WO2020235587A1 - Dérivé de tandospirone - Google Patents

Dérivé de tandospirone Download PDF

Info

Publication number
WO2020235587A1
WO2020235587A1 PCT/JP2020/019911 JP2020019911W WO2020235587A1 WO 2020235587 A1 WO2020235587 A1 WO 2020235587A1 JP 2020019911 W JP2020019911 W JP 2020019911W WO 2020235587 A1 WO2020235587 A1 WO 2020235587A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
formula
administration
clozapine
Prior art date
Application number
PCT/JP2020/019911
Other languages
English (en)
Japanese (ja)
Inventor
近藤　隆
阿部　仁
正佳 倉知
鈴木　道雄
上原　隆
Original Assignee
国立大学法人富山大学
学校法人金沢医科大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人富山大学, 学校法人金沢医科大学 filed Critical 国立大学法人富山大学
Priority to JP2021520813A priority Critical patent/JPWO2020235587A1/ja
Publication of WO2020235587A1 publication Critical patent/WO2020235587A1/fr

Links

Images

Classifications

    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/72—4,7-Endo-alkylene-iso-indoles
    • C07D209/76—4,7-Endo-alkylene-iso-indoles with oxygen atoms in positions 1 and 3

Definitions

  • the present invention relates to tandospirone derivatives.
  • Central nervous system diseases are known as psychiatric and neurological diseases. Schizophrenia, bipolar disorder, depression, autism spectrum disorder, anxiety disorder, adjustment disorder, Alzheimer's disease, dementia, epilepsy, and Parkinson's disease are typical central nervous system diseases.
  • Schizophrenia is a mental dysfunction in which the ability to organize (integrate) mental functions such as thoughts, behaviors, and emotions declines over a long period of time, and hallucinations, delusions, abnormal behaviors, decreased motivation, and cognition during the course of the disorder. Various symptoms such as dysfunction appear.
  • the prevalence of schizophrenia is about 1%, and it is a disease with a high incidence. It develops mainly in adolescence and progresses chronically.
  • Positive symptoms include hallucinations, delusions, impaired self-consciousness that feels controlled by someone, impaired thinking that causes disorganized conversations and behaviors, and abnormal behaviors that are extremely agitated or behave strangely.
  • Negative symptoms include flattening of emotions that cause poor expression of emotions, decreased motivation, decreased thinking ability, decreased relationships with people, and impaired interpersonal communication that leads to autism.
  • cognitive dysfunction intellectual abilities such as memory, thinking, understanding, calculation, learning, language, and judgment appear.
  • Negative symptoms of schizophrenia and the cause of cognitive dysfunction are associated with volume loss in the patient's frontal cortex, and one of the major causes of volume loss in the frontal cortex is thought to be a decrease in parvalbumin-positive GABA neurons.
  • Parvalbumin-positive GABA neurons are cells that are present in the cerebral neocortex and express parvalbumin among inhibitory neurons (cerebral neocortical interneurons) that release GABA ( ⁇ -aminobutyric acid).
  • Non-Patent Document 1 suggests that the decrease in parvalbumin-positive GABA neurons in an animal model of schizophrenia is mediated by oxidative stress.
  • NMDA N-methyl-D-aspartate
  • the pillars of treatment for central nervous system diseases such as schizophrenia are treatment by medication and psychiatric rehabilitation.
  • Some central nervous system diseases, such as schizophrenia mentioned above, are caused by a decrease in nerve cells or damage to nerve cells, and for such diseases, , Neuroprotective drugs are effective.
  • an object of the present invention is to provide a candidate compound for an active ingredient of a drug for central nervous system diseases or a novel compound that can be a precursor thereof.
  • a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof is as follows.
  • R 1 , R 2 and R 3 are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and an alkoxy group having 1 to 6 carbon atoms, and are R 1 , R. at least one of the 2 and R 3 one is a hydroxy group.
  • R 1 , R 2 and R 3 are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and a methoxy group, respectively, and among R 1 , R 2 and R 3 .
  • [5] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydroxy groups and R 3 is a hydrogen atom, respectively, in the formula (1).
  • the pharmaceutical composition according to [6] which is a neuroprotective agent.
  • the pharmaceutical composition according to [6] or [7] which is a therapeutic agent for a central nervous system disease.
  • a method for protecting nerves wherein the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof is administered to a patient.
  • a method for treating a central nervous system disease wherein the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof is administered to a patient.
  • a method for treating schizophrenia wherein the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof is administered to a patient.
  • the compound of the present invention is a novel compound that can be a candidate compound for an active ingredient of a drug for central nervous system diseases or a precursor thereof.
  • the 1 H-NMR spectrum of compound A is shown.
  • the spectrum of 13 C-NMR of compound A is shown.
  • the 1 H-NMR spectrum of compound B is shown.
  • the spectrum of 13 C-NMR of compound B is shown.
  • the 1 H-NMR spectrum of Compound C is shown.
  • the spectrum of 13 C-NMR of compound C is shown.
  • the 1 H-NMR spectrum of compound D is shown.
  • the spectrum of 13 C-NMR of compound D is shown.
  • 6 is a graph showing the results of measuring the antioxidant activity of compounds I, A, B, C, clozapine and olanzapine by the APF method. It is a graph which shows the antioxidant activity measurement result by the HPF method of compounds I, A, B, C, clozapine and olanzapine.
  • 6 is a graph showing the results of measuring the antioxidant activity of compounds I, A, B, C, clozapine and olanzapine by the DCFH method. It is a graph which shows the result of the methamphetamine-induced transfer momentum measurement for compound A. It is a graph which shows the result of the methamphetamine-induced transfer momentum measurement for compound B. It is a graph which shows the result of the methamphetamine-induced transfer momentum measurement about clozapine. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex for compound A. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex for compound B.
  • R 1 , R 2 and R 3 are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and an alkoxy group having 1 to 6 carbon atoms, and are R 1 , R. at least one of the 2 and R 3 one is a hydroxy group.
  • R 1 , R 2 and R 3 are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and a methoxy group, respectively, and among R 1 , R 2 and R 3 . It is preferable that at least one is a hydroxy group.
  • Compounds in which at least one of R 1 , R 2 and R 3 is a hydroxy group and the remaining group is a hydrogen atom, a hydroxy group, or a methoxy group and a pharmaceutically acceptable salt thereof have antioxidant activity. It is expensive and can be easily manufactured by the manufacturing method described later.
  • R 1 is a methoxy group
  • R 2 is a hydroxy group
  • R 3 is a hydrogen atom.
  • Such compounds are (3aR * , 4S * , 7R * , 7aS * ) -2- (4- (4- (4-hydroxy-3-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H- 4,7-Metanoisoindole-1,3 (2H) -dione.
  • the compound and its pharmaceutically acceptable salt have high antioxidant activity.
  • the compound is a compound represented by the following formula (2).
  • R 1 is a hydroxy group
  • R 2 is a methoxy group
  • R 3 is a hydrogen atom.
  • Such compounds are (3aR * , 4S * , 7R * , 7aS * ) -2- (4- (4- (3-hydroxy-4-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H- 4,7-Metanoisoindole-1,3 (2H) -dione.
  • the compound and its pharmaceutically acceptable salt also have high antioxidant activity.
  • the compound is a compound represented by the following formula (3).
  • R 1 and R 2 are hydroxy groups and R 3 is a hydrogen atom in the formula (1), respectively.
  • Such compounds are (3aR * , 4S * , 7R * , 7aS * ) -2- (4- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H-4, 7-Metanoisoindole-1,3 (2H) -dione.
  • the compound and its pharmaceutically acceptable salt also have high antioxidant activity.
  • the compound is a compound represented by the following formula (4).
  • pharmaceutically acceptable salt is not particularly limited as long as it forms a salt with the compound represented by the formula (1) and is pharmaceutically acceptable, and is, for example, inorganic. Examples thereof include acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts and the like.
  • inorganic acid salts include hydrochlorides, hydrobromates, sulfates, nitrates, phosphates and the like
  • organic acid salts include acetates, succinates, fumarates and maleines.
  • Carboates such as acid salts, tartrates, citrates, lactates, stearate, benzoates, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, benzenesulfonic acids
  • examples include sulfonates such as salts.
  • inorganic base salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salts, ammonium salts and the like.
  • organic base salts include organic base salts. Examples thereof include diethylamine salt, diethanolamine salt, meglumin salt, N, N'-dibenzylethylenediamine salt and the like.
  • acidic amino acid salts include aspartate, glutamic acid and the like
  • basic amino acid salts include arginine salt, lysine salt, ornithine salt and the like.
  • compound according to the present invention means a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • Tandospirone is a 5- HT1A receptor partial agonist and is used as a drug for improving anxiety / depressive symptoms of psychosomatic disorder and neurosis.
  • tandospirone can prevent cognitive impairment in schizophrenia model animals (rats) (Horiguchi et al., Neuropathic psychiatry, 2012, Vol. 37, No. 10, p. 2175-2183), and schizophrenia. It has been reported to have neuroprotective effects such as improving the memory function of patients (Sumiyoshi et al., American Journal of Psychiatry, 2001, Vol. 158, p.1722-1725).
  • the compound of the following formula (6) is apocynin.
  • Apocynin was isolated from Picrorhizakurroa, a plant of the genus Koouren from the Western Himalayas, which was used as a folk medicine for liver / heart disease, jaundice, and asthma.
  • Apocynin inhibits NADPH oxidase activity and inhibits the production of reactive oxygen species. Therefore, it has antioxidant activity and exhibits a wide range of anti-inflammatory effects.
  • the compound according to the present invention having a part of each structure of tandospirone and apocynin has an antioxidant effect and a neuroprotective effect at the same time. Furthermore, since tandospirone and apocynin are compounds that have been used as pharmaceuticals for a long time or have been contained in folk medicine, it is considered that the compound according to the present invention is highly safe for the human body.
  • the compound according to the present invention Since the compound according to the present invention has high antioxidant activity, it may be used as an active ingredient of a pharmaceutical composition for preventing and treating various diseases.
  • Reactive oxygen species that are overproduced in the body cause protein oxidation, lipid oxidation, nucleic acid decomposition, etc., damage cells, cause dysfunction, and affect the progression of pathological conditions.
  • the target disease of the pharmaceutical composition containing the compound according to the present invention as an active ingredient is a disease induced or promoted by overproduction of active oxygen in the body.
  • the antioxidant activity of the compounds according to the present invention may improve the symptoms of diseases caused by such oxidative stress.
  • the compound according to the present invention is considered to have a neuroprotective effect, and may be used as an active ingredient of a neuroprotective drug.
  • neuroprotective drug refers to a drug that reduces the degree of disease caused by impaired nerve cell function.
  • the compound according to the present invention exerts a particularly effective effect on central nervous system diseases due to its antioxidant activity and neuroprotective action, and may be used as an active ingredient of a therapeutic agent for central nervous system diseases.
  • Diseases targeted by the therapeutic agent for central nervous system diseases containing the compound according to the present invention include schizophrenia and other neuropsychiatric diseases in which oxidative stress has been reported to be involved in the pathological condition, for example, Alzheimer's disease. , Parkinson's disease, bipolar disorder, depression, anxiety disorder, schizophrenia, epilepsy and the like.
  • tandospirone which is the parent substance of the present invention, is approved for insurance coverage for psychosomatic disorders.
  • psychosomatic disorder is a condition in which psychosocial factors are closely involved in the onset and course of physical illness, and organic or functional disorders are recognized.
  • physical symptoms associated with other psychosomatic disorders such as neuropathy and depression are excluded.
  • digestive ulcers, bronchial asthma, migraine, and irritable bowel syndrome are mentioned. Therefore, the compound according to the present invention may be effective for these psychosomatic disorders as well as the parent substance.
  • Non-Patent Document 1 suggests that the decrease in parvalbumin-positive GABA neurons in an animal model of schizophrenia is mediated by oxidative stress.
  • the main hypothesis of schizophrenia is that decreased function of NMDA receptors on GABAergic neurons causes oxidative stress, resulting in a decrease in parvalbumin-positive GABA neurons, resulting in a decrease in parvalbumin-positive GABA neurons. Synchronous firing on a large number of controlled pyramidal neurons is impaired, resulting in cognitive dysfunction and numerous psychological symptoms.
  • the antioxidant action of the compound according to the present invention may reduce oxidative stress in the frontal cortex and improve negative symptoms of schizophrenia and cognitive dysfunction. That is, the compound according to the present invention may be suitably used as an active ingredient of a therapeutic agent for schizophrenia.
  • clozapine which is used as a therapeutic agent for schizophrenia, has a serious side effect of agranulocytosis, but clozapine-induced agranulocytosis causes oxidative stress and apoptosis of granulocytes. (Fehsel et al., Journal of Clinical Psychopahrmacology, 2005, Vol. 25, p. 419-426) and clozapine-induced agranulocytosis of glutathione precursor N-acetylcysteine, which has antioxidant activity. Suppression of schizophrenia (Williams et al., Molecular Therapy, 2000, Vol. 58, p. 207-216) has been reported. On the other hand, since the compound according to the present invention has an antioxidant effect contrary to clozapine, it may be used as a therapeutic agent for schizophrenia without the side effect of agranulocytosis instead of clozapine.
  • the target patient of the pharmaceutical composition containing the compound according to the present invention as an active ingredient is preferably a human or a non-human mammal.
  • a form of the pharmaceutical composition for example, oral administration with tablets, capsules, granules, powders, syrups, etc., or parenteral administration with injections, suppositories, inhalants, transdermal absorbents, external preparations, etc. Administration is mentioned.
  • the compound according to the present invention may be used alone or as another pharmaceutically acceptable excipient, binder, bulking agent, disintegrant, surfactant. Agents, lubricants, dispersants, buffers, preservatives, flavoring agents, odorants, fragrances, coatings, carriers, diluents, colorants and the like can be used in appropriate combinations.
  • the compound according to the present invention may function as the active ingredient of the pharmaceutical composition itself, or may be a precursor of the active ingredient of the pharmaceutical composition. That is, the compound according to the present invention may be used as a precursor, and the final compound obtained by chemically changing the compound according to the present invention may function as an active ingredient of the pharmaceutical composition. Such chemical changes may be made in vitro or in vivo.
  • the compound of the formula (1) can be produced, for example, by dehydrating and condensing the compound of the following formula (7) and the compound of the following formula (8).
  • R 1, R 2 and R 3 are the same as R 1, R 2 and R 3 in the formula (1). However, as described later, it may be protected by R 1, R 2 and / or R 3 is protected if necessary group.
  • the compound of the formula (7) is N- (4-piperazinylbutyl) bicyclo [2.2.1] heptane-2,3-dicarboxyimide, and is, for example, Japanese Patent Application Laid-Open No. 62-1323179. (Or, it can be prepared by the method described in European Patent Application Publication No. 0196096 (A2)).
  • the compound of the formula (1) can be produced by dissolving the compound of the formula (7) and the formula (8) in a solvent and adding a dehydration condensing agent.
  • R 1 , R 2 and / or R 3 of formula (1) are highly active groups, these groups may be protected with protecting groups, if necessary.
  • a protecting group a known protecting group can be used.
  • R 1 , R 2 and / or R 3 are hydroxy groups, a benzyl group or the like can be used as the protecting group.
  • the target compound can be obtained by removing the protecting group after the reaction, if necessary.
  • the introduction and removal of these protecting groups can be carried out by known methods such as Peter G. et al. M. Wuts, "Greene's Protective Groups in Organic Synthesis, 5th Edition", 2014, may be carried out according to the method described in Wiley.
  • the dehydration condensing agent examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N, N'-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBT), and diphenylphosphoryl.
  • Acid azide (DPPA) 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride n hydrate (DMT-MM), 2-methyl-6 -Known dehydration condensing agents such as nitrobenzoic acid anhydride (MNBA) can be used, and these can be used alone or in combination of two or more.
  • the dehydration condensing agent is EDC.
  • the solvent used for dehydration condensation examples include dichloromethane, tert-butanol, tetrahydrofuran, chloroform, diethyl ether, benzene, cyclohexane, n-hexane, acetonitrile, dimethylformamide, tert-butylmethyl ether and dimethylacetamide.
  • the solvent is a mixed solvent of dichloromethane and tert-butanol or tetrahydrofuran.
  • the generated compound of formula (1) can be appropriately purified, washed and dried. Further, when the compound of the formula (1) is used, it can be appropriately dissolved in a solvent before use.
  • the solvent used for the dehydration condensation described above can also be suitably used when the compound of the formula (1) is used.
  • Compound A [Composite synthesis] (Synthesis of Compound A) (3aR * , 4S * , 7R * , 7aS * ) -2- (4- (4- (4-hydroxy-3-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H-4 by the following method , 7-Metanoisoindole-1,3 (2H) -dione (hereinafter referred to as "Compound A”) was synthesized.
  • Compound A is a compound having the structure of the above formula (2), and in the formula (1), R 1 is a methoxy group, R 2 is a hydroxy group, and R 3 is a hydrogen atom. Is.
  • N- (4-piperazinylbutyl) bicyclo [2.2.1] heptane-2,3-dicarboxyimide (compound of formula (7), hereinafter referred to as "compound I") 504 mg, 4-hydroxy- 358 mg of 3-methoxybenzoic acid and 701 mg of EDC were dissolved in a mixture of 12.5 mL of dichloromethane and 0.35 mL of tert-butanol. After stirring at room temperature for 1 hour, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and further with saturated brine. The obtained residue was purified by silica gel column chromatography to obtain white amorphous compound A (455 mg).
  • Compound B (Synthesis of compound B) (3aR * , 4S * , 7R * , 7aS * )-2- (4- (4- (3-hydroxy-4-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H-4 by the following method , 7-Metanoisoindole-1,3 (2H) -dione (hereinafter referred to as "Compound B”) was synthesized.
  • Compound B is a compound having the structure of the above formula (3), and in the formula (1), R 1 is a hydroxy group, R 2 is a methoxy group, and R 3 is a hydrogen atom. Is.
  • Compound C (Synthesis of compound C) (3aR * , 4S * , 7R * , 7aS * ) -2- (4- (4- (3,4-dihydroxybenzoyl) piperazine-1-yl) butyl) hexahydro-1H-4,7 by the following method -Metanoisoindole-1,3 (2H) -dione (hereinafter referred to as "Compound C”) was synthesized.
  • Compound C is a compound having the structure of the above formula (4), and in the formula (1), both R 1 and R 2 are hydroxy groups, and R 3 is a hydrogen atom.
  • Compound D is a compound in which R 1 and R 2 are benzyloxy groups (-OBn) and R 3 is a hydrogen atom in the formula (1).
  • R 1 and R 2 are benzyloxy groups (-OBn) and R 3 is a hydrogen atom in the formula (1).
  • R 1 and R 2 are benzyloxy groups (-OBn) and R 3 is a hydrogen atom in the formula (1).
  • THF tetrahydrofuran
  • the solid was filtered off using a filter paper, and the residue obtained by concentration was purified by silica gel column chromatography to obtain a pale red amorphous compound C (687 mg).
  • FIG. 1 1 H-NMR of compound A
  • FIG. 2 13 C-NMR of compound A
  • FIG. 3 1 H-NMR of compound B
  • FIG. 4 13 C-NMR of compound B
  • FIG. 5 of compound C. 1 1 H-NMR
  • FIG. 6 13 C-NMR of compound C
  • 7 1 1 H-NMR of compound D
  • FIG. 8 13 C-NMR of compound D.
  • fluorescent reagent As a fluorescent reagent, one of three types, aminophenylfluorescein (APF method), hydroxyphenylfluorescein (HPF method), 2', 7'-dichlorodihydrofluorescein (DCFH method), has a fluorescent reagent concentration of 2.5 ⁇ M. It was added so as to become. In the DCFH method, the antioxidant activity of clozapine was measured by changing the concentration of clozapine to 25 ⁇ M and 50 ⁇ M in addition to the concentration of 100 ⁇ M.
  • APF method aminophenylfluorescein
  • HPF method hydroxyphenylfluorescein
  • DCFH method 2', 7'-dichlorodihydrofluorescein
  • hydroxyl radicals as active oxygen species ( ⁇ OH) and hypochlorite ion (OCl -) can be measured scavenging activity
  • the HPF process scavenging activity of hydroxyl radicals as active oxygen species ( ⁇ OH)
  • the scavenging activity of hydrogen peroxide (H 2 O 2 ) as an active oxygen species can be measured.
  • the cells were further cultured for 15 minutes and then irradiated with X-rays (dose 10 Gy). Immediately after irradiation, the fluorescence intensity of each cell was measured by the flow cytometry method.
  • (result) 9 to 11 show the results of antioxidant activity measurement by the APF method, the HPF method, and the DCFH method, respectively.
  • the vertical axis represents the fluorescence intensity of each cell suspension when the fluorescence intensity when the control cell suspension is not irradiated with X-rays is 1, and "*" in the figure represents the fluorescence intensity of each cell suspension.
  • the t-test with the significance level set to 5% shows that there is a significant difference.
  • 9 and 10 are graphs of control, compounds I, A, B, C, clozapine, and olanzapine from the left. The left figure of FIG.
  • FIG. 11 is a graph of control, compounds I, A, B, C and clozapine from the left, and the right figure of FIG. 11 is a graph of control, 25 ⁇ M clozapine, 50 ⁇ M clozapine, 100 ⁇ M clozapine and 100 ⁇ M olanzapine from the left. Is.
  • Neonatal MK-801 Group MK-801 (Sigma-Aldrich, St. Louis, Missouri, USA) 0.2 mg / kg body weight, an N-methyl-D-aspartate glutamate receptor (NMDA receptor) antagonist It was subcutaneously administered once a day.
  • Neonatal saline group Saline 0.2 mg / kg body weight was subcutaneously administered once a day. Weaned on the 21st day after birth, and then bred every 4 to 6 animals. According to Reference 1 above, rats administered with MK-801 at an early age exhibit schizophrenia-like symptoms at an early stage of maturity.
  • methamphetamine-induced transfer momentum was measured as follows.
  • a transfer motion measuring device (AMB-2020, Ohara Medical Industry Co., Ltd., Tokyo, Japan) was used to measure the transfer momentum.
  • the measurement of the transfer momentum is described in 2. above.
  • Rats administered with Compounds A to C, clozapine or olanzapine were subjected to 57 days after birth (24 hours after the final administration of compounds A, B, C, clozapine or olanzapine). Each rat was weighed prior to the transfer momentum measurement.
  • methamphetamine 1.0 mg / kg (Dainippon Sumitomo Pharmaceutical Co., Ltd., Tokyo, Japan) was subcutaneously administered, and methamphetamine-induced transfer momentum was measured for 90 minutes.
  • the increase in methamphetamine-induced transfer momentum can be used as a model for positive symptoms of schizophrenia.
  • FIGS. 12 to 14 are graphs showing the results of methamphetamine-induced transfer momentum measurement for compound A, compound B, and clozapine, respectively.
  • the vertical axis indicates the amount of transfer momentum per 90 minutes, and in the figure, “*” indicates that there is a significant difference in the Bonferroni test with the significance level of 5%.
  • FIGS. 15-19 are graphs showing the results of glutathione concentration measurements in the medial prefrontal cortex for compounds A, B, C, clozapine, and olanzapine, respectively.
  • the vertical axis indicates the total glutathione concentration per tissue weight, and in the figure, “*” indicates that there is a significant difference in the Bonferroni test with the significance level of 5%.
  • FIGS. 20 and 21 are graphs showing the oxidized glutathione / reduced glutathione ratio in the medial prefrontal cortex for compounds A and C, respectively. From the left, the neonatal saline group to which physiological saline was administered 57 days after birth, the neonatal saline group to which the drug (compound A or C) was administered 57 days after birth, and neoplasia. The graph of the group to which the physiological saline was administered 57 days after birth in the childhood MK-801 group, and the group to which the drug (compound A or C) was administered 57 days after birth in the neonatal MK-801 group is shown.
  • Administration of olanzapine and clozapine did not show any significant changes.
  • FIGS. 22-26 are graphs showing the results of cell density of parvalbumin-positive GABA nerves in the medial prefrontal cortex for compounds A, B, C, clozapine, and olanzapine, respectively. Is. In each figure, the vertical axis indicates the cell density of parvalbumin-positive GABA nerve, and in the figure, “*” indicates that there is a significant difference in the Bonferroni test with the significance level of 5%.
  • compound A administration, compound B administration, and compound C administration all improved the parvalbumin-positive GABA nerve count decreased by neonatal MK-801 treatment.

Abstract

La présente invention concerne un composé répondant à la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci qui peut être utilisé en tant que principe actif d'un médicament pour des maladies du système nerveux central ou en tant que composé candidat pour un précurseur dudit principe actif. Dans la formule (1), R1, R2 et R3 représentent chacun indépendamment une substance choisie dans le groupe constitué par un atome d'hydrogène, un groupe hydroxy et un groupe alcoxy ayant de 1 à 6 atomes de carbone, et au moins l'un de R1, R2 et R3 représente un groupe hydroxy.
PCT/JP2020/019911 2019-05-21 2020-05-20 Dérivé de tandospirone WO2020235587A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2021520813A JPWO2020235587A1 (fr) 2019-05-21 2020-05-20

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2019095359 2019-05-21
JP2019-095359 2019-05-21

Publications (1)

Publication Number Publication Date
WO2020235587A1 true WO2020235587A1 (fr) 2020-11-26

Family

ID=73458313

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2020/019911 WO2020235587A1 (fr) 2019-05-21 2020-05-20 Dérivé de tandospirone

Country Status (2)

Country Link
JP (1) JPWO2020235587A1 (fr)
WO (1) WO2020235587A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63132887A (ja) * 1987-10-27 1988-06-04 Sumitomo Pharmaceut Co Ltd 新規なイミド誘導体
WO1998037893A1 (fr) * 1997-02-26 1998-09-03 Sumitomo Pharmaceuticals Co., Ltd. Antagoniste du recepteur dopaminergique d4

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63132887A (ja) * 1987-10-27 1988-06-04 Sumitomo Pharmaceut Co Ltd 新規なイミド誘導体
WO1998037893A1 (fr) * 1997-02-26 1998-09-03 Sumitomo Pharmaceuticals Co., Ltd. Antagoniste du recepteur dopaminergique d4

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PRABHASH NATH TRIPATHIA, PAVAN SRIVASTAVA, PIYOOSH SHARMA, MANISH KUMAR TRIPATHI, ANKIT SETH, AVANISH TRIPATHI, SACHCHIDA NAND RAI: "Biphenyl-3-oxo-1, 2, 4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory", BIOORGANIC CHEMISTRY, vol. 85, 15 December 2018 (2018-12-15), pages 82 - 96, XP055762811 *
UEHARA, TAKASHI ET AL.: "Development of original drug discovery technology, Tandospirone derivative with antioxidant function-Creation of new neuroprotective drugs", THE CHEMICAL INDUSTRY, vol. 71, 1 May 2020 (2020-05-01), pages 298 - 305 *

Also Published As

Publication number Publication date
JPWO2020235587A1 (fr) 2020-11-26

Similar Documents

Publication Publication Date Title
ES2920681T3 (es) Compuestos
JP6902025B2 (ja) 聴覚損失の予防および治療のための方法および組成物
CA3019012A1 (fr) Procedes d'utilisation de (2r, 6r)-hydroxynorketamine et de (2s,6s)-hydroxynorketamine dans le traitement de la depression, de l'anxiete, de l'anhedonie, de l'ideation suicidaire et de troubles de stress post-traumatiques
Chen et al. A potent multi-functional neuroprotective derivative of tetramethylpyrazine
US10946013B2 (en) Methods for treating central nervous system disorders using vdac inhibitors
JP2013506716A (ja) クロフェレマーなどのプロアントシアニジンオリゴマーを用いて疾患を治療する方法
JP7190612B2 (ja) 置換ピペリジン化合物及びその用途
JP2021507944A (ja) 運動ニューロン疾患を含む神経障害のための組成物および治療方法
US11311551B2 (en) Use of H3K9me3 modulation for enhancing cognitive function
CN106632181A (zh) 噢哢曼尼希碱类化合物、其制备方法和用途
CA3103958A1 (fr) Activateurs de la reponse a une proteine non depliee
EA005856B1 (ru) Тетрагидротиопиранфталазиноновые производные в качестве ингибиторов pde4
JP2022527401A (ja) 炎症性障害を治療するための化合物および方法
CN108553456A (zh) 苯甲酸及其衍生物的新用途
WO2020235587A1 (fr) Dérivé de tandospirone
WO2020143762A1 (fr) Pamoate de kétamine et son utilisation
EP3325478B1 (fr) Nouveau composé thérapeutique et utilisation en thérapie
CN104860847B (zh) 利凡斯的明和咖啡酸、阿魏酸的二聚体,其制备方法及其药物组合物
WO2020132378A2 (fr) Compositions et méthodes de traitement de troubles neurologiques comprenant la dépression
EP3165522B1 (fr) Composé de quinoléine cyclopropylique insaturée utilisé en tant qu'antagoniste du récepteur des leucotriènes et son utilisation therapeutique
WO2017124969A1 (fr) Dérivé cyclique de la dicaféoylspermidine et son utilisation
CN1114318A (zh) 新型嘌呤衍生物及其药学上允许的盐
CN113185447A (zh) 邻苯二甲酰半胱酰胺类化合物、其制备方法和用途
US9629866B2 (en) Use of cordycepin in manufacture of medicaments for anti-depression
JP7295145B2 (ja) 神経変性疾患を治療するための医薬及びその使用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20809062

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021520813

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20809062

Country of ref document: EP

Kind code of ref document: A1