬学的に許容される塩がさらに好ましい。これらは、単独でも組み合わされていてもよい。
As the LAT1 inhibitor, any drug that inhibits LAT1 and / or LAT1 gene and reduces or inhibits the activity / function of LAT1, including a competitive inhibitor of LAT1, a non-competitive inhibitor, etc., 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine (hereinafter referred to as compound (1)), 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (hereinafter , referred to as BCH), O-[(5-amino-2-phenylbenzoxazol-7-yl)methyl]-3,5-dichloro-L-tyrosine (hereinafter referred to as compound (2)) (hereinafter collectively referred to as (hereinafter referred to as compound (L)) or a pharmaceutically acceptable salt thereof, more preferably compound (1) or BCH or a pharmaceutically acceptable salt thereof, and compound (1) or a pharmaceutically acceptable salt thereof. are more preferred. These may be used alone or in combination.
化合物（Ｌ）の薬学的に許容される塩は、薬学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等を包含する。
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.
化合物（Ｌ）の薬学的に許容される酸付加塩としては、塩酸塩、硫酸塩、臭化水素酸塩、硝酸塩、リン酸塩等の無機酸塩、酢酸塩、メシル酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、酒石酸塩等の有機酸塩があげられ、薬学的に許容される金属塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等があげられ、薬学的に許容されるアンモニウム塩としては、アンモニウム塩、テトラメチルアンモニウム塩等の塩があげられ、薬学的に許容される有機アミン付加塩としては、モルホリン、ピペリジン等の付加塩があげられ、薬学的に許容されるアミノ酸付加塩としては、グリシン、フェニルアラニン、リジン、アスパラギン酸、グルタミン酸等の付加塩があげられる。
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.
次に、化合物（Ｌ）の製造方法について説明する。
Next, the method for producing compound (L) will be described.
化合物（Ｌ）の製造方法は、公知であり、特に限定されないが、例えば化合物（１）については、ＷＯ２０１４／１１２６４６等に記載の方法またはそれらに準じた方法により、化合物（２）については、ＷＯ２００３／０６６５７４等に記載の方法またはそれらに準じた方法により、それぞれ製造することができる。各製造法における目的化合物は、有機合成化学で常用される精製法、例えば濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して単離精製することができる。また、ＢＣＨについては、古くから知られている化合物であり、各社からの市販品として入手することもできる。
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. Also, BCH is a compound that has been known for a long time and can be obtained as a commercial product from each company.
化合物（Ｌ）には、立体異性体が存在し得るが、本発明の医薬組成物、膵癌治療剤、膵癌治療用医薬組成物、キット、膵癌治療用キット、膵癌治療剤の製造のための使用および膵癌の治療方法には、これらを含め、全ての可能な異性体およびそれらの混合物を使用することができ、本発明の化合物（Ｌ）には、これらを含め、全ての可能な異性体およびそれらの混合物が包含される。
Although 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.
化合物（Ｌ）の塩を取得したいとき、化合物（Ｌ）が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物（Ｌ）を適当な溶媒に溶解または懸濁し、酸または塩基を加えて単離、精製すればよい。
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.
また、化合物（Ｌ）およびその薬学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明の医薬組成物、膵癌治療剤、膵癌治療用医薬組成物、キット、膵癌治療用キット、膵癌治療剤の製造のための使用および膵癌の治療方法に使用することができ、本発明の化合物（Ｌ）またはその薬学的に許容される塩に包含される。
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阻害剤としては、ｍＴＯＲ（哺乳類ラパマイシン標的蛋白質）に結合し、細胞増殖シグナルを阻害するもの等、ｍＴＯＲを直接的若しくは間接的に標的にする、またはｍＴＯＲの活性／機能を低減若しくは阻害する薬剤であればいずれでもよいが、ラパマイシン、エベロリムス、テムシロリムス等があげられ、ラパマイシンまたはエベロリムスが好ましい。これらは、単独でも組み合わされていてもよい。
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.
セロトニン阻害剤としては、セロトニン各受容体に拮抗するもの、セロトニンの再取り込みを阻害または遮断するもの等であればいずれでもよいが、セロトニン再取り込み阻害剤、中でも選択的セロトニン再取り込み阻害剤が好ましく、例えばフルボキサミン、パロキセチン、セルトラリン、エスシタロプラム、ミルナシプラン、フルオキセチン、シタロプラム等があげられ、フルオキセチンまたはセルトラリンが好ましい。これらは、単独でも組み合わされていてもよい。
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.
これらのｍＴＯＲ阻害剤およびセロトニン阻害剤は、それぞれ薬学的に許容される塩またはそれらの水または各種溶媒との付加物の形として存在することもあるが、これらの塩または付加物も本発明の医薬組成物、膵癌治療剤、膵癌治療用医薬組成物、キット、膵癌治療用キット、膵癌治療剤の製造のための使用および膵癌の治療方法に使用することができる。
These 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.
薬学的に許容される塩としては、前記化合物（Ｌ）の薬学的に許容される塩として例示した塩等があげられる。
Examples of the pharmaceutically acceptable salt include the salts exemplified as the pharmaceutically acceptable salts of the compound (L).
本発明の医薬組成物およびキットは、例えば膵癌等の癌等の治療等に使用することができる。
The pharmaceutical composition and kit of the present invention can be used, for example, for treatment of cancer such as pancreatic cancer.
本発明の医薬組成物、膵癌治療剤、膵癌治療用医薬組成物、キット、膵癌治療用キット、膵癌治療剤の製造のための使用および膵癌の治療方法で使用される化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤とは、これらそれぞれの有効成分を含有するように製剤化したものであれば、単剤（合剤）としてでも複数の製剤の組合せとしてでも使用または投与することができるが、中でも２つ以上の製剤の組合せが好ましい。また、これら製剤は、例えば錠剤、注射剤等の形態として用いることが好ましい。複数の製剤の組合せとして使用または投与する際には、これらは同時にまたは時間を置いて別々に使用または投与することができる。時間を置いて別々に使用または投与する際には、組み合わせる製剤の特性（作用発現時間、作用発現ピーク等）に合わせて時間を置けばよく、その間隔、および使用または投与の順番は特に限定されないが、例えば５分間～１ヶ月間、好ましくは５分間～１週間、より好ましくは５分間～７２時間、さらに好ましくは３０分間～３０時間の間隔を置いて使用または投与される。
Compound (1) or BCH used in the pharmaceutical composition, therapeutic agent for pancreatic cancer, pharmaceutical composition for treating pancreatic cancer, kit, kit for treating pancreatic cancer, therapeutic agent for pancreatic cancer, and method for treating pancreatic cancer of the present invention, or 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. When using or administering 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.
これら製剤は、それぞれ有効成分の他に製剤学的に許容される希釈剤、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、水、生理食塩水、植物油可溶化剤、等張化剤、保存剤、抗酸化剤等を適宜用いて常法により作成することができる。
錠剤の調製にあたっては、例えば乳糖等の賦形剤、澱粉等の崩壊剤、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤等を常法に従って用いればよい。
注射剤の調製にあたっては、水、生理食塩水、大豆油等の植物油、各種の溶剤、可溶化剤、等張化剤、保存剤、抗酸化剤等を常法に従って用いればよい。 These 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.
In preparing tablets, for example, 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.
In the preparation of injections, 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.
錠剤の調製にあたっては、例えば乳糖等の賦形剤、澱粉等の崩壊剤、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤等を常法に従って用いればよい。
注射剤の調製にあたっては、水、生理食塩水、大豆油等の植物油、各種の溶剤、可溶化剤、等張化剤、保存剤、抗酸化剤等を常法に従って用いればよい。 These 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.
In preparing tablets, for example, 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.
In the preparation of injections, 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.
上記の目的で、化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤とを複数の製剤の組合せとして使用または投与する場合には、それぞれの用量および投与回数は投与形態、患者の年齢、体重、症状等により異なるが、例えばＬＡＴ１阻害剤が化合物（１）またはその薬学的に許容される塩の場合、通常一日当たり、化合物（１）またはその薬学的に許容される塩とｍＴＯＲ剤またはセロトニン阻害剤とを、それぞれ以下の用量で投与するのが好ましい。
For the above purposes, when using or administering a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or serotonin inhibitor as a combination of multiple formulations, each Dosage and administration frequency vary depending on dosage form, patient age, body weight, symptoms, etc. For example, when 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.
経口的に、例えば錠剤として投与する場合、化合物（１）またはその薬学的に許容される塩とｍＴＯＲ剤またはセロトニン阻害剤とを、例えば、成人一人当たり、それぞれ０．０１～１０００ｍｇと０．００１～１０００ｍｇまたは０．０１～１０００ｍｇ、好ましくは．０．０５～５００ｍｇと０．００５～５００ｍｇまたは０．０５～５００ｍｇ、さらに好ましくは０．１～２００ｍｇと０．０１～２００ｍｇまたは０．１～２００ｍｇ、通常一日一回ないし数回にわけて、同時にまたは時間を置いて別々に投与する。
When administered orally, for example, as a tablet, 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.
非経口的に、例えば注射剤として投与する場合、化合物（１）またはその薬学的に許容される塩とｍＴＯＲ剤またはセロトニン阻害剤とを、例えば、成人一人当たり、それぞれ０．００１～１０００ｍｇと０．０００１～１０００ｍｇまたは０．００１～１０００ｍｇ、好ましくは．０．００５～５００ｍｇと０．０００５～５００ｍｇまたは０．００５～５００ｍｇ、さらに好ましくは０．０１～２００ｍｇと０．００１～２００ｍｇまたは０．０１～２００ｍｇ、通常一日一回ないし数回にわけて、同時にまたは時間を置いて別々に投与する。
When administered parenterally, for example, as an injection, 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.
また、例えばＬＡＴ１阻害剤がＢＣＨまたはその薬学的に許容される塩の場合、通常一日当たり、ＢＣＨまたはその薬学的に許容される塩とｍＴＯＲ剤またはセロトニン阻害剤とを、それぞれ以下の用量で投与するのが好ましい。
Further, for example, when 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.
経口的に、例えば錠剤として投与する場合、ＢＣＨまたはその薬学的に許容される塩とｍＴＯＲ剤またはセロトニン阻害剤とを、例えば、成人一人当たり、それぞれ０．００１～１０ｇと０．００１～１０００ｍｇまたは０．０１～１０００ｍｇ、好ましくは．０．００５～５ｇと０．００５～５００ｍｇまたは０．０５～５００ｍｇ、さらに好ましくは０．０１～２ｇと０．０１～２００ｍｇまたは０．１～２００ｍｇ、通常一日一回ないし数回にわけて、同時にまたは時間を置いて別々に投与する。
When administered orally, for example, as a tablet, 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.
非経口的に、例えば注射剤として投与する場合、ＢＣＨまたはその薬学的に許容される塩とｍＴＯＲ剤またはセロトニン阻害剤とを、例えば、成人一人当たり、それぞれ０．０００１～１０ｇと０．０００１～１０００ｍｇまたは０．００１～１０００ｍｇ、好ましくは．０．０００５～５ｇと０．０００５～５００ｍｇまたは０．００５～５００ｍｇ、さらに好ましくは０．００１～２ｇと０．００１～２００ｍｇまたは０．０１～２００ｍｇ、通常一日一回ないし数回にわけて、同時にまたは時間を置いて別々に投与する。
When administered parenterally, for example, as an injection, 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.
また上記の目的で、化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤とを単剤として使用または投与する場合には、それぞれの用量および投与回数は投与形態、患者の年齢、体重、症状等により異なるが、上記の複数の製剤の組合せとして使用または投与する場合のそれぞれの用量で１つの製剤として調製し、使用または投与するのが好ましい。
For the above purposes, when using or administering a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or serotonin inhibitor as a single agent, 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. .
化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤とは、例えばＬＡＴ１阻害剤が化合物（１）またはその薬学的に許容される塩の場合、化合物（１）またはその薬学的に許容される塩に対しｍＴＯＲ剤またはセロトニン阻害剤０．００１～１００００重量％の範囲で組み合わされる。より具体的には、例えば、化合物（１）またはその薬学的に許容される塩に対し、ラパマイシン０．０１～１００重量％、エベロリムス０．００１～１００重量％、フルオキセチン１～１００００重量％、セルトラリン１～１００００重量％の範囲でそれぞれ組み合わされる。ＬＡＴ１阻害剤がＢＣＨまたはその薬学的に許容される塩の場合、ＢＣＨまたはその薬学的に許容される塩に対しｍＴＯＲ剤またはセロトニン阻害剤０．００００１～１００重量％の範囲で組み合わされる。より具体的には、例えば、ＢＣＨまたはその薬学的に許容される塩に対し、ラパマイシン０．０００１～１重量％、エベロリムス０．００００１～１重量％、フルオキセチン０．０１～１００重量％、セルトラリン０．０１～１００重量％の範囲でそれぞれ組み合わされる。
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. When the LAT1 inhibitor is BCH or a pharmaceutically acceptable salt thereof, 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.
複数の製剤の組合せとして投与する際には、例えば（ａ）化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤を含有する第１成分と、（ｂ）ｍＴＯＲ剤またはセロトニン阻害剤を含有する第２成分とを、それぞれ上記のように別途製剤化し、キットとして作成しておき、このキットを用いてそれぞれの成分を同時にまたは時間を置いて、同一対象に対して同一経路または異なった経路で投与することもできる。
When administered as a combination of multiple formulations, 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.
該キットは、例えば保存する際に外部の温度や光による内容物である成分の変性、容器からの化学成分の溶出等がみられない容器であれば材質、形状等は特に限定されない２つ以上の容器（例えばバイアル、バッグ等）と内容物とからなり、内容物である上記第１成分と第２成分とが別々の経路（例えばチューブ等）または同一の経路を介して投与可能な形態を有するものが用いられる。具体的には、錠剤、注射剤等のキットがあげられる。
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. Two or more A container (e.g. vial, bag, etc.) and contents, and the 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. Specific examples include kits such as tablets and injections.
また、本発明の膵癌の治療方法は、上記で記載した医薬組成物、膵癌治療剤、膵癌治療用医薬組成物、キットまたは膵癌治療用キットで使用される化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤との使用または投与方法と同様にして実施できる。すなわち、化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤とを、それぞれの有効成分を含有するように製剤化し、例えば単剤としてまたは複数の製剤の組合せとして、好ましくは２つ以上の製剤を組み合わせて投与することにより実施できる。複数の製剤を組み合わせて投与する際には、これら製剤は、同時にまたは時間を置いて別々に投与することができ、上記で記載したようなキットを用いて投与することもできる。
In addition, 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.
次に、化合物（１）若しくはＢＣＨまたはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ剤またはセロトニン阻害剤とを併用投与することによる効果について試験例により具体的に説明する。
なお、以下の試験例では、各試験化合物として、特に断りのない限り、以下のものを使用した。
・化合物（１）：自製
・フルオキセチン：フルオキセチン塩酸塩（Ｓｅｌｌｅｋ ｃｈｅｍ社；Ｃａｔａｌｏｇ Ｎｏ．Ｓ１３３３）
・セルトラリン：セルトラリン塩酸塩 ≧９８％（ＨＰＬＣ）（Ｓｉｇｍａ社；Ｃａｔａｌｏｇ Ｎｏ．Ｓ６３１９）
・ラパマイシン：ラパマイシン ≧９５％（ＨＰＬＣ）（Ｓｉｇｍａ社；Ｃａｔａｌｏｇ Ｎｏ．Ｒ０３９５）
・エベロリムス：エベロリムス ≧９８％（Ｃａｙｍａｎ ｃｈｅｍｉｃａｌ社；Ｃａｔａｌｏｇ Ｎｏ．１１５９７）
・ＢＣＨ（２－アミノビシクロ－（２．２．１）－ヘプタン－２－カルボン酸）：（Ｓｅｌｌｅｋ ｃｈｅｍ社；Ｃａｔａｌｏｇ Ｎｏ．Ｓ６８９４） Next, the effects of combined administration of a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor will be specifically described using test examples.
In addition, in the following test examples, the following compounds were used as test compounds unless otherwise specified.
- Compound (1): Self-produced - Fluoxetine: Fluoxetine hydrochloride (Sellek chem; Catalog No. S1333)
- Sertraline: sertraline hydrochloride ≥ 98% (HPLC) (Sigma; Catalog No. S6319)
- Rapamycin: Rapamycin ≧95% (HPLC) (Sigma; Catalog No. R0395)
- everolimus: everolimus ≧98% (Cayman chemical; Catalog No. 11597)
- BCH (2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid): (Sellek chem; Catalog No. S6894)
なお、以下の試験例では、各試験化合物として、特に断りのない限り、以下のものを使用した。
・化合物（１）：自製
・フルオキセチン：フルオキセチン塩酸塩（Ｓｅｌｌｅｋ ｃｈｅｍ社；Ｃａｔａｌｏｇ Ｎｏ．Ｓ１３３３）
・セルトラリン：セルトラリン塩酸塩 ≧９８％（ＨＰＬＣ）（Ｓｉｇｍａ社；Ｃａｔａｌｏｇ Ｎｏ．Ｓ６３１９）
・ラパマイシン：ラパマイシン ≧９５％（ＨＰＬＣ）（Ｓｉｇｍａ社；Ｃａｔａｌｏｇ Ｎｏ．Ｒ０３９５）
・エベロリムス：エベロリムス ≧９８％（Ｃａｙｍａｎ ｃｈｅｍｉｃａｌ社；Ｃａｔａｌｏｇ Ｎｏ．１１５９７）
・ＢＣＨ（２－アミノビシクロ－（２．２．１）－ヘプタン－２－カルボン酸）：（Ｓｅｌｌｅｋ ｃｈｅｍ社；Ｃａｔａｌｏｇ Ｎｏ．Ｓ６８９４） Next, the effects of combined administration of a LAT1 inhibitor such as compound (1) or BCH or a pharmaceutically acceptable salt thereof and an mTOR agent or a serotonin inhibitor will be specifically described using test examples.
In addition, in the following test examples, the following compounds were used as test compounds unless otherwise specified.
- Compound (1): Self-produced - Fluoxetine: Fluoxetine hydrochloride (Sellek chem; Catalog No. S1333)
- Sertraline: sertraline hydrochloride ≥ 98% (HPLC) (Sigma; Catalog No. S6319)
- Rapamycin: Rapamycin ≧95% (HPLC) (Sigma; Catalog No. R0395)
- everolimus: everolimus ≧98% (Cayman chemical; Catalog No. 11597)
- BCH (2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid): (Sellek chem; Catalog No. S6894)
試験例１ 化合物（１）／フルオキセチン併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞、ｍＰＫＣ－１細胞およびＰＡＮＣ－１細胞
培地：ダルベッコ改変イーグル培地（ＤＭＥＭ）（高グルコース）＋１０％ウシ胎児血清（ＦＣＳ）＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（５μＭ）、フルオキセチン（５μＭまたは１０μＭ）、化合物（１）（５μＭ）＋フルオキセチン（５μＭまたは１０μＭ） Test Example 1 Growth inhibitory effect on pancreatic cancer cell lines by combined use of compound (1)/fluoxetine (n=6/group)
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 μM), fluoxetine (5 μM or 10 μM), compound (1) (5 μM) + fluoxetine (5 μM or 10 μM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞、ｍＰＫＣ－１細胞およびＰＡＮＣ－１細胞
培地：ダルベッコ改変イーグル培地（ＤＭＥＭ）（高グルコース）＋１０％ウシ胎児血清（ＦＣＳ）＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（５μＭ）、フルオキセチン（５μＭまたは１０μＭ）、化合物（１）（５μＭ）＋フルオキセチン（５μＭまたは１０μＭ） Test Example 1 Growth inhibitory effect on pancreatic cancer cell lines by combined use of compound (1)/fluoxetine (n=6/group)
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 μM), fluoxetine (5 μM or 10 μM), compound (1) (5 μM) + fluoxetine (5 μM or 10 μM)
細胞を、９６穴プレートに２，５００細胞／穴で播種し、培地中で終夜培養して接着させた。培地を吸引した後、０．１％のジメチルスルホキシド（ＤＭＳＯ）を含む培地に試験化合物を添加して作成した試験液を、１００μＬ／穴添加した。その後、２４時間後、４８時間後および７２時間後に、ＷＳＴアッセイ［試薬：Ｎａｃａｌａｉ社 Ｃｅｌｌ Ｃｏｕｎｔｉｎｇ Ｒｅａｇｅｎｔｓ（Ｃｅｌｌ Ｃｏｕｎｔ Ｒｅａｇｅｎｔ ＳＦ）］を行った。結果を図１に示す。
図１からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合よりはるかに高い抑制効果が得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 100 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% dimethylsulfoxide (DMSO) was added. Then, after 24 hours, 48 hours and 72 hours, WST assay [reagent: Nacalai Cell Counting Reagents (Cell Count Reagent SF)] was performed. The results are shown in FIG.
As can be seen from FIG. 1, the combination group of compound (1) and fluoxetine exhibited a much higher inhibitory effect on proliferation of various pancreatic cancer cell lines than when each drug was used alone.
図１からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合よりはるかに高い抑制効果が得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 100 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% dimethylsulfoxide (DMSO) was added. Then, after 24 hours, 48 hours and 72 hours, WST assay [reagent: Nacalai Cell Counting Reagents (Cell Count Reagent SF)] was performed. The results are shown in FIG.
As can be seen from FIG. 1, the combination group of compound (1) and fluoxetine exhibited a much higher inhibitory effect on proliferation of various pancreatic cancer cell lines than when each drug was used alone.
試験例２ 化合物（１）／フルオキセチン併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞およびｍＰＫＣ－１細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（３μＭ）、フルオキセチン（３μＭ）、化合物（１）（３μＭ）＋フルオキセチン（３μＭ） Test Example 2 Growth inhibitory effect on pancreatic cancer cell lines by combined use of compound (1)/fluoxetine (n=6/group)
Cell lines used: MIA PaCa-2 cells and mPKC-1 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (3 µM), fluoxetine (3 µM), compound (1) (3 μM) + fluoxetine (3 μM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞およびｍＰＫＣ－１細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（３μＭ）、フルオキセチン（３μＭ）、化合物（１）（３μＭ）＋フルオキセチン（３μＭ） Test Example 2 Growth inhibitory effect on pancreatic cancer cell lines by combined use of compound (1)/fluoxetine (n=6/group)
Cell lines used: MIA PaCa-2 cells and mPKC-1 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (3 µM), fluoxetine (3 µM), compound (1) (3 μM) + fluoxetine (3 μM)
細胞を、９６穴プレートに２，５００細胞／穴で播種し、培地中で終夜培養して接着させた。培地を吸引した後、０．１％のＤＭＳＯを含む培地に試験化合物を添加して作成した試験液を、２００μＬ／穴添加した。直後より、Ｉｎｃｕｃｙｔｅ（登録商標）（Ｓａｒｔｏｒｉｕｓ）を用いて、穴のコンフルエンシーを経時的に評価した。結果を図２に示す。
図２からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 200 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 2, the combination group of compound (1) and fluoxetine exhibited a higher inhibitory effect on the proliferation of various pancreatic cancer cell lines than when each drug was used alone.
図２からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 200 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 2, the combination group of compound (1) and fluoxetine exhibited a higher inhibitory effect on the proliferation of various pancreatic cancer cell lines than when each drug was used alone.
試験例３ 化合物（１）／フルオキセチン併用による膵癌細胞株細胞のＣａｓｐａｓｅ ３／７活性に対する効果（ｎ＝４／群）
試験例１において、試験液添加４８時間後に９６穴プレートを１３，５００回転／分で１分間遠心し、上清を回収した。次いで、回収した上清を再利用の９６穴プレートに区画を決めて２５μＬずつ滴下し、同量（２５μＬ）のＣａｓｐａｓｅ ３／７アッセイ液［Ｃａｓｐａｓｅ－Ｇｌｏ ３／７（登録商標）Ａｓｓａｙ（Ｐｒｏｍｅｇａ ＃Ｇ８０９０－８０９３）］を連続分注器で注入し、アルミホイルで覆った。室温で１時間放置後、プレートリーダー［Ｔｈｅｒｍｏ Ｓｃｅｉｅｎｔｉｆｉｃ（商標） Ｖａｒｉｏｓｋａｎ（商標） ＬＵＸマルチモードマイクロプレートリーダー］でＣａｓｐａｓｅ ３／７活性を測定した。結果を図３に示す。
図３からわかるように、各種膵癌細胞株細胞のＣａｓｐａｓｅ ３／７活性に対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い活性増強効果が得られた。中でもＭＩＡ ＰａＣａ－２細胞およびＰＡＮＣ－１細胞では、はるかに高い活性増強効果が得られた。 Test Example 3 Effect of compound (1)/fluoxetine combination onCaspase 3/7 activity of pancreatic cancer cell line (n=4/group)
In 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 μL was added dropwise, and the same amount (25 μL) ofCaspase 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. After standing at room temperature for 1 hour, caspase 3/7 activity was measured with a plate reader [Thermo Scientific™ Varioskan™ LUX multimode microplate reader]. The results are shown in FIG.
As can be seen from FIG. 3, in the group of combination use of compound (1) and fluoxetine, a higher activity-enhancing effect was obtained with respect to thecaspase 3/7 activity of various pancreatic cancer cell lines than when each drug was used alone. was taken. Among them, MIA PaCa-2 cells and PANC-1 cells exhibited a much higher activity-enhancing effect.
試験例１において、試験液添加４８時間後に９６穴プレートを１３，５００回転／分で１分間遠心し、上清を回収した。次いで、回収した上清を再利用の９６穴プレートに区画を決めて２５μＬずつ滴下し、同量（２５μＬ）のＣａｓｐａｓｅ ３／７アッセイ液［Ｃａｓｐａｓｅ－Ｇｌｏ ３／７（登録商標）Ａｓｓａｙ（Ｐｒｏｍｅｇａ ＃Ｇ８０９０－８０９３）］を連続分注器で注入し、アルミホイルで覆った。室温で１時間放置後、プレートリーダー［Ｔｈｅｒｍｏ Ｓｃｅｉｅｎｔｉｆｉｃ（商標） Ｖａｒｉｏｓｋａｎ（商標） ＬＵＸマルチモードマイクロプレートリーダー］でＣａｓｐａｓｅ ３／７活性を測定した。結果を図３に示す。
図３からわかるように、各種膵癌細胞株細胞のＣａｓｐａｓｅ ３／７活性に対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い活性増強効果が得られた。中でもＭＩＡ ＰａＣａ－２細胞およびＰＡＮＣ－１細胞では、はるかに高い活性増強効果が得られた。 Test Example 3 Effect of compound (1)/fluoxetine combination on
In 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 μL was added dropwise, and the same amount (25 μL) of
As can be seen from FIG. 3, in the group of combination use of compound (1) and fluoxetine, a higher activity-enhancing effect was obtained with respect to the
試験例４ 化合物（１）／フルオキセチン併用による膵癌細胞株細胞のアポトーシスに対する効果（ｎ＝３／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ
試験化合物：ＤＭＳＯ（対照）、化合物（１）（５μＭ）、フルオキセチン（５μＭ）、化合物（１）（５μＭ）＋フルオキセチン（５μＭ） Test Example 4 Effect on apoptosis of pancreatic cancer cell line cells by combined use of compound (1)/fluoxetine (n=3/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM
Test compounds: DMSO (control), compound (1) (5 μM), fluoxetine (5 μM), compound (1) (5 μM) + fluoxetine (5 μM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ
試験化合物：ＤＭＳＯ（対照）、化合物（１）（５μＭ）、フルオキセチン（５μＭ）、化合物（１）（５μＭ）＋フルオキセチン（５μＭ） Test Example 4 Effect on apoptosis of pancreatic cancer cell line cells by combined use of compound (1)/fluoxetine (n=3/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM
Test compounds: DMSO (control), compound (1) (5 μM), fluoxetine (5 μM), compound (1) (5 μM) + fluoxetine (5 μM)
細胞を、６穴プレートに１．５ｘ１０５細胞／穴で播種し、培地中で４８時間培養した。その後、細胞をトリプシンで剥がし、細胞数を揃えてＡｎｎｅｘｉｎ Ｖアッセイ［使用キット：Ｉｎｖｉｔｒｏｇｅｎ（商標） ｅＢｉｏｓｃｉｅｎｃｅ（商標）社 Ａｎｎｅｘｉｎ Ｖ Ａｐｏｐｔｏｓｉｓ Ｄｅｔｅｃｔｉｏｎ Ｋｉｔ ＦＩＴＣ ２００ｔｅｓｔｓ（＃８８－８００５－７４）］を行った。すなわち、上記キットのプロトコールに従って染色を行い、ＦＣＭ解析を行った。結果を図４に示す。
図４からわかるように、ＭＩＡ ＰａＣａ－２細胞のアポトーシスに対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合よりはるかに高い亢進作用が得られた。 Cells were seeded in 6-well plates at 1.5×10 5 cells/well and cultured in medium for 48 hours. After that, the cells were detached with trypsin, and the Annexin V assay [kit used: Invitrogen (trademark) eBioscience (trademark) Annexin V Apoptosis Detection Kit FITC 200tests (#88-8005-74)] was performed by aligning the cell numbers. That is, staining was performed according to the protocol of the kit, and FCM analysis was performed. The results are shown in FIG.
As can be seen from FIG. 4, the compound (1) and fluoxetine combination group exhibited a much higher enhancement effect on the apoptosis of MIA PaCa-2 cells than when each drug was used alone.
図４からわかるように、ＭＩＡ ＰａＣａ－２細胞のアポトーシスに対して、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合よりはるかに高い亢進作用が得られた。 Cells were seeded in 6-well plates at 1.5×10 5 cells/well and cultured in medium for 48 hours. After that, the cells were detached with trypsin, and the Annexin V assay [kit used: Invitrogen (trademark) eBioscience (trademark) Annexin V Apoptosis Detection Kit FITC 200tests (#88-8005-74)] was performed by aligning the cell numbers. That is, staining was performed according to the protocol of the kit, and FCM analysis was performed. The results are shown in FIG.
As can be seen from FIG. 4, the compound (1) and fluoxetine combination group exhibited a much higher enhancement effect on the apoptosis of MIA PaCa-2 cells than when each drug was used alone.
試験例５ 化合物（１）／フルオキセチン併用によるマウスｘｅｎｏｇｒａｆｔモデルへの経口投与の効果（ｎ＝６～７／群）
試験化合物：対照、化合物（１）（５０ｍｇ／ｋｇ／日）、フルオキセチン（５ｍｇ／ｋｇ／日）、化合物（１）（５０ｍｇ／ｋｇ／日）＋フルオキセチン（５ｍｇ／ｋｇ／日） Test Example 5 Compound (1)/fluoxetine combination effect of oral administration to mouse xenograft model (n=6-7/group)
Test compounds: control, compound (1) (50 mg/kg/day), fluoxetine (5 mg/kg/day), compound (1) (50 mg/kg/day) + fluoxetine (5 mg/kg/day)
試験化合物：対照、化合物（１）（５０ｍｇ／ｋｇ／日）、フルオキセチン（５ｍｇ／ｋｇ／日）、化合物（１）（５０ｍｇ／ｋｇ／日）＋フルオキセチン（５ｍｇ／ｋｇ／日） Test Example 5 Compound (1)/fluoxetine combination effect of oral administration to mouse xenograft model (n=6-7/group)
Test compounds: control, compound (1) (50 mg/kg/day), fluoxetine (5 mg/kg/day), compound (1) (50 mg/kg/day) + fluoxetine (5 mg/kg/day)
８週齢の雌ｃ５７ＢＬ／６Ｊマウスの背部にｍＰＫＣ－１細胞を１ｘ１０７／マウスで移植した（ｎ＝８／群）。その後、試験化合物を平日１回／日投与、土日非投与を３週間繰り返して投与し、１９日目にマウスを解剖した。途中、毎週月曜日と木曜日に、３種混合ｉｐ麻酔下で腫瘍体積（短径ｘ長径ｘ高さ／２）を測定し、解剖時に腫瘍重量を測定した。結果を図５に示す。
図５からわかるように、マウスｘｅｎｏｇｒａｆｔモデルにおいて、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い腫瘍縮小効果が得られた。 8-week-old female c57BL/6J mice were implanted with mPKC-1 cells at 1×10 7 /mouse on the back (n=8/group). After that, the test compound was administered once a day on weekdays and not administered on weekends for 3 weeks, and the mice were dissected on the 19th day. On the way, every Monday and Thursday, the tumor volume (minor axis×major axis×height/2) was measured under ip anesthesia mixed with three types of anesthesia, and the tumor weight was measured at the time of dissection. The results are shown in FIG.
As can be seen from FIG. 5, in the mouse xenograft model, the combined use group of compound (1) and fluoxetine exhibited a higher tumor reduction effect than the use of each drug alone.
図５からわかるように、マウスｘｅｎｏｇｒａｆｔモデルにおいて、化合物（１）とフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い腫瘍縮小効果が得られた。 8-week-old female c57BL/6J mice were implanted with mPKC-1 cells at 1×10 7 /mouse on the back (n=8/group). After that, the test compound was administered once a day on weekdays and not administered on weekends for 3 weeks, and the mice were dissected on the 19th day. On the way, every Monday and Thursday, the tumor volume (minor axis×major axis×height/2) was measured under ip anesthesia mixed with three types of anesthesia, and the tumor weight was measured at the time of dissection. The results are shown in FIG.
As can be seen from FIG. 5, in the mouse xenograft model, the combined use group of compound (1) and fluoxetine exhibited a higher tumor reduction effect than the use of each drug alone.
試験例６ 化合物（１）／フルオキセチンまたはセルトラリン併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（３μＭ）、化合物（１）（３μＭ）＋フルオキセチンまたはセルトラリン（０．７５－６μＭ） Test Example 6 Compound (1)/fluoxetine or sertraline combined growth inhibitory effect on pancreatic cancer cell lines (n = 6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (3 µM), compound (1) (3 µM) + fluoxetine or sertraline (0. 75-6 μM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（３μＭ）、化合物（１）（３μＭ）＋フルオキセチンまたはセルトラリン（０．７５－６μＭ） Test Example 6 Compound (1)/fluoxetine or sertraline combined growth inhibitory effect on pancreatic cancer cell lines (n = 6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (3 µM), compound (1) (3 µM) + fluoxetine or sertraline (0. 75-6 μM)
細胞を、９６穴プレートに２，５００細胞／穴で播種し、培地中で終夜培養して接着させた。培地を吸引した後、０．１％のＤＭＳＯを含む培地に試験化合物を添加して作成した試験液を、２００μＬ／穴添加した。直後より、Ｉｎｃｕｃｙｔｅ（登録商標）（Ｓａｒｔｏｒｉｕｓ）を用いて、穴のコンフルエンシーを経時的に評価した。結果を図６に示す。
図６からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、化合物（１）とフルオキセチンまたはセルトラリンとの併用群では、それぞれの薬剤を単独で用いた場合よりはるかに高い抑制効果が用量依存的に得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 200 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 6, the combined use of compound (1) and fluoxetine or sertraline showed a dose-dependent inhibitory effect on the proliferation of MIA PaCa-2 cells, which was much higher than when each drug was used alone. obtained on purpose.
図６からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、化合物（１）とフルオキセチンまたはセルトラリンとの併用群では、それぞれの薬剤を単独で用いた場合よりはるかに高い抑制効果が用量依存的に得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 200 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 6, the combined use of compound (1) and fluoxetine or sertraline showed a dose-dependent inhibitory effect on the proliferation of MIA PaCa-2 cells, which was much higher than when each drug was used alone. obtained on purpose.
試験例７ 化合物（１）／ラパマイシン併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞、ｍＰＫＣ－１細胞、ＢｘＰＣ－３細胞およびＰＡＮＣ－１細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（２．５μＭまたは５μＭ）、ラパマイシン（５０ｎＭまたは１００ｎＭ）、化合物（１）（２．５μＭまたは５μＭ）＋ラパマイシン（５０ｎＭまたは１００ｎＭ） Test Example 7 Growth inhibitory effect on pancreatic cancer cell lines by combined use of compound (1) / rapamycin (n = 6 / group)
Cell lines used: MIA PaCa-2 cells, mPKC-1 cells, BxPC-3 cells and PANC-1 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (2. 5 μM or 5 μM), rapamycin (50 nM or 100 nM), compound (1) (2.5 μM or 5 μM) + rapamycin (50 nM or 100 nM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞、ｍＰＫＣ－１細胞、ＢｘＰＣ－３細胞およびＰＡＮＣ－１細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（２．５μＭまたは５μＭ）、ラパマイシン（５０ｎＭまたは１００ｎＭ）、化合物（１）（２．５μＭまたは５μＭ）＋ラパマイシン（５０ｎＭまたは１００ｎＭ） Test Example 7 Growth inhibitory effect on pancreatic cancer cell lines by combined use of compound (1) / rapamycin (n = 6 / group)
Cell lines used: MIA PaCa-2 cells, mPKC-1 cells, BxPC-3 cells and PANC-1 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (2. 5 μM or 5 μM), rapamycin (50 nM or 100 nM), compound (1) (2.5 μM or 5 μM) + rapamycin (50 nM or 100 nM)
細胞を、９６穴プレートに２，５００細胞／穴で播種し、培地中で終夜培養して接着させた。培地を吸引した後、０．１％のＤＭＳＯを含む培地に試験化合物を添加して作成した試験液を、１００μＬ／穴添加した。その後、２４時間後、４８時間後および７２時間後に、ＷＳＴアッセイ［試薬：Ｎａｃａｌａｉ社 Ｃｅｌｌ Ｃｏｕｎｔｉｎｇ Ｒｅａｇｅｎｔｓ（Ｃｅｌｌ Ｃｏｕｎｔ Ｒｅａｇｅｎｔ ＳＦ）］を行った。結果を図７に示す。
図７からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とラパマイシンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 100 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Then, after 24 hours, 48 hours and 72 hours, WST assay [reagent: Nacalai Cell Counting Reagents (Cell Count Reagent SF)] was performed. The results are shown in FIG.
As can be seen from FIG. 7, the combined use of compound (1) and rapamycin exhibited a higher inhibitory effect on the proliferation of various pancreatic cancer cell lines than when each drug was used alone.
図７からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とラパマイシンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 100 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Then, after 24 hours, 48 hours and 72 hours, WST assay [reagent: Nacalai Cell Counting Reagents (Cell Count Reagent SF)] was performed. The results are shown in FIG.
As can be seen from FIG. 7, the combined use of compound (1) and rapamycin exhibited a higher inhibitory effect on the proliferation of various pancreatic cancer cell lines than when each drug was used alone.
試験例８ 化合物（１）／エベロリムス併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞、ｍＰＫＣ－１細胞、ＢｘＰＣ－３細胞およびＰＡＮＣ－１細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（２．５μＭまたは５μＭ）、エベロリムス（５０ｎＭまたは１００ｎＭ）、化合物（１）（２．５μＭまたは５μＭ）＋エベロリムス（５０ｎＭまたは１００ｎＭ） Test Example 8 Compound (1)/everolimus combined growth inhibitory effect on pancreatic cancer cell lines (n = 6/group)
Cell lines used: MIA PaCa-2 cells, mPKC-1 cells, BxPC-3 cells and PANC-1 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (2. 5 μM or 5 μM), everolimus (50 nM or 100 nM), compound (1) (2.5 μM or 5 μM) + everolimus (50 nM or 100 nM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞、ｍＰＫＣ－１細胞、ＢｘＰＣ－３細胞およびＰＡＮＣ－１細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、化合物（１）（２．５μＭまたは５μＭ）、エベロリムス（５０ｎＭまたは１００ｎＭ）、化合物（１）（２．５μＭまたは５μＭ）＋エベロリムス（５０ｎＭまたは１００ｎＭ） Test Example 8 Compound (1)/everolimus combined growth inhibitory effect on pancreatic cancer cell lines (n = 6/group)
Cell lines used: MIA PaCa-2 cells, mPKC-1 cells, BxPC-3 cells and PANC-1 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), compound (1) (2. 5 μM or 5 μM), everolimus (50 nM or 100 nM), compound (1) (2.5 μM or 5 μM) + everolimus (50 nM or 100 nM)
細胞を、９６穴プレートに２，５００細胞／穴で播種し、培地中で終夜培養して接着させた。培地を吸引した後、０．１％のＤＭＳＯを含む培地に試験化合物を添加して作成した試験液を、１００μＬ／穴添加した。その後、２４時間後、４８時間後および７２時間後に、ＷＳＴアッセイ［試薬：Ｎａｃａｌａｉ社 Ｃｅｌｌ Ｃｏｕｎｔｉｎｇ Ｒｅａｇｅｎｔｓ（Ｃｅｌｌ Ｃｏｕｎｔ Ｒｅａｇｅｎｔ ＳＦ）］を行った。結果を図８に示す。
図８からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とエベロリムスとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。
上記の結果から、化合物（１）またはその薬理的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを併用して用いることにより、それぞれを単剤として用いた場合よりさらに優れた膵癌治療効果が得られると考えられる。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 100 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Then, after 24 hours, 48 hours and 72 hours, WST assay [reagent: Nacalai Cell Counting Reagents (Cell Count Reagent SF)] was performed. The results are shown in FIG.
As can be seen from FIG. 8, in the combination group of compound (1) and everolimus, a higher inhibitory effect was obtained on proliferation of various pancreatic cancer cell lines than when each drug was used alone.
From the above results, the combined use of compound (1) or a pharmacologically acceptable salt thereof and an mTOR inhibitor or a serotonin inhibitor has a pancreatic cancer therapeutic effect that is even more excellent than when each is used as a single agent. is obtained.
図８からわかるように、各種膵癌細胞株細胞の増殖に対して、化合物（１）とエベロリムスとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。
上記の結果から、化合物（１）またはその薬理的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを併用して用いることにより、それぞれを単剤として用いた場合よりさらに優れた膵癌治療効果が得られると考えられる。 Cells were seeded at 2,500 cells/well in 96-well plates and cultured overnight in medium to allow adherence. After aspirating the medium, 100 μL/well of a test solution prepared by adding a test compound to a medium containing 0.1% DMSO was added. Then, after 24 hours, 48 hours and 72 hours, WST assay [reagent: Nacalai Cell Counting Reagents (Cell Count Reagent SF)] was performed. The results are shown in FIG.
As can be seen from FIG. 8, in the combination group of compound (1) and everolimus, a higher inhibitory effect was obtained on proliferation of various pancreatic cancer cell lines than when each drug was used alone.
From the above results, the combined use of compound (1) or a pharmacologically acceptable salt thereof and an mTOR inhibitor or a serotonin inhibitor has a pancreatic cancer therapeutic effect that is even more excellent than when each is used as a single agent. is obtained.
試験例９ ＢＣＨ／エベロリムス併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、ＢＣＨ（６ｍＭ）、エベロリムス（５０ｎＭ）、ＢＣＨ（６ｍＭ）＋エベロリムス（５０ｎＭ） Test Example 9 Growth inhibitory effect on pancreatic cancer cell lines by combination of BCH/everolimus (n = 6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), BCH (6 mM), everolimus (50 nM), BCH (6 mM) + everolimus (50 nM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、ＢＣＨ（６ｍＭ）、エベロリムス（５０ｎＭ）、ＢＣＨ（６ｍＭ）＋エベロリムス（５０ｎＭ） Test Example 9 Growth inhibitory effect on pancreatic cancer cell lines by combination of BCH/everolimus (n = 6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), BCH (6 mM), everolimus (50 nM), BCH (6 mM) + everolimus (50 nM)
細胞を、培地中で２，５００細胞／ｍＬとなるよう調整し、９６穴プレートに１００μＬずつ分注した。翌日、培地に試験化合物を添加して作成した試験液を、１８０μＬ／穴添加した。直後より、Ｉｎｃｕｃｙｔｅ（登録商標）（Ｓａｒｔｏｒｉｕｓ）を用いて、穴のコンフルエンシーを経時的に評価した。結果を図９に示す。
図９からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、ＢＣＨとエベロリムスとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were adjusted to 2,500 cells/mL in medium and 100 μL aliquots were dispensed into 96-well plates. On the next day, 180 μL/well of a test solution prepared by adding the test compound to the medium was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 9, the combined use of BCH and everolimus exhibited a higher inhibitory effect on the proliferation of MIA PaCa-2 cells than the use of each drug alone.
図９からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、ＢＣＨとエベロリムスとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were adjusted to 2,500 cells/mL in medium and 100 μL aliquots were dispensed into 96-well plates. On the next day, 180 μL/well of a test solution prepared by adding the test compound to the medium was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 9, the combined use of BCH and everolimus exhibited a higher inhibitory effect on the proliferation of MIA PaCa-2 cells than the use of each drug alone.
試験例１０ ＢＣＨ／フルオキセチン併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、ＢＣＨ（６ｍＭ）、フルオキセチン（３μＭ）、ＢＣＨ（６ｍＭ）＋フルオキセチン（３μＭ） Test Example 10 Growth inhibitory effect on pancreatic cancer cell lines by combination of BCH/fluoxetine (n=6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), BCH (6 mM), fluoxetine (3 µM), BCH (6 mM) + fluoxetine (3 µM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、ＢＣＨ（６ｍＭ）、フルオキセチン（３μＭ）、ＢＣＨ（６ｍＭ）＋フルオキセチン（３μＭ） Test Example 10 Growth inhibitory effect on pancreatic cancer cell lines by combination of BCH/fluoxetine (n=6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), BCH (6 mM), fluoxetine (3 µM), BCH (6 mM) + fluoxetine (3 µM)
細胞を、培地中で２，５００細胞／ｍＬとなるよう調整し、９６穴プレートに１００μＬずつ分注した。翌日、培地に試験化合物を添加して作成した試験液を、１６０μＬ／穴添加した。直後より、Ｉｎｃｕｃｙｔｅ（登録商標）（Ｓａｒｔｏｒｉｕｓ）を用いて、穴のコンフルエンシーを経時的に評価した。結果を図１０に示す。
図１０からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、ＢＣＨとフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were adjusted to 2,500 cells/mL in medium and 100 μL aliquots were dispensed into 96-well plates. On the next day, 160 μL/well of a test solution prepared by adding the test compound to the medium was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 10, the combined use of BCH and fluoxetine exhibited a higher inhibitory effect on the proliferation of MIA PaCa-2 cells than the use of each drug alone.
図１０からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、ＢＣＨとフルオキセチンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were adjusted to 2,500 cells/mL in medium and 100 μL aliquots were dispensed into 96-well plates. On the next day, 160 μL/well of a test solution prepared by adding the test compound to the medium was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 10, the combined use of BCH and fluoxetine exhibited a higher inhibitory effect on the proliferation of MIA PaCa-2 cells than the use of each drug alone.
試験例１１ ＢＣＨ／セルトラリン併用による膵癌細胞株細胞に対する増殖抑制効果（ｎ＝６／群）
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、ＢＣＨ（６ｍＭ）、セルトラリン（３μＭ）、ＢＣＨ（６ｍＭ）＋セルトラリン（３μＭ） Test Example 11 Growth inhibitory effect on pancreatic cancer cell lines by combined use of BCH/sertraline (n = 6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), BCH (6 mM), sertraline (3 µM), BCH (6 mM) + sertraline (3 µM)
使用細胞株：ＭＩＡ ＰａＣａ－２細胞
培地：ＤＭＥＭ（高グルコース）＋１０％ＦＣＳ＋アンピシリン
試験化合物：ＤＭＳＯ（対照）、ＢＣＨ（６ｍＭ）、セルトラリン（３μＭ）、ＢＣＨ（６ｍＭ）＋セルトラリン（３μＭ） Test Example 11 Growth inhibitory effect on pancreatic cancer cell lines by combined use of BCH/sertraline (n = 6/group)
Cell line used: MIA PaCa-2 cells Medium: DMEM (high glucose) + 10% FCS + ampicillin Test compounds: DMSO (control), BCH (6 mM), sertraline (3 µM), BCH (6 mM) + sertraline (3 µM)
細胞を、培地中で２，５００細胞／ｍＬとなるよう調整し、９６穴プレートに１００μＬずつ分注した。翌日、培地に試験化合物を添加して作成した試験液を、１６０μＬ／穴添加した。直後より、Ｉｎｃｕｃｙｔｅ（登録商標）（Ｓａｒｔｏｒｉｕｓ）を用いて、穴のコンフルエンシーを経時的に評価した。結果を図１１に示す。
図１１からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、ＢＣＨとセルトラリンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were adjusted to 2,500 cells/mL in medium and 100 μL aliquots were dispensed into 96-well plates. On the next day, 160 μL/well of a test solution prepared by adding the test compound to the medium was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 11, the combined use of BCH and sertraline exhibited a higher inhibitory effect on the proliferation of MIA PaCa-2 cells than the use of each drug alone.
図１１からわかるように、ＭＩＡ ＰａＣａ－２細胞の増殖に対して、ＢＣＨとセルトラリンとの併用群では、それぞれの薬剤を単独で用いた場合より高い抑制効果が得られた。 Cells were adjusted to 2,500 cells/mL in medium and 100 μL aliquots were dispensed into 96-well plates. On the next day, 160 μL/well of a test solution prepared by adding the test compound to the medium was added. Immediately after, the confluency of the wells was evaluated over time using Incucyte® (Sartorius). The results are shown in FIG.
As can be seen from FIG. 11, the combined use of BCH and sertraline exhibited a higher inhibitory effect on the proliferation of MIA PaCa-2 cells than the use of each drug alone.
実施例１
錠剤（化合物（１））
１） 化合物（１） ３０ ｇ
２） 乳糖 ５０ ｇ
３） トウモロコシデンプン １５ ｇ
４） カルボキシメチルセルロースカルシウム ４４ ｇ
５） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １４０ ｇ
１）、２）および３）の全量並びに３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたり化合物（１）３０ｍｇを含有する錠剤１０００錠を得る。 Example 1
Tablet (compound (1))
1) Compound (1) 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. Thus, 1000 tablets each containing 30 mg of compound (1) are obtained.
錠剤（化合物（１））
１） 化合物（１） ３０ ｇ
２） 乳糖 ５０ ｇ
３） トウモロコシデンプン １５ ｇ
４） カルボキシメチルセルロースカルシウム ４４ ｇ
５） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １４０ ｇ
１）、２）および３）の全量並びに３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたり化合物（１）３０ｍｇを含有する錠剤１０００錠を得る。 Example 1
Tablet (compound (1))
1) Compound (1) 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. Thus, 1000 tablets each containing 30 mg of compound (1) are obtained.
実施例２
錠剤（エベロリムス）
１） エベロリムス １ ｇ
２） 乳糖 ７９ ｇ
３） トウモロコシデンプン １５ ｇ
４） カルボキシメチルセルロースカルシウム ４４ ｇ
５） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １４０ ｇ
１）、２）および３）の全量並びに３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたりエベロリムス１ｍｇを含有する錠剤１０００錠を得る。 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.
錠剤（エベロリムス）
１） エベロリムス １ ｇ
２） 乳糖 ７９ ｇ
３） トウモロコシデンプン １５ ｇ
４） カルボキシメチルセルロースカルシウム ４４ ｇ
５） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １４０ ｇ
１）、２）および３）の全量並びに３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたりエベロリムス１ｍｇを含有する錠剤１０００錠を得る。 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.
実施例３
錠剤（フルオキセチン）
１） フルオキセチン ３０ ｇ
２） 乳糖 ５０ ｇ
３） トウモロコシデンプン １５ ｇ
４） カルボキシメチルセルロースカルシウム ４４ ｇ
５） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １４０ ｇ
１）、２）および３）の全量並びに３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたりフルオキセチン３０ｍｇを含有する錠剤１０００錠を得る。 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.
錠剤（フルオキセチン）
１） フルオキセチン ３０ ｇ
２） 乳糖 ５０ ｇ
３） トウモロコシデンプン １５ ｇ
４） カルボキシメチルセルロースカルシウム ４４ ｇ
５） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １４０ ｇ
１）、２）および３）の全量並びに３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたりフルオキセチン３０ｍｇを含有する錠剤１０００錠を得る。 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.
実施例４
錠剤（化合物（１）とフルオキセチン）
１） 化合物（１） ３０ ｇ
２） フルオキセチン ３０ ｇ
３） 乳糖 ５０ ｇ
４） トウモロコシデンプン １５ ｇ
５） カルボキシメチルセルロースカルシウム ４４ ｇ
６） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １７０ ｇ
１）、２）、３）および４）の全量並びに３０ｇの５）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの５）および１ｇの６）を混合し、打錠機により打錠する。このようにして、１錠あたり化合物（１）３０ｍｇおよびフルオキセチン３０ｍｇを含有する錠剤１０００錠を得る。 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.
錠剤（化合物（１）とフルオキセチン）
１） 化合物（１） ３０ ｇ
２） フルオキセチン ３０ ｇ
３） 乳糖 ５０ ｇ
４） トウモロコシデンプン １５ ｇ
５） カルボキシメチルセルロースカルシウム ４４ ｇ
６） ステアリン酸マグネシウム １ ｇ
１０００錠 計 １７０ ｇ
１）、２）、３）および４）の全量並びに３０ｇの５）を水で練合し、真空乾燥後、整粒を行う。得られた整粒末に１４ｇの５）および１ｇの６）を混合し、打錠機により打錠する。このようにして、１錠あたり化合物（１）３０ｍｇおよびフルオキセチン３０ｍｇを含有する錠剤１０００錠を得る。 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.
実施例５
注射剤（化合物（１））
１） 化合物（１） １ ｇ
２） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）を２）に溶解させ、３）および４）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたり化合物（１）２ｍｇを含有する）を得る。 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 μm 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). .
注射剤（化合物（１））
１） 化合物（１） １ ｇ
２） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）を２）に溶解させ、３）および４）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたり化合物（１）２ｍｇを含有する）を得る。 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 μm 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). .
実施例６
注射剤（ラパマイシン）
１） ラパマイシン ０．０２ ｇ
２） 精製大豆油 １０１．９８ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）を２）に溶解させ、３）および４）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりラパマイシン０．０４ｍｇを含有する）を得る。 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 μm 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).
注射剤（ラパマイシン）
１） ラパマイシン ０．０２ ｇ
２） 精製大豆油 １０１．９８ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）を２）に溶解させ、３）および４）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりラパマイシン０．０４ｍｇを含有する）を得る。 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 μm 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).
実施例７
注射剤（セルトラリン）
１） セルトラリン １ ｇ
２） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）を２）に溶解させ、３）および４）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりセルトラリン２ｍｇを含有する）を得る。 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 μm 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).
注射剤（セルトラリン）
１） セルトラリン １ ｇ
２） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）を２）に溶解させ、３）および４）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりセルトラリン２ｍｇを含有する）を得る。 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 μm 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).
実施例８
注射剤（化合物（１）とラパマイシン）
１） 化合物（１） ０．９８ ｇ
２） ラパマイシン ０．０２ ｇ
３） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）および２）を３）に溶解させ、４）および５）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたり化合物（１）１．９６ｍｇおよびラパマイシン０．０４ｍｇを含有する）を得る。 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 μm 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).
注射剤（化合物（１）とラパマイシン）
１） 化合物（１） ０．９８ ｇ
２） ラパマイシン ０．０２ ｇ
３） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８６０ ｍＬ
１０００ ｍＬ
１）および２）を３）に溶解させ、４）および５）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたり化合物（１）１．９６ｍｇおよびラパマイシン０．０４ｍｇを含有する）を得る。 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 μm 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).
実施例９
カプセル（化合物（１））
１）化合物（１） ３０ ｍｇ
２）微粉末セルロース １０ ｍｇ
３）乳糖 １９ ｍｇ
４）ステアリン酸マグネシウム １ ｍｇ
計 ６０ ｍｇ
１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 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.
カプセル（化合物（１））
１）化合物（１） ３０ ｍｇ
２）微粉末セルロース １０ ｍｇ
３）乳糖 １９ ｍｇ
４）ステアリン酸マグネシウム １ ｍｇ
計 ６０ ｍｇ
１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 Example 9
Capsule (compound (1))
1) Compound (1) 30 mg
2)
3) Lactose 19 mg
4)
Total 60mg
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
実施例１０
カプセル（エベロリムス）
１）エベロリムス １ ｍｇ
２）微粉末セルロース ２０ ｍｇ
３）乳糖 ３８ ｍｇ
４）ステアリン酸マグネシウム １ ｍｇ
計 ６０ ｍｇ
１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 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.
カプセル（エベロリムス）
１）エベロリムス １ ｍｇ
２）微粉末セルロース ２０ ｍｇ
３）乳糖 ３８ ｍｇ
４）ステアリン酸マグネシウム １ ｍｇ
計 ６０ ｍｇ
１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 Example 10
Capsules (Everolimus)
1)
2)
3) Lactose 38 mg
4)
Total 60mg
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
実施例１１
カプセル（フルオキセチン）
１）フルオキセチン ３０ ｍｇ
２）微粉末セルロース １０ ｍｇ
３）乳糖 １９ ｍｇ
４）ステアリン酸マグネシウム １ ｍｇ
計 ６０ ｍｇ
１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 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.
カプセル（フルオキセチン）
１）フルオキセチン ３０ ｍｇ
２）微粉末セルロース １０ ｍｇ
３）乳糖 １９ ｍｇ
４）ステアリン酸マグネシウム １ ｍｇ
計 ６０ ｍｇ
１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 Example 11
capsule (fluoxetine)
1)
2)
3) Lactose 19 mg
4)
Total 60mg
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
実施例１２
カプセル（化合物（１）とフルオキセチン）
１）化合物（１） ３０ ｍｇ
２）フルオキセチン ３０ ｍｇ
３）微粉末セルロース １０ ｍｇ
４）乳糖 １９ ｍｇ
５）ステアリン酸マグネシウム １ ｍｇ
計 ９０ ｍｇ
１）、２）、３）、４）および５）を混合して、ゼラチンカプセルに充填する。 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.
カプセル（化合物（１）とフルオキセチン）
１）化合物（１） ３０ ｍｇ
２）フルオキセチン ３０ ｍｇ
３）微粉末セルロース １０ ｍｇ
４）乳糖 １９ ｍｇ
５）ステアリン酸マグネシウム １ ｍｇ
計 ９０ ｍｇ
１）、２）、３）、４）および５）を混合して、ゼラチンカプセルに充填する。 Example 12
Capsule (compound (1) and fluoxetine)
1) Compound (1) 30 mg
2)
3)
4) Lactose 19 mg
5)
Total 90mg
1), 2), 3), 4) and 5) are mixed and filled into gelatin capsules.
実施例１３
注射剤（ＢＣＨとラパマイシン）
１） ＢＣＨ ９．９８ ｇ
２） ラパマイシン ０．０２ ｇ
３） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８５１ ｍＬ
１０００ ｍＬ
１）および２）を３）に溶解させ、４）および５）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりＢＣＨ１９．９６ｍｇおよびラパマイシン０．０４ｍｇを含有する）を得る。 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 μm 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). ).
注射剤（ＢＣＨとラパマイシン）
１） ＢＣＨ ９．９８ ｇ
２） ラパマイシン ０．０２ ｇ
３） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８５１ ｍＬ
１０００ ｍＬ
１）および２）を３）に溶解させ、４）および５）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりＢＣＨ１９．９６ｍｇおよびラパマイシン０．０４ｍｇを含有する）を得る。 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 μm 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). ).
実施例１４
注射剤（ＢＣＨとセルトラリン）
１） ＢＣＨ ９ ｇ
２） セルトラリン １ ｇ
３） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８５１ ｍＬ
１０００ ｍＬ
１）および２）を３）に溶解させ、４）および５）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりＢＣＨ１８ｍｇおよびセルトラリン２ｍｇを含有する）を得る。 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. After aseptic filtration of the resulting dispersion using a 0.2 μm disposable membrane filter, 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).
注射剤（ＢＣＨとセルトラリン）
１） ＢＣＨ ９ ｇ
２） セルトラリン １ ｇ
３） 精製大豆油 １００ ｇ
３） 精製卵黄レシチン １２ ｇ
４） 注射用グリセリン ２５ ｇ
５） 注射用蒸留水 ８５１ ｍＬ
１０００ ｍＬ
１）および２）を３）に溶解させ、４）および５）を加える。得られた混合物を注射用蒸留水で１０００ｍＬとして練合・乳化する。得られた分散液を０．２μｍのディスポーザブル型メンブランフィルターを用いて無菌濾過後、ガラスバイアルに２ｍＬずつ無菌的に充填して、注射剤（１バイアルあたりＢＣＨ１８ｍｇおよびセルトラリン２ｍｇを含有する）を得る。 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. After aseptic filtration of the resulting dispersion using a 0.2 μm disposable membrane filter, 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).
本発明により、膵癌治療薬等としてより治療効果の高いことが期待できる、５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩等のＬＡＴ１阻害剤とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有する医薬組成物等が提供される。
According to the present invention, 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] 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.
本出願は、日本で出願された特願２０２１－１１６９２２（出願日：２０２１年７月１５日）を基礎としており、その内容は本明細書に全て包含されるものである。
This application is based on Japanese Patent Application No. 2021-116922 (filing date: July 15, 2021) filed in Japan, the contents of which are all incorporated herein.
Claims (43)
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有する医薬組成物。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof and mTOR A pharmaceutical composition containing an inhibitor or a serotonin inhibitor.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、請求項１記載の医薬組成物。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( The pharmaceutical composition according to claim 1, which is trifluoromethyl)phenoxy]pentan-1-amine.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、請求項１または２記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
- ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、請求項３記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the mTOR inhibitor is rapamycin or everolimus.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、請求項１または２記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
- セロトニン阻害剤がフルオキセチンまたはセルトラリンである、請求項５記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the serotonin inhibitor is fluoxetine or sertraline.
- 医薬組成物が膵癌治療用医薬組成物である、請求項１または２記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, which is a pharmaceutical composition for treating pancreatic cancer.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを含有し、それらを同時にまたは時間を置いて別々に投与するための膵癌治療剤。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof and mTOR A therapeutic agent for pancreatic cancer containing an inhibitor or a serotonin inhibitor for simultaneous or separate administration thereof.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、請求項８記載の膵癌治療剤。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( The therapeutic agent for pancreatic cancer according to claim 8, which is trifluoromethyl)phenoxy]pentan-1-amine.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、請求項８または９記載の膵癌治療剤。 The therapeutic agent for pancreatic cancer according to claim 8 or 9, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
- ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、請求項１０記載の膵癌治療剤。 The therapeutic agent for pancreatic cancer according to claim 10, wherein the mTOR inhibitor is rapamycin or everolimus.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、請求項８または９記載の膵癌治療剤。 The therapeutic agent for pancreatic cancer according to claim 8 or 9, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
- セロトニン阻害剤がフルオキセチンまたはセルトラリンである、請求項１２記載の膵癌治療剤。 The therapeutic agent for pancreatic cancer according to claim 12, wherein the serotonin inhibitor is fluoxetine or sertraline.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤と同時にまたは時間を置いて別々に投与する膵癌治療における使用のための５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。 5-Phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-amino for use in treating pancreatic cancer administered simultaneously or separately with mTOR inhibitors or serotonin inhibitors Bicyclo[2.2.1]heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンである、請求項１４記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( 5-Phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2. 1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、請求項１４または１５記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。 The 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2. 2.1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
- ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、請求項１６記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。 17. The 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane- of claim 16, wherein the mTOR inhibitor is rapamycin or everolimus. 2-carboxylic acid or a pharmaceutically acceptable salt thereof.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、請求項１４または１５記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2. 2.1] Heptane-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
- セロトニン阻害剤がフルオキセチンまたはセルトラリンである、請求項１８記載の５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩。 5-Phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane- of claim 18, wherein the serotonin inhibitor is fluoxetine or sertraline 2-carboxylic acid or a pharmaceutically acceptable salt thereof.
- （ａ）５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩を含有する第１成分と（ｂ）ｍＴＯＲ阻害剤またはセロトニン阻害剤を含有する第２成分とを有することを特徴とするキット。 (a) 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or pharmaceutically acceptable thereof A kit comprising a first component containing a salt and (b) a second component containing an mTOR inhibitor or a serotonin inhibitor.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンまたはその薬学的に許容される塩である、請求項２０記載のキット。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( 21. The kit of claim 20, which is trifluoromethyl)phenoxy]pentan-1-amine or a pharmaceutically acceptable salt thereof.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、請求項２０または２１記載のキット。 The kit according to claim 20 or 21, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
- ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、請求項２２記載のキット。 The kit according to claim 22, wherein the mTOR inhibitor is rapamycin or everolimus.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、請求項２０または２１記載のキット。 The kit according to claim 20 or 21, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
- セロトニン阻害剤がフルオキセチンまたはセルトラリンである、請求項２４記載のキット。 The kit according to claim 24, wherein the serotonin inhibitor is fluoxetine or sertraline.
- キットが膵癌治療用キットである請求項２０または２１記載のキット。 The kit according to claim 20 or 21, which is a pancreatic cancer treatment kit.
- 膵癌治療剤の製造のための５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸またはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤との使用。 5-Phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid for the production of a pancreatic cancer therapeutic agent or pharmaceuticals thereof Use of a Pharmaceutically Acceptable Salt with an mTOR Inhibitor or a Serotonin Inhibitor.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンまたはその薬学的に許容される塩である、請求項２７記載の使用。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( The use according to claim 27, which is trifluoromethyl)phenoxy]pentan-1-amine or a pharmaceutically acceptable salt thereof.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、請求項２７または２８記載の使用。 Use according to claim 27 or 28, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
- ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、請求項２９記載の使用。 The use according to claim 29, wherein the mTOR inhibitor is rapamycin or everolimus.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、請求項２７または２８記載の使用。 Use according to claim 27 or 28, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
- セロトニン阻害剤がフルオキセチンまたはセルトラリンである、請求項３１記載の使用。 The use according to claim 31, wherein the serotonin inhibitor is fluoxetine or sertraline.
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンまたはその薬学的に許容される塩とｍＴＯＲ阻害剤またはセロトニン阻害剤とを同時にまたは時間を置いて別々に投与することを特徴とする、膵癌の治療方法。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( A method of treating pancreatic cancer, comprising administering trifluoromethyl)phenoxy]pentan-1-amine or a pharmaceutically acceptable salt thereof and an mTOR inhibitor or a serotonin inhibitor simultaneously or separately with an interval .
- ５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミン若しくは２－アミノビシクロ［２．２．１］ヘプタン－２－カルボン酸が５－フェニル－５－［４－（トリフルオロメチル）フェノキシ］ペンタン－１－アミンまたはその薬学的に許容されるである、請求項３３記載の治療方法。 5-phenyl-5-[4-(trifluoromethyl)phenoxy]pentan-1-amine or 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is 5-phenyl-5-[4-( 34. The method of treatment of claim 33, which is trifluoromethyl)phenoxy]pentan-1-amine or pharmaceutically acceptable thereof.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がｍＴＯＲ阻害剤である、請求項３３または３４記載の治療方法。 The method of treatment according to claim 33 or 34, wherein the mTOR inhibitor or serotonin inhibitor is an mTOR inhibitor.
- ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスである、請求項３５記載の治療方法。 The therapeutic method according to claim 35, wherein the mTOR inhibitor is rapamycin or everolimus.
- ｍＴＯＲ阻害剤またはセロトニン阻害剤がセロトニン阻害剤である、請求項３３または３４記載の治療方法。 The method of treatment according to claim 33 or 34, wherein the mTOR inhibitor or serotonin inhibitor is a serotonin inhibitor.
- セロトニン阻害剤がフルオキセチンまたはセルトラリンである、請求項３７記載の治療方法。 The therapeutic method according to claim 37, wherein the serotonin inhibitor is fluoxetine or sertraline.
- ＬＡＴ１阻害剤とセロトニン阻害剤とを含有する医薬組成物。 A pharmaceutical composition containing a LAT1 inhibitor and a serotonin inhibitor.
- ＬＡＴ１阻害剤とセロトニン阻害剤とを含有し、それらを同時にまたは時間を置いて別々に投与するための膵癌治療剤。 A therapeutic agent for pancreatic cancer containing a LAT1 inhibitor and a serotonin inhibitor, which are administered simultaneously or separately at intervals.
- （ａ）ＬＡＴ１阻害剤を含有する第１成分と（ｂ）セロトニン阻害剤を含有する第２成分とを有することを特徴とするキット。 A kit comprising (a) a first component containing a LAT1 inhibitor and (b) a second component containing a serotonin inhibitor.
- 膵癌治療剤の製造のためのＬＡＴ１阻害剤とセロトニン阻害剤との使用。 The use of LAT1 inhibitors and serotonin inhibitors for the production of therapeutic agents for pancreatic cancer.
- ＬＡＴ１阻害剤とセロトニン阻害剤とを同時にまたは時間を置いて別々に投与することを特徴とする、膵癌の治療方法。 A therapeutic method for pancreatic cancer, characterized by administering a LAT1 inhibitor and a serotonin inhibitor simultaneously or separately at an interval.
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| WO2014112646A1 (en) * | 2013-01-21 | 2014-07-24 | 国立大学法人大阪大学 | Phenoxyalkylamine compound |
| WO2015173970A1 (en) * | 2014-05-15 | 2015-11-19 | ジェイファーマ株式会社 | Anti-malignant tumor agent composition |
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| 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 * |
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