WO2023233994A1 - Pharmaceutical composition and autophagy activator - Google Patents

Pharmaceutical composition and autophagy activator Download PDF

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WO2023233994A1
WO2023233994A1 PCT/JP2023/018146 JP2023018146W WO2023233994A1 WO 2023233994 A1 WO2023233994 A1 WO 2023233994A1 JP 2023018146 W JP2023018146 W JP 2023018146W WO 2023233994 A1 WO2023233994 A1 WO 2023233994A1
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group
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alkoxycarbonyl
alkyl
substituted
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龍 永田
万穂 濱▲崎▼
泰生 森
誉志史 植田
志咲子 庄司
かな子 福田
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国立大学法人京都大学
国立大学法人大阪大学
株式会社AutoPhagyGO
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating lung diseases, kidney diseases, skin diseases, liver disorders, eye diseases, etc., and an autophagy activator.
  • Autophagy In addition to being responsible for decomposing and recycling intracellular substances, autophagy also works to eliminate harmful substances that appear within cells (abnormal protein clumps, invading bacteria, damaged mitochondria, etc.). Autophagy contributes to keeping cells in each tissue healthy. Autophagy is essential for the basic functions of cells in the lungs, kidneys, skin, eyes, etc., and exerts a protective effect on cells under conditions where these tissues are acutely or chronically damaged. Therefore, autophagy activation is an effective preventive and therapeutic method for diseases caused by autophagy deficiency in these tissues (Non-Patent Document 1).
  • the present invention covers lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer).
  • One purpose is to provide the following.
  • One object of the present invention is to provide a novel autophagy activator that activates cellular autophagy.
  • Item 1 Contains at least one compound selected from the group consisting of the compound represented by the following formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, and is used to treat lung diseases (excluding pulmonary fibrosis), renal disease. Diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome A pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of , and musculoskeletal diseases (excluding muscular dystrophy).
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different
  • m represents an integer from 0 to 5
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbon
  • Item 2. The pharmaceutical composition according to Item 1, wherein the disease is at least one disease selected from the group consisting of renal disease (excluding renal fibrosis), liver disorder, eye disease, and skin disease.
  • Item 3. In the compound represented by the formula (1), A represents a carbon atom or a nitrogen atom, B represents a carbon atom or a nitrogen atom, R 1 represents a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and when there is more than one, may be the same or different; m represents an integer from 0 to 4, R 2 is a fluorine atom; a chlorine atom; a bromine atom; a trifluoromethyl group; a trichloromethyl group; a tribromomethyl group; a
  • A represents a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group, and when there is more than one, may be the same or different
  • m represents an integer from 0 to 3
  • R 2 is a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1 to C4 alkyl group; a C2 to C4 acyloxy group; a C2 to C4 alkoxycarbonyl group; a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group
  • A represents a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a chlorine atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, or a trichloromethyl group, and when there are multiple groups, they may be the same or different
  • m represents an integer from 0 to 2
  • R 2 is selected from the group consisting of a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group.
  • Item 6 The compound represented by the formula (1) is at least one compound selected from the group consisting of a compound represented by the following formula (1-1) and a compound represented by the following formula (1-2). , the pharmaceutical composition according to item 1 or 2.
  • R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
  • m represents an integer from 0 to 5
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • a and B do not represent a carbon atom at the same time
  • R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the
  • Section 7. Item 3. The pharmaceutical composition according to item 1 or 2, wherein the compound represented by formula (1) is any of the compounds shown below.
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different
  • m represents an integer from 0 to 5
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbon
  • Item 9. The autophagy activator according to item 8, wherein the cell is at least one selected from the group consisting of kidney cells, skin cells, eye cells, and hepatocytes.
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and when there is more than one, may be the same or different
  • m represents an integer from 0 to 4
  • R 2 is a fluorine atom; a chlorine atom; a bromine atom; a trifluoromethyl group; a trichloromethyl group; a tribromomethyl group; a C1 to
  • A represents a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group, and when there is more than one, may be the same or different
  • m represents an integer from 0 to 3
  • R 2 is a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1 to C4 alkyl group; a C2 to C4 acyloxy group; a C2 to C4 alkoxycarbonyl group; a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group
  • An amide group which may be substituted with
  • A represents a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a chlorine atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, or a trichloromethyl group, and when there are multiple groups, they may be the same or different
  • m represents an integer from 0 to 2
  • R 2 is selected from the group consisting of a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group.
  • the autophagy activator according to any one of items 8 to 11.
  • Item 13 The compound represented by the formula (1) is at least one compound selected from the group consisting of a compound represented by the following formula (1-1) and a compound represented by the following formula (1-2). , the autophagy activator according to item 8 or 9.
  • R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
  • m represents an integer from 0 to 5
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • a and B do not represent a carbon atom at the same time
  • R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the
  • the pharmaceutical composition of the present invention contains a compound having the effect of activating autophagy or a pharmaceutically acceptable salt thereof, and therefore is useful for the prevention or treatment of kidney diseases, skin diseases, liver disorders, eye diseases, etc. It is.
  • the autophagy activator of the present invention is useful for enhancing cellular autophagy activity.
  • FIG. 1 shows the results of Western blotting of the autophagy markers LC-I, LC-II, and ⁇ -action observed in Test Example 1, and the luminescence intensity obtained under the conditions of Bafilomycin A1(+). It is a graph showing ⁇ intensity obtained by subtracting the luminescence intensity obtained under the conditions of +).
  • the cells used in the test were human alveolar basal epithelial adenocarcinoma cells (A549 cells).
  • FIG. 2 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • FIG. 3 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was the compound obtained in Example 1, and the cells were osteosarcoma cells (U2OS cells).
  • FIG. 4 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was the compound obtained in Example 1, and the cells were liver cancer cells (HepG2 cells).
  • FIG. 5 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was the compound obtained in Example 1, and the cells were epidermal keratinocytes (PSVK1 cells).
  • FIG. 6 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was the compound obtained in Example 1, and the cells were retinal pigment epithelial cells (RPE cells).
  • FIG. 7 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was cannabidiol and the cells were cervical epithelioid carcinoma cells (HeLa cells).
  • FIG. 8 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was cannabidiol and the cells were osteosarcoma cells (U2OS cells).
  • FIG. 9 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test was cannabidiol, and the cells were liver cancer cells (HepG2 cells).
  • FIG. 10 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2.
  • the sample used in the test is cannabidiol and the cells are retinal pigment epithelial cells (RPE cells).
  • RPE cells retinal pigment epithelial cells
  • the "halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Preferable examples include fluorine atom, chlorine atom, and bromine atom, and more preferably fluorine atom and chlorine atom.
  • the "alkyl group” includes, for example, a C1-C8 alkyl group containing a linear, branched, or cyclic structure, preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group. groups, particularly preferably C1-C3 alkyl groups.
  • linear or branched alkyl groups include methyl group, ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, isobutyl group, and tert-butyl group.
  • alkyl groups containing a cyclic structure examples include cyclopropyl group, cyclopropylmethyl group, cyclobutyl group, cyclo Examples include butylmethyl group, cyclopentyl group, cyclopentylmethyl group, cyclohexyl group, cyclohexylmethyl group, cyclohexylethyl group, and the like.
  • Preferred examples include methyl group, ethyl group, 2-propyl group, t-butyl group, and cyclopropyl group.
  • the "alkyl group substituted with a halogen atom” includes, for example, the alkyl group substituted with a halogen atom and having a linear, branched, or cyclic structure.
  • the number of substituents an alkyl group has is 1 to the maximum number that can be substituted, preferably 3 to the maximum number that can be substituted.
  • there is a plurality of halogen atoms they may be the same or different, but are preferably the same.
  • Examples include C1 to C4 alkyl groups substituted with the maximum number of substitutable halogen atoms, preferably C1 to C3 alkyl groups substituted with the maximum number of substitutable halogen atoms, more preferably substitutable A C1-C2 alkyl group substituted with the maximum number of halogen atoms, particularly preferably a trihalogenomethyl group.
  • alkyl groups substituted with halogen atoms include perfluoro-n-butyl group, perfluoro-t-butyl group, perfluoro-n-propyl group, perfluoro-i-propyl group, pentylfluoroethyl group, Trifluoromethyl group, perchloro-n-butyl group, perchloro-t-butyl group, perchloro-n-propyl group, perchloro-i-propyl group, pentachloroethyl group, trichloromethyl group, perbromo-n-butyl group, perbromo -t-butyl group, perbromo-n-propyl group, perbromo-i-propyl group, pentabromoethyl group, tribromomethyl group, periodo-n-butyl group, periodo-t-butyl group, periodo-n-propyl group , periodo-i-propyl
  • Preferred examples of the alkyl group substituted with a halogen atom include a pentylfluoroethyl group, a trifluoromethyl group, a pentachloroethyl group, a trichloromethyl group, a pentabromoethyl group, a tribromomethyl group, a pentaiodoethyl group, and a triiodoethyl group.
  • a methyl group is mentioned, a trifluoromethyl group, a trichloromethyl group, and a tribromomethyl group are more preferable, and a trifluoromethyl group and a trichloromethyl group are even more preferable.
  • the "alkoxy group” includes, for example, a C1-C8 alkoxy group containing a linear, branched, or cyclic structure, preferably a C1-C6 alkoxy group, more preferably a C1-C4 alkoxy group. groups, particularly preferably C1-C3 alkoxy groups.
  • linear or branched alkoxy groups include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, isobutoxy group, and tert-butoxy group.
  • alkoxy groups containing a cyclic structure include cyclopropoxy group, cyclopropylmethoxy group, cyclobutyroxy group, cyclobutylmethoxy group, cyclopentyloxy group, cyclopentylmethoxy group, cyclohexyloxy group, cyclohexylmethoxy group, cyclohexylethoxy group, etc.
  • Preferred examples include methoxy group, ethoxy group, 2-propoxy group, tert-butoxy group, and cyclopropoxy group.
  • the "acyloxy group” includes, for example, a C2-C9 acyloxy group containing a linear, branched, or cyclic structure, preferably a C2-C7 acyloxy group, more preferably a C2-C5 acyloxy group. groups, particularly preferably C2-C4 acyloxy groups.
  • the linear or branched acyloxy group includes a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propoxycarbonyl group, a 2-propoxycarbonyl group, a 1-butoxycarbonyl group, a 2-butoxycarbonyl group, Examples include isobutoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, neopentyloxycarbonyl group, n-hexyloxycarbonyl group, isohexyloxycarbonyl group, and 3-methylpentyloxycarbonyl group.
  • Acyloxy groups containing a cyclic structure include cyclopropoxycarbonyl group, cyclopropylmethoxycarbonyl group, cyclobutyroxycarbonyl group, cyclobutylmethoxycarbonyl group, cyclopentyloxycarbonyl group, cyclopentylmethoxycarbonyl group, cyclohexyloxycarbonyl group, cyclohexylmethoxy Examples include carbonyl group, cyclohexylethoxycarbonyl group, and the like. Preferred examples include methoxycarbonyl group, ethoxycarbonyl group, 2-propoxycarbonyl group, tert-butoxycarbonyl group, and cyclopropoxycarbonyl group.
  • the "alkoxycarbonyl group” includes a carbonyl group bonded to the alkoxy group, such as a carbonyl group bonded to a C1 to C8 alkoxy group, which has a linear, branched, or cyclic structure. and is preferably a C2-C7 alkoxycarbonyl group, more preferably a C2-C5 alkoxycarbonyl group, particularly preferably a C2-C4 alkoxycarbonyl group.
  • linear or branched alkoxy groups constituting the alkoxycarbonyl group include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, isobutoxy group, tert- Examples include butoxy group, n-pentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, and 3-methylpentyloxy group.
  • alkoxy groups containing a cyclic structure constituting an alkoxycarbonyl group include a cyclopropoxy group, a cyclopropylmethoxy group, a cyclobutyroxy group, a cyclobutylmethoxy group, a cyclopentyloxy group, a cyclopentylmethoxy group, a cyclohexyloxy group, and a cyclohexylmethoxy group. , cyclohexylethoxy group, and the like.
  • Preferred examples of the alkoxy group constituting the alkoxycarbonyl group include methoxy group, ethoxy group, 2-propoxy group, tert-butoxy group, and cyclopropoxy group.
  • an amide group which may be substituted with one or two groups selected from the group consisting of an alkyl group and an alkoxycarbonyl group refers to an amide group, a mono- or di-alkyl amide group, a mono- or di- It includes an alkoxycarbonylamide group, an alkyl group, and an amide group di-substituted with an alkoxycarbonyl group, preferably an amide group or a dialkylamide group, and more preferably a dialkylamide group.
  • the substituents may be the same or different.
  • Examples of the monoalkyl amide group include amide groups mono-substituted with the above-mentioned alkyl groups, preferably amide groups mono-substituted with C1-C4 alkyl groups, more preferably amide groups mono-substituted with C1-C3 alkyl groups. Among these groups, particularly preferred are methylamide and ethylamide groups.
  • Examples of dialkylamide groups include amide groups di-substituted with the above-mentioned alkyl groups, preferably amide groups di-substituted with C1-C4 alkyl groups, more preferably amide groups di-substituted with C1-C3 alkyl groups.
  • dimethylamide group diethylamide group, and ethylmethylamide group.
  • the monoalkoxycarbonylamide group include an amide group mono-substituted with the above-mentioned alkoxycarbonyl group, preferably an amide group mono-substituted with a C2-C5 alkoxycarbonyl group, more preferably a mono-substituted amide group with a C2-C4 alkoxycarbonyl group.
  • Substituted amide groups particularly preferred are methoxycarbonylamide and ethoxycarbonylamide groups.
  • the dialkoxycarbonylamide group includes an amide group di-substituted with the alkoxycarbonyl group described above, preferably an amide group di-substituted with a C2-C5 alkoxycarbonyl group, more preferably a di-substituted amide group with a C2-C4 alkoxycarbonyl group.
  • Substituted amide groups particularly preferred are di(methoxycarbonyl)amide and di(ethoxycarbonyl)amide groups.
  • the amide group substituted with an alkyl group and an alkoxycarbonyl group includes an amide group di-substituted with the alkyl group and the alkoxycarbonyl group, preferably a di-substituted amide group with a C1-C4 alkyl group and a C2-C5 alkoxycarbonyl group.
  • a substituted amide group more preferably a di-substituted amide group with a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group, particularly preferably a methylmethoxycarbonylamide group, a methylethoxycarbonylamide group, an ethylmethoxycarbonylamide group, Examples include ethyl ethoxycarbonylamide group.
  • the number of substituents that the piperidinylcarbonyl group has is The number is 0 to 5, preferably 0 to 4, more preferably 0 to 3, even more preferably 0 to 2, particularly preferably 0 or 1.
  • the piperidinylcarbonyl group has a substituent at least one substituent is attached to the carbon atom at the 3-position of the piperidine ring (specifically, the 3-position when the nitrogen atom constituting the piperidine ring is the 1-position). Preferably, they are bonded.
  • substituents include the above-mentioned alkyl group and the above-mentioned alkoxycarbonyl group, preferably a C1-C4 alkyl group, a C2-C5 alkoxycarbonyl group, more preferably a C1-C3 alkyl group, a C2-C4 alkoxycarbonyl group. Particularly preferred are a methyl group, an ethyl group, a methoxycarbonyl group, and an ethoxycarbonyl group.
  • the number of substituents that the pyrrolidinylcarbonyl group has is The number is 0 to 4, preferably 0 to 3, more preferably 0 to 2, particularly preferably 0 or 1. When there are multiple substituents, they may be the same or different.
  • the pyrrolidinylcarbonyl group has a substituent at least one substituent is attached to the carbon atom at the 3-position of the pyrrolidine ring (specifically, the 3-position when the nitrogen atom constituting the pyrrolidine ring is the 1-position). Preferably, they are bonded.
  • substituents include the above-mentioned alkyl group and the above-mentioned alkoxycarbonyl group, preferably a C1-C4 alkyl group, a C2-C5 alkoxycarbonyl group, more preferably a C1-C3 alkyl group, a C2-C4 alkoxycarbonyl group. Particularly preferred are a methyl group, an ethyl group, a methoxycarbonyl group, and an ethoxycarbonyl group.
  • the pharmaceutical composition of the present invention can be used to treat lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancers (lung cancer, prostate cancer, and A composition for preventing or treating at least one disease selected from the group consisting of breast cancer (excluding breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome, and musculoskeletal diseases (excluding muscular dystrophy). It is a thing.
  • the pharmaceutical composition of the present invention contains one or more selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition and autophagy activator of the present invention contain at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof. do.
  • the present inventors have discovered that these compounds and their pharmaceutically acceptable salts have the effect of activating cellular autophagy.
  • autophagy is activated, recycling of intracellular substances and elimination of intracellular harmful substances, which have been stagnant or delayed due to decreased autophagy activity, become active, thereby restoring the original basic functions of cells.
  • At least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol can be used to treat lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive Functional disorders, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome, and musculoskeletal diseases (excluding muscular dystrophy) ) is effective in preventing or treating at least one disease selected from the group consisting of:
  • Autophagy refers to a system in which intracellular organelles or proteins are degraded via autophagosome formation.
  • activation of autophagy refers to a state in which the intracellular protein recycling mechanism is activated by inducing or promoting autophagy within the cell. Specifically, it includes the formation of an isolation membrane, the elongation of an isolation membrane, A state in which at least one process among phagosome formation and fusion of autophagosomes and lysosomes is induced or promoted.
  • Autophagy activity can be confirmed by a conventionally known method for measuring autophagy activity.
  • methods for measuring autophagy activity include methods for detecting autophagy marker proteins.
  • autophagy marker proteins include LC3 (rat microtubule-associated protein 1 light chain 3).
  • LC3-I rat microtubule-associated protein 1 light chain 3
  • LC3-II There are two forms of LC3: LC3-I and LC3-II. When LC3 exists in the cytoplasm, it exists as LC3-I, and LC3-I is converted to lipidated LC3-II during autophagosome formation, and can be incorporated into the inner and outer membranes of autophagosomes.
  • autophagy activity can be confirmed by detecting LC3-I and LC3-II and measuring the conversion rate to LC3-II (Kabeya Y., Mizushima N., Ueno T., Yamamoto A., Kirisako T., Noda T., Kominami E., Ohsumi Y., Yoshimori T.: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. The EMBO Journal, 19: 5720-5728 (2000)).
  • Autophagy activity can also be confirmed by expressing in cells tfLC3, which is a tandem fusion of two types of fluorescent proteins (mRFP and EGFP) to LC3 (Kimura S., Noda T., Yoshimori T.: Dissection of the Autophagosome Maturation Process by a Novel Reporter Protein, Tandem Fluorescent-Tagged LC3. Autophagy 3:452-460 (2007)).
  • mRFP and EGFP fluorescent proteins
  • EGFP disappears in an (auto)lysosomal environment, so the lower the ratio of EGFP amount/mRFP amount in a cell, the more activated autophagy is.
  • a fluorescence microscope can be used to measure the amount of fluorescence in cells, and analysis software can be used to calculate the amount of fluorescence.
  • Compound represented by formula (1) (also referred to herein as "compound (1)”) Equation (1) is as follows.
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different
  • m represents an integer from 0 to 5
  • R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups
  • Formula (1) may be Formula (1-1) or Formula (1-2).
  • Compound (1) is a compound represented by the following formula (1-1) (herein also referred to as “compound (1-1)”) or a compound represented by the following formula (1-2) (hereinafter also referred to as “compound (1-1)”). In the specification, it may also be referred to as “compound (1-2)”).
  • Compound (1-1) and compound (1-2) are new compounds. [In formula (1-1), R 1 , R 2 , m, and n are the same as in formula (1).
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • a and B do not represent a carbon atom at the same time
  • R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different
  • R 2 and n are the same as in formula (1).
  • A represents a carbon atom or a nitrogen atom
  • B represents a carbon atom or a nitrogen atom
  • a and B do not represent carbon atoms at the same time.
  • a and B are both carbon atoms
  • A is a carbon atom and B is a nitrogen atom
  • A is a nitrogen atom and B is a carbon atom
  • a and B are both nitrogen atoms. That is, the ring containing A and B is a benzene ring, pyridine ring, or pyridazine ring in formulas (1) and (1-1), and is a pyridine ring or pyridazine ring in formula (1-2).
  • the combination of A and B is that both A and B are carbon atoms, A is a carbon atom and B is a nitrogen atom, or A is a nitrogen atom and B is a carbon atom. It is preferable that A and B are both carbon atoms, or that A is a nitrogen atom and B is a carbon atom.
  • formula (1-2) as a combination of A and B, it is preferable that A is a carbon atom and B is a nitrogen atom, or A is a nitrogen atom and B is a carbon atom, and A is a nitrogen atom and B is a carbon atom. More preferably, it is an atom.
  • the carbon atom may have a substituent R 1 .
  • R 1 is preferably a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and a fluorine atom, A chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group are more preferable, and a chlorine atom, a C1-C3 alkyl group, a C1 -C3 alkoxy group, C2-C4 alkoxycarbonyl group, trifluoromethyl group, or trichloromethyl group is more preferred
  • R 1 is located at the ortho position to the carbon atom directly bonding to the nitrogen atom constituting (NH) p among the carbon atoms constituting the benzene ring. Preferably, it is bonded to at least one of two carbon atoms.
  • R 1 bonded to the carbon atom located at the ortho position include an alkoxy group or an alkoxycarbonyl group, preferably a C2-C5 alkoxycarbonyl group, more preferably a C2-C4 alkoxycarbonyl group, and a methoxycarbonyl group or an ethoxycarbonyl group.
  • a carbonyl group is more preferred, and an ethoxycarbonyl group is particularly preferred.
  • the ring to which R 1 is bonded is a benzene ring, and among the carbon atoms constituting the benzene ring, it is located at the meta position with respect to the carbon atom directly bonded to the nitrogen atom constituting (NH) p .
  • a halogen atom is preferable, a chlorine atom or a fluorine atom is more preferable, and a fluorine atom is particularly preferable.
  • R 1 is the carbon atom that directly bonds to the nitrogen atom that constitutes (NH)p among the carbon atoms that constitute the pyridine ring or pyridazine ring. It is preferable to bond to a carbon atom located between A and A.
  • R 1 may be, for example, a halogen atom, an alkyl group, an alkoxy group, or an alkoxycarbonyl group, and may be a fluorine atom, a chlorine atom, a C1-C4 alkyl A C1-C4 alkoxy group or a C2-C5 alkoxycarbonyl group is preferred, a C1-C4 alkoxy group is more preferred, and a methoxy group or an ethoxy group is particularly preferred.
  • R 3 may be a halogen atom, an alkyl group, an alkoxy group, or an alkoxycarbonyl group, preferably a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a C2-C5 alkoxycarbonyl group, A C1-C4 alkoxy group is more preferred, and a methoxy group or an ethoxy group is particularly preferred.
  • m is preferably an integer of 0 to 4, more preferably an integer of 0 to 3, even more preferably 0, 1, or 2, even more preferably 0 or 1, and particularly preferably 1.
  • R 2 When there is a plurality of R 2 s, they may be the same or different.
  • R2 fluorine atom; chlorine atom; bromine atom; trifluoromethyl group; trichloromethyl group; tribromomethyl group; C1 to C4 alkyl group; C2 to C5 acyloxy group; C2 to C5 alkoxycarbonyl group; C1 to C3
  • An optionally substituted pyrrolidinylcarbonyl group is preferred, and includes a
  • R 2 is one of the two carbon atoms located at the ortho position to the carbon atom directly bonded to the nitrogen atom forming the piperazine ring, among the carbon atoms forming the benzene ring to which R 2 is bonded. Or, it is preferable that it is bonded to two atoms, and more preferably that it is bonded to one ortho-position carbon atom. R 2 may be bonded to a carbon atom located at the para position. R 2 is (a) bonded to only one of the two carbon atoms in the ortho position, (b) one of the two carbon atoms in the ortho position and a carbon atom in the para position.
  • R2 is (a) bonded to only one of the two carbon atoms in the ortho position, or (b) bonded to one of the two carbon atoms in the ortho position and the carbon in the para position. More preferably, it is bonded to an atom.
  • R2 bonded to the carbon atom located at the ortho position is preferably a halogen atom, a trihalogenomethyl group, or a C1-C3 alkyl group, and is preferably a fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, methyl group, or An ethyl group is more preferred, and a chlorine atom, a trifluoromethyl group, or a methyl group is particularly preferred.
  • R2 bonded to the carbon atom located at the para position is substituted with one or two groups selected from the group consisting of, for example, a halogen atom, an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group.
  • an amide group which may be substituted a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of an alkyl group and an alkoxycarbonyl group; or a group consisting of an alkyl group and an alkoxycarbonyl group It may be a pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from: chlorine atom; bromine atom; fluorine atom; C1-C3 alkyl group; C2-C4 acyloxy group; C2 -C4 alkoxycarbonyl group; amide group optionally substituted with one or two groups selected from the group consisting of C1-C3 alkyl group and C2-C4 alkoxycarbonyl group; C1-C3 alkyl group and C2-C4 A piperidinylcarbonyl group optionally substituted with one or more groups selected from the group consisting of alkoxycarbonyl groups; or selected from the group consisting of C1-C3 al
  • a pyrrolidinylcarbonyl group which may be substituted with one or more groups is preferred, and is selected from a chlorine atom; a methyl group; an ethyl group; a methoxycarbonyl group; an ethoxycarbonyl group; an amide group; a C1-C3 alkyl group.
  • n is preferably an integer of 0 to 4, more preferably an integer of 0 to 3, even more preferably 0, 1, or 2, even more preferably 1 or 2, and particularly preferably 2.
  • q is preferably 1.
  • compound (1), compound (1-1), or compound (1-2) can be used as (a) to (e), (g), (h), (j), or (k) above. It may be a compound as shown.
  • compound (1), compound (1-1), or compound (1-2) is a compound represented by (a) to (d), (g), (h), or (k) above. It may be.
  • Compound (1) or compound (1-1) is 2-(4-(2-chloro-4-piperidine-1-carbonyl)phenyl)piperazin-1-yl)-N-(2-ethoxyphenyl ) Acetamide is particularly preferred.
  • Compound (1), compound (1-1), and compound (1-2) can be produced by known production methods for known compounds included therein.
  • the novel compound can be produced, for example, by appropriately modifying or combining Production Methods 1 or 2 detailed below, methods similar thereto, known methods, and the like.
  • Each compound used as a raw material compound may be used as a salt.
  • the method shown below is merely an example, and other methods can be used as appropriate based on the knowledge of those skilled in organic synthesis.
  • the compound represented by formula (1A) can be produced by the synthesis scheme shown in Reaction Scheme-1 below. That is, the compound represented by formula (1A) can be produced from the compound represented by formula (2), the compound represented by formula (3), and the compound represented by formula (6).
  • X is a halogen atom
  • D is a protecting group
  • A, B, R 1 , m, R 2 and n are the same as above.
  • Examples of X include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom, with a bromine atom being preferred.
  • Examples of D include protective groups such as a halogen atom, a tert-butyl group, a phenyl group, a methyl group, and an ethyl group, with a tert-butoxy group being preferred.
  • R 2 is preferably an alkoxycarbonyl group and a halogen atom. More preferably, an alkoxycarbonyl group is bonded to the carbon atom at the para position. More preferably, an alkoxycarbonyl group is bonded to the carbon atom at the para position, and a halogen atom is bonded to the carbon atom at the ortho position.
  • Step 1 that is, the step of reacting the compound represented by formula (2) with the compound represented by formula (3) (which may be a hydrochloride) to synthesize the compound represented by formula (4),
  • the compound represented by formula (3) for example, 2-(4-(2-chlorophenyl)piperazin-1-yl)acetic acid (CAS No. 119357-76-5) can be used as a commercially available product, and its hydrochloric acid Salt (CAS No. 856843-13-5) can be produced by the method described in Journal of the American Chemical Society 1955, 77, 1, 40-42, and other compounds can be commercially available, and can be produced by known production methods. or by appropriately modifying a known manufacturing method.
  • inert solvents used in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, dichloromethane, chloroform, dichloroethane, and tetrachloride.
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane
  • aromatic hydrocarbon solvents such as toluene, benzene, and xylene
  • dichloromethane chloroform
  • dichloroethane dichloroethane
  • tetrachloride examples include halogenated hydrocarbon solvents such as carbon, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF),
  • bases include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, and cesium carbonate.
  • metal hydrides such as sodium hydride and potassium hydride
  • metal hydroxides such as potassium hydroxide and sodium hydroxide
  • metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, and cesium carbonate.
  • Examples include carbonates, alkyl amines such as triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.
  • the amount of the compound represented by formula (2) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (3). mol, more preferably 0.9 to 1.5 mol.
  • the amount of the base to be used is usually 1 mole or more, preferably 1 to 5 times the mole, more preferably 1 to 2 times the mole, per 1 mole of the compound represented by formula (3).
  • the reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably 0°C to 40°C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
  • Step 2 that is, the step of converting the compound represented by formula (4) into the compound represented by formula (5), can be performed, for example, by treating the compound represented by formula (4) with an acidic organic solvent. be.
  • Examples of the acidic organic solvent in this reaction include 1,4-dioxane containing hydrochloric acid. Two or more of these solvents may be used as a mixture in an appropriate ratio. The amount of the acidic organic solvent to be used may be an amount sufficient to oxidize the compound represented by formula (4).
  • Step 3 that is, the step of reacting the compound represented by formula (5) with the compound represented by formula (6) to synthesize the compound represented by formula (1A), is carried out using, for example, a base and a condensation reaction in an inert solvent. It can be carried out in the presence of an agent. Details of the inert solvent and base are the same as above.
  • condensing agent examples include 1-[dimethylamino(dimethyliminio)methyl]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (herein, (also referred to as "HATU").
  • the amount of the compound represented by formula (6) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (5). mol, more preferably 0.9 to 1.5 mol.
  • the amount of the condensing agent used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, more preferably 0.5 mol or more, per 1 mol of the compound represented by formula (5).
  • the amount is 9 to 1.5 moles.
  • the reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably 0°C to 40°C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
  • the corresponding carboxylic acid can be obtained by treating this compound in the presence of a base in an inert solvent, for example. It can be converted into a body.
  • a suitable substituent is introduced into this carboxylic acid.
  • the corresponding amide group or pipe as R2 is reacted with a compound corresponding to the substituent (e.g. piperidine, amine, etc.).
  • a compound represented by formula (1A) having a peridinylcarbonyl group can also be obtained. Details of the inert solvent, base and condensing agent are the same as above.
  • the amount of the compound corresponding to the substituent such as piperidine or amine is usually 0.5 mol or more per 1 mol of the compound represented by formula (1A) in which R 2 is an alkoxycarbonyl group.
  • the amount is 0.8 mol or more, preferably 0.9 to 10 mol, more preferably 0.9 to 8 mol.
  • the reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably 0°C to 40°C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
  • the compound represented by formula (1A) can be produced according to the synthesis scheme shown in Reaction Scheme-2 below. That is, the compound represented by formula (1A) can be produced from the compound represented by formula (6), the compound represented by formula (7), and the compound represented by formula (3).
  • Step 1 that is, the step of reacting the compound represented by formula (6) with the compound represented by formula (7) to synthesize the compound represented by formula (8), is performed in the presence of a base in an inert solvent, for example. You can do it below. Details of the inert solvent and base are the same as above.
  • the amount of the compound represented by formula (7) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (6). mol, more preferably 0.9 to 1.5 mol.
  • the reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably -10°C to 40°C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
  • Step 2 that is, the step of reacting the compound represented by formula (8) with the compound represented by formula (3) to synthesize the compound represented by formula (1A), is performed in the presence of a base in an inert solvent, for example. You can do it below. Details of the inert solvent and base are the same as above.
  • the amount of the compound represented by formula (3) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (8). mol, more preferably 0.9 to 1.5 mol.
  • the reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably -10°C to 40°C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
  • Cannabidiol Cannabidiol is 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1, which is shown by the chemical structural formula below. 3-Benzenediol, which was discovered by the present inventors to have an autophagy activating effect. Cannabidiol can be produced by known methods or obtained from natural products.
  • Compounds represented by formula (1) according to the present invention (compounds represented by formula (1) include compounds represented by formula (1-1) and formula (1-2), unless otherwise specified. ) and its intermediate compounds can be produced by the above production method, and the starting material compound, the compound represented by formula (1) according to the present invention, and its intermediate compounds can be produced by the above-mentioned production method.
  • the compound can be synthesized using techniques known or known at the time of this application (for example, B. R.
  • the functional groups are protected with an appropriate protecting group using a known method, and after the reaction is completed, The protecting group can be deprotected by a known method.
  • Each of the target compounds obtained according to the above reaction formula can be isolated and purified. For example, after cooling the reaction mixture, isolation procedures such as filtration, concentration, extraction, etc. are carried out to separate the crude reaction product, and then the crude reaction product is subjected to common methods such as column chromatography, recrystallization, etc. It can be isolated and purified from the reaction mixture by subjecting it to purification procedures.
  • the compound represented by formula (1) and the starting material compounds, intermediate compounds, etc. shown in each of the above reaction formulas include solvates with a solvent added (e.g., hydrates, ethanolates, etc.) Compounds that are in the form of are included.
  • the intermediate compound obtained in each of the above reaction schemes, the starting material compound, the compound represented by formula (1), and cannabidiol have isomers (E, Z, cis, trans ), isomers due to the presence of asymmetric carbon (R, S form, ⁇ , ⁇ form, enantiomer, diastereomer), optically active form with optical rotation (D, L, d, l form), chromatography Polar substances (highly polar, low polar), equilibrium compounds, rotamers, mixtures of these in arbitrary proportions, and racemic mixtures include isomers such as geometric isomers, stereoisomers, and optical isomers due to separation. In this case, all isomers are included.
  • optical isomers can be separated using various known separation methods (for example, optical resolution by crystallization, direct optical resolution by chromatography, etc.).
  • Pharmaceutically acceptable salts of the compound represented by formula (1) and cannabidiol are not particularly limited, and include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts and magnesium salts; Metal salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids; hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, etc.
  • Inorganic acid salts acetate, carbonate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonic acid
  • organic acid salts such as salts, benzenesulfonates, and ascorbates. These salts can be produced according to conventional methods.
  • Various isomers can be isolated by known separation methods. For example, a racemic compound can be led to a sterically pure isomer by a general optical resolution method (eg, optical resolution by crystallization, direct optical resolution by chromatography, etc.). Furthermore, optically active compounds can also be produced by using appropriate optically active raw materials.
  • a general optical resolution method eg, optical resolution by crystallization, direct optical resolution by chromatography, etc.
  • optically active compounds can also be produced by using appropriate optically active raw materials.
  • the starting material compounds, intermediate compounds, and target compounds represented in each of the above reaction schemes can be used in an appropriate salt form.
  • one or more atoms can be substituted with one or more isotopic atoms.
  • isotopic atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O, and the like.
  • compositions comprising at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable salt thereof. may contain a carrier acceptable to
  • the pharmaceutical composition of the present invention comprises at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition. This is what I did.
  • the pharmaceutical composition of the present invention comprises at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It can be prepared using, for example, a conventional method.
  • the carrier include commonly used fillers, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, and other diluents or excipients.
  • the pharmaceutical composition of the present invention can be selected from various forms depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, Examples include suppositories, injections (solutions, suspensions, etc.), ointments, inhalants, and the like.
  • a wide variety of known carriers can be used as carriers for forming tablets, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose, water, ethanol, Propanol, simple syrup, glucose solution, starch solution, gelatin solution, methylcellulose, potassium phosphate, polyvinylpyrrolidone, carboxymethylcellulose, binder such as shellac, sodium alginate, dried starch, powdered agar, powdered laminaran, calcium carbonate, sodium bicarbonate.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose, water, ethanol, Propanol, simple syrup, glucose solution, starch solution, gelatin solution, methylcellulose, potassium phosphate, polyvinylpyrrolidone, carboxymethylcellulose, binder such as shellac, sodium alginate, dried starch
  • polyoxyethylene sorbitan fatty acid esters sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, stearin, cocoa butter, hydrogenated oils, etc.
  • disintegrants such as lactose, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, stearin, cocoa butter, hydrogenated oils, etc.
  • disintegration inhibitors such as lactose, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, stearin, cocoa butter, hydrogenated oils, etc.
  • disintegration inhibitors such as lactose, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, stearin, cocoa butter, hydrogenated oils, etc.
  • the tablet may be a tablet coated with a conventional tablet shell, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.
  • a conventional tablet shell for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.
  • a wide variety of known carriers can be used as carriers for forming pills, including excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth, and gelatin. , binders such as ethanol, and disintegrants such as laminaran and agar.
  • a wide variety of known carriers can be used as carriers for forming suppositories, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like.
  • solutions, emulsions and suspensions are preferably sterilized and isotonic with blood.
  • diluent used in preparing these solutions, emulsions and suspensions a wide variety of known diluents can be used, such as water, ethanol, propylene glycol, polyoxylated isostearyl alcohol, and ethoxylated isostearyl alcohol. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • sufficient amounts of salt, glycerin, glucose, etc. can be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffering agents, painless agents, etc. can be included in the pharmaceutical preparation.
  • coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc., and other pharmaceuticals can be contained as necessary.
  • Ointments come in the form of paste, cream, or gel, and when preparing these forms, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. are used. can.
  • diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. are used. can.
  • Inhalants are preparations that are intended to be applied to the bronchi or lungs by inhaling the active ingredient as an aerosol, and include powder inhalants, inhalation liquids, inhalation aerosols, and the like.
  • Powder inhalants are preparations that are inhaled as an aerosol of powdered solid particles, and are usually manufactured by making the active ingredient into fine particles and mixing them with additives such as lactose as necessary to make them homogeneous. can.
  • Inhalation liquids refer to liquid inhalants that are applied with a nebulizer or the like, and can usually be produced by adding and mixing the active ingredients with a solvent, an appropriate tonicity agent, a pH adjuster, etc.
  • Inhalation aerosols are metered dose inhalants that spray a fixed amount of active ingredient together with a propellant filled in a container.
  • Inhalation aerosols are usually made into a solution or suspension by adding a solvent and appropriate dispersants, stabilizers, etc. to the active ingredient, and then filling the solution or suspension with a liquid propellant into a pressure-resistant container, which is fitted with a metering valve. It can be manufactured by
  • the pharmaceutical composition of the present invention may contain colorants, preservatives, fragrances, flavors, sweeteners, etc., or other pharmaceuticals, as necessary.
  • the amount of at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, contained in the pharmaceutical composition of the present invention is particularly It can be appropriately selected from a wide range without limitation, but it is usually 0.5 to 90% by weight, 1 to 85% by weight, preferably 1 to 80% by weight in the pharmaceutical composition.
  • the method of administering the pharmaceutical composition of the present invention is not particularly limited, and it is administered in a manner depending on various formulation forms, patient age, sex, disease state, and other conditions.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.
  • they can be administered intravenously alone or mixed with normal replacement fluids such as glucose or amino acids, or if necessary, they can be administered alone intramuscularly, intradermally, subcutaneously, intraperitoneally, etc. It can be administered to In the case of suppositories, they are administered rectally.
  • Inhalants are administered nasally.
  • the dosage of the pharmaceutical composition of the present invention may be selected in consideration of the usage, patient's age, sex, degree of disease, and other conditions, and can be selected from the group consisting of the compound represented by formula (1) and cannabidiol.
  • At least one compound selected from the following or a pharmaceutically acceptable salt thereof is usually administered in an amount of 0.01 to 100 mg, preferably 0.1 to 50 mg per kg of body weight per day. It is administered in one to several divided doses, or at intervals of once every 2, 3, 4, 5, 6 days, 1 week, 2 weeks, or 4 weeks.
  • the dosage varies depending on various conditions, so a dosage smaller than the above range may be sufficient in some cases, and a dosage exceeding the above range may be necessary in other cases.
  • the pharmaceutical composition of the present invention can also be used as a concomitant drug in combination with other drugs.
  • the pharmaceutical composition of the present invention may be used in combination with, for example, an anticancer drug.
  • Anticancer drugs include antitumor antibiotics such as doxorubicin, idarubidin, and mitomycin C, microtubule inhibitors such as docetaxel and vincristine, platinum agents such as carboplatin, cisplatin, and oxaliplatin, and histone deacetylases such as vorinostat.
  • HDAC HDAC
  • kinase inhibitors such as sunitinib, imatinib, gefetinib, erlotinib, afatinib, dasatinib, trametinib
  • topoisomerase inhibitors such as irinotecan, etoposide
  • calcineurin inhibitors such as cyclosporine, tacrolimus, cyclophosphamide, bendamustine
  • Alkylating drugs such as iosfamide and dacarbazine
  • antimetabolites such as pentostatin, fludarabine, cladribine, methotrexate, 5-fluorouracil, 6-mercaptopurine, and enocitabine
  • molecular targeted drugs such as rituximab, cetuximab, and trastuzumab
  • proteasome inhibitors such as bortezomib.
  • Hormone therapy drugs such as tamoxifen and bicaldamide, anti-PD-1 antibodies such as nivolumab, pembrolizumab, and pidilizumab, anti-PD-L1 antibodies such as atezolizumab, avelumab, or durvalumab, BMS-936559, and anti-CTLA drugs such as ipilimumab or tremelimumab. 4 antibodies can be mentioned. Combination use with these anticancer agents is preferable for use in cancer prevention or treatment.
  • the pharmaceutical composition of the present invention may be used in combination with, for example, an SGLT2 inhibitor such as dapagliflozin, an ACE inhibitor such as enalapril, an ARB such as candesartan, and the like. Combination use with these drugs is preferred for the prevention or treatment of renal diseases.
  • the pharmaceutical composition of the present invention may be used in combination with, for example, a VEGF antibody such as ranibismumab, a PGF2 ⁇ -related drug such as latanoprost, and the like. Combination use with these drugs is preferred for use in the prevention or treatment of eye diseases.
  • the pharmaceutical composition of the present invention may be used in combination with, for example, a ⁇ -lactam antibiotic such as meropenem.
  • Combination use with these drugs is preferred for the prevention or treatment of bacterial infections and viral infections.
  • the pharmaceutical composition of the present invention may be used in combination with, for example, a TNF ⁇ antibody such as adalimumab. Combination use with these drugs is preferred for use in the prevention or treatment of autoimmune diseases.
  • Diseases that can be prevented or treated with the pharmaceutical composition of the present invention include lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, Examples include cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome, and musculoskeletal diseases (excluding muscular dystrophy).
  • Preferred diseases are renal diseases (excluding renal fibrosis), liver disorders, eye diseases, and skin diseases, and more preferred diseases are renal diseases and skin diseases.
  • one of the diseases targeted for prevention or treatment is lung diseases other than pulmonary fibrosis.
  • Pulmonary diseases include chronic obstructive pulmonary disease (COPD), cystic fibrosis, etc., with COPD being preferred.
  • COPD chronic obstructive pulmonary disease
  • kidney diseases include acute kidney injury, chronic kidney disease, diabetic nephropathy, etc., with acute kidney injury and chronic kidney disease being preferred.
  • reproductive dysfunction one of the diseases targeted for prevention or treatment is reproductive dysfunction.
  • reproductive dysfunction include female infertility, male infertility, and endometriosis.
  • liver damage one of the diseases targeted for prevention or treatment is liver damage.
  • Liver disorders include nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cholestasis, hyperammonemia, etc.
  • NASH nonalcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • one of the diseases to be prevented or treated is an eye disease.
  • Eye diseases include glaucoma, age-related macular degeneration, retinitis pigmentosa, etc., with glaucoma and age-related macular degeneration being preferred.
  • one of the diseases targeted for prevention or treatment is a skin disease.
  • skin diseases include keloids, scleroderma, and psoriasis, with psoriasis being preferred.
  • one of the diseases targeted for prevention or treatment is cancer other than lung cancer, prostate cancer, and breast cancer.
  • cancer include melanoma, pancreatic cancer, cervical cancer, osteosarcoma, liver cancer, and skin cancer, with cervical cancer, osteosarcoma, liver cancer, and skin cancer being preferred.
  • one of the diseases targeted for prevention or treatment is bacterial infection.
  • bacterial infections include rickettsiosis, tuberculosis, group A streptococcal infection, and staphylococcus aureus infection, with tuberculosis and group A streptococcal infection being preferred.
  • one of the diseases to be prevented or treated is a viral infection.
  • viral infections include HIV-1, chikungunya fever, West Nile encephalitis, and the like, with West Nile encephalitis being preferred.
  • one of the diseases targeted for prevention or treatment is an autoimmune disease.
  • autoimmune diseases include Crohn's disease, ulcerative colitis, and rheumatoid arthritis, with Crohn's disease being preferred.
  • one of the diseases targeted for prevention or treatment is metabolic syndrome.
  • metabolic syndrome examples include obesity, type 2 diabetes, and the like, with obesity being preferred.
  • one of the diseases to be prevented or treated is musculoskeletal diseases other than muscular dystrophy.
  • musculoskeletal diseases include degenerative myopathy, Paget's disease of bone (PDB), osteoarthritis, and osteoporosis, with osteoporosis being preferred.
  • the autophagy activator of the present invention has an action of activating cellular autophagy and contains at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol. In addition to the compound or its pharmaceutically acceptable salt, it may contain a pharmaceutically acceptable carrier.
  • the content of at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol in the autophagy activator, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition The content can be the same.
  • Various matters such as the form of the autophagy activator can be the same as the corresponding various matters in the pharmaceutical composition.
  • autophagy of cells can be improved in vivo or in vitro.
  • Enhances activity can be, for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more (preferably 2 times or more, more preferably 2.5 times or more).
  • Examples of cells to which the autophagy activator is applied include lung cells, kidney cells, reproductive cells, liver cells, eye cells, skin cells, cancer cells, muscle cells, and bone cells.
  • Preferred cells are kidney cells, skin cells, eye cells, and liver cells.
  • the cells may be used alone or in combination of two or more.
  • the cells may be human cells or non-human mammalian cells.
  • one of the target cells is lung cells.
  • lung cells include alveolar basal epithelial gland cells.
  • one of the target cells is kidney cells.
  • renal cells include renal glomerular endothelial cells, renal proximal tubular epithelial cells, renal cortical epithelial cells, renal epithelial cells, renal mesangial cells, renal tubular epithelial cells, and the like.
  • one of the target cells is a germ cell.
  • germ cells include cervical epithelioid cells.
  • one of the target cells is hepatocytes.
  • hepatocytes include hepatic parenchymal cells and hepatic non-parenchymal cells.
  • one of the target cells is an eye cell.
  • eye cells include retinal pigment epithelial cells.
  • one of the target cells is skin cells.
  • skin cells include epidermal keratinocytes.
  • one of the target cells is cancer cells.
  • cancer cells include liver cancer cells, osteosarcoma cells, lung cancer cells, prostate cancer cells, and breast cancer cells. Lung cancer cells, prostate cancer cells, and breast cancer cells may be removed from the cancer cells.
  • one of the target cells is a muscle cell.
  • one of the target cells is bone cells.
  • the present invention covers lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer). , bacterial infections, viral infections, autoimmune diseases, metabolic syndromes, and musculoskeletal diseases (excluding muscular dystrophy).
  • the present invention may include methods for preventing or treating at least one disease selected from the group consisting of metabolic syndrome and musculoskeletal diseases (excluding muscular dystrophy).
  • the present invention covers lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer).
  • lung diseases excluding pulmonary fibrosis
  • renal diseases excluding renal fibrosis
  • reproductive dysfunction liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer).
  • bacterial infection, viral infection, autoimmune disease, metabolic syndrome, and musculoskeletal disease (excluding muscular dystrophy).
  • the present invention provides at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, for activating cellular autophagy. may include use.
  • the present invention provides at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable thereof, for the production of a cellular autophagy activator. May include the use of salts.
  • Bromoacetic acid bromide (0.87 mL, 9.99 mmol) was added dropwise to a solution of 2-ethoxyaniline (1.37 g, 9.99 mmol) and triethylamine (1.462 mL, 10.49 mmol) in dichloromethane (20 mL) at 0°C. Then, the reaction mixture was stirred at 0° C. for 1 hour to obtain a reaction solution containing 2-bromo-N-(2-ethoxyphenyl)acetamide. The obtained reaction solution was used as it was in the reactions of Examples 8 and 9.
  • Bromoacetic acid bromide (0.26 mL, 3 mmol) was added dropwise to a solution of 2-aminobenzoic acid methyl ester (453 mg, 3 mmol) and triethylamine (1.254 mL, 9 mmol) in dichloromethane (15 mL) at 0°C, and the reaction mixture was diluted. Stirred at 0°C for 1 hour. Subsequently, a solution of 1-(2-(trifluoromethyl)phenyl)piperazine (691 mg, 3 mmol) in DMF (10 mL) was added dropwise at 0°C, stirred overnight at room temperature, saturated ammonium chloride water was added, and ethyl acetate was added.
  • Test example 1 Evaluation of autophagy activation effect (Western blotting method) The autophagy activation effect of the compound obtained in Example 1 (herein also referred to as "Compound A”) was measured by Western blotting.
  • A549 cells human alveolar basal epithelial adenocarcinoma cells
  • DMEM medium Dulbecco's modified Eagle medium
  • PBS phosphate buffered saline
  • each well was filled with DMEM medium containing DMSO (final concentration 0.1%), DMEM medium containing Compound A (final concentration 30 nM) as a test substance, or Earle's Balanced Salt Solution (herein referred to as "EBSS"). (Also referred to as "A starvation state of cells is induced.") was added in 3 mL portions and cultured for 6 hours.
  • DMSO dimethyl sulfoxide
  • Compound A final concentration 30 nM
  • Bafilomycin A1 final concentration 250 nM
  • Bafilomycin A1 is a vacuolar-type H + -ATPase (V-ATPase)-specific inhibitor that inhibits acidification of lysosomes, inhibits the process of autophagosome fusion with lysosomes, and suppresses autophagy.
  • V-ATPase vacuolar-type H + -ATPase
  • RIPA buffer Radio-Immunoprecipitation Assay buffer
  • Sample buffer was added to the collected supernatant to denature it, and electrophoresis was performed on a 15% polyacrylamide gel. After electrophoresis, it was transferred to a nitrocellulose membrane. Blocking was performed with Blocking buffer, and the primary antibodies were anti-LC3 (1000-fold dilution) and anti- ⁇ -actin (10000-fold dilution), and the secondary antibodies were anti-rabbit (2000-fold dilution) and anti-mouse (2000-fold dilution).
  • LC3-I (16 kDa), LC3-II (14 kDa) and ⁇ -actin (42 kDa) were detected using ELC Western Blotting Detection Reagents (Amersham Bioscience) as a luminescent reagent. Image J was used to analyze the luminescence intensity.
  • Test example 2 Evaluation of autophagy activation effect (method to measure tfLC3 expression level) The autophagy activating effect of the compound obtained in Example 1 and cannabidiol was evaluated by measuring the expression level of tfLC3.
  • tfLC3 is a protein in which two types of fluorescent proteins (mRFP and EGFP) are tandemly fused to LC3, an autophagy marker.
  • JCRB cell bank Cervical epithelioid cancer cells HeLa cells (JCRB cell bank: JCRB9004) Osteosarcoma cell U2OS cell (ECACC:92022711) Liver cancer cells HepG2 cells (JCRB cell bank: JCRB1054) Epidermal keratinocytes PSVK1 cells (JCRB cell bank: JCRB1093) Retinal pigment epithelial cells RPE cells (Lonza:00194987)
  • the obtained HeLa cells, U2OS cells, HepG2 cells, and RPE cells were seeded in a 96-well plate.
  • As the culture medium a DMEM medium containing 10% fetal bovine serum, penicillin (final concentration 100 units/ml), streptomycin (final concentration 0.1 mg/ml), and L-glutamine (final concentration 2 mM) was used.
  • the obtained PSVK1 cells were seeded into a 96-well plate coated with collagen I.
  • EpiLife medium (ThermoFisher, Cat: MEPI500CA) containing Human Keratinocyte Growth Supplement, penicillin (final concentration 100 units/ml), streptomycin (final concentration 0.1 mg/ml), and amino acids was used as the culture medium.
  • the 96-well plate was placed in an incubator, and the cells were cultured for 24 hours at 37° C. and 5% CO 2 .
  • the sample solution used was prepared by dissolving the sample (Compound A or cannabidiol) in DMSO.
  • the sample concentration in the sample solution was adjusted so that the sample concentration (sample concentration in the culture solution) when the sample solution (1 ⁇ l) was added to the culture solution (1000 ⁇ l) was a predetermined concentration.
  • cannabidiol was not cultured using PSVK1 cells.
  • Example 1 The lower the EGFP/mRFP ratio, the more activated autophagy is evaluated.

Abstract

The purpose of the present invention is to provide a pharmaceutical composition for treating or preventing diseases such as pulmonary diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver damage, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infection, viral infection, autoimmune diseases, metabolic syndrome, musculoskeletal diseases (excluding muscular dystrophy), and the like.　The present invention pertains to a pharmaceutical composition that contains at least one compound selected from the group consisting of cannabidiol and compounds represented by formula (1), or a pharmaceutically acceptable salt thereof, and that is for treating or preventing at least one disease selected from the group consisting of pulmonary diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver damage, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infection, viral infection, autoimmune diseases, metabolic syndrome, musculoskeletal diseases (excluding muscular dystrophy), and the like.

Description

医薬組成物及びオートファジー活性化剤Pharmaceutical composition and autophagy activator
　本発明は、肺疾患、腎疾患、皮膚疾患、肝障害、眼疾患等を予防又は治療するための医薬組成物、及びオートファジー活性化剤に関する。 The present invention relates to a pharmaceutical composition for preventing or treating lung diseases, kidney diseases, skin diseases, liver disorders, eye diseases, etc., and an autophagy activator.
　オートファジーは、細胞内物質の分解及びリサイクルを担う他、細胞内に出現した有害物（異常なタンパク質の塊、侵入してきた細菌、傷ついたミトコンドリア等）を排除する働きをする。オートファジーは、各組織の細胞が健全に保たれることに寄与している。オートファジーは、肺、腎臓、皮膚、眼等の細胞の基本機能に必須であり、これらの組織が急性あるいは慢性的なダメージを受ける条件下で、細胞の保護効果を発揮する。従って、これら組織において、オートファジー不全により引き起こされる疾患には、オートファジー活性化が有効な予防法及び治療法となる（非特許文献１）。 In addition to being responsible for decomposing and recycling intracellular substances, autophagy also works to eliminate harmful substances that appear within cells (abnormal protein clumps, invading bacteria, damaged mitochondria, etc.). Autophagy contributes to keeping cells in each tissue healthy. Autophagy is essential for the basic functions of cells in the lungs, kidneys, skin, eyes, etc., and exerts a protective effect on cells under conditions where these tissues are acutely or chronically damaged. Therefore, autophagy activation is an effective preventive and therapeutic method for diseases caused by autophagy deficiency in these tissues (Non-Patent Document 1).
　本発明は、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患を予防又は治療するための新たな医薬組成物の提供を一つの目的とする。
　本発明は、細胞のオートファジーを活性化させる新規なオートファジー活性化剤の提供を一つの目的とする。 The present invention covers lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer). A new pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of , bacterial infection, viral infection, autoimmune disease, metabolic syndrome, and musculoskeletal disease (excluding muscular dystrophy). One purpose is to provide the following.
One object of the present invention is to provide a novel autophagy activator that activates cellular autophagy.
　本発明者らは、上記課題を解決すべく、鋭意検討した結果、式（１）で表される化合物及びカンナビジオールからなる群から選択される化合物が、細胞のオートファジーの働きを活性化できることを見出し、本発明を完成した。代表的な本発明は以下の通りである。 In order to solve the above problems, the present inventors have conducted intensive studies and found that a compound selected from the group consisting of the compound represented by formula (1) and cannabidiol can activate the function of cellular autophagy. They discovered this and completed the present invention. Representative examples of the present invention are as follows.
項１．
下記式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩を含有し、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患を予防又は治療するための医薬組成物。
Figure JPOXMLDOC01-appb-C000011
 ［式中、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～５の整数を示し、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示し、
ｐは、０又は１を示し、
ｑは、０又は１を示す。］
項２．
前記疾患が、腎疾患（腎線維症を除く）、肝障害、眼疾患、及び皮膚疾患からなる群から選択される少なくとも１種の疾患である、項１に記載の医薬組成物。
項３．
前記式（１）で表わされる化合物において、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、フッ素原子、塩素原子、臭素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ５アシルオキシ基、Ｃ２～Ｃ５アルコキシカルボニル基、又はトリハロゲノメチル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～４の整数を示し、
Ｒ２は、フッ素原子；塩素原子；臭素原子；トリフルオロメチル基；トリクロロメチル基；トリブロモメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ５アシルオキシ基；Ｃ２～Ｃ５アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～４の整数を示し、
ｐは、０又は１を示し、
ｑは、０又は１を示す、
項１又は２に記載の医薬組成物。
項４．
前記式（１）で表わされる化合物において、
Ａは、窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、トリクロロメチル基、又はトリブロモメチル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～３の整数を示し、
Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アシルオキシ基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～３の整数を示し、
ｐは、１を示し、
ｑは、１を示す、
項１～３のいずれか一項に記載の医薬組成物。
項５．
前記式（１）で表わされる化合物において、
Ａは、窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、塩素原子、Ｃ１～Ｃ３アルキル基、Ｃ１～Ｃ３アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、又はトリクロロメチル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～２の整数を示し、
Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～３の整数を示し、
ｐは、１を示し、
ｑは、１を示す、
項１～４のいずれか一項に記載の医薬組成物。
項６．
前記式（１）で表わされる化合物が、下記式（１－１）で表される化合物及び下記式（１－２）で表される化合物からなる群から選択される少なくとも１種の化合物である、項１又は２に記載の医薬組成物。
Figure JPOXMLDOC01-appb-C000012
 ［式中、
Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～５の整数を示し、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示す。］及び
式（１－２）
Figure JPOXMLDOC01-appb-C000013
 ［式中、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ａ及びＢは、同時に炭素原子を示さず、
Ｒ３は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示す。］。
項７．
前記式（１）で表される化合物が、以下に示されたいずれかの化合物である、項１又は２に記載の医薬組成物。
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
 項８．
下記式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩を含有する、細胞のオートファジー活性化剤。
Figure JPOXMLDOC01-appb-C000016
 ［式中、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～５の整数を示し、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示し、
ｐは、０又は１を示し、
ｑは、０又は１を示す。］
項９．
前記細胞が、腎細胞、皮膚細胞、眼細胞、及び肝細胞からなる群から選択される少なくとも１種である、項８に記載のオートファジー活性化剤。
項１０．
前記式（１）で表わされる化合物において、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、フッ素原子、塩素原子、臭素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ５アシルオキシ基、Ｃ２～Ｃ５アルコキシカルボニル基、又はトリハロゲノメチル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～４の整数を示し、
Ｒ２は、フッ素原子；塩素原子；臭素原子；トリフルオロメチル基；トリクロロメチル基；トリブロモメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ５アシルオキシ基；Ｃ２～Ｃ５アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～４の整数を示し、
ｐは、０又は１を示し、
ｑは、０又は１を示す、
項８又は９に記載のオートファジー活性化剤。
項１１．
前記式（１）で表わされる化合物において、
Ａは、窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、トリクロロメチル基、又はトリブロモメチル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～３の整数を示し、
Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アシルオキシ基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～３の整数を示し、
ｐは、１を示し、
ｑは、１を示す、
項８～１０のいずれか一項に記載のオートファジー活性化剤。
項１２．
前記式（１）で表わされる化合物において、
Ａは、窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、塩素原子、Ｃ１～Ｃ３アルキル基、Ｃ１～Ｃ３アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、又はトリクロロメチル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～２の整数を示し、
Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～３の整数を示し、
ｐは、１を示し、
ｑは、１を示す、
項８～１１のいずれか一項に記載のオートファジー活性化剤。
項１３．
前記式（１）で表わされる化合物が、下記式（１－１）で表される化合物及び下記式（１－２）で表される化合物からなる群から選択される少なくとも１種の化合物である、項８又は９に記載のオートファジー活性化剤。
Figure JPOXMLDOC01-appb-C000017
 ［式中、
Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～５の整数を示し、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示す。］及び
式（１－２）
Figure JPOXMLDOC01-appb-C000018
 ［式中、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ａ及びＢは、同時に炭素原子を示さず、
Ｒ３は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示す。］。
項１４．
前記式（１）で表される化合物が、以下に示されたいずれかの化合物である、項８又は９に記載のオートファジー活性化剤。
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
 Item 1.
Contains at least one compound selected from the group consisting of the compound represented by the following formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, and is used to treat lung diseases (excluding pulmonary fibrosis), renal disease. Diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome A pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of , and musculoskeletal diseases (excluding muscular dystrophy).
Figure JPOXMLDOC01-appb-C000011
 [In the formula,
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
m represents an integer from 0 to 5,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5,
p represents 0 or 1,
q represents 0 or 1. ]
Item 2.
Item 2. The pharmaceutical composition according to Item 1, wherein the disease is at least one disease selected from the group consisting of renal disease (excluding renal fibrosis), liver disorder, eye disease, and skin disease.
Item 3.
In the compound represented by the formula (1),
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and when there is more than one, may be the same or different;
m represents an integer from 0 to 4,
R 2 is a fluorine atom; a chlorine atom; a bromine atom; a trifluoromethyl group; a trichloromethyl group; a tribromomethyl group; a C1 to C4 alkyl group; a C2 to C5 acyloxy group; a C2 to C5 alkoxycarbonyl group; a C1 to C3 alkyl and an amide group which may be substituted with one or two groups selected from the group consisting of C2-C4 alkoxycarbonyl groups; selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; A piperidinylcarbonyl group which may be substituted with one or more groups; or substituted with one or more groups selected from the group consisting of C1 to C3 alkyl groups and C2 to C4 alkoxycarbonyl groups; represents a pyrrolidinyl carbonyl group that may be
n represents an integer from 0 to 4,
p represents 0 or 1,
q indicates 0 or 1,
Item 3. Pharmaceutical composition according to item 1 or 2.
Item 4.
In the compound represented by the formula (1),
A represents a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group, and when there is more than one, may be the same or different;
m represents an integer from 0 to 3,
R 2 is a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1 to C4 alkyl group; a C2 to C4 acyloxy group; a C2 to C4 alkoxycarbonyl group; a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group An amide group which may be substituted with one or two groups selected from the group consisting of; one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; a piperidinylcarbonyl group which may be substituted with; or a pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group Indicates a group, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 3;
p indicates 1,
q indicates 1,
The pharmaceutical composition according to any one of Items 1 to 3.
Item 5.
In the compound represented by the formula (1),
A represents a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a chlorine atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, or a trichloromethyl group, and when there are multiple groups, they may be the same or different,
m represents an integer from 0 to 2,
R 2 is selected from the group consisting of a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group. an amide group which may be substituted with one or two groups; or an amide group which may be substituted with one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; Indicates a good piperidinyl carbonyl group, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 3;
p indicates 1,
q indicates 1,
The pharmaceutical composition according to any one of Items 1 to 4.
Item 6.
The compound represented by the formula (1) is at least one compound selected from the group consisting of a compound represented by the following formula (1-1) and a compound represented by the following formula (1-2). , the pharmaceutical composition according to item 1 or 2.
Figure JPOXMLDOC01-appb-C000012
 [In the formula,
R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
m represents an integer from 0 to 5,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5. ] and formula (1-2)
Figure JPOXMLDOC01-appb-C000013
 [In the formula,
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
A and B do not represent a carbon atom at the same time,
R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5. ].
Section 7.
Item 3. The pharmaceutical composition according to item 1 or 2, wherein the compound represented by formula (1) is any of the compounds shown below.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
 Section 8.
A cellular autophagy activator containing at least one compound selected from the group consisting of the compound represented by the following formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000016
 [In the formula,
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
m represents an integer from 0 to 5,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5,
p represents 0 or 1,
q represents 0 or 1. ]
Item 9.
Item 9. The autophagy activator according to item 8, wherein the cell is at least one selected from the group consisting of kidney cells, skin cells, eye cells, and hepatocytes.
Item 10.
In the compound represented by the formula (1),
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and when there is more than one, may be the same or different;
m represents an integer from 0 to 4,
R 2 is a fluorine atom; a chlorine atom; a bromine atom; a trifluoromethyl group; a trichloromethyl group; a tribromomethyl group; a C1 to C4 alkyl group; a C2 to C5 acyloxy group; a C2 to C5 alkoxycarbonyl group; a C1 to C3 alkyl and an amide group which may be substituted with one or two groups selected from the group consisting of C2-C4 alkoxycarbonyl groups; selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; A piperidinylcarbonyl group which may be substituted with one or more groups; or substituted with one or more groups selected from the group consisting of C1 to C3 alkyl groups and C2 to C4 alkoxycarbonyl groups; represents a pyrrolidinyl carbonyl group that may be
n represents an integer from 0 to 4,
p represents 0 or 1,
q indicates 0 or 1,
The autophagy activator according to item 8 or 9.
Item 11.
In the compound represented by the formula (1),
A represents a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group, and when there is more than one, may be the same or different;
m represents an integer from 0 to 3,
R 2 is a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1 to C4 alkyl group; a C2 to C4 acyloxy group; a C2 to C4 alkoxycarbonyl group; a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group An amide group which may be substituted with one or two groups selected from the group consisting of; one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; a piperidinylcarbonyl group which may be substituted with; or a pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group Indicates a group, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 3;
p indicates 1,
q indicates 1,
The autophagy activator according to any one of items 8 to 10.
Item 12.
In the compound represented by the formula (1),
A represents a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a chlorine atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, or a trichloromethyl group, and when there are multiple groups, they may be the same or different,
m represents an integer from 0 to 2,
R 2 is selected from the group consisting of a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group. an amide group which may be substituted with one or two groups; or an amide group which may be substituted with one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; Indicates a good piperidinyl carbonyl group, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 3;
p indicates 1,
q indicates 1,
The autophagy activator according to any one of items 8 to 11.
Item 13.
The compound represented by the formula (1) is at least one compound selected from the group consisting of a compound represented by the following formula (1-1) and a compound represented by the following formula (1-2). , the autophagy activator according to item 8 or 9.
Figure JPOXMLDOC01-appb-C000017
 [In the formula,
R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
m represents an integer from 0 to 5,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5. ] and formula (1-2)
Figure JPOXMLDOC01-appb-C000018
 [In the formula,
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
A and B do not represent a carbon atom at the same time,
R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5. ].
Section 14.
Item 10. The autophagy activator according to item 8 or 9, wherein the compound represented by formula (1) is any of the compounds shown below.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
　本発明の医薬組成物は、オートファジーを活性化する作用を有する化合物またはその薬学的に許容される塩を含有するため、腎疾患、皮膚疾患、肝障害、眼疾患等の予防又は治療に有用である。本発明のオートファジー活性化剤は、細胞のオートファジー活性の増強に有用である。 The pharmaceutical composition of the present invention contains a compound having the effect of activating autophagy or a pharmaceutically acceptable salt thereof, and therefore is useful for the prevention or treatment of kidney diseases, skin diseases, liver disorders, eye diseases, etc. It is. The autophagy activator of the present invention is useful for enhancing cellular autophagy activity.
図１は、試験例１において観察されたオートファジーマーカーLC-I、LC-II、及びβ-actionのウエスタンブロットの結果と、Bafilomycin A1(+)の条件で得られた発光強度からBafilomycin A1(+)の条件で得られた発光強度を控除して得られたΔintensityを表すグラフである。試験に使用された細胞はヒト肺胞基底上皮腺癌細胞（Ａ５４９細胞）である。Figure 1 shows the results of Western blotting of the autophagy markers LC-I, LC-II, and β-action observed in Test Example 1, and the luminescence intensity obtained under the conditions of Bafilomycin A1(+). It is a graph showing Δintensity obtained by subtracting the luminescence intensity obtained under the conditions of +). The cells used in the test were human alveolar basal epithelial adenocarcinoma cells (A549 cells). 図２は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルは実施例１で得られた化合物であり、細胞は子宮頸部類上皮がん細胞（ＨｅＬａ細胞）である。FIG. 2 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was the compound obtained in Example 1, and the cells were cervical epithelioid carcinoma cells (HeLa cells). 図３は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルは実施例１で得られた化合物であり、細胞は骨肉腫細胞（Ｕ２ＯＳ細胞）である。FIG. 3 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was the compound obtained in Example 1, and the cells were osteosarcoma cells (U2OS cells). 図４は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルは実施例１で得られた化合物であり、細胞は肝がん細胞（ＨｅｐＧ２細胞）である。FIG. 4 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was the compound obtained in Example 1, and the cells were liver cancer cells (HepG2 cells). 図５は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルは実施例１で得られた化合物であり、細胞は表皮角化細胞（ＰＳＶＫ１細胞）である。FIG. 5 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was the compound obtained in Example 1, and the cells were epidermal keratinocytes (PSVK1 cells). 図６は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルは実施例１で得られた化合物であり、細胞は網膜色素上皮細胞（ＲＰＥ細胞）である。FIG. 6 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was the compound obtained in Example 1, and the cells were retinal pigment epithelial cells (RPE cells). 図７は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルはカンナビジオールであり、細胞は子宮頸部類上皮がん細胞（ＨｅＬａ細胞）である。FIG. 7 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was cannabidiol and the cells were cervical epithelioid carcinoma cells (HeLa cells). 図８は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルはカンナビジオールであり、細胞は骨肉腫細胞（Ｕ２ＯＳ細胞）である。FIG. 8 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was cannabidiol and the cells were osteosarcoma cells (U2OS cells). 図９は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルはカンナビジオールであり、細胞は肝がん細胞（ＨｅｐＧ２細胞）である。FIG. 9 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test was cannabidiol, and the cells were liver cancer cells (HepG2 cells). 図１０は、試験例２において得られたtfLC3に含まれる２種類の蛍光タンパク質（mRFP及びEGFP）の蛍光強度比（GFP/RFP）を示すグラフである。試験に使用された、サンプルはカンナビジオールであり、細胞は網膜色素上皮細胞（ＲＰＥ細胞）である。FIG. 10 is a graph showing the fluorescence intensity ratio (GFP/RFP) of two types of fluorescent proteins (mRFP and EGFP) contained in tfLC3 obtained in Test Example 2. The sample used in the test is cannabidiol and the cells are retinal pigment epithelial cells (RPE cells).
　本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられる。 All publications, patents, and patent applications cited herein are incorporated by reference in their entirety.
　本発明において「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子およびヨウ素原子が挙げられる。好ましくはフッ素原子、塩素原子、及び臭素原子、より好ましくはフッ素原子、及び塩素原子が挙げられる。 In the present invention, the "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferable examples include fluorine atom, chlorine atom, and bromine atom, and more preferably fluorine atom and chlorine atom.
　本発明において「アルキル基」としては、例えば、直鎖状、分枝状、又は環状構造を含む、Ｃ１～Ｃ８アルキル基が挙げられ、好ましくはＣ１～Ｃ６アルキル基、より好ましくはＣ１～Ｃ４アルキル基、特に好ましくはＣ１～Ｃ３アルキル基である。具体的には、直鎖状または分枝状のアルキル基としては、メチル基、エチル基、１－プロピル基、２－プロピル基、１－ブチル基、２－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ネオペンチル基、ｎ－ヘキシル基、イソヘキシル基、３－メチルペンチル基等が挙げられ、環状構造を含むアルキル基としては、シクロプロピル基、シクロプロピルメチル基、シクロブチル基、シクロブチルメチル基、シクロペンチル基、シクロペンチルメチル基、シクロヘキシル基、シクロヘキシルメチル基、シクロヘキシルエチル基等が挙げられる。好ましくは、メチル基、エチル基、２－プロピル基、ｔ－ブチル基、シクロプロピル基等が挙げられる。 In the present invention, the "alkyl group" includes, for example, a C1-C8 alkyl group containing a linear, branched, or cyclic structure, preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group. groups, particularly preferably C1-C3 alkyl groups. Specifically, linear or branched alkyl groups include methyl group, ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, isobutyl group, and tert-butyl group. group, n-pentyl group, neopentyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, etc., and examples of alkyl groups containing a cyclic structure include cyclopropyl group, cyclopropylmethyl group, cyclobutyl group, cyclo Examples include butylmethyl group, cyclopentyl group, cyclopentylmethyl group, cyclohexyl group, cyclohexylmethyl group, cyclohexylethyl group, and the like. Preferred examples include methyl group, ethyl group, 2-propyl group, t-butyl group, and cyclopropyl group.
　本発明において「ハロゲン原子で置換されたアルキル基」としては、例えば、ハロゲン原子で置換された、直鎖状、分枝状、又は環状構造を含む、前記アルキル基が挙げられる。アルキル基が有する置換基の数は１～置換可能な最大の数であり、好ましくは３～置換可能な最大の数である。当該ハロゲン原子が複数あるときは同一でも異なってもよいが、同一であることが好ましい。例えば、置換可能な最大の数のハロゲン原子で置換されたＣ１～Ｃ４アルキル基が挙げられ、好ましくは置換可能な最大の数のハロゲン原子で置換されたＣ１～Ｃ３アルキル基、より好ましくは置換可能な最大の数のハロゲン原子で置換されたＣ１～Ｃ２アルキル基、特に好ましくはトリハロゲノメチル基である。ハロゲン原子で置換されたアルキル基の例としては、パーフルオロ－ｎ－ブチル基、パーフルオロ－ｔ－ブチル基、パーフルオロ－ｎ－プロピル基、パーフルオロ－ｉ－プロピル基、ペンチルフルオロエチル基、トリフルオロメチル基、パークロロ－ｎ－ブチル基、パークロロ－ｔ－ブチル基、パークロロ－ｎ－プロピル基、パークロロ－ｉ－プロピル基、ペンタクロロエチル基、トリクロロメチル基、パーブロモ－ｎ－ブチル基、パーブロモ－ｔ－ブチル基、パーブロモ－ｎ－プロピル基、パーブロモ－ｉ－プロピル基、ペンタブロモエチル基、トリブロモメチル基、パーヨード－ｎ－ブチル基、パーヨード－ｔ－ブチル基、パーヨード－ｎ－プロピル基、パーヨード－ｉ－プロピル基、ペンタヨードエチル基、トリヨードメチル基が挙げられる。ハロゲン原子で置換されたアルキル基の好ましい例としては、ペンチルフルオロエチル基、トリフルオロメチル基、ペンタクロロエチル基、トリクロロメチル基、ペンタブロモエチル基、トリブロモメチル基、ペンタヨードエチル基、トリヨードメチル基が挙げられ、トリフルオロメチル基、トリクロロメチル基、トリブロモメチル基がより好ましく、トリフルオロメチル基、トリクロロメチル基がより一層好ましい。 In the present invention, the "alkyl group substituted with a halogen atom" includes, for example, the alkyl group substituted with a halogen atom and having a linear, branched, or cyclic structure. The number of substituents an alkyl group has is 1 to the maximum number that can be substituted, preferably 3 to the maximum number that can be substituted. When there is a plurality of halogen atoms, they may be the same or different, but are preferably the same. Examples include C1 to C4 alkyl groups substituted with the maximum number of substitutable halogen atoms, preferably C1 to C3 alkyl groups substituted with the maximum number of substitutable halogen atoms, more preferably substitutable A C1-C2 alkyl group substituted with the maximum number of halogen atoms, particularly preferably a trihalogenomethyl group. Examples of alkyl groups substituted with halogen atoms include perfluoro-n-butyl group, perfluoro-t-butyl group, perfluoro-n-propyl group, perfluoro-i-propyl group, pentylfluoroethyl group, Trifluoromethyl group, perchloro-n-butyl group, perchloro-t-butyl group, perchloro-n-propyl group, perchloro-i-propyl group, pentachloroethyl group, trichloromethyl group, perbromo-n-butyl group, perbromo -t-butyl group, perbromo-n-propyl group, perbromo-i-propyl group, pentabromoethyl group, tribromomethyl group, periodo-n-butyl group, periodo-t-butyl group, periodo-n-propyl group , periodo-i-propyl group, pentaiodoethyl group, and triiodomethyl group. Preferred examples of the alkyl group substituted with a halogen atom include a pentylfluoroethyl group, a trifluoromethyl group, a pentachloroethyl group, a trichloromethyl group, a pentabromoethyl group, a tribromomethyl group, a pentaiodoethyl group, and a triiodoethyl group. A methyl group is mentioned, a trifluoromethyl group, a trichloromethyl group, and a tribromomethyl group are more preferable, and a trifluoromethyl group and a trichloromethyl group are even more preferable.
　本発明において「アルコキシ基」としては、例えば、直鎖状、分枝状、又は環状構造を含む、Ｃ１～Ｃ８アルコキシ基が挙げられ、好ましくはＣ１～Ｃ６アルコキシ基、より好ましくはＣ１～Ｃ４アルコキシ基、特に好ましくはＣ１～Ｃ３アルコキシ基である。具体的には、直鎖状または分枝状のアルコキシ基としては、メトキシ基、エトキシ基、１－プロポキシ基、２－プロポキシ基、１－ブトキシ基、２－ブトキシ基、イソブトキシ基、ｔｅｒｔ－ブトキシ基、ｎ－ペンチルオキシ基、ネオペンチルオキシ基、ｎ－ヘキシルオキシ基、イソヘキシルオキシ基、３－メチルペンチルオキシ基等が挙げられる。環状構造を含むアルコキシ基としては、シクロプロポキシ基、シクロプロピルメトキシ基、シクロブチロキシ基、シクロブチルメトキシ基、シクロペンチロキシ基、シクロペンチルメトキシ基、シクロヘキシロキシ基、シクロヘキシルメトキシ基、シクロヘキシルエトキシ基等が挙げられる。好ましくは、メトキシ基、エトキシ基、２－プロポキシ基、ｔｅｒｔ－ブトキシ基、シクロプロポキシ基等が挙げられる。 In the present invention, the "alkoxy group" includes, for example, a C1-C8 alkoxy group containing a linear, branched, or cyclic structure, preferably a C1-C6 alkoxy group, more preferably a C1-C4 alkoxy group. groups, particularly preferably C1-C3 alkoxy groups. Specifically, linear or branched alkoxy groups include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, isobutoxy group, and tert-butoxy group. group, n-pentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, 3-methylpentyloxy group and the like. Examples of alkoxy groups containing a cyclic structure include cyclopropoxy group, cyclopropylmethoxy group, cyclobutyroxy group, cyclobutylmethoxy group, cyclopentyloxy group, cyclopentylmethoxy group, cyclohexyloxy group, cyclohexylmethoxy group, cyclohexylethoxy group, etc. Can be mentioned. Preferred examples include methoxy group, ethoxy group, 2-propoxy group, tert-butoxy group, and cyclopropoxy group.
　本発明において「アシルオキシ基」としては、例えば、直鎖状、分枝状、又は環状構造を含む、Ｃ２～Ｃ９アシルオキシ基が挙げられ、好ましくはＣ２～Ｃ７アシルオキシ基、より好ましくはＣ２～Ｃ５アシルオキシ基、特に好ましくはＣ２～Ｃ４アシルオキシ基である。具体的には、直鎖状または分枝状のアシルオキシ基としては、メトキシカルボニル基、エトキシカルボニル基、１－プロポキシカルボニル基、２－プロポキシカルボニル基、１－ブトキシカルボニル基、２－ブトキシカルボニル基、イソブトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ｎ－ペンチルオキシカルボニル基、ネオペンチルオキシカルボニル基、ｎ－ヘキシルオキシカルボニル基、イソヘキシルオキシカルボニル基、３－メチルペンチルオキシカルボニル基等が挙げられる。環状構造を含むアシルオキシ基としては、シクロプロポキシカルボニル基、シクロプロピルメトキシカルボニル基、シクロブチロキシカルボニル基、シクロブチルメトキシカルボニル基、シクロペンチロキシカルボニル基、シクロペンチルメトキシカルボニル基、シクロヘキシロキシカルボニル基、シクロヘキシルメトキシカルボニル基、シクロヘキシルエトキシカルボニル基等が挙げられる。好ましくは、メトキシカルボニル基、エトキシカルボニル基、２－プロポキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、シクロプロポキシカルボニル基等が挙げられる。 In the present invention, the "acyloxy group" includes, for example, a C2-C9 acyloxy group containing a linear, branched, or cyclic structure, preferably a C2-C7 acyloxy group, more preferably a C2-C5 acyloxy group. groups, particularly preferably C2-C4 acyloxy groups. Specifically, the linear or branched acyloxy group includes a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propoxycarbonyl group, a 2-propoxycarbonyl group, a 1-butoxycarbonyl group, a 2-butoxycarbonyl group, Examples include isobutoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, neopentyloxycarbonyl group, n-hexyloxycarbonyl group, isohexyloxycarbonyl group, and 3-methylpentyloxycarbonyl group. Acyloxy groups containing a cyclic structure include cyclopropoxycarbonyl group, cyclopropylmethoxycarbonyl group, cyclobutyroxycarbonyl group, cyclobutylmethoxycarbonyl group, cyclopentyloxycarbonyl group, cyclopentylmethoxycarbonyl group, cyclohexyloxycarbonyl group, cyclohexylmethoxy Examples include carbonyl group, cyclohexylethoxycarbonyl group, and the like. Preferred examples include methoxycarbonyl group, ethoxycarbonyl group, 2-propoxycarbonyl group, tert-butoxycarbonyl group, and cyclopropoxycarbonyl group.
　本発明において「アルコキシカルボニル基」としては、前記アルコキシ基と結合したカルボニル基が挙げられ、例えば直鎖状、分枝状、又は環状構造を含む、Ｃ１～Ｃ８アルコキシ基と結合したカルボニル基が挙げられ、好ましくはＣ２～Ｃ７アルコキシカルボニル基、より好ましくはＣ２～Ｃ５アルコキシカルボニル基、特に好ましくはＣ２～Ｃ４アルコキシカルボニル基である。アルコキシカルボニル基を構成する直鎖状または分枝状のアルコキシ基としては、メトキシ基、エトキシ基、１－プロポキシ基、２－プロポキシ基、１－ブトキシ基、２－ブトキシ基、イソブトキシ基、ｔｅｒｔ－ブトキシ基、ｎ－ペンチルオキシ基、ネオペンチルオキシ基、ｎ－ヘキシルオキシ基、イソヘキシルオキシ基、３－メチルペンチルオキシ基等が挙げられる。アルコキシカルボニル基を構成する環状構造を含むアルコキシ基としては、シクロプロポキシ基、シクロプロピルメトキシ基、シクロブチロキシ基、シクロブチルメトキシ基、シクロペンチロキシ基、シクロペンチルメトキシ基、シクロヘキシロキシ基、シクロヘキシルメトキシ基、シクロヘキシルエトキシ基等が挙げられる。アルコキシカルボニル基を構成するアルコキシ基としては、好ましくは、メトキシ基、エトキシ基、２－プロポキシ基、ｔｅｒｔ－ブトキシ基、シクロプロポキシ基等が挙げられる。 In the present invention, the "alkoxycarbonyl group" includes a carbonyl group bonded to the alkoxy group, such as a carbonyl group bonded to a C1 to C8 alkoxy group, which has a linear, branched, or cyclic structure. and is preferably a C2-C7 alkoxycarbonyl group, more preferably a C2-C5 alkoxycarbonyl group, particularly preferably a C2-C4 alkoxycarbonyl group. Examples of linear or branched alkoxy groups constituting the alkoxycarbonyl group include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, 1-butoxy group, 2-butoxy group, isobutoxy group, tert- Examples include butoxy group, n-pentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, and 3-methylpentyloxy group. Examples of alkoxy groups containing a cyclic structure constituting an alkoxycarbonyl group include a cyclopropoxy group, a cyclopropylmethoxy group, a cyclobutyroxy group, a cyclobutylmethoxy group, a cyclopentyloxy group, a cyclopentylmethoxy group, a cyclohexyloxy group, and a cyclohexylmethoxy group. , cyclohexylethoxy group, and the like. Preferred examples of the alkoxy group constituting the alkoxycarbonyl group include methoxy group, ethoxy group, 2-propoxy group, tert-butoxy group, and cyclopropoxy group.
　本発明において「アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基」は、アミド基、モノ又はジ－アルキルアミド基、モノ又はジ－アルコキシカルボニルアミド基、アルキル基及びアルコキシカルボニル基でジ置換されたアミド基を包含し、好ましくはアミド基、ジアルキルアミド基、より好ましくはジアルキルアミド基である。アミド基が２つの基で置換される場合、置換基は同一でも異なってもよい。モノアルキルアミド基としては、前記アルキル基でモノ置換されたアミド基が挙げられ、好ましくはＣ１～Ｃ４アルキル基でモノ置換されたアミド基、より好ましくはＣ１～Ｃ３アルキル基でモノ置換されたアミド基が挙げられ、特に好ましくはメチルアミド基、エチルアミド基が挙げられる。ジアルキルアミド基としては、前記アルキル基でジ置換されたアミド基が挙げられ、好ましくはＣ１～Ｃ４アルキル基でジ置換されたアミド基、より好ましくはＣ１～Ｃ３アルキル基でジ置換されたアミド基、特に好ましくはジメチルアミド基、ジエチルアミド基、エチルメチルアミド基が挙げられる。モノアルコキシカルボニルアミド基としては、前記アルコキシカルボニル基でモノ置換されたアミド基が挙げられ、好ましくはＣ２～Ｃ５アルコキシカルボニル基でモノ置換されたアミド基、より好ましくはＣ２～Ｃ４アルコキシカルボニル基でモノ置換されたアミド基、特に好ましくはメトキシカルボニルアミド、エトキシカルボニルアミド基が挙げられる。ジアルコキシカルボニルアミド基としては、前記アルコキシカルボニル基でジ置換されたアミド基が挙げられ、好ましくはＣ２～Ｃ５アルコキシカルボニル基でジ置換されたアミド基、より好ましくはＣ２～Ｃ４アルコキシカルボニル基でジ置換されたアミド基、特に好ましくはジ（メトキシカルボニル）アミド、ジ（エトキシカルボニル）アミド基が挙げられる。アルキル基及びアルコキシカルボニル基で置換されたアミド基としては、前記アルキル基と前記アルコキシカルボニル基でジ置換されたアミド基が挙げられ、好ましくはＣ１～Ｃ４アルキル基とＣ２～Ｃ５アルコキシカルボニル基でジ置換されたアミド基、より好ましくはＣ１～Ｃ３アルキル基とＣ２～Ｃ４アルコキシカルボニル基でジ置換されたアミド基、特に好ましくはメチルメトキシカルボニルアミド基、メチルエトキシカルボニルアミド基、エチルメトキシカルボニルアミド基、エチルエトキシカルボニルアミド基が挙げられる。 In the present invention, "an amide group which may be substituted with one or two groups selected from the group consisting of an alkyl group and an alkoxycarbonyl group" refers to an amide group, a mono- or di-alkyl amide group, a mono- or di- It includes an alkoxycarbonylamide group, an alkyl group, and an amide group di-substituted with an alkoxycarbonyl group, preferably an amide group or a dialkylamide group, and more preferably a dialkylamide group. When an amide group is substituted with two groups, the substituents may be the same or different. Examples of the monoalkyl amide group include amide groups mono-substituted with the above-mentioned alkyl groups, preferably amide groups mono-substituted with C1-C4 alkyl groups, more preferably amide groups mono-substituted with C1-C3 alkyl groups. Among these groups, particularly preferred are methylamide and ethylamide groups. Examples of dialkylamide groups include amide groups di-substituted with the above-mentioned alkyl groups, preferably amide groups di-substituted with C1-C4 alkyl groups, more preferably amide groups di-substituted with C1-C3 alkyl groups. Particularly preferred are dimethylamide group, diethylamide group, and ethylmethylamide group. Examples of the monoalkoxycarbonylamide group include an amide group mono-substituted with the above-mentioned alkoxycarbonyl group, preferably an amide group mono-substituted with a C2-C5 alkoxycarbonyl group, more preferably a mono-substituted amide group with a C2-C4 alkoxycarbonyl group. Substituted amide groups, particularly preferred are methoxycarbonylamide and ethoxycarbonylamide groups. The dialkoxycarbonylamide group includes an amide group di-substituted with the alkoxycarbonyl group described above, preferably an amide group di-substituted with a C2-C5 alkoxycarbonyl group, more preferably a di-substituted amide group with a C2-C4 alkoxycarbonyl group. Substituted amide groups, particularly preferred are di(methoxycarbonyl)amide and di(ethoxycarbonyl)amide groups. The amide group substituted with an alkyl group and an alkoxycarbonyl group includes an amide group di-substituted with the alkyl group and the alkoxycarbonyl group, preferably a di-substituted amide group with a C1-C4 alkyl group and a C2-C5 alkoxycarbonyl group. A substituted amide group, more preferably a di-substituted amide group with a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group, particularly preferably a methylmethoxycarbonylamide group, a methylethoxycarbonylamide group, an ethylmethoxycarbonylamide group, Examples include ethyl ethoxycarbonylamide group.
　本発明において「アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基」においてピペリジニルカルボニル基が有する置換基の数は０～５であり、好ましくは０～４、より好ましくは０～３、より一層好ましくは０～２、特に好ましくは０又は１である。当該置換基が複数あるときは同一でも異なってもよい。ピペリジニルカルボニル基が置換基を有する場合、少なくとも１個の置換基がピペリジン環の３位（詳細には、ピペリジン環を構成する窒素原子を１位とした場合の３位）の炭素原子に結合していることが好ましい。置換基としては、例えば前記のアルキル基及び前記のアルコキシカルボニル基が挙げられ、好ましくはＣ１～Ｃ４アルキル基、Ｃ２～Ｃ５アルコキシカルボニル基、より好ましくはＣ１～Ｃ３アルキル基、Ｃ２～Ｃ４アルコキシカルボニル基、特に好ましくはメチル基、エチル基、メトキシカルボニル基、エトキシカルボニル基が挙げられる。 In the present invention, in the "piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups", the number of substituents that the piperidinylcarbonyl group has is The number is 0 to 5, preferably 0 to 4, more preferably 0 to 3, even more preferably 0 to 2, particularly preferably 0 or 1. When there are multiple substituents, they may be the same or different. When the piperidinylcarbonyl group has a substituent, at least one substituent is attached to the carbon atom at the 3-position of the piperidine ring (specifically, the 3-position when the nitrogen atom constituting the piperidine ring is the 1-position). Preferably, they are bonded. Examples of the substituent include the above-mentioned alkyl group and the above-mentioned alkoxycarbonyl group, preferably a C1-C4 alkyl group, a C2-C5 alkoxycarbonyl group, more preferably a C1-C3 alkyl group, a C2-C4 alkoxycarbonyl group. Particularly preferred are a methyl group, an ethyl group, a methoxycarbonyl group, and an ethoxycarbonyl group.
　本発明において「アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基」においてピロリジニルカルボニル基が有する置換基の数は０～４であり、好ましくは０～３、より好ましくは０～２、特に好ましくは０又は１である。当該置換基が複数あるときは同一でも異なってもよい。ピロリジニルカルボニル基が置換基を有する場合、少なくとも１個の置換基がピロリジン環の３位（詳細には、ピロリジン環を構成する窒素原子を１位とした場合の３位）の炭素原子に結合していることが好ましい。置換基としては、例えば前記のアルキル基及び前記のアルコキシカルボニル基が挙げられ、好ましくはＣ１～Ｃ４アルキル基、Ｃ２～Ｃ５アルコキシカルボニル基、より好ましくはＣ１～Ｃ３アルキル基、Ｃ２～Ｃ４アルコキシカルボニル基、特に好ましくはメチル基、エチル基、メトキシカルボニル基、エトキシカルボニル基が挙げられる。 In the present invention, in the "pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups", the number of substituents that the pyrrolidinylcarbonyl group has is The number is 0 to 4, preferably 0 to 3, more preferably 0 to 2, particularly preferably 0 or 1. When there are multiple substituents, they may be the same or different. When the pyrrolidinylcarbonyl group has a substituent, at least one substituent is attached to the carbon atom at the 3-position of the pyrrolidine ring (specifically, the 3-position when the nitrogen atom constituting the pyrrolidine ring is the 1-position). Preferably, they are bonded. Examples of the substituent include the above-mentioned alkyl group and the above-mentioned alkoxycarbonyl group, preferably a C1-C4 alkyl group, a C2-C5 alkoxycarbonyl group, more preferably a C1-C3 alkyl group, a C2-C4 alkoxycarbonyl group. Particularly preferred are a methyl group, an ethyl group, a methoxycarbonyl group, and an ethoxycarbonyl group.
　本発明の医薬組成物は、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患を予防又は治療するための組成物である。本発明の医薬組成物は、式（１）で表される化合物及びカンナビジオールからなる群から選択される１種又は２種以上、あるいはその薬学的に許容される塩を含有する。 The pharmaceutical composition of the present invention can be used to treat lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancers (lung cancer, prostate cancer, and A composition for preventing or treating at least one disease selected from the group consisting of breast cancer (excluding breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome, and musculoskeletal diseases (excluding muscular dystrophy). It is a thing. The pharmaceutical composition of the present invention contains one or more selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof.
　本発明の医薬組成物及びオートファジー活性化剤は、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩を含有する。これらの化合物及びその薬学的に許容される塩が、細胞のオートファジー（Autophagy）を活性化する作用を有することが本発明者らによって見出された。オートファジーが活性化されると、オートファジーの活性の低下により停滞又は遅延していた細胞内物質のリサイクルと細胞内有害物の排除が活発となることによって本来の細胞の基本機能が回復する。このため、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物は、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患の予防又は治療に有効である。 The pharmaceutical composition and autophagy activator of the present invention contain at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof. do. The present inventors have discovered that these compounds and their pharmaceutically acceptable salts have the effect of activating cellular autophagy. When autophagy is activated, recycling of intracellular substances and elimination of intracellular harmful substances, which have been stagnant or delayed due to decreased autophagy activity, become active, thereby restoring the original basic functions of cells. Therefore, at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol can be used to treat lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive Functional disorders, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome, and musculoskeletal diseases (excluding muscular dystrophy) ) is effective in preventing or treating at least one disease selected from the group consisting of:
　「オートファジー」とは、細胞内において、細胞内小器官又はタンパク質が、オートファゴソーム形成を経由して、分解されるシステムをいう。また、オートファジーの活性化は、細胞内におけるオートファジーの誘導又は促進により細胞内タンパク質のリサイクル機構が活性化している状態をいい、具体的には、隔離膜の形成、隔離膜の伸長、オートファゴソームの形成、オートファゴソームとリソソームとの融合のうち、少なくともいずれか１つの過程が誘導又は促進されている状態をいう。 "Autophagy" refers to a system in which intracellular organelles or proteins are degraded via autophagosome formation. In addition, activation of autophagy refers to a state in which the intracellular protein recycling mechanism is activated by inducing or promoting autophagy within the cell. Specifically, it includes the formation of an isolation membrane, the elongation of an isolation membrane, A state in which at least one process among phagosome formation and fusion of autophagosomes and lysosomes is induced or promoted.
　オートファジーの活性は、従来公知のオートファジー活性測定方法により確認することができる。そのようなオートファジー活性測定方法として、オートファジーマーカータンパク質を検出する方法が挙げられる。オートファジーマーカータンパク質としては、例えば、LC3（rat microtubule-associated protein 1 light chain 3）が挙げられる。LC3には２つの形態、つまりLC3-I及びLC3-IIがある。LC3は、細胞質中に存在するときはLC3-Iとして存在し、LC3-Iはオートファゴソームの形成時に脂質付加型のLC3-IIへ変換され、オートファゴソームの内膜及び外膜に取り込まれることが知られている。したがって、LC3-I及びLC3-IIを検出し、LC3-IIへの変換率を測定することで、オートファジー活性を確認できる（Kabeya Y., Mizushima N., Ueno T., Yamamoto A., Kirisako T., Noda T., Kominami E., Ohsumi Y., Yoshimori T.: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. The EMBO Journal, 19: 5720-5728 (2000)）。 Autophagy activity can be confirmed by a conventionally known method for measuring autophagy activity. Examples of such methods for measuring autophagy activity include methods for detecting autophagy marker proteins. Examples of autophagy marker proteins include LC3 (rat microtubule-associated protein 1 light chain 3). There are two forms of LC3: LC3-I and LC3-II. When LC3 exists in the cytoplasm, it exists as LC3-I, and LC3-I is converted to lipidated LC3-II during autophagosome formation, and can be incorporated into the inner and outer membranes of autophagosomes. Are known. Therefore, autophagy activity can be confirmed by detecting LC3-I and LC3-II and measuring the conversion rate to LC3-II (Kabeya Y., Mizushima N., Ueno T., Yamamoto A., Kirisako T., Noda T., Kominami E., Ohsumi Y., Yoshimori T.: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. The EMBO Journal, 19: 5720-5728 (2000)).
　オートファジーの活性は、LC3に２種類の蛍光タンパク質（mRFP及びEGFP）をタンデムに融合したtfLC3を細胞で発現させることでも確認することができる（Kimura S., Noda T., Yoshimori T.: Dissection of the Autophagosome Maturation Process by a Novel Reporter Protein, Tandem Fluorescent-Tagged LC3. Autophagy 3:452-460（2007））。本手法によれば、（オート）リソソーム環境下においてEGFPが消失するため、細胞中のEGFP量／mRFP量の比が低くなるほど、オートファジーが活性化していることを示す。細胞中の蛍光量の測定には、例えば、蛍光顕微鏡を使用でき、蛍光量の算出には解析ソフトウェアを使用できる。 Autophagy activity can also be confirmed by expressing in cells tfLC3, which is a tandem fusion of two types of fluorescent proteins (mRFP and EGFP) to LC3 (Kimura S., Noda T., Yoshimori T.: Dissection of the Autophagosome Maturation Process by a Novel Reporter Protein, Tandem Fluorescent-Tagged LC3. Autophagy 3:452-460 (2007)). According to this method, EGFP disappears in an (auto)lysosomal environment, so the lower the ratio of EGFP amount/mRFP amount in a cell, the more activated autophagy is. For example, a fluorescence microscope can be used to measure the amount of fluorescence in cells, and analysis software can be used to calculate the amount of fluorescence.
式（１）で表される化合物（本明細書中、「化合物（１）」とも称する。）
　式（１）は次のとおりである。
Figure JPOXMLDOC01-appb-C000021
 ［式中、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
ｍは、０～５の整数を示し、
Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
ｎは、０～５の整数を示し、
ｐは、０又は１を示し、
ｑは、０又は１を示す。］ Compound represented by formula (1) (also referred to herein as "compound (1)")
Equation (1) is as follows.
Figure JPOXMLDOC01-appb-C000021
 [In the formula,
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
m represents an integer from 0 to 5,
R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
n represents an integer from 0 to 5,
p represents 0 or 1,
q represents 0 or 1. ]
　式（１）は、式（１－１）又は式（１－２）であってもよい。化合物（１）は下記式（１－１）で表わされる化合物（本明細書中、「化合物（１－１）」とも称する。」）又は下記式（１－２）で表される化合物（本明細書中、「化合物（１－２）」とも称する。」）であってよい。化合物（１－１）及び化合物（１－２）は新規な化合物である。
Figure JPOXMLDOC01-appb-C000022
 ［式（１－１）中、Ｒ１、Ｒ２、ｍ、及びｎは、式（１）と同じ。］
Figure JPOXMLDOC01-appb-C000023
 ［式（１－２）中、
Ａは、炭素原子又は窒素原子を示し、
Ｂは、炭素原子又は窒素原子を示し、
Ａ及びＢは、同時に炭素原子を示さず、
Ｒ３は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
Ｒ２、及びｎは、式（１）と同じ。］ Formula (1) may be Formula (1-1) or Formula (1-2). Compound (1) is a compound represented by the following formula (1-1) (herein also referred to as "compound (1-1)") or a compound represented by the following formula (1-2) (hereinafter also referred to as "compound (1-1)"). In the specification, it may also be referred to as "compound (1-2)"). Compound (1-1) and compound (1-2) are new compounds.
Figure JPOXMLDOC01-appb-C000022
 [In formula (1-1), R 1 , R 2 , m, and n are the same as in formula (1). ]
Figure JPOXMLDOC01-appb-C000023
 [In formula (1-2),
A represents a carbon atom or a nitrogen atom,
B represents a carbon atom or a nitrogen atom,
A and B do not represent a carbon atom at the same time,
R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different,
R 2 and n are the same as in formula (1). ]
　化合物（１）及び（１－１）から以下に示される化合物が除かれてもよい。
Figure JPOXMLDOC01-appb-C000024
 The compounds shown below may be excluded from compounds (1) and (1-1).
Figure JPOXMLDOC01-appb-C000024
　化合物（１）及び（１－１）から以下に示される化合物が除かれてもよい。
Figure JPOXMLDOC01-appb-C000025
 The compounds shown below may be excluded from compounds (1) and (1-1).
Figure JPOXMLDOC01-appb-C000025
　Ａは、炭素原子又は窒素原子を示し、Ｂは炭素原子又は窒素原子を示す。但し、式（１－２）においては、Ａ及びＢは、同時に炭素原子を示さない。
　Ａ及びＢの組み合わせとしては、Ａ及びＢがともに炭素原子、Ａが炭素原子及びＢが窒素原子、Ａが窒素原子及びＢが炭素原子、Ａ及びＢがともに窒素原子のいずれかである。つまりＡ及びＢを含有する環は、式（１）及び（１－１）において、ベンゼン環、ピリジン環、またはピリダジン環であり、式（１－２）において、ピリジン環又はピリダジン環である。
　式（１）及び（１－１）において、Ａ及びＢの組み合わせとしては、Ａ及びＢがともに炭素原子、Ａが炭素原子及びＢが窒素原子、又はＡが窒素原子及びＢが炭素原子であることが好ましく、Ａ及びＢがともに炭素原子又はＡが窒素原子及びＢが炭素原子であることがより好ましい。
　式（１－２）において、Ａ及びＢの組み合わせとしては、Ａが炭素原子及びＢが窒素原子、又はＡが窒素原子及びＢが炭素原子であることが好ましく、Ａが窒素原子及びＢが炭素原子であることがより好ましい。
　Ａ及びＢのいずれか又は両方が炭素原子であるときは、当該炭素原子は置換基Ｒ１を有してもよい。 A represents a carbon atom or a nitrogen atom, and B represents a carbon atom or a nitrogen atom. However, in formula (1-2), A and B do not represent carbon atoms at the same time.
As a combination of A and B, A and B are both carbon atoms, A is a carbon atom and B is a nitrogen atom, A is a nitrogen atom and B is a carbon atom, and A and B are both nitrogen atoms. That is, the ring containing A and B is a benzene ring, pyridine ring, or pyridazine ring in formulas (1) and (1-1), and is a pyridine ring or pyridazine ring in formula (1-2).
In formulas (1) and (1-1), the combination of A and B is that both A and B are carbon atoms, A is a carbon atom and B is a nitrogen atom, or A is a nitrogen atom and B is a carbon atom. It is preferable that A and B are both carbon atoms, or that A is a nitrogen atom and B is a carbon atom.
In formula (1-2), as a combination of A and B, it is preferable that A is a carbon atom and B is a nitrogen atom, or A is a nitrogen atom and B is a carbon atom, and A is a nitrogen atom and B is a carbon atom. More preferably, it is an atom.
When either or both of A and B is a carbon atom, the carbon atom may have a substituent R 1 .
　Ｒ１が複数あるときは同一であっても異なってもよい。Ｒ１としては、フッ素原子、塩素原子、臭素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ５アシルオキシ基、Ｃ２～Ｃ５アルコキシカルボニル基、又はトリハロゲノメチル基が好ましく、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、トリクロロメチル基、又はトリブロモメチル基がより好ましく、塩素原子、Ｃ１～Ｃ３アルキル基、Ｃ１～Ｃ３アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、又はトリクロロメチル基がさらに好ましく、塩素原子、メトキシ基、エトキシ基、メトキシカルボニル基、又はエトキシカルボニル基が特に好ましい。 When there is a plurality of R 1 's, they may be the same or different. R 1 is preferably a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and a fluorine atom, A chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group are more preferable, and a chlorine atom, a C1-C3 alkyl group, a C1 -C3 alkoxy group, C2-C4 alkoxycarbonyl group, trifluoromethyl group, or trichloromethyl group is more preferred, and chlorine atom, methoxy group, ethoxy group, methoxycarbonyl group, or ethoxycarbonyl group is particularly preferred.
　Ｒ１は、Ｒ１が結合する環がベンゼン環であるときは、ベンゼン環を構成する炭素原子のうち、（ＮＨ）ｐを構成する窒素原子と直接結合する炭素原子に対してオルト位に位置する２個の炭素原子のうちの少なくとも１個に結合していることが好ましい。オルト位に位置する炭素原子に結合するＲ１としては、例えばアルコキシ基又はアルコキシカルボニル基が挙げられ、Ｃ２～Ｃ５アルコキシカルボニル基が好ましく、Ｃ２～Ｃ４アルコキシカルボニル基がより好ましく、メトキシカルボニル基又はエトキシカルボニル基がさらに好ましく、エトキシカルボニル基が特に好ましい。 When the ring to which R 1 is bonded is a benzene ring, R 1 is located at the ortho position to the carbon atom directly bonding to the nitrogen atom constituting (NH) p among the carbon atoms constituting the benzene ring. Preferably, it is bonded to at least one of two carbon atoms. Examples of R 1 bonded to the carbon atom located at the ortho position include an alkoxy group or an alkoxycarbonyl group, preferably a C2-C5 alkoxycarbonyl group, more preferably a C2-C4 alkoxycarbonyl group, and a methoxycarbonyl group or an ethoxycarbonyl group. A carbonyl group is more preferred, and an ethoxycarbonyl group is particularly preferred.
　Ｒ１は、Ｒ１が結合する環がベンゼン環であって、ベンゼン環を構成する炭素原子のうち、（ＮＨ）ｐを構成する窒素原子と直接結合する炭素原子に対してメタ位に位置する２個の炭素原子のいずれか又は両方に結合している場合、ハロゲン原子であることが好ましく、塩素原子又はフッ素原子であることがより好ましく、フッ素原子が特に好ましい。 In R 1 , the ring to which R 1 is bonded is a benzene ring, and among the carbon atoms constituting the benzene ring, it is located at the meta position with respect to the carbon atom directly bonded to the nitrogen atom constituting (NH) p . When bonded to either or both of two carbon atoms, a halogen atom is preferable, a chlorine atom or a fluorine atom is more preferable, and a fluorine atom is particularly preferable.
　Ｒ１は、Ａ及びＢを含む環がピリジン環又はピリダジン環であるときは、ピリジン環又はピリダジン環を構成する炭素原子のうち、（ＮＨ）ｐを構成する窒素原子と直接結合する炭素原子とＡとの間に位置する炭素原子に結合することが好ましい。
　Ｒ１は、Ａ及びＢを含む環がピリジン環又はピリダジン環であるときは、例えばハロゲン原子、アルキル基、アルコキシ基、又はアルコキシカルボニル基であってよく、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はＣ２～Ｃ５アルコキシカルボニル基が好ましく、Ｃ１～Ｃ４アルコキシ基がより好ましく、メトキシ基又はエトキシ基が特に好ましい。 When the ring containing A and B is a pyridine ring or a pyridazine ring, R 1 is the carbon atom that directly bonds to the nitrogen atom that constitutes (NH)p among the carbon atoms that constitute the pyridine ring or pyridazine ring. It is preferable to bond to a carbon atom located between A and A.
When the ring containing A and B is a pyridine ring or a pyridazine ring, R 1 may be, for example, a halogen atom, an alkyl group, an alkoxy group, or an alkoxycarbonyl group, and may be a fluorine atom, a chlorine atom, a C1-C4 alkyl A C1-C4 alkoxy group or a C2-C5 alkoxycarbonyl group is preferred, a C1-C4 alkoxy group is more preferred, and a methoxy group or an ethoxy group is particularly preferred.
　Ｒ３は、ハロゲン原子、アルキル基、アルコキシ基、又はアルコキシカルボニル基であってよく、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はＣ２～Ｃ５アルコキシカルボニル基が好ましく、Ｃ１～Ｃ４アルコキシ基がより好ましく、メトキシ基又はエトキシ基が特に好ましい。 R 3 may be a halogen atom, an alkyl group, an alkoxy group, or an alkoxycarbonyl group, preferably a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a C2-C5 alkoxycarbonyl group, A C1-C4 alkoxy group is more preferred, and a methoxy group or an ethoxy group is particularly preferred.
　ｍとしては、０～４の整数が好ましく、０～３の整数がより好ましく、０、１、又は２がさらに好ましく、０又は１がさらに好ましく、１が特に好ましい。 m is preferably an integer of 0 to 4, more preferably an integer of 0 to 3, even more preferably 0, 1, or 2, even more preferably 0 or 1, and particularly preferably 1.
　式（１）における下記に表わされる部分構造
Figure JPOXMLDOC01-appb-C000026
 、及び式（１－１）における下記に表わされる部分構造
Figure JPOXMLDOC01-appb-C000027
 ［両部分構造において、＊は部分構造（ＮＨ）ｐを構成する窒素原子と結合する側を示し、他の符号は前記と同意義を示す。］
としては、下記の構造（下記の構造中、Ｒはアルキル基、好適にはＣ１～Ｃ４アルキル基、より好適にはＣ１～Ｃ２アルキル基を示し、Ｈａｌはハロゲン原子、好適には塩素原子又はフッ素原子を示す。）が好ましい。
Figure JPOXMLDOC01-appb-C000028
 　前記部分構造としては、下記の構造がより好ましい。
Figure JPOXMLDOC01-appb-C000029
 The substructure shown below in formula (1)
Figure JPOXMLDOC01-appb-C000026
 , and the partial structure represented below in formula (1-1)
Figure JPOXMLDOC01-appb-C000027
 [In both partial structures, * indicates the side bonding to the nitrogen atom constituting the partial structure (NH) p, and the other symbols have the same meanings as above. ]
(In the following structure, R represents an alkyl group, preferably a C1-C4 alkyl group, more preferably a C1-C2 alkyl group, and Hal represents a halogen atom, preferably a chlorine atom or a fluorine atom. (indicates an atom) is preferred.
Figure JPOXMLDOC01-appb-C000028
 As the partial structure, the following structure is more preferable.
Figure JPOXMLDOC01-appb-C000029
　Ｒ２が複数あるときは同一であっても異なってもよい。Ｒ２としては、フッ素原子；塩素原子；臭素原子；トリフルオロメチル基；トリクロロメチル基；トリブロモメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ５アシルオキシ基；Ｃ２～Ｃ５アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基が好ましく、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アシルオキシ基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基がより好ましく、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基がさらに好ましく、塩素原子；トリフルオロメチル基；トリクロロメチル基；メチル基；エチル基；メトキシカルボニル基；エトキシカルボニル基；アミド基；Ｃ１～Ｃ３アルキル基から選択される１種又は２種の基で置換されたアミド基；ピペリジニルカルボニル基；或いはメトキシカルボニル基及びエトキシカルボニル基から選択される１種又は２種以上の基で置換されたピペリジニルカルボニル基がさらに好ましい。 When there is a plurality of R 2 s, they may be the same or different. As R2 , fluorine atom; chlorine atom; bromine atom; trifluoromethyl group; trichloromethyl group; tribromomethyl group; C1 to C4 alkyl group; C2 to C5 acyloxy group; C2 to C5 alkoxycarbonyl group; C1 to C3 An amide group optionally substituted with one or two groups selected from the group consisting of alkyl groups and C2-C4 alkoxycarbonyl groups; selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups a piperidinylcarbonyl group which may be substituted with one or more groups; or one or more groups selected from the group consisting of a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group; An optionally substituted pyrrolidinylcarbonyl group is preferred, and includes a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 acyloxy group; a C2-C4 alkoxycarbonyl group; An amide group optionally substituted with one or two groups selected from the group consisting of alkyl groups and C2-C4 alkoxycarbonyl groups; selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups a piperidinylcarbonyl group which may be substituted with one or more groups; or one or more groups selected from the group consisting of a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group; An optionally substituted pyrrolidinylcarbonyl group is more preferred, and includes a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2- An amide group which may be substituted with one or two groups selected from the group consisting of C4 alkoxycarbonyl groups; or one group selected from the group consisting of C1 to C3 alkyl groups and C2 to C4 alkoxycarbonyl groups; A piperidinylcarbonyl group which may be substituted with two or more types of groups is more preferred, and includes a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a methyl group; an ethyl group; a methoxycarbonyl group; an ethoxycarbonyl group; an amide group; - Amide group substituted with one or two groups selected from C3 alkyl groups; piperidinylcarbonyl group; or substituted with one or more groups selected from methoxycarbonyl group and ethoxycarbonyl group More preferred are piperidinylcarbonyl groups.
　Ｒ２は、Ｒ２の結合するベンゼン環を構成する炭素原子のうち、ピペラジン環を構成する窒素原子と直接結合する炭素原子に対してオルト位に位置する２個の炭素原子のうちの１個又は２個に結合していることが好ましく、１個のオルト位炭素原子に結合していることがより好ましい。Ｒ２は、パラ位に位置する炭素原子に結合してもよい。Ｒ２は、（ａ）オルト位の２個の炭素原子のうちの１個のみに結合していること、（ｂ）オルト位の２個の炭素原子のうちの１個とパラ位の炭素原子に結合していること、及び（ｃ）オルト位の２個の炭素原子のうちの１個とメタ位の２個の炭素原子のうちの１個に結合していることが好ましい。Ｒ２は、（ａ）オルト位の２個の炭素原子のうちの１個のみに結合していること、又は（ｂ）オルト位の２個の炭素原子のうちの１個とパラ位の炭素原子に結合していることがより好ましい。 R 2 is one of the two carbon atoms located at the ortho position to the carbon atom directly bonded to the nitrogen atom forming the piperazine ring, among the carbon atoms forming the benzene ring to which R 2 is bonded. Or, it is preferable that it is bonded to two atoms, and more preferably that it is bonded to one ortho-position carbon atom. R 2 may be bonded to a carbon atom located at the para position. R 2 is (a) bonded to only one of the two carbon atoms in the ortho position, (b) one of the two carbon atoms in the ortho position and a carbon atom in the para position. and (c) preferably one of the two carbon atoms at the ortho position and one of the two carbon atoms at the meta position. R2 is (a) bonded to only one of the two carbon atoms in the ortho position, or (b) bonded to one of the two carbon atoms in the ortho position and the carbon in the para position. More preferably, it is bonded to an atom.
　オルト位に位置する炭素原子に結合するＲ２としては、ハロゲン原子、トリハロゲノメチル基、又はＣ１～Ｃ３アルキル基が好ましく、フッ素原子、塩素原子、臭素原子、トリフルオロメチル基、メチル基、又はエチル基がより好ましく、塩素原子、トリフルオロメチル基、又はメチル基が特に好ましい。 R2 bonded to the carbon atom located at the ortho position is preferably a halogen atom, a trihalogenomethyl group, or a C1-C3 alkyl group, and is preferably a fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, methyl group, or An ethyl group is more preferred, and a chlorine atom, a trifluoromethyl group, or a methyl group is particularly preferred.
　パラ位に位置する炭素原子に結合するＲ２は、例えばハロゲン原子、アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基であってよく、塩素原子；臭素原子；フッ素原子；Ｃ１～Ｃ３アルキル基；Ｃ２～Ｃ４アシルオキシ基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基が好ましく、塩素原子；メチル基；エチル基；メトキシカルボニル基；エトキシカルボニル基；アミド基；Ｃ１～Ｃ３アルキル基から選択される１種又は２種の基で置換されたアミド基；ピペリジニルカルボニル基；或いはメトキシカルボニル基及びエトキシカルボニル基から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基がさらに好ましい。 R2 bonded to the carbon atom located at the para position is substituted with one or two groups selected from the group consisting of, for example, a halogen atom, an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group. an amide group which may be substituted; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of an alkyl group and an alkoxycarbonyl group; or a group consisting of an alkyl group and an alkoxycarbonyl group It may be a pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from: chlorine atom; bromine atom; fluorine atom; C1-C3 alkyl group; C2-C4 acyloxy group; C2 -C4 alkoxycarbonyl group; amide group optionally substituted with one or two groups selected from the group consisting of C1-C3 alkyl group and C2-C4 alkoxycarbonyl group; C1-C3 alkyl group and C2-C4 A piperidinylcarbonyl group optionally substituted with one or more groups selected from the group consisting of alkoxycarbonyl groups; or selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups. A pyrrolidinylcarbonyl group which may be substituted with one or more groups is preferred, and is selected from a chlorine atom; a methyl group; an ethyl group; a methoxycarbonyl group; an ethoxycarbonyl group; an amide group; a C1-C3 alkyl group. amide group substituted with one or two groups; piperidinylcarbonyl group; or piperidinyl optionally substituted with one or more groups selected from methoxycarbonyl group and ethoxycarbonyl group; More preferred is a carbonyl group.
　ｎとしては、０～４の整数が好ましく、０～３の整数がより好ましく、０、１、又は２がさらに好ましく、１又は２がさらに好ましく、２が特に好ましい。 n is preferably an integer of 0 to 4, more preferably an integer of 0 to 3, even more preferably 0, 1, or 2, even more preferably 1 or 2, and particularly preferably 2.
　式（１）、（１－１）及び（１－２）において下記に表わされる部分構造
Figure JPOXMLDOC01-appb-C000030
 ［ここで、＊はピペラジン環を構成する窒素原子と結合する側を示す。］
としては、下記の構造が好ましい。
Figure JPOXMLDOC01-appb-C000031
 The partial structure represented below in formulas (1), (1-1) and (1-2)
Figure JPOXMLDOC01-appb-C000030
 [Here, * indicates the side bonded to the nitrogen atom constituting the piperazine ring. ]
The following structure is preferable.
Figure JPOXMLDOC01-appb-C000031
　ｐとしては、１が好ましい。 As p, 1 is preferable.
　ｑとしては、１が好ましい。 q is preferably 1.
　化合物（１）、化合物（１－１）、又は化合物（１－２）としては、以下の（ａ）～（ｍ）に示す化合物を例示できる。
化合物（ａ）　３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸メチルエステル
化合物（ｂ）　２－（４－（２－クロロ－４－ピぺリジン－１－カルボニル）フェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド
化合物（ｃ）　３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）－Ｎ，Ｎ－ジメチルベンズアミド
化合物（ｄ）　１－（３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）ベンゾイル）ピぺリジン－４－カルボン酸メチルエステル
化合物（ｅ）　Ｎ－（４－クロロ－２－メトキシフェニル）－２－（４－（２－クロロフェニル）ピペラジン－１－イル）アセトアミド
化合物（ｆ）　２－（２－（４－（２－クロロフェニル）ピペラジン－１－イル）アセトアミド）安息香酸メチルエステル
化合物（ｇ）　２－（２－（４－（２－トリフルオロメチル）フェニル）ピペラジン－１－イル）アセトアミド）安息香酸メチルエステル
化合物（ｈ）　２－（４－（２，５－ジクロロフェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド
化合物（ｉ）　２－（４－（２，４－ジクロロフェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド
化合物（ｊ）　２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（３－メトキシピリジン－４－イル）アセトアミド
化合物（ｋ）　２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（２－メトキシピリジン－３－イル）アセトアミド
化合物（ｌ）　（４－（５－クロロ－２－メチルフェニル）ピペラジン－１－イル）（３－フルオロフェニル）メタノン
化合物（ｍ）　２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000033
 As the compound (1), the compound (1-1), or the compound (1-2), the following compounds (a) to (m) can be exemplified.
Compound (a) 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid methyl ester compound (b) 2-(4-( 2-chloro-4-piperidine-1-carbonyl)phenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide compound (c) 3-chloro-4-(4-(2-(( 2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)-N,N-dimethylbenzamide compound (d) 1-(3-chloro-4-(4-(2-((2-ethoxyphenyl) ) Amino)-2-oxoethyl)piperazin-1-yl)benzoyl)piperidine-4-carboxylic acid methyl ester compound (e) N-(4-chloro-2-methoxyphenyl)-2-(4-(2 -chlorophenyl)piperazin-1-yl)acetamide compound (f) 2-(2-(4-(2-chlorophenyl)piperazin-1-yl)acetamido)benzoic acid methyl ester compound (g) 2-(2-(4) -(2-trifluoromethyl)phenyl)piperazin-1-yl)acetamido)benzoic acid methyl ester compound (h) 2-(4-(2,5-dichlorophenyl)piperazin-1-yl)-N-(2- Ethoxyphenyl)acetamide compound (i) 2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide compound (j) 2-(4-(2,3- Dimethylphenyl)piperazin-1-yl)-N-(3-methoxypyridin-4-yl)acetamide compound (k) 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-N-( 2-methoxypyridin-3-yl)acetamide compound (l) (4-(5-chloro-2-methylphenyl)piperazin-1-yl)(3-fluorophenyl)methanone compound (m) 2-(4-( 2,3-dimethylphenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000033
　また、化合物（１）、化合物（１－１）、又は化合物（１－２）は、上記の（ａ）～（ｅ）、（ｇ）、（ｈ）、（ｊ）、又は（ｋ）として示される化合物であってよい。さらにまた、化合物（１）、化合物（１－１）、又は化合物（１－２）は、上記の（ａ）～（ｄ）、（ｇ）、（ｈ）、又は（ｋ）として示される化合物であってよい。 In addition, compound (1), compound (1-1), or compound (1-2) can be used as (a) to (e), (g), (h), (j), or (k) above. It may be a compound as shown. Furthermore, compound (1), compound (1-1), or compound (1-2) is a compound represented by (a) to (d), (g), (h), or (k) above. It may be.
　化合物（１）又は化合物（１－１）としては、２－（４－（２－クロロ－４－ピぺリジン－１－カルボニル）フェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミドが特に好ましい。 Compound (1) or compound (1-1) is 2-(4-(2-chloro-4-piperidine-1-carbonyl)phenyl)piperazin-1-yl)-N-(2-ethoxyphenyl ) Acetamide is particularly preferred.
　化合物（１）、化合物（１－１）、及び化合物（１－２）は、これに包含される公知化合物については公知製造法により製造できる。新規化合物については、例えば以下に詳述する製造法１又は２、これらに準ずる方法、公知の方法等を適宜変更、組み合わせること等によって製造することができる。原料化合物として用いられる化合物は、それぞれ塩として用いてもよい。なお、以下に示す方法は単なる例示であり、有機合成に習熟している者の知識に基づき、適宜、他の方法で製造することもできる。 Compound (1), compound (1-1), and compound (1-2) can be produced by known production methods for known compounds included therein. The novel compound can be produced, for example, by appropriately modifying or combining Production Methods 1 or 2 detailed below, methods similar thereto, known methods, and the like. Each compound used as a raw material compound may be used as a salt. The method shown below is merely an example, and other methods can be used as appropriate based on the knowledge of those skilled in organic synthesis.
　製造における各反応において、必要に応じて、官能基を保護することができる。保護基並びにその保護および脱保護の技術は、公知の方法、例えば、T.W.Greene and P.G.M.Wuts,“Protective Groups in Organic Synthesis”,3rd Ed.,John Wiley and Sons,inc.,New York(1999)に記載の方法を適宜適用できる。 In each reaction during production, functional groups can be protected as necessary. Protective groups and their protection and deprotection techniques are described by known methods, such as T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999). The methods described can be applied as appropriate.
［製造法１］
　一実施形態において、式（１Ａ）で表される化合物は、下記の反応工程式－１で示される合成スキ－ムで製造することができる。すなわち、式（１Ａ）で表される化合物は、式（２）で表される化合物と式（３）で表される化合物と式（６）で表わされる化合物から製造することができる。
Figure JPOXMLDOC01-appb-C000034
 ［式中、Ｘはハロゲン原子であり、Ｄは保護基であり、Ａ、Ｂ、Ｒ１、ｍ、Ｒ２、及びｎは前記と同じ。］ [Manufacturing method 1]
In one embodiment, the compound represented by formula (1A) can be produced by the synthesis scheme shown in Reaction Scheme-1 below. That is, the compound represented by formula (1A) can be produced from the compound represented by formula (2), the compound represented by formula (3), and the compound represented by formula (6).
Figure JPOXMLDOC01-appb-C000034
 [In the formula, X is a halogen atom, D is a protecting group, and A, B, R 1 , m, R 2 and n are the same as above. ]
　Ｘとしては、例えば、塩素原子、フッ素原子、臭素原子、ヨウ素原子を挙げることができ、臭素原子が好ましい。 Examples of X include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom, with a bromine atom being preferred.
　Ｄとしては、ハロゲン原子、ｔｅｒｔ－ブチル基、フェニル基、メチル基、エチル基等の保護基を挙げることができ、ｔｅｒｔ－ブトキシ基が好ましい。 Examples of D include protective groups such as a halogen atom, a tert-butyl group, a phenyl group, a methyl group, and an ethyl group, with a tert-butoxy group being preferred.
　製造法１において、Ｒ２は、アルコキシカルボニル基及びハロゲン原子であることが好ましい。パラ位の炭素原子にアルコキシカルボニル基が結合していることがより好ましい。パラ位の炭素原子にアルコキシカルボニル基が結合し、且つ、オルト位の炭素原子にハロゲン原子が結合していることがより好ましい。 In Production Method 1, R 2 is preferably an alkoxycarbonyl group and a halogen atom. More preferably, an alkoxycarbonyl group is bonded to the carbon atom at the para position. More preferably, an alkoxycarbonyl group is bonded to the carbon atom at the para position, and a halogen atom is bonded to the carbon atom at the ortho position.
　工程１、すなわち式（２）で表される化合物と式（３）で表される化合物（塩酸塩であってもよい）を反応させて式（４）で表わされる化合物を合成する工程は、例えば不活性溶媒中、塩基の存在下で行うことができる。式（３）で表わされる化合物としては、例えば2－（4－（2－クロロフェニル）ピペラジン－1－イル）酢酸（CAS No.119357-76-5）であれば市販品を使用でき、その塩酸塩（CAS No. 856843-13-5）はJournal of the American Chemical Society 1955, 77, 1, 40-42に記載の方法により製造でき、その他の化合物も市販品を使用でき、公知の製造法により製造でき、又は公知の製造法を適宜変更することにより製造できる。 Step 1, that is, the step of reacting the compound represented by formula (2) with the compound represented by formula (3) (which may be a hydrochloride) to synthesize the compound represented by formula (4), For example, it can be carried out in an inert solvent in the presence of a base. As the compound represented by formula (3), for example, 2-(4-(2-chlorophenyl)piperazin-1-yl)acetic acid (CAS No. 119357-76-5) can be used as a commercially available product, and its hydrochloric acid Salt (CAS No. 856843-13-5) can be produced by the method described in Journal of the American Chemical Society 1955, 77, 1, 40-42, and other compounds can be commercially available, and can be produced by known production methods. or by appropriately modifying a known manufacturing method.
　この反応における、不活性溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメトキシメタン等のエーテル系溶媒、トルエン、ベンゼン、キシレン等の芳香族炭化水素系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、アセトン等のケトン系溶媒、ジメチルスルホキシド、Ｎ、Ｎ－ジメチルホルムアミド（ＤＭＦ）、アセトニトリル等の非プロトン溶媒、ピリジン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。 Examples of inert solvents used in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, dichloromethane, chloroform, dichloroethane, and tetrachloride. Examples include halogenated hydrocarbon solvents such as carbon, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF), acetonitrile, and pyridine. Two or more of these solvents may be used as a mixture in an appropriate ratio.
　塩基としては、例えば水素化ナトリウム、水素化カリウム等の金属ヒドリド、水酸化カリウム、水酸化ナトリウム等の金属水酸化物、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム等の金属炭酸塩、トリエチルアミン、エチルジイソプロピルアミン等のアルキルアミン類、ナトリウムメトキシド、カリウムｔ－ブトキシド等の金属アルコキシドが挙げられる。 Examples of bases include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, and cesium carbonate. Examples include carbonates, alkyl amines such as triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.
　式（２）で表される化合物の使用量は、式（３）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the compound represented by formula (2) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (3). mol, more preferably 0.9 to 1.5 mol.
　塩基の使用量は、式（３）で表される化合物１モルに対して、通常１モル以上、好ましくは１～５倍モル、より好ましくは１～２倍モルである。 The amount of the base to be used is usually 1 mole or more, preferably 1 to 5 times the mole, more preferably 1 to 2 times the mole, per 1 mole of the compound represented by formula (3).
　反応温度は、通常－２０℃～溶媒の沸点より１０℃高い温度、好ましくは０℃～４０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 The reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably 0°C to 40°C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
　工程２、すなわち式（４）で表される化合物を式（５）で表される化合物へ変換する工程は、例えば式（４）で表される化合物を酸性有機溶媒で処理することにより可能である。 Step 2, that is, the step of converting the compound represented by formula (4) into the compound represented by formula (5), can be performed, for example, by treating the compound represented by formula (4) with an acidic organic solvent. be.
　この反応における、酸性有機溶媒としては、塩酸含有１，４－ジオキサン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。酸性有機溶媒の使用量は式（４）で表わされる化合物を酸化できる程度の量であればよい。 Examples of the acidic organic solvent in this reaction include 1,4-dioxane containing hydrochloric acid. Two or more of these solvents may be used as a mixture in an appropriate ratio. The amount of the acidic organic solvent to be used may be an amount sufficient to oxidize the compound represented by formula (4).
　工程３、すなわち式（５）で表される化合物と式（６）で表される化合物を反応させて式（１Ａ）で表わされる化合物を合成する工程は、例えば不活性溶媒中、塩基及び縮合剤の存在下で行うことができる。不活性溶媒及び塩基の詳細は前記と同様である。 Step 3, that is, the step of reacting the compound represented by formula (5) with the compound represented by formula (6) to synthesize the compound represented by formula (1A), is carried out using, for example, a base and a condensation reaction in an inert solvent. It can be carried out in the presence of an agent. Details of the inert solvent and base are the same as above.
　縮合剤としては、例えば１‐［ジメチルアミノ（ジメチルイミニオ）メチル］‐１Ｈ‐１，２，３‐トリアゾロ［４，５‐ｂ］ピリジン３‐オキシド・ヘキサフルオロホスファート（本明細書中、「ＨＡＴＵ」とも称する。）等が挙げられる。 Examples of the condensing agent include 1-[dimethylamino(dimethyliminio)methyl]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (herein, (also referred to as "HATU").
　式（６）で表される化合物の使用量は、式（５）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the compound represented by formula (6) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (5). mol, more preferably 0.9 to 1.5 mol.
　縮合剤の使用量は、式（５）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the condensing agent used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, more preferably 0.5 mol or more, per 1 mol of the compound represented by formula (5). The amount is 9 to 1.5 moles.
　反応温度は、通常－２０℃～溶媒の沸点より１０℃高い温度、好ましくは０℃～４０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 The reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably 0°C to 40°C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
　工程３によって、Ｒ２がアルコキシカルボニル基である式（１Ａ）で表される化合物を得た場合、この化合物を、例えば不活性溶媒中、塩基の存在下で処理することによって、対応するカルボン酸体に変換してもよい。次いで、このカルボン酸体に適当な置換基を導入する。例えば不活性溶媒中、縮合剤の存在下、必要に応じてさらに塩基の存在下で、置換基に対応する化合物（例えばピペリジン、アミン等）と反応させて、Ｒ２として対応するアミド基又はピペリジニルカルボニル基を有する式（１Ａ）で表される化合物を得ることもできる。不活性溶媒、塩基及び縮合剤の詳細は前記と同様である。 When a compound represented by the formula (1A) in which R 2 is an alkoxycarbonyl group is obtained in step 3, the corresponding carboxylic acid can be obtained by treating this compound in the presence of a base in an inert solvent, for example. It can be converted into a body. Next, a suitable substituent is introduced into this carboxylic acid. For example, in an inert solvent, in the presence of a condensing agent, and optionally in the presence of a base, the corresponding amide group or pipe as R2 is reacted with a compound corresponding to the substituent (e.g. piperidine, amine, etc.). A compound represented by formula (1A) having a peridinylcarbonyl group can also be obtained. Details of the inert solvent, base and condensing agent are the same as above.
　この場合、ピペリジン、アミン等の置換基に対応する化合物の使用量は、Ｒ２がアルコキシカルボニル基である式（１Ａ）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～１０モル、より好ましくは０．９～８モルである。反応温度は、通常－２０℃～溶媒の沸点より１０℃高い温度、好ましくは０℃～４０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 In this case, the amount of the compound corresponding to the substituent such as piperidine or amine is usually 0.5 mol or more per 1 mol of the compound represented by formula (1A) in which R 2 is an alkoxycarbonyl group. The amount is 0.8 mol or more, preferably 0.9 to 10 mol, more preferably 0.9 to 8 mol. The reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably 0°C to 40°C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
［製造法２］
　一実施形態において、式（１Ａ）で表される化合物は、下記の反応工程式－２で示される合成スキームで製造することができる。すなわち、式（１Ａ）で表される化合物は、式（６）で表される化合物と式（７）で表される化合物と式（３）で表される化合物から製造することができる。 [Manufacturing method 2]
In one embodiment, the compound represented by formula (1A) can be produced according to the synthesis scheme shown in Reaction Scheme-2 below. That is, the compound represented by formula (1A) can be produced from the compound represented by formula (6), the compound represented by formula (7), and the compound represented by formula (3).
Figure JPOXMLDOC01-appb-C000035
 ［式中、Ｘ、Ｄ、Ａ、Ｂ、Ｒ１、ｍ、Ｒ２、及びｎは前記と同じ。］
Figure JPOXMLDOC01-appb-C000035
 [Wherein, X, D, A, B, R 1 , m, R 2 and n are the same as above. ]
　工程１、すなわち式（６）で表される化合物と式（７）で表される化合物を反応させて式（８）で表わされる化合物を合成する工程は、例えば不活性溶媒中、塩基の存在下で行うことができる。不活性溶媒及び塩基の詳細は前記と同様である。 Step 1, that is, the step of reacting the compound represented by formula (6) with the compound represented by formula (7) to synthesize the compound represented by formula (8), is performed in the presence of a base in an inert solvent, for example. You can do it below. Details of the inert solvent and base are the same as above.
　式（７）で表される化合物の使用量は、式（６）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the compound represented by formula (7) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (6). mol, more preferably 0.9 to 1.5 mol.
　反応温度は、通常－２０℃～溶媒の沸点より１０℃高い温度、好ましくは－１０℃～４０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 The reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably -10°C to 40°C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
　工程２、すなわち式（８）で表される化合物と式（３）で表される化合物を反応させて式（１Ａ）で表わされる化合物を合成する工程は、例えば不活性溶媒中、塩基の存在下で行うことができる。不活性溶媒及び塩基の詳細は前記と同様である。 Step 2, that is, the step of reacting the compound represented by formula (8) with the compound represented by formula (3) to synthesize the compound represented by formula (1A), is performed in the presence of a base in an inert solvent, for example. You can do it below. Details of the inert solvent and base are the same as above.
　式（３）で表される化合物の使用量は、式（８）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the compound represented by formula (3) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, per 1 mol of the compound represented by formula (8). mol, more preferably 0.9 to 1.5 mol.
　反応温度は、通常－２０℃～溶媒の沸点より１０℃高い温度、好ましくは－１０℃～４０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 The reaction temperature is usually -20°C to 10°C higher than the boiling point of the solvent, preferably -10°C to 40°C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.
カンナビジオール
　カンナビジオールは、下の化学構造式で示される2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-Benzenediolであり、本発明者らによってオートファジー活性化作用を有することが見出された。カンナビジオールは公知の方法により製造するか、天然物から得ることができる。
Figure JPOXMLDOC01-appb-C000036
 Cannabidiol Cannabidiol is 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1, which is shown by the chemical structural formula below. 3-Benzenediol, which was discovered by the present inventors to have an autophagy activating effect. Cannabidiol can be produced by known methods or obtained from natural products.
Figure JPOXMLDOC01-appb-C000036
　本発明による式（１）で表される化合物（式（１）で表される化合物には、特に断りがない限り、式（１－１）で表される化合物及び式（１－２）で表される化合物が包含される。）及びその中間体化合物は、上記の製造法により製造することができ、また、出発原料化合物、本発明による式（１）で表される化合物、及びその中間体化合物は、本明細書の実施例等に記載された合成方法に基づき本出願時に既知または公知の技術（例えば、B. R. Kiran et al., SYNTHESIS, EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF SUBSTITUTED 1,2-BENZOXAZOLONE AND 3-CHLORO-1,2-BENZOXAZOLE DERIVATIVES, International Journal of Pharmaceutical Sciences and Research, 2015; 6: 2918-2925.）を参酌して製造することもできる。 Compounds represented by formula (1) according to the present invention (compounds represented by formula (1) include compounds represented by formula (1-1) and formula (1-2), unless otherwise specified. ) and its intermediate compounds can be produced by the above production method, and the starting material compound, the compound represented by formula (1) according to the present invention, and its intermediate compounds can be produced by the above-mentioned production method. The compound can be synthesized using techniques known or known at the time of this application (for example, B. R. Kiran et al., SYNTHESIS, EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF SUBSTITUTED 1,2-BENZOXAZOLONE AND 3-CHLORO-1,2-BENZOXAZOLE DERIVATIVES, International Journal of Pharmaceutical Sciences and Research, 2015; 6: 2918-2925.
　上記反応式のそれぞれに示された出発原料化合物及び中間体化合物は、反応に供する前に、必要に応じて、公知の方法を用いて官能基を適当な保護基で保護し、反応終了後、公知の方法で当該保護基を脱保護することができる。 Before the starting material compounds and intermediate compounds shown in each of the above reaction formulas are subjected to the reaction, if necessary, the functional groups are protected with an appropriate protecting group using a known method, and after the reaction is completed, The protecting group can be deprotected by a known method.
　上記の反応式に従って得られる目的化合物のそれぞれを単離および精製することができる。例えば、反応混合物を冷却した後に、粗反応生成物を分離するために濾過、濃縮、抽出等の単離手順を行い、その後粗反応生成物を、カラムクロマトグラフィー、再結晶化等の一般的な精製手順に供することにより、反応混合物から単離および精製することができる。 Each of the target compounds obtained according to the above reaction formula can be isolated and purified. For example, after cooling the reaction mixture, isolation procedures such as filtration, concentration, extraction, etc. are carried out to separate the crude reaction product, and then the crude reaction product is subjected to common methods such as column chromatography, recrystallization, etc. It can be isolated and purified from the reaction mixture by subjecting it to purification procedures.
　式（１）で表される化合物、及び上記反応式のそれぞれに示された出発原料化合物、中間体化合物等には、溶媒が付加した溶媒和物（例えば、水和物、エタノール和物等）の形態である化合物が含まれる。 The compound represented by formula (1) and the starting material compounds, intermediate compounds, etc. shown in each of the above reaction formulas include solvates with a solvent added (e.g., hydrates, ethanolates, etc.) Compounds that are in the form of are included.
　上記各反応工程式において得られる中間体化合物、出発原料化合物、式（１）で表される化合物、及びカンナビジオールに、二重結合、環、縮合環における異性体（Ｅ、Ｚ、シス、トランス体）、不斉炭素の存在等による異性体（Ｒ、Ｓ体、α、β体、エナンチオマー、ジアステレオマー）、旋光性を有する光学活性体（Ｄ、Ｌ、ｄ、ｌ体）、クロマトグラフ分離による極性体（高極性体、低極性体）、平衡化合物、回転異性体、これらの任意の割合の混合物、ラセミ混合物は幾何異性体、立体異性体、光学異性体などの異性体が存在する場合には、全ての異性体が包含される。例えば、光学異性体は、公知の各種の分割法（例えば、結晶化による光学分割、クロマトグラフィーによる直接光学分割する方法等）を利用して分離することができる。 The intermediate compound obtained in each of the above reaction schemes, the starting material compound, the compound represented by formula (1), and cannabidiol have isomers (E, Z, cis, trans ), isomers due to the presence of asymmetric carbon (R, S form, α, β form, enantiomer, diastereomer), optically active form with optical rotation (D, L, d, l form), chromatography Polar substances (highly polar, low polar), equilibrium compounds, rotamers, mixtures of these in arbitrary proportions, and racemic mixtures include isomers such as geometric isomers, stereoisomers, and optical isomers due to separation. In this case, all isomers are included. For example, optical isomers can be separated using various known separation methods (for example, optical resolution by crystallization, direct optical resolution by chromatography, etc.).
　式（１）で表される化合物及びカンナビジオールの薬学的に許容される塩としては、特に制限されず、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；亜鉛塩等の無機金属塩；トリエチルアミン、トリエタノールアミン、トリヒドロキシメチルアミノメタン、アミノ酸等の有機塩基塩；塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、硝酸塩等の無機酸塩；酢酸塩、炭酸塩、プロピオン酸塩、コハク酸塩、乳酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、メタンスルホン酸塩、ｐ－トルエンスルホン酸塩、ベンゼンスルホン酸塩、アスコルビン酸塩等の有機酸塩等が挙げられる。これらの塩は常法に従って製造することができる。 Pharmaceutically acceptable salts of the compound represented by formula (1) and cannabidiol are not particularly limited, and include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts and magnesium salts; Metal salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids; hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, etc. Inorganic acid salts: acetate, carbonate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonic acid Examples include organic acid salts such as salts, benzenesulfonates, and ascorbates. These salts can be produced according to conventional methods.
　各種の異性体は公知の分離法により単離できる。例えば、ラセミ化合物は一般的な光学分割法（例えば、結晶化による光学分割、クロマトグラフィーによる直接光学分割する方法等）により、立体的に純粋な異性体に導くことができる。また、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Various isomers can be isolated by known separation methods. For example, a racemic compound can be led to a sterically pure isomer by a general optical resolution method (eg, optical resolution by crystallization, direct optical resolution by chromatography, etc.). Furthermore, optically active compounds can also be produced by using appropriate optically active raw materials.
　上記反応工程式のそれぞれに表される出発原料化合物、中間体化合物、及び目的化合物を適切な塩形態で使用することができる。 The starting material compounds, intermediate compounds, and target compounds represented in each of the above reaction schemes can be used in an appropriate salt form.
　式（１）で表される化合物及びカンナビジオールでは、１つまたは複数の原子を１つまたは複数の同位体原子で置換することができる。同位体原子の例としては重水素（２Ｈ）、三重水素（３Ｈ）、１３Ｃ、１４Ｎ、１８Ｏ等が挙げられる。 In the compound represented by formula (1) and cannabidiol, one or more atoms can be substituted with one or more isotopic atoms. Examples of isotopic atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O, and the like.
医薬組成物
　本発明の医薬組成物は、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩に加え、薬学的に許容される担体を含有してもよい。 Pharmaceutical Composition The pharmaceutical composition of the present invention comprises at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable salt thereof. may contain a carrier acceptable to
　本発明の医薬組成物は、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩を医薬組成物の形態に製剤したものである。本発明の医薬組成物は、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物又はその薬学的に許容される塩と、薬学的に許容される担体とを用いて、例えば常法により、調製され得る。当該担体としては、通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤等の希釈剤あるいは賦形剤が挙げられる。 The pharmaceutical composition of the present invention comprises at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition. This is what I did. The pharmaceutical composition of the present invention comprises at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It can be prepared using, for example, a conventional method. Examples of the carrier include commonly used fillers, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, and other diluents or excipients.
　本発明の医薬組成物としては、治療目的に応じて種々の形態の中から選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤（液剤、懸濁剤等）、軟膏剤、吸入剤等が挙げられる。 The pharmaceutical composition of the present invention can be selected from various forms depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, Examples include suppositories, injections (solutions, suspensions, etc.), ointments, inhalants, and the like.
　錠剤の成形に使用する担体としては、公知のものを広く使用でき、例えば、乳糖、白糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース等の賦形剤、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、メチルセルロース、リン酸カリウム、ポリビニルピロリドン、カルボキシメチルセルロース、セラック等の結合剤、アルギン酸ナトリウム、乾燥デンプン、寒天末、ラミナラン末、炭酸カルシウム、炭酸水素ナトリウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、ステアリン、カカオバター、水素添加油等の崩壊抑制剤、グリセリン、デンプン等の保湿剤、デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、精製タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコール等の滑沢剤等が挙げられる。 A wide variety of known carriers can be used as carriers for forming tablets, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose, water, ethanol, Propanol, simple syrup, glucose solution, starch solution, gelatin solution, methylcellulose, potassium phosphate, polyvinylpyrrolidone, carboxymethylcellulose, binder such as shellac, sodium alginate, dried starch, powdered agar, powdered laminaran, calcium carbonate, sodium bicarbonate. , polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, stearin, cocoa butter, hydrogenated oils, etc. Examples include disintegration inhibitors, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. It will be done.
　さらに、錠剤は、必要に応じて通常の錠皮を施した錠剤、例えば、糖衣剤、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。 Furthermore, the tablet may be a tablet coated with a conventional tablet shell, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.
　丸剤の成形に使用する担体としては、公知のものを広く使用でき、例えば、ブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤、ラミナラン、寒天等の崩壊剤等が挙げられる。 A wide variety of known carriers can be used as carriers for forming pills, including excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth, and gelatin. , binders such as ethanol, and disintegrants such as laminaran and agar.
　坐剤の成形に使用する担体としては、公知のものを広く使用でき、例えば、ポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等が挙げられる。 A wide variety of known carriers can be used as carriers for forming suppositories, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like.
　注射剤として調製される場合は、液剤、乳剤および懸濁剤は殺菌され、かつ血液と等張であるのが好ましい。これらの液剤、乳剤および懸濁剤の調製の際に使用する希釈剤としては、公知のものを広く使用することができ、例えば、水、エタノール、プロピレングリコール、ポリオキシ化イソステアリルアルコール、エトキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等が挙げられる。なお、注射剤の場合、等張性の溶液を調製するのに十分な量の食塩、グリセリン、ブドウ糖等を医薬製剤中に含有させることができ、また通常の溶解補助剤、緩衝剤、無痛化剤等を含有させることができ、更に必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有させることができる。 When prepared as an injection, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. As the diluent used in preparing these solutions, emulsions and suspensions, a wide variety of known diluents can be used, such as water, ethanol, propylene glycol, polyoxylated isostearyl alcohol, and ethoxylated isostearyl alcohol. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In the case of injections, sufficient amounts of salt, glycerin, glucose, etc. can be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffering agents, painless agents, etc. can be included in the pharmaceutical preparation. In addition, coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc., and other pharmaceuticals can be contained as necessary.
　軟膏剤は、ペースト、クリーム、またはゲルなどの形態があり、これらの形態に調製するに際しては、希釈剤として、例えば、白色ワセリン、パラフィン、グリセリン、セルロース誘導体、ポリエチレングリコール、シリコーン、ベントナイト等を使用できる。 Ointments come in the form of paste, cream, or gel, and when preparing these forms, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. are used. can.
　吸入剤は、有効成分をエアゾールとして吸入させることにより、気管支または肺に適用することを目的とした製剤であり、粉末吸入剤、吸入液剤、吸入エアゾール剤等が含まれる。粉末吸入剤は、粉末状固体粒子のエアゾールとして吸入する製剤をいい、通常、有効成分を微細な粒子とし、必要に応じて乳糖等の添加剤と混和して均質とすることにより製造することができる。吸入液剤は、ネブライザ等により適用する液状の吸入剤をいい、通常、有効成分に溶剤および適切な等張化剤、ｐＨ調節剤等を加え、混和することにより製造できる。吸入エアゾール剤は、容器に充填した噴射剤と共に、一定量の有効成分を噴霧する定量噴霧式吸入剤である。吸入エアゾール剤は、通常、有効成分に溶剤および適切な分散剤、安定化剤等を加えて、溶液または懸濁液とし、液状の噴射剤と共に耐圧性の容器に充填し、定量バルブを装着することにより製造することができる。 Inhalants are preparations that are intended to be applied to the bronchi or lungs by inhaling the active ingredient as an aerosol, and include powder inhalants, inhalation liquids, inhalation aerosols, and the like. Powder inhalants are preparations that are inhaled as an aerosol of powdered solid particles, and are usually manufactured by making the active ingredient into fine particles and mixing them with additives such as lactose as necessary to make them homogeneous. can. Inhalation liquids refer to liquid inhalants that are applied with a nebulizer or the like, and can usually be produced by adding and mixing the active ingredients with a solvent, an appropriate tonicity agent, a pH adjuster, etc. Inhalation aerosols are metered dose inhalants that spray a fixed amount of active ingredient together with a propellant filled in a container. Inhalation aerosols are usually made into a solution or suspension by adding a solvent and appropriate dispersants, stabilizers, etc. to the active ingredient, and then filling the solution or suspension with a liquid propellant into a pressure-resistant container, which is fitted with a metering valve. It can be manufactured by
　本発明の医薬組成物は、必要に応じて、着色剤、保存剤、香料、風味剤、甘味剤など、又は他の医薬品を含有してもよい。 The pharmaceutical composition of the present invention may contain colorants, preservatives, fragrances, flavors, sweeteners, etc., or other pharmaceuticals, as necessary.
　本発明の医薬組成物中に含有される式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩の量は、特に限定されず広い範囲内から適宜選択することができるが、医薬組成物中に、通常、０．５～９０質量％、１～８５質量％、好ましくは１～８０質量％である。 The amount of at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, contained in the pharmaceutical composition of the present invention is particularly It can be appropriately selected from a wide range without limitation, but it is usually 0.5 to 90% by weight, 1 to 85% by weight, preferably 1 to 80% by weight in the pharmaceutical composition.
　本発明の医薬組成物の投与方法は特に制限されず、各種製剤形態、患者の年齢、性別、疾患の状態、その他の条件に応じた方法で投与される。例えば、錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には経口投与される。また、注射剤の場合には、単独であるいはブドウ糖、アミノ酸等の通常の補液と混合して静脈内に投与したり、更には必要に応じて単独で筋肉内、皮内、皮下、腹腔内等に投与することができる。坐剤の場合には、直腸内に投与される。吸入剤の場合には経鼻投与される。 The method of administering the pharmaceutical composition of the present invention is not particularly limited, and it is administered in a manner depending on various formulation forms, patient age, sex, disease state, and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they can be administered intravenously alone or mixed with normal replacement fluids such as glucose or amino acids, or if necessary, they can be administered alone intramuscularly, intradermally, subcutaneously, intraperitoneally, etc. It can be administered to In the case of suppositories, they are administered rectally. Inhalants are administered nasally.
　本発明の医薬組成物の投与量は、用法、患者の年齢、性別、疾患の程度、その他の条件を考慮して選択すればよく、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物又はその薬学的に許容される塩が、通常、１日あたり体重１ｋｇに対して０．０１～１００ｍｇ、好ましくは０．１～５０ｍｇとなる量で、１日あたり１回～数回に分けて、あるいは２日、３日、４日、５日、６日、１週間、２週間または４週間に１回の間隔で投与される。投与量は、種々の条件で変動するので、上記範囲より少ない投与量で充分な場合もあるし、また上記範囲を超えた投与量が必要な場合もある。 The dosage of the pharmaceutical composition of the present invention may be selected in consideration of the usage, patient's age, sex, degree of disease, and other conditions, and can be selected from the group consisting of the compound represented by formula (1) and cannabidiol. At least one compound selected from the following or a pharmaceutically acceptable salt thereof is usually administered in an amount of 0.01 to 100 mg, preferably 0.1 to 50 mg per kg of body weight per day. It is administered in one to several divided doses, or at intervals of once every 2, 3, 4, 5, 6 days, 1 week, 2 weeks, or 4 weeks. The dosage varies depending on various conditions, so a dosage smaller than the above range may be sufficient in some cases, and a dosage exceeding the above range may be necessary in other cases.
　また、本発明の医薬組成物は、他の薬剤と組み合わせた併用剤とすることもできる。本発明の医薬組成物は、例えば、抗がん剤と併用してもよい。抗がん剤としては、ドキソルビシン、イダルビジン、マイトマイシンＣ等の抗腫瘍性抗生物質、ドセタキセル、ビンクリスチン等の微小管阻害剤、カルボプラチン、シスプラチン、オキサリプラチン等のプラチナ製剤、ボリノスタット等のヒストン脱アセチル化酵素（HDAC）阻害剤、スニチニブ、イマチニブ、ゲフェチニブ、エルロチニブ、アファチニブ、ダサチニブ、トラメチニブ等のキナーゼ阻害剤、イリノテカン、エトポシド等のトポイソメラーゼ阻害剤、シクロスポリン、タクロリムス等のカルシニューリン阻害薬、シクロホスファミド、ベンダムスチン、イオスファミド、ダカルバジン等のアルキル化薬、ペントスタチン、フルダラビン、クラドリビン、メソトレキセート、５－フルオロウラシル、６－メルカプトプリン、エノシタビン等の代謝拮抗薬、リツキシマブ、セツキシマブ、トラスツズマブ等の分子標的薬、ボルテゾミブ等のプロテアソーム阻害剤、タモキシフェン、ビカルダミド等のホルモン療法薬、ニボルマブ、ペンブロリズマブ、ピジリズマブ等の抗ＰＤ－１抗体、アテゾリズマブ、アベルマブ、又はデュルバルマブ、ＢＭＳ－９３６５５９等の抗ＰＤ－Ｌ１抗体、イピリムマブ又はトレメリムマブ等の抗ＣＴＬＡ－４抗体を挙げることができる。これらの抗がん剤との併用は、癌の予防又は治療の用途において好ましい。
　本発明の医薬組成物は、例えば、ダパグリフロジン等のSGLT2阻害薬、エナラプリル等のACE阻害剤、カンデサルタン等のARB等と併用してもよい。これらの薬剤との併用は、腎疾患の予防又は治療の用途において好ましい。
　本発明の医薬組成物は、例えば、ラニビスマブ等のVEGF抗体、ラタノプロスト等のPGF2α関連薬等と併用してもよい。これらの薬剤との併用は、眼疾患の予防又は治療の用途において好ましい。
　本発明の医薬組成物は、例えば、メロペネム等のβラクタム系抗生物質等と併用してもよい。これらの薬剤との併用は、細菌感染症及びウイルス感染症の予防又は治療の用途において好ましい。
　本発明の医薬組成物は、例えば、アダリムマブ等のTNFα抗体等と併用してもよい。これらの薬剤との併用は、自己免疫疾患の予防又は治療の用途において好ましい。 Moreover, the pharmaceutical composition of the present invention can also be used as a concomitant drug in combination with other drugs. The pharmaceutical composition of the present invention may be used in combination with, for example, an anticancer drug. Anticancer drugs include antitumor antibiotics such as doxorubicin, idarubidin, and mitomycin C, microtubule inhibitors such as docetaxel and vincristine, platinum agents such as carboplatin, cisplatin, and oxaliplatin, and histone deacetylases such as vorinostat. (HDAC) inhibitors, kinase inhibitors such as sunitinib, imatinib, gefetinib, erlotinib, afatinib, dasatinib, trametinib, topoisomerase inhibitors such as irinotecan, etoposide, calcineurin inhibitors such as cyclosporine, tacrolimus, cyclophosphamide, bendamustine, Alkylating drugs such as iosfamide and dacarbazine, antimetabolites such as pentostatin, fludarabine, cladribine, methotrexate, 5-fluorouracil, 6-mercaptopurine, and enocitabine, molecular targeted drugs such as rituximab, cetuximab, and trastuzumab, and proteasome inhibitors such as bortezomib. Hormone therapy drugs such as tamoxifen and bicaldamide, anti-PD-1 antibodies such as nivolumab, pembrolizumab, and pidilizumab, anti-PD-L1 antibodies such as atezolizumab, avelumab, or durvalumab, BMS-936559, and anti-CTLA drugs such as ipilimumab or tremelimumab. 4 antibodies can be mentioned. Combination use with these anticancer agents is preferable for use in cancer prevention or treatment.
The pharmaceutical composition of the present invention may be used in combination with, for example, an SGLT2 inhibitor such as dapagliflozin, an ACE inhibitor such as enalapril, an ARB such as candesartan, and the like. Combination use with these drugs is preferred for the prevention or treatment of renal diseases.
The pharmaceutical composition of the present invention may be used in combination with, for example, a VEGF antibody such as ranibismumab, a PGF2α-related drug such as latanoprost, and the like. Combination use with these drugs is preferred for use in the prevention or treatment of eye diseases.
The pharmaceutical composition of the present invention may be used in combination with, for example, a β-lactam antibiotic such as meropenem. Combination use with these drugs is preferred for the prevention or treatment of bacterial infections and viral infections.
The pharmaceutical composition of the present invention may be used in combination with, for example, a TNFα antibody such as adalimumab. Combination use with these drugs is preferred for use in the prevention or treatment of autoimmune diseases.
　本発明の医薬組成物の予防又は治療対象となる疾患としては、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、筋骨格系疾患（筋ジストロフィーを除く）等が挙げられる。好ましい疾患は、腎疾患（腎線維症を除く）、肝障害、眼疾患、皮膚疾患であり、より好ましい疾患は腎疾患、皮膚疾患である。 Diseases that can be prevented or treated with the pharmaceutical composition of the present invention include lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, Examples include cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome, and musculoskeletal diseases (excluding muscular dystrophy). Preferred diseases are renal diseases (excluding renal fibrosis), liver disorders, eye diseases, and skin diseases, and more preferred diseases are renal diseases and skin diseases.
　本発明において、予防又は治療の対象となる疾患の一つは、肺線維症を除いた肺疾患である。肺疾患としては、慢性閉塞性肺疾患（ＣＯＰＤ）、嚢胞性線維症等が挙げられ、ＣＯＰＤが好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is lung diseases other than pulmonary fibrosis. Pulmonary diseases include chronic obstructive pulmonary disease (COPD), cystic fibrosis, etc., with COPD being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、腎線維症を除いた腎疾患である。腎疾患としては、急性腎障害、慢性腎臓病、糖尿病性腎症等が挙げられ、急性腎障害、慢性腎臓病が好ましい。 In the present invention, one of the diseases to be prevented or treated is renal diseases other than renal fibrosis. Kidney diseases include acute kidney injury, chronic kidney disease, diabetic nephropathy, etc., with acute kidney injury and chronic kidney disease being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、生殖機能障害である。生殖機能障害としては、女性不妊症、男性不妊症、子宮内膜症等が挙げられる。 In the present invention, one of the diseases targeted for prevention or treatment is reproductive dysfunction. Examples of reproductive dysfunction include female infertility, male infertility, and endometriosis.
　本発明において、予防又は治療の対象となる疾患の一つは、肝障害である。肝障害としては、非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）、非アルコール性脂肪肝炎（ＮＡＳＨ）、肝硬変、胆汁うっ滞、高アンモニア血症等が挙げられ、非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）、非アルコール性脂肪肝炎（ＮＡＳＨ）が好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is liver damage. Liver disorders include nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cholestasis, hyperammonemia, etc. , non-alcoholic steatohepatitis (NASH) is preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、眼疾患である。眼疾患としては、緑内障、加齢性黄斑変性症、網膜色素変性症等が挙げられ、緑内障、加齢性黄斑変性症が好ましい。 In the present invention, one of the diseases to be prevented or treated is an eye disease. Eye diseases include glaucoma, age-related macular degeneration, retinitis pigmentosa, etc., with glaucoma and age-related macular degeneration being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、皮膚疾患である。皮膚疾患としては、ケロイド、強皮症、乾癬等が挙げられ、乾癬が好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is a skin disease. Examples of skin diseases include keloids, scleroderma, and psoriasis, with psoriasis being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、肺がん、前立腺がん、及び乳がんを除いた癌である。癌としては、黒色腫、膵臓がん、子宮頸がん、骨肉腫、肝がん、皮膚がん等が挙げられ、子宮頸がん、骨肉腫、肝がん、皮膚がんが好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is cancer other than lung cancer, prostate cancer, and breast cancer. Examples of cancer include melanoma, pancreatic cancer, cervical cancer, osteosarcoma, liver cancer, and skin cancer, with cervical cancer, osteosarcoma, liver cancer, and skin cancer being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、細菌感染症である。細菌感染症としては、リケッチア症、結核、Ａ群レンサ球菌感染症、黄色ブドウ球菌感染症等が挙げられ、結核、Ａ群レンサ球菌感染症が好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is bacterial infection. Examples of bacterial infections include rickettsiosis, tuberculosis, group A streptococcal infection, and staphylococcus aureus infection, with tuberculosis and group A streptococcal infection being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、ウイルス感染症である。ウイルス感染症としては、HIV-1、チクングニア熱、ウエストナイル脳炎等が挙げられ、ウエストナイル脳炎が好ましい。 In the present invention, one of the diseases to be prevented or treated is a viral infection. Examples of viral infections include HIV-1, chikungunya fever, West Nile encephalitis, and the like, with West Nile encephalitis being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、自己免疫疾患である。自己免疫疾患しては、クローン病、潰瘍性大腸炎、関節リウマチ等が挙げられ、クローン病が好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is an autoimmune disease. Examples of autoimmune diseases include Crohn's disease, ulcerative colitis, and rheumatoid arthritis, with Crohn's disease being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、メタボリックシンドロームである。メタボリックシンドロームしては、肥満、２型糖尿病等が挙げられ、肥満が好ましい。 In the present invention, one of the diseases targeted for prevention or treatment is metabolic syndrome. Examples of metabolic syndrome include obesity, type 2 diabetes, and the like, with obesity being preferred.
　本発明において、予防又は治療の対象となる疾患の一つは、筋ジストロフィーを除いた筋骨格系疾患である。筋骨格系疾患としては、変性ミオパチー、骨Paget病（ＰＤＢ）、変形性関節症、骨粗鬆症等が挙げられ、骨粗鬆症が好ましい。 In the present invention, one of the diseases to be prevented or treated is musculoskeletal diseases other than muscular dystrophy. Examples of musculoskeletal diseases include degenerative myopathy, Paget's disease of bone (PDB), osteoarthritis, and osteoporosis, with osteoporosis being preferred.
オートファジー活性化剤
　本発明のオートファジー活性化剤は、細胞のオートファジーを活性化作用を有し、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩に加え、薬学的に許容される担体を含有してもよい。オートファジー活性化剤における式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩の含有量は、前記医薬組成物における含有量と同様とできる。オートファジー活性化剤の形態等種々の事項は、前記医薬組成物における対応する種々の事項と同様とできる。 Autophagy activator The autophagy activator of the present invention has an action of activating cellular autophagy and contains at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol. In addition to the compound or its pharmaceutically acceptable salt, it may contain a pharmaceutically acceptable carrier. The content of at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol in the autophagy activator, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition The content can be the same. Various matters such as the form of the autophagy activator can be the same as the corresponding various matters in the pharmaceutical composition.
　式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物又はその薬学的に許容される塩を含有することによって、生体内又は生体外において、細胞のオートファジー活性を増強する。増強の程度は、例えば1.1倍以上、1.2倍以上、1.3倍以上、1.4倍以上、1.5倍以上（好ましくは2倍以上、より好ましくは2.5倍以上）とできる。 By containing at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, autophagy of cells can be improved in vivo or in vitro. Enhances activity. The degree of enhancement can be, for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more (preferably 2 times or more, more preferably 2.5 times or more).
　オートファジー活性化剤の適用対象となる細胞としては、例えば肺細胞、腎細胞、生殖細胞、肝細胞、眼細胞、皮膚細胞、癌細胞、筋細胞、骨細胞等が挙げられる。好ましい細胞は、腎細胞、皮膚細胞、眼細胞、肝細胞である。細胞は、１種単独でも２種以上を併用してもよい。細胞は、ヒトの細胞であっても、非ヒト哺乳類の細胞であってもよい。 Examples of cells to which the autophagy activator is applied include lung cells, kidney cells, reproductive cells, liver cells, eye cells, skin cells, cancer cells, muscle cells, and bone cells. Preferred cells are kidney cells, skin cells, eye cells, and liver cells. The cells may be used alone or in combination of two or more. The cells may be human cells or non-human mammalian cells.
　本発明において、対象となる細胞の一つは、肺細胞である。肺細胞としては、肺胞基底上皮腺細胞等が挙げられる。 In the present invention, one of the target cells is lung cells. Examples of lung cells include alveolar basal epithelial gland cells.
　本発明において、対象となる細胞の一つは、腎細胞である。腎細胞としては、腎糸球体内皮細胞、腎臓近位尿細管上皮細胞、腎皮質上皮細胞、腎上皮細胞、腎メサンギウム細胞、尿細管上皮細胞等が挙げられる。 In the present invention, one of the target cells is kidney cells. Examples of renal cells include renal glomerular endothelial cells, renal proximal tubular epithelial cells, renal cortical epithelial cells, renal epithelial cells, renal mesangial cells, renal tubular epithelial cells, and the like.
　本発明において、対象となる細胞の一つは、生殖細胞である。生殖細胞としては、子宮頸部類上皮細胞等が挙げられる。 In the present invention, one of the target cells is a germ cell. Examples of germ cells include cervical epithelioid cells.
　本発明において、対象となる細胞の一つは、肝細胞である。肝細胞としては、肝実質細胞、肝非実質細胞等が挙げられる。 In the present invention, one of the target cells is hepatocytes. Examples of hepatocytes include hepatic parenchymal cells and hepatic non-parenchymal cells.
　本発明において、対象となる細胞の一つは、眼細胞である。眼細胞としては、網膜色素上皮細胞等が挙げられる。 In the present invention, one of the target cells is an eye cell. Examples of eye cells include retinal pigment epithelial cells.
　本発明において、対象となる細胞の一つは、皮膚細胞である。皮膚細胞としては、表皮角化細胞等が挙げられる。 In the present invention, one of the target cells is skin cells. Examples of skin cells include epidermal keratinocytes.
　本発明において、対象となる細胞の一つは、癌細胞である。癌細胞としては、肝がん細胞、骨肉腫細胞、肺がん細胞、前立腺がん細胞、乳がん細胞等が挙げられる。癌細胞からは、肺がん細胞、前立腺がん細胞、乳がん細胞が除かれてもよい。 In the present invention, one of the target cells is cancer cells. Examples of cancer cells include liver cancer cells, osteosarcoma cells, lung cancer cells, prostate cancer cells, and breast cancer cells. Lung cancer cells, prostate cancer cells, and breast cancer cells may be removed from the cancer cells.
　本発明において、対象となる細胞の一つは、筋細胞である。 In the present invention, one of the target cells is a muscle cell.
　本発明において、対象となる細胞の一つは、骨細胞である。 In the present invention, one of the target cells is bone cells.
　本発明は、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患の予防又は治療を要する対象に、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩の有効量を投与することを含む、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患の予防又は治療方法を包含し得る。 The present invention covers lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer). , bacterial infections, viral infections, autoimmune diseases, metabolic syndromes, and musculoskeletal diseases (excluding muscular dystrophy). ) and cannabidiol, or a pharmaceutically acceptable salt thereof, for pulmonary diseases (excluding pulmonary fibrosis) , kidney disease (excluding renal fibrosis), reproductive dysfunction, liver disorder, eye disease, skin disease, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infection, viral infection, autoimmune disease, The present invention may include methods for preventing or treating at least one disease selected from the group consisting of metabolic syndrome and musculoskeletal diseases (excluding muscular dystrophy).
　本発明は、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患の予防又は治療するための医薬組成物の製造のための、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩の使用を包含し得る。 The present invention covers lung diseases (excluding pulmonary fibrosis), renal diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer). , bacterial infection, viral infection, autoimmune disease, metabolic syndrome, and musculoskeletal disease (excluding muscular dystrophy). may include the use of at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof.
　本発明は、細胞のオートファジーを活性化するための、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩の使用を包含し得る。 The present invention provides at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, for activating cellular autophagy. may include use.
　本発明は、細胞のオートファジー活性化剤の製造のための、式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩の使用を包含し得る。 The present invention provides at least one compound selected from the group consisting of the compound represented by formula (1) and cannabidiol, or a pharmaceutically acceptable thereof, for the production of a cellular autophagy activator. May include the use of salts.
　以下、実施例等によって本発明の一実施態様を更に詳細に説明するが、本発明はこれらに限定されない。 Hereinafter, one embodiment of the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
参考例１Reference example 1
２－（４－（２－クロロフェニル）ピペラジン－１－イル）酢酸ｔｅｒｔブチルエステル2-(4-(2-chlorophenyl)piperazin-1-yl)acetic acid tert-butyl ester
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　2－クロロフェニルピペラジン（１．９６６ｇ、１０mmol；C1102（東京化成社））、2－ブロモ酢酸tertブチルエステル（１．９５ｇ、１０mmol）、トリエチルアミン（２．０９mＬ、１５mmol）のＴＨＦ（４０ｍＬ）溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、2－（4－（2－クロロフェニル）ピペラジン－1－イル）ブロモ酢酸tertブチルエステル（２．７４ｇ）を得た。収率８８％。 A THF (40 mL) solution of 2-chlorophenylpiperazine (1.966 g, 10 mmol; C1102 (Tokyo Kasei)), 2-bromoacetic acid tert-butyl ester (1.95 g, 10 mmol), and triethylamine (2.09 mL, 15 mmol) was heated to room temperature. The mixture was stirred overnight, saturated ammonium chloride water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-(4-(2-chlorophenyl)piperazin-1-yl)bromoacetic acid tert-butyl ester (2.74 g). Yield 88%.
参考例２Reference example 2
２－（４－（２－クロロフェニル）ピペラジン－１－イル）酢酸　塩酸塩2-(4-(2-chlorophenyl)piperazin-1-yl)acetic acid hydrochloride
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　参考例１で得た2－（4－（2－クロロフェニル）ピペラジン－1－イル）ブロモ酢酸tertブチルエステルを過剰の塩酸及び酢酸エチルで処理し、2－（4－（2－クロロフェニル）ピペラジン－1－イル）酢酸　塩酸塩を得た。 The 2-(4-(2-chlorophenyl)piperazin-1-yl)bromoacetic acid tert-butyl ester obtained in Reference Example 1 was treated with excess hydrochloric acid and ethyl acetate to give 2-(4-(2-chlorophenyl)piperazine-1-yl). 1-yl)acetic acid hydrochloride was obtained.
参考例３Reference example 3
２－ブロモ－Ｎ－（２－エトキシフェニル）アセトアミド（CAS349120-97-4）2-Bromo-N-(2-ethoxyphenyl)acetamide (CAS349120-97-4)
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　２－エトキシアニリン（１．３７ｇ、９．９９mmol）とトリエチルアミン（１．４６２ｍL、１０．４９mmol）のジクロロメタン（２０ｍL）の溶液に、ブロモ酢酸ブロミド（０．８７ｍL、９．９９mmol）を０℃で滴下し、反応混合物を０℃で１時間撹拌し、２－ブロモ－Ｎ－（２－エトキシフェニル）アセトアミドを含む反応液を得た。得られた反応溶液をそのまま実施例８及び９の反応に用いた。 Bromoacetic acid bromide (0.87 mL, 9.99 mmol) was added dropwise to a solution of 2-ethoxyaniline (1.37 g, 9.99 mmol) and triethylamine (1.462 mL, 10.49 mmol) in dichloromethane (20 mL) at 0°C. Then, the reaction mixture was stirred at 0° C. for 1 hour to obtain a reaction solution containing 2-bromo-N-(2-ethoxyphenyl)acetamide. The obtained reaction solution was used as it was in the reactions of Examples 8 and 9.
参考例４Reference example 4
４－（４－（２－（ｔｅｒｔ－ブトキシ）－２－オキソエチル）ピペラジン－１－イル）－３－クロロ安息香酸メチルエステル4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-3-chlorobenzoic acid methyl ester
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　３－クロロ－４－（ピペラジン－１－イル）安息香酸メチルエステル（２．５４ｇ、９．９７mmol；ST-0611（Combi-Blocks社））、2－ブロモ酢酸tertブチルエステル（２．０４２ｇ、１０．４７mmol）、トリエチルアミン（２．０８５mＬ、１４．９６mmol）のＤＭＦ（４０ｍＬ）溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、４－（４－（２－（ｔｅｒｔ－ブトキシ）－２－オキソエチル）ピペラジン－１－イル）－３－クロロ安息香酸メチルエステル（３．８１８ｇ）を得た。収率１００％。
LC-MS: r.t. 1.96 min., m/z 369.1 (M++1)。 3-chloro-4-(piperazin-1-yl)benzoic acid methyl ester (2.54 g, 9.97 mmol; ST-0611 (Combi-Blocks)), 2-bromoacetic acid tert-butyl ester (2.042 g, 10 A solution of triethylamine (2.085 mL, 14.96 mmol) in DMF (40 mL) was stirred at room temperature overnight, saturated ammonium chloride water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-3-chlorobenzoic acid methyl ester (3 .818g) was obtained. Yield 100%.
LC-MS: rt 1.96 min., m/z 369.1 (M + +1).
参考例５Reference example 5
２－（４－（２－（クロロ－４－（メトキシカルボニル）フェニル）ピペラジン－１－イル）酢酸　塩酸塩2-(4-(2-(chloro-4-(methoxycarbonyl)phenyl)piperazin-1-yl)acetic acid hydrochloride
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　４－（４－（２－（ｔｅｒｔ－ブトキシ）－２－オキソエチル）ピペラジン－１－イル）－３－クロロ安息香酸メチルエステル（１．３７９ｇ、３．１５mmol）を４Ｎ塩酸－１，４－ジオキサン（１３ｍＬ）で処理し、溶媒を留去、乾燥し２－（４－（２－（クロロ－４－（メトキシカルボニル）フェニル）ピペラジン－１－イル）酢酸　塩酸塩（１．１ｇ）を得た。収率８０％。
LC-MS: r.t. 1.44 min., m/z 313.0 (M+ + 1)。 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-3-chlorobenzoic acid methyl ester (1.379 g, 3.15 mmol) was dissolved in 4N hydrochloric acid-1,4-dioxane. (13 mL), evaporated the solvent, and dried to obtain 2-(4-(2-(chloro-4-(methoxycarbonyl)phenyl)piperazin-1-yl)acetic acid hydrochloride (1.1 g). .Yield 80%.
LC-MS: rt 1.44 min., m/z 313.0 (M + + 1).
実施例１Example 1
３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸メチルエステル（化合物（ａ））3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid methyl ester (compound (a))
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　２－（４－（２－（クロロ－４－（メトキシカルボニル）フェニル）ピペラジン－１－イル）酢酸　塩酸塩（３４９．２ｍｇ，１．０mmol）、２－エトキシアニリン（１６５ｍｇ、１．２mmol）、ＨＡＴＵ（４５６ｍｇ、１．２mmol）とトリエチルアミン（４１０μＬ、３．０mmol）のＤＭＦ（５ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸メチルエステル（１１３．３ｍｇ、Ｒｆ＝０．４５（１：１ヘキサン／酢酸エチル））を得た。収率２６％。
１H NMR (CDCl３, 400 MHz) δ9.85 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 8.05 (d, 1 H, J = 1.6 Hz), 7.91 (dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (dd, 1 H, J = 2.0, 8.0 Hz), 6.96 (dt, 1 H, J = 1.6, 8.0 Hz), 6.87 (dd, 1 H, J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.90 (s, 3 H), 3.20 - 3.30 (br, 4 H), 3.25 (s, 2 H), 2.80 - 2.90 (bt, 4H), 1.50 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 2.57 min., m/z 432.2 (M+ + 1)。 2-(4-(2-(chloro-4-(methoxycarbonyl)phenyl)piperazin-1-yl)acetic acid hydrochloride (349.2 mg, 1.0 mmol), 2-ethoxyaniline (165 mg, 1.2 mmol), A solution of HATU (456 mg, 1.2 mmol) and triethylamine (410 μL, 3.0 mmol) in DMF (5 mL) was stirred at room temperature overnight, added with saturated ammonium chloride water, and extracted with ethyl acetate. The organic layer was extracted with magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to give 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazine. -1-yl)benzoic acid methyl ester (113.3 mg, Rf=0.45 (1:1 hexane/ethyl acetate)) was obtained. Yield 26%.
1 H NMR (CDCl 3 , 400 MHz) δ9.85 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 8.05 (d, 1 H, J = 1.6 Hz), 7.91 ( dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (dd, 1 H, J = 2.0, 8.0 Hz), 6.96 (dt, 1 H, J = 1.6, 8.0 Hz), 6.87 (dd, 1 H, J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.90 (s, 3 H), 3.20 - 3.30 (br, 4 H), 3.25 (s, 2 H), 2.80 - 2.90 (bt, 4H), 1.50 (t, 3 H, J = 6.8 Hz), LC-MS: rt 2.57 min., m/z 432.2 (M + +1).
実施例２Example 2
２－（４－（２－クロロ－４－ピぺリジン－１－カルボニル）フェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド（化合物（ｂ））2-(4-(2-chloro-4-piperidine-1-carbonyl)phenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide (compound (b))
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
実施例２－１
３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸 Example 2-1
3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸メチルエステル（２００ｍｇ、０．４６３mmol）を５：２ジメトキシエタン／１Ｎ水酸化ナトリウム（７ｍＬ）で処理し、１Ｎ塩酸で中和し酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸（１６４ｍｇ）を得た。収率８５％。
１H NMR (CDCl３, 400 MHz) δ9.83 (bs, 1 H), 8.43 (dd, 1 H, J = 1.6, 8.0 Hz), 7.39 (d, 1 H, J = 8.0 Hz), 7.08 (d, 1 H, J = 2.0 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 6.99 (dd, 1 H, J = 1.6, 8.0 Hz), 6.96 (dt, 1 H, J = 2.0, 8.0 Hz), 6.87 (dd, 1 H, J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.62 - 3.78 (br, 2 H), 3.25 (s, 2 H), 3.11- 3.21 (br, 4H), 2.76 - 2.88 (br, 4 H), 1.63 - 1.73 (br, 1 H), 1.50 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 1.97 min., m/z 418.2 (M+ + 1)。 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid methyl ester (200 mg, 0.463 mmol) in 5:2 dimethoxyethane/ The mixture was treated with 1N sodium hydroxide (7 mL), neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid ( 164 mg) was obtained. Yield 85%.
1 H NMR (CDCl 3 , 400 MHz) δ9.83 (bs, 1 H), 8.43 (dd, 1 H, J = 1.6, 8.0 Hz), 7.39 (d, 1 H, J = 8.0 Hz), 7.08 ( d, 1 H, J = 2.0 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 6.99 (dd, 1 H, J = 1.6, 8.0 Hz), 6.96 (dt, 1 H, J = 2.0, 8.0 Hz), 6.87 (dd, 1 H, J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.62 - 3.78 (br, 2 H), 3.25 (s, 2 H ), 3.11- 3.21 (br, 4H), 2.76 - 2.88 (br, 4 H), 1.63 - 1.73 (br, 1 H), 1.50 (t, 3 H, J = 6.8 Hz), LC-MS: rt 1.97 min., m/z 418.2 (M + + 1).
実施例２－２
２－（４－（２－クロロ－４－ピぺリジン－１－カルボニル）フェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド Example 2-2
2-(4-(2-chloro-4-piperidine-1-carbonyl)phenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸（１６４ｍｇ，０．３９２mmol）、ピぺリジン（２０１ｍｇ、２．３５５mmol）とＨＡＴＵ（２２４ｍｇ、０．５８９mmol）のＤＭＦ（２ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸メチルエステル（１７８．６ｍｇ）を得た。収率９４％。
１H NMR (CDCl３, 400 MHz) δ9.87 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.53 (d, 1 H, J = 2.0 Hz), 7.29 (dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (d, 1 H, J = 8.0 Hz), 6.96 (dt, 1 H, J = 1.2, 7.6 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.52 - 3.75 (br, 2 H), 3.31 - 3.52 (br, 2 H), 3.25 (s, 2 H), 3.12 - 3.22 (br, 4H), 2.80 - 2.88 (brt, 4 H), 1.65 - 1.73 (br, 4 H), 1.54 - 1.65 (br, 2 H), 1.51 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 2.31 min., m/z 485.1 (M+ + 1)。 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid (164 mg, 0.392 mmol), piperidine (201 mg, 2. A solution of 355 mmol) and HATU (224 mg, 0.589 mmol) in DMF (2 mL) was stirred at room temperature overnight, added with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to obtain 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)). -2-oxoethyl)piperazin-1-yl)benzoic acid methyl ester (178.6 mg) was obtained. Yield 94%.
1 H NMR (CDCl 3 , 400 MHz) δ9.87 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.53 (d, 1 H, J = 2.0 Hz), 7.29 ( dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (d, 1 H, J = 8.0 Hz), 6.96 (dt, 1 H, J = 1.2, 7.6 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.52 - 3.75 (br, 2 H), 3.31 - 3.52 (br, 2 H), 3.25 (s, 2 H), 3.12 - 3.22 (br, 4H), 2.80 - 2.88 (brt, 4 H), 1.65 - 1.73 (br, 4 H), 1.54 - 1.65 (br, 2 H) , 1.51 (t, 3H, J = 6.8 Hz), LC-MS: rt 2.31 min., m/z 485.1 (M + + 1).
実施例３Example 3
３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）－Ｎ，Ｎ－ジメチルベンズアミド（化合物（ｃ））3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)-N,N-dimethylbenzamide (compound (c))
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸（２０．９ｍｇ，０．０５mmol）、ジメチルアミン（１１．３ｍｇ、０．２５mmol）、ＨＡＴＵ（２８．５ｍｇ、０．０７５mmol）とトリエチルアミン（２０．９μＬ、０．１５mmol）のＤＭＦ（１ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）－Ｎ，Ｎ－ジメチルベンズアミド（２２．２ｍｇ、Ｒｆ＝０．３３（１：２ヘキサン／酢酸エチル））を得た。収率１００％。
１H NMR (CDCl３, 400 MHz) δ9.86 (bs, 1 H), 8.44 (dd, 1 H, J = 2.0, 8.0 Hz), 7.46 (d, 1 H, J = 2.0 Hz), 7.33 (dd, 1 H, J = 2.0, 8.0 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (d, 1 H, J = 8.0 Hz), 6.96 (dt, 1 H, J = 1.6, 8.0 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.25 (s, 2 H), 3.12 - 3.22 (br, 4H), 3.08 (bs, 3 H), 3.04 (bs, 3 H), 2.81 - 2.87 (br, 4 H), 1.50 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 1.93 min., m/z 445.2 (M+ + 1)。 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid (20.9 mg, 0.05 mmol), dimethylamine (11.3 mg , 0.25 mmol), HATU (28.5 mg, 0.075 mmol) and triethylamine (20.9 μL, 0.15 mmol) in DMF (1 mL) was stirred at room temperature overnight, saturated aqueous ammonium chloride was added, and ethyl acetate was added. Extracted with. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to obtain 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)). -2-oxoethyl)piperazin-1-yl)-N,N-dimethylbenzamide (22.2 mg, Rf=0.33 (1:2 hexane/ethyl acetate)) was obtained. Yield 100%.
1 H NMR (CDCl 3 , 400 MHz) δ9.86 (bs, 1 H), 8.44 (dd, 1 H, J = 2.0, 8.0 Hz), 7.46 (d, 1 H, J = 2.0 Hz), 7.33 ( dd, 1 H, J = 2.0, 8.0 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (d, 1 H, J = 8.0 Hz), 6.96 (dt, 1 H, J = 1.6, 8.0 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.25 (s, 2 H), 3.12 - 3.22 (br, 4H) , 3.08 (bs, 3 H), 3.04 (bs, 3 H), 2.81 - 2.87 (br, 4 H), 1.50 (t, 3 H, J = 6.8 Hz), LC-MS: rt 1.93 min., m /z 445.2 (M + + 1).
実施例４Example 4
１－（３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）ベンゾイル）ピぺリジン－４－カルボン酸メチルエステル（化合物（ｄ））1-(3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoyl)piperidine-4-carboxylic acid methyl ester (compound ( d))
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸（１０５ｍｇ，０．２５１mmol）、ピぺリジン－４－カルボン酸メチルエステル（４３．２ｍｇ、０．３０２mmol）とＨＡＴＵ（１４３ｍｇ、０．３７７mmol）のＤＭＦ（２ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、１－（３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）ベンゾイル）ピぺリジン－４－カルボン酸メチルエステル（１１７ｍｇ）を得た。収率８６％。
１H NMR (CDCl３, 400 MHz) δ9.86 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.43 (d, 1 H, J = 2.0 Hz), 7.30 (dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (d, 1 H, J = 8.0 Hz), 6.96 (dt, 1 H, J = 1.6, 7.6 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.71 (s, 3 H), 3.25 (s, 2 H), 3.52 - 3.75 (br, 2 H), 3.31 - 3.52 (br, 2 H), 3.25 (s, 2 H), 3.12 - 3.22 (br, 4H), 3.0 - 3.12 (br, 1 H), 2.80 - 2.88 (brt, 4 H), 2.60 (tt, 1 H, J = 4.0, 6.8 Hz), 1.85 - 2.10 (br, 2 H), 1.65 - 1.80 (br, 2 H), 1.51 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 2.26 min., m/z 543.2 (M+ + 1)。 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)benzoic acid (105 mg, 0.251 mmol), piperidine-4-carboxylic acid A solution of methyl ester (43.2 mg, 0.302 mmol) and HATU (143 mg, 0.377 mmol) in DMF (2 mL) was stirred at room temperature overnight, added with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to obtain 1-(3-chloro-4-(4-(2-((2-ethoxyphenyl) ) Amino)-2-oxoethyl)piperazin-1-yl)benzoyl)piperidine-4-carboxylic acid methyl ester (117 mg) was obtained. Yield 86%.
1 H NMR (CDCl 3 , 400 MHz) δ9.86 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.43 (d, 1 H, J = 2.0 Hz), 7.30 ( dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 7.03 (d, 1 H, J = 8.0 Hz), 6.96 (dt, 1 H, J = 1.6, 7.6 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.71 (s, 3 H), 3.25 (s, 2 H), 3.52 - 3.75 (br, 2 H), 3.31 - 3.52 (br, 2 H), 3.25 (s, 2 H), 3.12 - 3.22 (br, 4H), 3.0 - 3.12 (br, 1 H), 2.80 - 2.88 (brt, 4 H), 2.60 (tt, 1 H, J = 4.0, 6.8 Hz), 1.85 - 2.10 (br, 2 H), 1.65 - 1.80 (br, 2 H), 1.51 (t, 3 H, J = 6.8 Hz), LC-MS: rt 2.26 min., m/z 543.2 (M + + 1).
実施例５Example 5
Ｎ－（４－クロロ－２－メトキシフェニル）－２－（４－（２－クロロフェニル）ピペラジン－１－イル）アセトアミド（化合物（ｅ））N-(4-chloro-2-methoxyphenyl)-2-(4-(2-chlorophenyl)piperazin-1-yl)acetamide (compound (e))
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　２－（４－（２－クロロフェニル）ピペラジン－１－イル）酢酸（２５．５ｍｇ，０．１mmol）、４－クロロ－２－メトキシアニリン　塩酸塩（２３．３ｍｇ、０．１２mmol）、ＨＡＴＵ（５７．１ｍｇ、０．１５mmol）とトリエチルアミン（６９．８μＬ、０．５mmol）のＤＭＦ（１ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、Ｎ－（４－クロロ－２－メトキシフェニル）－２－（４－（２－クロロフェニル）ピペラジン－１－イル）アセトアミド（２１．３ｍｇ、Ｒｆ＝０．２（１：２ヘキサン／酢酸エチル））を得た。収率５４％。
１H NMR (CDCl３, 400 MHz) δ9.78 (bs, 1 H), 8.34 (dd, 1 H, J = 1.6, 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.29 (dd, 1 H, J = 2.0, 8.4 Hz), 7.06 (d, 1 H, J = 8.0 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 6.96 (dt, 1 H, J = 1.2, 7.6 Hz), 6.87 (s, 1 H), 3.90 (s, 3 H), 3.25 (s, 2 H), 3.08 - 3.20 (br, 4H), 2.76 - 2.88 (br, 4 H), LC-MS: r.t. 2.38 min., m/z 394.1 (M+)。 2-(4-(2-chlorophenyl)piperazin-1-yl)acetic acid (25.5 mg, 0.1 mmol), 4-chloro-2-methoxyaniline hydrochloride (23.3 mg, 0.12 mmol), HATU (57 A solution of triethylamine (69.8 μL, 0.5 mmol) in DMF (1 mL) was stirred at room temperature overnight, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to obtain N-(4-chloro-2-methoxyphenyl)-2-(4-(2- Chlorophenyl)piperazin-1-yl)acetamide (21.3 mg, Rf=0.2 (1:2 hexane/ethyl acetate)) was obtained. Yield 54%.
1 H NMR (CDCl 3 , 400 MHz) δ9.78 (bs, 1 H), 8.34 (dd, 1 H, J = 1.6, 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.29 ( dd, 1 H, J = 2.0, 8.4 Hz), 7.06 (d, 1 H, J = 8.0 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 6.96 (dt, 1 H, J = LC -MS: rt 2.38 min., m/z 394.1 (M + ).
実施例６Example 6
２－（２－（４－（２－クロロフェニル）ピペラジン－１－イル）アセトアミド）安息香酸メチルエステル（化合物（ｆ））2-(2-(4-(2-chlorophenyl)piperazin-1-yl)acetamido)benzoic acid methyl ester (compound (f))
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　２－（４－（２－クロロフェニル）ピペラジン－１－イル）酢酸（１３．２ｍｇ，０．０５２mmol）、２－アミノ安息香酸メチルエステル（２３．５ｍｇ、０．１５５mmol）、トリエチルアミン（３６．１μL、０．２５９mmol）とＨＡＴＵ（３９．４ｍｇ、０．１０４mmol）のＤＭＦ（０．５ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、３－クロロ－４－（４－（２－（（２－エトキシフェニル）アミノ）－２－オキソエチル）ピペラジン－１－イル）安息香酸メチルエステル（２．０ｍｇ）を得た。収率１０％。
１H NMR (CDCl３, 400 MHz) δ12.10 (bs, 1 H), 8.80 (d, 1 H, J = 8.8 Hz), 8.04 (d, 1 H, J = 8.4 Hz), 7.55 (t, 1 H, J = 8.4 Hz), 7.38 (d, 1 H, J = 8.0 Hz), 7.25 (t, 1 H, J = 8.0 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 7.10 (t, 1 H, J = 8.0 Hz), 6.99 (t, 1 H. J = 8.0 Hz), 3.92 (s, 3 H), 3.29 (s, 2 H), 3.20 - 3.28 (br, 4H), 2.80 - 2.88 (br, 4 H), LC-MS: r.t. 2.89 min., m/z 388.1 (M+ + 1)。 2-(4-(2-chlorophenyl)piperazin-1-yl)acetic acid (13.2 mg, 0.052 mmol), 2-aminobenzoic acid methyl ester (23.5 mg, 0.155 mmol), triethylamine (36.1 μL, A solution of 0.259 mmol) and HATU (39.4 mg, 0.104 mmol) in DMF (0.5 mL) was stirred at room temperature overnight, added with saturated ammonium chloride water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to obtain 3-chloro-4-(4-(2-((2-ethoxyphenyl)amino)). -2-oxoethyl)piperazin-1-yl)benzoic acid methyl ester (2.0 mg) was obtained. Yield 10%.
1 H NMR (CDCl 3 , 400 MHz) δ12.10 (bs, 1 H), 8.80 (d, 1 H, J = 8.8 Hz), 8.04 (d, 1 H, J = 8.4 Hz), 7.55 (t, 1 H, J = 8.4 Hz), 7.38 (d, 1 H, J = 8.0 Hz), 7.25 (t, 1 H, J = 8.0 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 7.10 ( t, 1 H. J = 8.0 Hz), 6.99 (t, 1 H. J = 8.0 Hz), 3.92 (s, 3 H), 3.29 (s, 2 H), 3.20 - 3.28 (br, 4H), 2.80 - 2.88 (br, 4H), LC-MS: rt 2.89 min., m/z 388.1 (M + + 1).
実施例７Example 7
２－（２－（４－（２－トリフルオロメチル）フェニル）ピペラジン－１－イル）アセトアミド）安息香酸メチルエステル（化合物（ｇ））2-(2-(4-(2-trifluoromethyl)phenyl)piperazin-1-yl)acetamido)benzoic acid methyl ester (compound (g))
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　２－アミノ安息香酸メチルエステル（４５３ｍｇ、３mmol）とトリエチルアミン（１．２５４ｍL、９mmol）のジクロロメタン（１５ｍL）の溶液に、ブロモ酢酸ブロミド（０．２６ｍL、３mmol）を０℃で滴下し、反応混合物を０℃で１時間撹拌した。続いて、１－（２－（トリフルオロメチル）フェニル）ピペラジン（６９１ｍｇ、３mmol）のDMF（１０ｍL）の溶液を0℃で滴下し、室温で終夜撹拌して、飽和塩化アンモニウム水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、２－（２－（４－（２－トリフルオロメチル）フェニル）ピペラジン－１－イル）アセトアミド）安息香酸メチルエステル（１５７ｍｇ）を得た。収率１２．４％。
１H NMR (CDCl３, 400 MHz) δ12.14 (bs, 1 H), 8.81 (d, 1 H, J = 8.0 Hz), 8.04 (dd, 1 H, J = 1.6, 8.0 Hz), 7.64 (d, 1 H, J = 8.0 Hz), 7.55 (dt, 1 H, J = 1.6, 8.4 Hz), 7.53 (d, 1 H, J = 7.6 Hz), 7.48 (d, 1 H, J = 7.6 Hz), 7.24 (t, 1 H, J = 7.6 Hz), 7.10 (t, 1 H, J = 8.0 Hz), 3.97 (s, 3 H), 3.28 (s, 2 H), 3.08 - 3.16 (br, 4H), 2.76 - 2.83 (br, 4 H), LC-MS: r.t. 3.04 min., m/z 422.2 (M+ + 1)。 Bromoacetic acid bromide (0.26 mL, 3 mmol) was added dropwise to a solution of 2-aminobenzoic acid methyl ester (453 mg, 3 mmol) and triethylamine (1.254 mL, 9 mmol) in dichloromethane (15 mL) at 0°C, and the reaction mixture was diluted. Stirred at 0°C for 1 hour. Subsequently, a solution of 1-(2-(trifluoromethyl)phenyl)piperazine (691 mg, 3 mmol) in DMF (10 mL) was added dropwise at 0°C, stirred overnight at room temperature, saturated ammonium chloride water was added, and ethyl acetate was added. Extracted with. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to obtain 2-(2-(4-(2-trifluoromethyl)phenyl)piperazine-1- yl)acetamido)benzoic acid methyl ester (157 mg) was obtained. Yield 12.4%.
1 H NMR (CDCl 3 , 400 MHz) δ12.14 (bs, 1 H), 8.81 (d, 1 H, J = 8.0 Hz), 8.04 (dd, 1 H, J = 1.6, 8.0 Hz), 7.64 ( d, 1 H, J = 8.0 Hz), 7.55 (dt, 1 H, J = 1.6, 8.4 Hz), 7.53 (d, 1 H, J = 7.6 Hz), 7.48 (d, 1 H, J = 7.6 Hz) ), 7.24 (t, 1 H, J = 7.6 Hz), 7.10 (t, 1 H, J = 8.0 Hz), 3.97 (s, 3 H), 3.28 (s, 2 H), 3.08 - 3.16 (br, 4H), 2.76 - 2.83 (br, 4H), LC-MS: rt 3.04 min., m/z 422.2 (M + + 1).
実施例８Example 8
２－（４－（２，５－ジクロロフェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド（化合物（ｈ））2-(4-(2,5-dichlorophenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide (compound (h))
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　１－（２，５－ジクロロフェニル）ピペラジン塩酸塩（80 ｍｇ、0.3 mmol）とトリエチルアミン（104μL、0.75 mmol）のDMF（2 ｍL）の溶液に２－ブロモ－N－（２－エトキシフェニル）アセトアミド（64.5 ｍｇ、0.25 mmol相当）のジクロロメタン溶液（64.5 ｍｇ、0.25 mmol相当）を0℃で滴下し、室温で終夜撹拌して、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、２－（４－（２，５－ジクロロフェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド（54.1 ｍｇ）を得た。収率５３％。
１H NMR (CDCl３, 400 MHz)δ9.85 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.29 (d, 1 H, J = 8.0 Hz), 7.29 (dd, 1 H, J = 2.0, 8.4 Hz), 7.04 (dt, 1 H, J = 2.0, 7.6 Hz), 6.98 - 7.00 (m, 2 H), 6.96 (dt, 1 H, J = 1.2, 8.0 Hz), 6.88 (dd, 1 H. J = 1.6, 8.0 Hz), 4.12 (q, 2 H, J = 6.8 Hz), 3.25 (s, 2 H), 3.08 - 3.18 (br, 4 H), 2.78 - 2.88 (brt, 4 H), 1.53 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 2.85 min., m/z 408.1 (M+ + 1)。 2-Bromo-N-(2-ethoxyphenyl)acetamide (2-bromo-N-(2-ethoxyphenyl)acetamide A dichloromethane solution (64.5 mg, equivalent to 0.25 mmol) of the mixture was added dropwise at 0° C., stirred overnight at room temperature, saturated ammonium chloride water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to give 2-(4-(2,5-dichlorophenyl)piperazin-1-yl)-N- (2-ethoxyphenyl)acetamide (54.1 mg) was obtained. Yield 53%.
1 H NMR (CDCl 3 , 400 MHz)δ9.85 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.29 (d, 1 H, J = 8.0 Hz), 7.29 ( dd, 1 H, J = 2.0, 8.4 Hz), 7.04 (dt, 1 H, J = 2.0, 7.6 Hz), 6.98 - 7.00 (m, 2 H), 6.96 (dt, 1 H, J = 1.2, 8.0 Hz), 6.88 (dd, 1 H. J = 1.6, 8.0 Hz), 4.12 (q, 2 H, J = 6.8 Hz), 3.25 (s, 2 H), 3.08 - 3.18 (br, 4 H), 2.78 - 2.88 (brt, 4 H), 1.53 (t, 3 H, J = 6.8 Hz), LC-MS: rt 2.85 min., m/z 408.1 (M + + 1).
実施例９Example 9
２－（４－（２，４－ジクロロフェニル）ピペラジン－１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド（化合物（ｉ））2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-N-(2-ethoxyphenyl)acetamide (compound (i))
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　１－（２，４－ジクロロフェニル）ピペラジン（69.3 ｍｇ、0.3 mmol）とトリエチルアミン（52μL、0.375 mmol）のDMF（2 ｍL）の溶液に2－ブロモ－N－（２－エトキシフェニル）アセトアミド（64.5 ｍｇ、0.25 mmol相当）のジクロロメタン溶液を0℃で滴下し、室温で終夜撹拌して、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、２－（４－（２，４－ジクロロフェニル）ピペラジンー１－イル）－Ｎ－（２－エトキシフェニル）アセトアミド（55.7 ｍｇ）を得た。収率５４．６％。１H NMR (CDCl３, 400 MHz) δ9.86 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.39 (d, 1 H, J = 2.0 Hz), 7.21 (dd, 1 H, J = 2.4, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 6.97 (dt, 1 H, J = 1.6, 8.0 Hz), 6.95 (d, 1 H, J = 8.4 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.25 (s, 2 H), 3.10 - 3.21 (br, 4 H), 2.78 - 2.88 (brt, 4 H), 1.51 (t, 3 H, J = 6.8 Hz), LC-MS: r.t. 2.86 min., m/z 408.1 (M+ + 1)。 2-Bromo-N-(2-ethoxyphenyl)acetamide (64.5 mg) in a solution of 1-(2,4-dichlorophenyl)piperazine (69.3 mg, 0.3 mmol) and triethylamine (52 μL, 0.375 mmol) in DMF (2 mL). , equivalent to 0.25 mmol) in dichloromethane was added dropwise at 0°C, stirred overnight at room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to give 2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-N-( 2-Ethoxyphenyl)acetamide (55.7 mg) was obtained. Yield 54.6%. 1 H NMR (CDCl 3 , 400 MHz) δ9.86 (bs, 1 H), 8.44 (dd, 1 H, J = 1.6, 8.0 Hz), 7.39 (d, 1 H, J = 2.0 Hz), 7.21 ( dd, 1 H, J = 2.4, 8.4 Hz), 7.03 (dt, 1 H, J = 2.0, 7.6 Hz), 6.97 (dt, 1 H, J = 1.6, 8.0 Hz), 6.95 (d, 1 H, J = 8.4 Hz), 6.87 (dd, 1 H. J = 1.6, 8.0 Hz), 4.11 (q, 2 H, J = 6.8 Hz), 3.25 (s, 2 H), 3.10 - 3.21 (br, 4 H ), 2.78 - 2.88 (brt, 4 H), 1.51 (t, 3 H, J = 6.8 Hz), LC-MS: rt 2.86 min., m/z 408.1 (M + + 1).
実施例１０Example 10
２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（３－メトキシピリジン－４－イル）アセトアミド（化合物（ｊ））2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-N-(3-methoxypyridin-4-yl)acetamide (compound (j))
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）酢酸　塩酸塩（０．３ｍｍｏｌ）、３－メトキシピリジン－４－アミン（０．３mmol）、ＨＡＴＵ（０．４mmol）とジイソプロピルエチルアミン（０．８mmol）のＤＭＦ（１ｍＬ）の溶液を室温で終夜撹拌し、飽和塩化アンモニウム水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（３－メトキシピリジン－４－イル）アセトアミド（１１．２ｍｇ、Ｒｆ＝０．３３（３：１ヘキサン／酢酸エチル））を得た。収率５％。
１H NMR (CDCl３, 400 MHz)δ10.05 (bs, 1 H), 8.33 (d, 1 H, J = 5.2 Hz), 8.23 (bd, 2 H), 7.12 (t, 1 H, J = 8.0 Hz), 6.94 (d, 2 H, J = 8.0 Hz), , 4.01 (s, 3 H), 3.26 (s, 2 H), 2.95 - 3.02 (br, 4H), 2.78 - 2.84 (br, 4 H), 2.28 (s, 3 H), 2.23 (s, 3 H), LC-MS: r.t. 1.54 min., m/z 355.0 (M+ + 1)。 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)acetic acid hydrochloride (0.3 mmol), 3-methoxypyridin-4-amine (0.3 mmol), HATU (0.4 mmol) and diisopropyl A solution of ethylamine (0.8 mmol) in DMF (1 mL) was stirred at room temperature overnight, added with saturated ammonium chloride water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to give 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-N- (3-methoxypyridin-4-yl)acetamide (11.2 mg, Rf=0.33 (3:1 hexane/ethyl acetate)) was obtained. Yield 5%.
1 H NMR (CDCl 3 , 400 MHz)δ10.05 (bs, 1 H), 8.33 (d, 1 H, J = 5.2 Hz), 8.23 (bd, 2 H), 7.12 (t, 1 H, J = 8.0 Hz), 6.94 (d, 2 H, J = 8.0 Hz), , 4.01 (s, 3 H), 3.26 (s, 2 H), 2.95 - 3.02 (br, 4H), 2.78 - 2.84 (br, 4 H), 2.28 (s, 3H), 2.23 (s, 3H), LC-MS: rt 1.54 min., m/z 355.0 (M + + 1).
実施例１１Example 11
２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（２－メトキシピリジン－３－イル）アセトアミド（化合物（ｋ））2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-N-(2-methoxypyridin-3-yl)acetamide (compound (k))
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）酢酸　塩酸塩（０．３ｍｍｏｌ）、２－メトキシピリジン－３－アミン（０．３mmol）、ＨＡＴＵ（０．４mmol）とジイソプロピルエチルアミン（０．８mmol）のＤＭＦ（１ｍＬ）の溶液を室温で終夜撹拌し、飽和重曹水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を順相分取液体クロマトグラフィーで精製し、２－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）－Ｎ－（２－メトキシピリジン－３－イル）アセトアミド（８５．３ｍｇ、Ｒｆ＝０．３８（３：１ヘキサン／酢酸エチル））を得た。収率８０％。
１H NMR (CDCl３, 400 MHz) δ9.78 (bs, 1 H), 8.60 (dd, 1 H, J = 7.6, 1.6 Hz), 7.86 (dd, 1 H, J = 5.2, 1.6 Hz), 7.12 (t, 1 H, J = 8.0 Hz), 6.96 (d, 1 H, J = 8.0 Hz), 6.94 (d, 1 H, J = 8.0 Hz), 6.91 (dd, 1 H, J = 7.6, 5.2 Hz), 4.04 (s, 3 H), 3.24 (s, 2 H), 2.97 - 3.01 (br, 4H), 2.78 - 2.84 (br, 4 H), 2.28 (s, 3 H), 2.23 (s, 3 H), LC-MS: r.t. 2.02 min., m/z 354.9 (M++ 1)。 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)acetic acid hydrochloride (0.3 mmol), 2-methoxypyridin-3-amine (0.3 mmol), HATU (0.4 mmol) and diisopropyl A solution of ethylamine (0.8 mmol) in DMF (1 mL) was stirred at room temperature overnight, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by normal phase preparative liquid chromatography to give 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-N- (2-methoxypyridin-3-yl)acetamide (85.3 mg, Rf=0.38 (3:1 hexane/ethyl acetate)) was obtained. Yield 80%.
1 H NMR (CDCl 3 , 400 MHz) δ9.78 (bs, 1 H), 8.60 (dd, 1 H, J = 7.6, 1.6 Hz), 7.86 (dd, 1 H, J = 5.2, 1.6 Hz), 7.12 (t, 1 H, J = 8.0 Hz), 6.96 (d, 1 H, J = 8.0 Hz), 6.94 (d, 1 H, J = 8.0 Hz), 6.91 (dd, 1 H, J = 7.6, 5.2 Hz), 4.04 (s, 3 H), 3.24 (s, 2 H), 2.97 - 3.01 (br, 4H), 2.78 - 2.84 (br, 4 H), 2.28 (s, 3 H), 2.23 (s , 3H), LC-MS: rt 2.02 min., m/z 354.9 (M + + 1).
試験例１
オートファジー活性化作用の評価（ウェスタンブロッティング法）
　実施例１で得られた化合物（本明細書中、「化合物Ａ」とも称する。）のオートファジー活性化作用をウェスタンブロッティング法で測定した。
　各ウェルにダルベッコ改変イーグル培地（本明細書中、「ＤＭＥＭ培地」とも称する。）が入った６ウェルプレートにA549細胞（ヒト肺胞基底上皮腺癌細胞）を播種し（1.0×105 cells/well）、１日培養した。リン酸緩衝生理食塩水（本明細書中、「ＰＢＳ」とも称する。）で細胞を洗浄した。次いで、３wellについては各ウェルに、ＤＭＳＯ（終濃度0.1％）を含むＤＭＥＭ培地、被験物質として化合物Ａ（終濃度30 nM）を含むＤＭＥＭ培地、又はEarle's Balanced Salt Solution（本明細書中、「ＥＢＳＳ」とも称する。細胞の飢餓状態を誘導する。)を3 mLずつ入れ、6時間培養した。別の３ウェルについては、ジメチルスルホキシド（本明細書中、「ＤＭＳＯ」とも称する。）（終濃度0.1％）、化合物Ａ（終濃度30 nM）、又はＥＢＳＳに加えてさらにBafilomycin A1(終濃度250 nM)を含むＤＭＥＭ培地を3 mLずつ入れ、6時間培養した。Bafilomycin A1は、vacuolar-typeH+-ATPase (V-ATPase) 特異的阻害剤であり、リソソームの酸性化を阻害することで、オートファゴソームがリソソームと融合する過程が阻害され、オートファジーが抑制される。培養されたA549細胞をＰＢＳ(-)で３回洗浄後、4℃のRadio-Immunoprecipitation Assay buffer（本明細書中、「RIPA buffer」とも称する。）を加え、氷上にて30分静置後、速やかにかつ丁寧に回収した。回収後、遠心(15000 rpm、4℃、30分間)し、上清を、タンパク質溶液として回収した。 Test example 1
Evaluation of autophagy activation effect (Western blotting method)
The autophagy activation effect of the compound obtained in Example 1 (herein also referred to as "Compound A") was measured by Western blotting.
A549 cells (human alveolar basal epithelial adenocarcinoma cells) were seeded in a 6-well plate containing Dulbecco's modified Eagle medium (herein also referred to as "DMEM medium") in each well (1.0 x 10 5 cells/ well) and cultured for 1 day. Cells were washed with phosphate buffered saline (also referred to herein as "PBS"). Next, for 3 wells, each well was filled with DMEM medium containing DMSO (final concentration 0.1%), DMEM medium containing Compound A (final concentration 30 nM) as a test substance, or Earle's Balanced Salt Solution (herein referred to as "EBSS"). (Also referred to as "A starvation state of cells is induced.") was added in 3 mL portions and cultured for 6 hours. For another three wells, dimethyl sulfoxide (also referred to herein as “DMSO”) (final concentration 0.1%), Compound A (final concentration 30 nM), or EBSS plus Bafilomycin A1 (final concentration 250 nM) was added. 3 mL each of DMEM medium containing nM) was added and cultured for 6 hours. Bafilomycin A1 is a vacuolar-type H + -ATPase (V-ATPase)-specific inhibitor that inhibits acidification of lysosomes, inhibits the process of autophagosome fusion with lysosomes, and suppresses autophagy. . After washing the cultured A549 cells three times with PBS(-), add Radio-Immunoprecipitation Assay buffer (herein also referred to as "RIPA buffer") at 4°C, and leave it on ice for 30 minutes. Collected quickly and carefully. After collection, it was centrifuged (15000 rpm, 4°C, 30 minutes), and the supernatant was collected as a protein solution.
　回収した上清に、Sample bufferを加えて変性し、15％ポリアクリルアミドゲルで電気泳動を行った。泳動後ニトロセルロース膜に転写した。Blocking bufferにてブロッキングを行い、一次抗体としてanti-LC3（1000倍希釈）及びanti-β-actin（10000倍希釈）、二次抗体としてanti-rabbit（2000倍希釈)及びanti-mouse（2000倍希釈)、発光試薬としてELC Western Blotting Detection Reagents(Amersham Bioscience)を使用して、LC3-I（16 kDa）、LC3-II（14 kDa）及びβ-actin（42 kDa）を検出した。発光強度の解析には、Image Jを用いた。 Sample buffer was added to the collected supernatant to denature it, and electrophoresis was performed on a 15% polyacrylamide gel. After electrophoresis, it was transferred to a nitrocellulose membrane. Blocking was performed with Blocking buffer, and the primary antibodies were anti-LC3 (1000-fold dilution) and anti-β-actin (10000-fold dilution), and the secondary antibodies were anti-rabbit (2000-fold dilution) and anti-mouse (2000-fold dilution). LC3-I (16 kDa), LC3-II (14 kDa) and β-actin (42 kDa) were detected using ELC Western Blotting Detection Reagents (Amersham Bioscience) as a luminescent reagent. Image J was used to analyze the luminescence intensity.
　Bafilomycin A1処置サンプル（Bafilomycin A1(+)）の発光強度からBafilomycin A1非処置サンプル（Bafilomycin A1(-)）の発光強度を控除した差（Δintensity）が大きいほどオートファジー活性化作用が強いと評価される。ウェスタンブロッティングの観察結果とΔintensityを図１に示す。化合物Ａ（実施例１で得られた化合物）はＤＭＳＯ処置サンプルと比較して高いオートファジー活性化作用を示した。なお、図１中、「飢餓」はＥＢＳＳ処置サンプルを表す。また、飢餓状態の細胞はオートファジー活性が高いことが知られている。 The larger the difference (Δintensity) obtained by subtracting the luminescence intensity of the Bafilomycin A1-treated sample (Bafilomycin A1(-)) from the luminescence intensity of the Bafilomycin A1-treated sample (Bafilomycin A1(-)), the stronger the autophagy activation effect. Ru. The observation results of Western blotting and Δintensity are shown in Figure 1. Compound A (the compound obtained in Example 1) showed a higher autophagy activation effect compared to the DMSO-treated sample. In addition, in FIG. 1, "starvation" represents the EBSS-treated sample. It is also known that starved cells have high autophagic activity.
試験例２
オートファジー活性化作用の評価（tfLC3の発現量を測定する方法）
　実施例１で得られた化合物及びカンナビジオールのオートファジー活性化作用をtfLC3の発現量を測定することにより評価した。tfLC3は、オートファジーマーカーであるLC3に２種類の蛍光タンパク質（mRFP及びEGFP）がタンデムに融合したタンパク質である。 Test example 2
Evaluation of autophagy activation effect (method to measure tfLC3 expression level)
The autophagy activating effect of the compound obtained in Example 1 and cannabidiol was evaluated by measuring the expression level of tfLC3. tfLC3 is a protein in which two types of fluorescent proteins (mRFP and EGFP) are tandemly fused to LC3, an autophagy marker.
　Bhargava et al.の手法（Bhargava K. H. et al.: Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex. Proceedings of the National Academy of Sciences of the United States of America 117：17003-17010（2020）｝に則り、レトロウイルスを用いて、下記の各種細胞についてそれぞれ、tfLC3を安定に発現する細胞株を取得した。
　細胞種：
子宮頸部類上皮がん細胞ＨｅＬａ細胞（ＪＣＲＢ細胞バンク：ＪＣＲＢ９００４）
骨肉腫細胞Ｕ２ＯＳ細胞（ＥＣＡＣＣ ：９２０２２７１１）
肝がん細胞ＨｅｐＧ２細胞（ＪＣＲＢ細胞バンク：ＪＣＲＢ１０５４）
表皮角化細胞ＰＳＶＫ１細胞（ＪＣＲＢ細胞バンク：ＪＣＲＢ１０９３）
網膜色素上皮細胞ＲＰＥ細胞（Ｌｏｎｚａ：００１９４９８７） Based on the method of Bhargava et al. (Bhargava K. H. et al.: Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex. Proceedings of the National Academy of Sciences of the United States of America 117: 17003-17010 (2020)) Using retroviruses, cell lines stably expressing tfLC3 were obtained for each of the following types of cells.
Cell type:
Cervical epithelioid cancer cells HeLa cells (JCRB cell bank: JCRB9004)
Osteosarcoma cell U2OS cell (ECACC:92022711)
Liver cancer cells HepG2 cells (JCRB cell bank: JCRB1054)
Epidermal keratinocytes PSVK1 cells (JCRB cell bank: JCRB1093)
Retinal pigment epithelial cells RPE cells (Lonza:00194987)
　取得した、ＨｅＬａ細胞、Ｕ２ＯＳ細胞、ＨｅｐＧ２細胞、及びＲＰＥ細胞を、９６ウェルプレートに播種した。培養培地としては、１０％牛胎児血清、ペニシリン（終濃度100 units/ml）、ストレプトマイシン（終濃度0.1 mg/ml）、及びＬ－グルタミン（終濃度2 mM）を含むＤＭＥＭ培地を使用した。
　取得した、ＰＳＶＫ１細胞をコラーゲンＩコーティングが施された９６ウェルプレートに播種した。培養培地としては、Human Keratinocyte Growth Supplement、ペニシリン（終濃度100 units/ml）、ストレプトマイシン（終濃度0.1 mg/ml）、及びアミノ酸を含むEpiLife培地（ThermoFisher, Cat: MEPI500CA）を使用した。
　９６ウェルプレートをインキュベータ内に静置して、３７℃、５％ＣＯ２条件下で細胞を２４時間培養した。 The obtained HeLa cells, U2OS cells, HepG2 cells, and RPE cells were seeded in a 96-well plate. As the culture medium, a DMEM medium containing 10% fetal bovine serum, penicillin (final concentration 100 units/ml), streptomycin (final concentration 0.1 mg/ml), and L-glutamine (final concentration 2 mM) was used.
The obtained PSVK1 cells were seeded into a 96-well plate coated with collagen I. EpiLife medium (ThermoFisher, Cat: MEPI500CA) containing Human Keratinocyte Growth Supplement, penicillin (final concentration 100 units/ml), streptomycin (final concentration 0.1 mg/ml), and amino acids was used as the culture medium.
The 96-well plate was placed in an incubator, and the cells were cultured for 24 hours at 37° C. and 5% CO 2 .
　培養されたＨｅＬａ細胞、Ｕ２ＯＳ細胞、ＨｅｐＧ２細胞、及びＰＳＶＫ１細胞を含む培養液にサンプル溶解液を添加し、９６ウェルプレートをインキュベータ内に静置して３７℃、５％ＣＯ２条件下で細胞をさらに２４時間培養した（ｎ＝３）。
　培養されたＲＰＥ細胞を含む培養液にサンプル溶解液を添加し、９６ウェルプレートをインキュベータ内に静置して３７℃、５％ＣＯ２条件下で細胞をさらに２４時間培養した。９６ウェルプレートを気密性チャンバー内に配置し、アネロパック・ケンキ５％（三菱ガス化学社製）をそのチャンバーに入れてチャンバーを密封し、インキュベータ内で１時間培養してＯ２濃度１％以下及びＣＯ２濃度５％程度の低酸素状態とし、さらに１時間培養した。９６ウェルプレートを低酸素化チャンバーから取り出し、インキュベータ内に静置してさらに１時間培養した（ｎ＝３）。 The sample lysate was added to the culture medium containing cultured HeLa cells, U2OS cells, HepG2 cells, and PSVK1 cells, and the 96-well plate was placed in an incubator to incubate the cells at 37°C and 5% CO2 . The cells were further cultured for 24 hours (n=3).
The sample lysate was added to the culture medium containing the cultured RPE cells, and the 96-well plate was placed in an incubator to further culture the cells at 37° C. and 5% CO 2 for 24 hours. Place a 96-well plate in an airtight chamber, put Aneropack Kenki 5% (manufactured by Mitsubishi Gas Chemical Co., Ltd.) into the chamber, seal the chamber, and incubate in an incubator for 1 hour to maintain an O2 concentration of 1% or less. The cells were cultured for an additional hour under hypoxic conditions with a CO 2 concentration of approximately 5%. The 96-well plate was removed from the hypoxic chamber, placed in an incubator, and further cultured for 1 hour (n=3).
　使用したサンプル溶解液は、サンプル（化合物Ａ又はカンナビジオール）をＤＭＳＯに溶解して調製した。サンプル溶解液におけるサンプル濃度は、培養液（1000μl）にサンプル溶解液（1μl）を添加した際のサンプル濃度（培養液におけるサンプル濃度）が所定濃度となるように調整した。
　ただし、カンナビジオールについては、ＰＳＶＫ１細胞を使用した培養を行わなかった。 The sample solution used was prepared by dissolving the sample (Compound A or cannabidiol) in DMSO. The sample concentration in the sample solution was adjusted so that the sample concentration (sample concentration in the culture solution) when the sample solution (1 μl) was added to the culture solution (1000 μl) was a predetermined concentration.
However, cannabidiol was not cultured using PSVK1 cells.
　さらに、次の培養も行った。
サンプル溶解液を培養液に添加しなかった他は上記と同様に培養した（ブランク；ｎ＝３）。
サンプル溶解液に代えてＤＭＳＯのみを添加した他は上記と同様に培養した（陰性対照；ｎ＝３）。
サンプルに代えて所定濃度のTorin1（オートファゴソーム形成を抑制するmTORの阻害剤）を使用した他は上記と同様に培養した（陽性対称；ｎ＝３）。 Furthermore, the following culture was performed.
Culture was carried out in the same manner as above except that the sample lysate was not added to the culture medium (blank; n=3).
Culture was carried out in the same manner as above except that only DMSO was added instead of the sample lysate (negative control; n=3).
Culture was carried out in the same manner as above, except that a predetermined concentration of Torin1 (an inhibitor of mTOR that suppresses autophagosome formation) was used instead of the sample (positive control; n = 3).
　培養終了後、各ウェル内の培養液を除去し、細胞をＰＢＳで２回洗浄した。続いて、ヘキスト色素（Hoechst33342）入り４％パラホルムアルデヒド・ＰＢＳを各ウェルに添加し、２０分間静置して細胞を固定化した。 After the culture was completed, the culture medium in each well was removed, and the cells were washed twice with PBS. Subsequently, 4% paraformaldehyde/PBS containing Hoechst dye (Hoechst 33342) was added to each well, and the cells were fixed by standing for 20 minutes.
　各ウェル内の上清を除去し、ＰＢＳにより２回洗浄した。細胞の観察には共焦点イメージサイトメーター（ＣＱ１；横河電機社製）を用い、蛍光量は画像解析ソフト（CellPathfinder；横河電機社製）を用いて算出した。化合物Ａが使用されたアッセイ結果を図２～６に示し、カンナビジオールが使用されたアッセイ結果を図７～１０に示す。アッセイ結果は、ブランクのEGFP／mRFP比を１とした相対値で表した。図中の「ＣＢＤ」はカンナビジオールを意味する。 The supernatant in each well was removed and washed twice with PBS. A confocal image cytometer (CQ1; manufactured by Yokogawa Electric Corporation) was used to observe the cells, and the amount of fluorescence was calculated using image analysis software (CellPathfinder; manufactured by Yokogawa Electric Corporation). The assay results in which Compound A was used are shown in Figures 2-6, and the assay results in which cannabidiol was used are shown in Figures 7-10. Assay results were expressed as relative values with the blank EGFP/mRFP ratio set at 1. "CBD" in the figure means cannabidiol.
　EGFP／mRFPの比が低くなるほど、オートファジーが活性化していると評価される。実施例１で得られた化合物及びカンナビジオールは、各種の細胞におけるオートファジーを活性化した。 The lower the EGFP/mRFP ratio, the more activated autophagy is evaluated. The compound obtained in Example 1 and cannabidiol activated autophagy in various cells.

Claims (14)

  1. 下記式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩を含有し、肺疾患（肺線維症を除く）、腎疾患（腎線維症を除く）、生殖機能障害、肝障害、眼疾患、皮膚疾患、癌（肺がん、前立腺がん、及び乳がんを除く）、細菌感染症、ウイルス感染症、自己免疫疾患、メタボリックシンドローム、及び筋骨格系疾患（筋ジストロフィーを除く）からなる群から選択される少なくとも１種の疾患を予防又は治療するための医薬組成物。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    Ａは、炭素原子又は窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～５の整数を示し、
    Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～５の整数を示し、
    ｐは、０又は１を示し、
    ｑは、０又は１を示す。］     Contains at least one compound selected from the group consisting of the compound represented by the following formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof, and is used to treat lung diseases (excluding pulmonary fibrosis), renal disease. Diseases (excluding renal fibrosis), reproductive dysfunction, liver disorders, eye diseases, skin diseases, cancer (excluding lung cancer, prostate cancer, and breast cancer), bacterial infections, viral infections, autoimmune diseases, metabolic syndrome A pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of , and musculoskeletal diseases (excluding muscular dystrophy).
    Figure JPOXMLDOC01-appb-C000001
     [In the formula,
    A represents a carbon atom or a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
    m represents an integer from 0 to 5,
    R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 5,
    p represents 0 or 1,
    q represents 0 or 1. ]
  2. 前記疾患が、腎疾患（腎線維症を除く）、肝障害、眼疾患、及び皮膚疾患からなる群から選択される少なくとも１種の疾患である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the disease is at least one disease selected from the group consisting of renal disease (excluding renal fibrosis), liver disorder, eye disease, and skin disease.
  3. 前記式（１）で表わされる化合物において、
    Ａは、炭素原子又は窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、フッ素原子、塩素原子、臭素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ５アシルオキシ基、Ｃ２～Ｃ５アルコキシカルボニル基、又はトリハロゲノメチル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～４の整数を示し、
    Ｒ２は、フッ素原子；塩素原子；臭素原子；トリフルオロメチル基；トリクロロメチル基；トリブロモメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ５アシルオキシ基；Ｃ２～Ｃ５アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～４の整数を示し、
    ｐは、０又は１を示し、
    ｑは、０又は１を示す、
    請求項１又は２に記載の医薬組成物。     In the compound represented by the formula (1),
    A represents a carbon atom or a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and when there is more than one, may be the same or different;
    m represents an integer from 0 to 4,
    R 2 is a fluorine atom; a chlorine atom; a bromine atom; a trifluoromethyl group; a trichloromethyl group; a tribromomethyl group; a C1 to C4 alkyl group; a C2 to C5 acyloxy group; a C2 to C5 alkoxycarbonyl group; a C1 to C3 alkyl and an amide group which may be substituted with one or two groups selected from the group consisting of C2-C4 alkoxycarbonyl groups; selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; A piperidinylcarbonyl group which may be substituted with one or more groups; or substituted with one or more groups selected from the group consisting of C1 to C3 alkyl groups and C2 to C4 alkoxycarbonyl groups; represents a pyrrolidinyl carbonyl group that may be
    n represents an integer from 0 to 4,
    p represents 0 or 1,
    q indicates 0 or 1,
    The pharmaceutical composition according to claim 1 or 2.
  4. 前記式（１）で表わされる化合物において、
    Ａは、窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、トリクロロメチル基、又はトリブロモメチル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～３の整数を示し、
    Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アシルオキシ基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～３の整数を示し、
    ｐは、１を示し、
    ｑは、１を示す、
    請求項１～３のいずれか一項に記載の医薬組成物。     In the compound represented by the formula (1),
    A represents a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group, and when there is more than one, may be the same or different;
    m represents an integer from 0 to 3,
    R 2 is a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1 to C4 alkyl group; a C2 to C4 acyloxy group; a C2 to C4 alkoxycarbonyl group; a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group An amide group which may be substituted with one or two groups selected from the group consisting of; one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; a piperidinylcarbonyl group which may be substituted with; or a pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group Indicates a group, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 3;
    p indicates 1,
    q indicates 1,
    Pharmaceutical composition according to any one of claims 1 to 3.
  5. 前記式（１）で表わされる化合物において、
    Ａは、窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、塩素原子、Ｃ１～Ｃ３アルキル基、Ｃ１～Ｃ３アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、又はトリクロロメチル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～２の整数を示し、
    Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～３の整数を示し、
    ｐは、１を示し、
    ｑは、１を示す、
    請求項１～４のいずれか一項に記載の医薬組成物。     In the compound represented by the formula (1),
    A represents a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a chlorine atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, or a trichloromethyl group, and when there are multiple groups, they may be the same or different,
    m represents an integer from 0 to 2,
    R 2 is selected from the group consisting of a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group. an amide group which may be substituted with one or two groups; or an amide group which may be substituted with one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; Indicates a good piperidinyl carbonyl group, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 3;
    p indicates 1,
    q indicates 1,
    Pharmaceutical composition according to any one of claims 1 to 4.
  6. 前記式（１）で表わされる化合物が、下記式（１－１）で表される化合物及び下記式（１－２）で表される化合物からなる群から選択される少なくとも１種の化合物である、請求項１又は２に記載の医薬組成物。
    Figure JPOXMLDOC01-appb-C000002
     ［式中、
    Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～５の整数を示し、
    Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～５の整数を示す。］及び
    式（１－２）
    Figure JPOXMLDOC01-appb-C000003
     ［式中、
    Ａは、炭素原子又は窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ａ及びＢは、同時に炭素原子を示さず、
    Ｒ３は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
    Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～５の整数を示す。］。     The compound represented by the formula (1) is at least one compound selected from the group consisting of a compound represented by the following formula (1-1) and a compound represented by the following formula (1-2). , the pharmaceutical composition according to claim 1 or 2.
    Figure JPOXMLDOC01-appb-C000002
     [In the formula,
    R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
    m represents an integer from 0 to 5,
    R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 5. ] and formula (1-2)
    Figure JPOXMLDOC01-appb-C000003
     [In the formula,
    A represents a carbon atom or a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    A and B do not represent a carbon atom at the same time,
    R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different,
    R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 5. ].
  7. 前記式（１）で表される化合物が、以下に示されたいずれかの化合物である、請求項１又は２に記載の医薬組成物。
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
         The pharmaceutical composition according to claim 1 or 2, wherein the compound represented by formula (1) is any of the compounds shown below.
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
  8. 下記式（１）で表される化合物及びカンナビジオールからなる群から選択される少なくとも１種の化合物、又はその薬学的に許容される塩を含有する、細胞のオートファジー活性化剤。
    Figure JPOXMLDOC01-appb-C000006
     ［式中、
    Ａは、炭素原子又は窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～５の整数を示し、
    Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～５の整数を示し、
    ｐは、０又は１を示し、
    ｑは、０又は１を示す。］     A cellular autophagy activator containing at least one compound selected from the group consisting of the compound represented by the following formula (1) and cannabidiol, or a pharmaceutically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000006
     [In the formula,
    A represents a carbon atom or a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
    m represents an integer from 0 to 5,
    R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 5,
    p represents 0 or 1,
    q represents 0 or 1. ]
  9. 前記細胞が、腎細胞、皮膚細胞、眼細胞、及び肝細胞からなる群から選択される少なくとも１種である、請求項８に記載のオートファジー活性化剤。 The autophagy activator according to claim 8, wherein the cell is at least one selected from the group consisting of kidney cells, skin cells, eye cells, and hepatocytes.
  10. 前記式（１）で表わされる化合物において、
    Ａは、炭素原子又は窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、フッ素原子、塩素原子、臭素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ５アシルオキシ基、Ｃ２～Ｃ５アルコキシカルボニル基、又はトリハロゲノメチル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～４の整数を示し、
    Ｒ２は、フッ素原子；塩素原子；臭素原子；トリフルオロメチル基；トリクロロメチル基；トリブロモメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ５アシルオキシ基；Ｃ２～Ｃ５アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～４の整数を示し、
    ｐは、０又は１を示し、
    ｑは、０又は１を示す、
    請求項８又は９に記載のオートファジー活性化剤。     In the compound represented by the formula (1),
    A represents a carbon atom or a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a fluorine atom, a chlorine atom, a bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C5 acyloxy group, a C2-C5 alkoxycarbonyl group, or a trihalogenomethyl group, and when there is more than one, may be the same or different;
    m represents an integer from 0 to 4,
    R 2 is a fluorine atom; a chlorine atom; a bromine atom; a trifluoromethyl group; a trichloromethyl group; a tribromomethyl group; a C1 to C4 alkyl group; a C2 to C5 acyloxy group; a C2 to C5 alkoxycarbonyl group; a C1 to C3 alkyl and an amide group which may be substituted with one or two groups selected from the group consisting of C2-C4 alkoxycarbonyl groups; selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; A piperidinylcarbonyl group which may be substituted with one or more groups; or substituted with one or more groups selected from the group consisting of C1 to C3 alkyl groups and C2 to C4 alkoxycarbonyl groups; represents a pyrrolidinyl carbonyl group that may be
    n represents an integer from 0 to 4,
    p represents 0 or 1,
    q indicates 0 or 1,
    The autophagy activator according to claim 8 or 9.
  11. 前記式（１）で表わされる化合物において、
    Ａは、窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、フッ素原子、塩素原子、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、トリクロロメチル基、又はトリブロモメチル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～３の整数を示し、
    Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アシルオキシ基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～３の整数を示し、
    ｐは、１を示し、
    ｑは、１を示す、
    請求項８～１０のいずれか一項に記載のオートファジー活性化剤。     In the compound represented by the formula (1),
    A represents a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a fluorine atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, a trichloromethyl group, or a tribromomethyl group, and when there is more than one, may be the same or different;
    m represents an integer from 0 to 3,
    R 2 is a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1 to C4 alkyl group; a C2 to C4 acyloxy group; a C2 to C4 alkoxycarbonyl group; a C1 to C3 alkyl group and a C2 to C4 alkoxycarbonyl group An amide group which may be substituted with one or two groups selected from the group consisting of; one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; a piperidinylcarbonyl group which may be substituted with; or a pyrrolidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group Indicates a group, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 3;
    p indicates 1,
    q indicates 1,
    The autophagy activator according to any one of claims 8 to 10.
  12. 前記式（１）で表わされる化合物において、
    Ａは、窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ｒ１は、塩素原子、Ｃ１～Ｃ３アルキル基、Ｃ１～Ｃ３アルコキシ基、Ｃ２～Ｃ４アルコキシカルボニル基、トリフルオロメチル基、又はトリクロロメチル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～２の整数を示し、
    Ｒ２は、フッ素原子；塩素原子；トリフルオロメチル基；トリクロロメチル基；Ｃ１～Ｃ４アルキル基；Ｃ２～Ｃ４アルコキシカルボニル基；Ｃ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；或いはＣ１～Ｃ３アルキル基及びＣ２～Ｃ４アルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～３の整数を示し、
    ｐは、１を示し、
    ｑは、１を示す、
    請求項８～１１のいずれか一項に記載のオートファジー活性化剤。     In the compound represented by the formula (1),
    A represents a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    R 1 represents a chlorine atom, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C2-C4 alkoxycarbonyl group, a trifluoromethyl group, or a trichloromethyl group, and when there are multiple groups, they may be the same or different,
    m represents an integer from 0 to 2,
    R 2 is selected from the group consisting of a fluorine atom; a chlorine atom; a trifluoromethyl group; a trichloromethyl group; a C1-C4 alkyl group; a C2-C4 alkoxycarbonyl group; a C1-C3 alkyl group and a C2-C4 alkoxycarbonyl group. an amide group which may be substituted with one or two groups; or an amide group which may be substituted with one or more groups selected from the group consisting of C1-C3 alkyl groups and C2-C4 alkoxycarbonyl groups; Indicates a good piperidinyl carbonyl group, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 3;
    p indicates 1,
    q indicates 1,
    The autophagy activator according to any one of claims 8 to 11.
  13. 前記式（１）で表わされる化合物が、下記式（１－１）で表される化合物及び下記式（１－２）で表される化合物からなる群から選択される少なくとも１種の化合物である、請求項８又は９に記載のオートファジー活性化剤。
    Figure JPOXMLDOC01-appb-C000007
     ［式中、
    Ｒ１は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
    ｍは、０～５の整数を示し、
    Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～５の整数を示す。］及び
    式（１－２）
    Figure JPOXMLDOC01-appb-C000008
     ［式中、
    Ａは、炭素原子又は窒素原子を示し、
    Ｂは、炭素原子又は窒素原子を示し、
    Ａ及びＢは、同時に炭素原子を示さず、
    Ｒ３は、ハロゲン原子、アルキル基、アルコキシ基、アシルオキシ基、アルコキシカルボニル基、又はハロゲン原子で置換されたアルキル基を示し、複数あるときは同一又は異なってよく、
    Ｒ２は、ハロゲン原子；トリハロゲノメチル基；アルキル基；アシルオキシ基；アルコキシカルボニル基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種の基で置換されてもよいアミド基；アルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピペリジニルカルボニル基；或いはアルキル基及びアルコキシカルボニル基からなる群から選択される１種又は２種以上の基で置換されてもよいピロリジニルカルボニル基を示し、複数あるときは同一又は異なってよく、
    ｎは、０～５の整数を示す。］。     The compound represented by the formula (1) is at least one compound selected from the group consisting of a compound represented by the following formula (1-1) and a compound represented by the following formula (1-2). , the autophagy activator according to claim 8 or 9.
    Figure JPOXMLDOC01-appb-C000007
     [In the formula,
    R 1 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there are multiple groups, they may be the same or different;
    m represents an integer from 0 to 5,
    R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 5. ] and formula (1-2)
    Figure JPOXMLDOC01-appb-C000008
     [In the formula,
    A represents a carbon atom or a nitrogen atom,
    B represents a carbon atom or a nitrogen atom,
    A and B do not represent a carbon atom at the same time,
    R 3 represents a halogen atom, an alkyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, or an alkyl group substituted with a halogen atom, and when there is more than one, they may be the same or different,
    R 2 is an amide group which may be substituted with one or two groups selected from the group consisting of a halogen atom; a trihalogenomethyl group; an alkyl group; an acyloxy group; an alkoxycarbonyl group; an alkyl group and an alkoxycarbonyl group; ; a piperidinylcarbonyl group which may be substituted with one or more groups selected from the group consisting of alkyl groups and alkoxycarbonyl groups; or one type selected from the group consisting of alkyl groups and alkoxycarbonyl groups or a pyrrolidinylcarbonyl group which may be substituted with two or more types of groups, and when there are multiple groups, they may be the same or different,
    n represents an integer from 0 to 5. ].
  14. 前記式（１）で表される化合物が、以下に示されたいずれかの化合物である、請求項８又は９に記載のオートファジー活性化剤。
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
         The autophagy activator according to claim 8 or 9, wherein the compound represented by formula (1) is one of the compounds shown below.
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
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