WO2023233994A1 - Composition pharmaceutique et activateur d'autophagie - Google Patents

Composition pharmaceutique et activateur d'autophagie 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 or sparfloxacin
    • 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.

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Abstract

L'objectif de la présente invention est de fournir une composition pharmaceutique pour le traitement ou la prévention de maladies telles que des maladies pulmonaires (à l'exclusion de la fibrose pulmonaire), des maladies rénales (à l'exclusion de la fibrose rénale), d'une dysfonction de la reproduction, d'une lésion hépatique, de maladies oculaires, de maladies de la peau, d'un cancer (à l'exclusion d'un cancer du poumon, d'un cancer de la prostate et d'un cancer du sein), d'une infection bactérienne, d'une infection virale, de maladies auto-immunes, du syndrome métabolique, de maladies musculo-squelettiques (à l'exclusion de la dystrophie musculaire), et similaire.　La présente invention concerne une composition pharmaceutique qui contient au moins un composé choisi dans le groupe constitué du cannabidiol et des composés représentés par la formule (1), ou un sel pharmaceutiquement acceptable de ceux-ci, et qui est destinée à traiter ou à prévenir au moins une maladie choisie dans le groupe constitué de maladies pulmonaires (à l'exclusion de la fibrose pulmonaire), de maladies rénales (à l'exclusion de la fibrose rénale), d'une dysfonction de la reproduction, de lésions hépatiques, de maladies oculaires, de maladies cutanées, d'un cancer (à l'exclusion d'un cancer du poumon, d'un cancer de la prostate et d'un cancer du sein), d'une infection bactérienne, d'une infection virale, de maladies auto-immunes, du syndrome métabolique, de maladies musculo-squelettiques (à l'exclusion de la dystrophie musculaire), et similaire.
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