WO2001055093A1 - Composes a base de n-arylhydrazide et leur utilisation en tant que medicaments - Google Patents

Composes a base de n-arylhydrazide et leur utilisation en tant que medicaments Download PDF

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Publication number
WO2001055093A1
WO2001055093A1 PCT/JP2001/000393 JP0100393W WO0155093A1 WO 2001055093 A1 WO2001055093 A1 WO 2001055093A1 JP 0100393 W JP0100393 W JP 0100393W WO 0155093 A1 WO0155093 A1 WO 0155093A1
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group
phenylamino
benzoic acid
hydrazide
phenyl
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PCT/JP2001/000393
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English (en)
Japanese (ja)
Inventor
Hisashi Shinkai
Hidekazu Ozeki
Yoshinori Kosugi
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Japan Tobacco Inc.
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Priority to AU2001227084A priority Critical patent/AU2001227084A1/en
Publication of WO2001055093A1 publication Critical patent/WO2001055093A1/fr

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    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to a novel N-arylhydrazide compound having an inhibitory effect on amyloid protein, and a pharmaceutical composition containing the N-arylhydrazide compound and useful as an anti-dementia drug.
  • dementia In old age, the brain degenerates and atrophies, leading to a decline in intellectual functions such as judgment, understanding, memory, and computation. This is what is commonly called dementia.
  • Cerebrovascular dementia occurs when cerebral arteriosclerosis or cerebral blood flow disorder prevents sufficient supply of nutrients and oxygen to the brain tissue, and may occur as a sequela of stroke. Many.
  • Alzheimer's type 1 dementia is caused by atrophy of nerve cells or loss of cell tissue in the cerebral cortex. Pathologically, the brain significantly atrophies, and at the end of the period, 900 In some cases, it is less than grams.
  • the therapeutic drugs for Alzheimer's dementia include tetrahydroaminoacridin hydrochloride (1,2,3,4-tetrahydro-9-acridinamine hydrochloride) and donezil hydrochloride (2-[(1-benzyl Drugs such as piperidine (41-yl) methyl] —5,6-dimethoxyindan-1-one hydrochloride) are known, but all have a primary effect on the activation of the acetylcholine nervous system. Therefore, in advanced diseases seen in Alzheimer's dementia, there is a long-awaited need for therapeutic agents that cause a mechanism different from existing anti-dementia agents, for example, therapeutic agents that suppress neuronal death.
  • Alzheimer's dementia shows characteristics such as loss of nerve cells, changes in neurofibrillary tangles, and senile plaques. This senile plaque is formed by the deposition of amyloid protein in the brain.
  • Amyloidosis is a process in which specific amyloid proteins are polymerized in the extracellular space as insoluble fibers and are deposited to cause structural and functional damage to organ tissues.
  • the main diseases caused by amyloid accumulation in the cerebral parenchyma and vascular wall are Alzheimer's disease. —Disease (AD), Down syndrome, dementia of sword fighters, cerebral amyloid vasculopathy and the like.
  • amyloidosis The types of amyloidosis are broadly classified into systemic amyloidosis and localized amyloidosis, and are also classified according to the amyloid that causes them. Currently, at least 15 different amyloid proteins have been reported, and it is thought that their onset mechanisms and biochemical roles are different.
  • amyloid /? Is an amyloid protein found in the brain of patients with Alzheimer's type 1 dementia, Down's syndrome, cerebrovascular amyloidosis, and hereditary amyloid cerebral hemorrhage (particularly Dutch type). It is thought to be one of the causes of the disease (Yamaguchiigaku, 44 (6), 319-327, 1995). In particular, deposition of amyloid 5 in the brain is the earliest pathological finding in the brain of Alzheimer's disease.
  • amyloid precursor protein whose production is increased or whose excretion / degradation is reduced is increased by processing or proteolysis. It is believed that amyloid then aggregates or polymerizes. This is thought to cause extracellular amyloid fibrils to damage neurons or cause deposition in the brain, resulting in cell dysfunction (Science, 250, 279, 1990). PMS, 88, 7247, 1991). It has also been suggested that amyloid may induce neuronal death (NeuroReport, 4, 523, 1993).
  • Diseases caused by excessive generation of such radicals or accumulation of lipid peroxide in the body include brain diseases (eg, cerebrovascular, hippocampus), cardiovascular diseases (eg, arteries), gastrointestinal diseases (eg, gastrointestinal tract, liver) , Kidney), respiratory diseases (eg, lungs, bronchi), urinary diseases (eg, kidneys), skin diseases, eye diseases, ear diseases, neurological diseases, etc., and are found in various parts of the body.
  • ischemic brain disease ischemic heart disease, ischemic liver disease, arteriosclerosis, hyperlipidemia, stroke, cerebral edema, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis Disease, seizures, central nervous injury after stroke, myocardial infarction, ventricular arrhythmia, rheumatoid arthritis, osteoarthritis, Behcet's syndrome, atopic dermatitis, burns, UV / radiation skin diseases, asthma, emphysema, Adult respiratory distress syndrome, inflammatory bowel disease, uveitis, autoimmune disease, infectious disease, retinopathy of prematurity, diabetic retinopathy, cataract, glaucoma, senile macular degeneration, cancer, peripheral neuronal degeneration, peripheral It shows symptoms such as circulatory disorders, Meniere's disease, pain, itching, hemolysis, and diseases caused by platelet aggregation.
  • a compound having an amyloid / agglutination inhibitory effect and also having an antioxidant effect can be greatly expected as an excellent therapeutic agent for Alzheimer's dementia or a therapeutic agent for various diseases caused by radicals. .
  • An object of the present invention is to provide a novel compound having an excellent amyloid / agglutination inhibitory action, a novel compound having an antioxidation action, or a novel compound having both of these actions.
  • An object of the present invention is to provide an anti-dementia drug and a remedy for amyloidosis having such an excellent action, particularly a remedy for Alzheimer's dementia.
  • hydrazide compounds there are several reports on the use of hydrazide compounds in medicine.
  • the following compound A known as indapamide
  • indapamide is already on the market as a diuretic antihypertensive.
  • Japanese Patent Application Laid-Open No. 7-118231 discloses a cytotoxic protective action of indapamide and a derivative thereof, and it has been shown that the compound protects against cytotoxicity caused by reactive oxygen species.
  • Compound indications include ischemic brain disease.
  • W09 1/01 979 Japanese Patent No. 253 1304, US Pat. No. 5,250,5278 shows an effect of enhancing cholinergic activity of the following compound B and the like, and amnesia and dementia are indicated as indications of the compound. Are listed.
  • W099 / 01421 shows kinase activity inhibitory effects of the following compounds C and D, and Alzheimer's disease is listed as an indication for these compounds.o
  • Japanese Patent Application Laid-Open No. 58-124765 discloses the following compound E and the like, and hypertension is mentioned as an indication of these compounds.
  • the publication does not disclose the compound of the present invention, and the hydrazide compound is Although there is a description that it can be used, there is no description about dementia or Alzheimer's disease.
  • US Pat. No. 2,808,416 discloses the following compound F and the like, and indicates that they are used as antioxidants for fats and oils.
  • the following compound J having a chemical structure partially similar to the compound of the present invention is known to have a strong antioxidant effect, and is a compound that has been tried to be applied to medicine. However, it cannot be administered to humans due to its teratogenicity.
  • the present inventors have found a novel compound having an amyloid-aggregation inhibitory action, particularly a novel compound having both an amyloid-aggregation inhibitory action and an antioxidant action, and completed the present invention.
  • the compound of the present invention is a novel compound having an excellent amyloid-aggregation inhibitory action, in particular, a novel compound having both an amyloid-agglutination inhibitory action and an antioxidant action, such as Alzheimer's disease, Down's syndrome, cerebrovascular amyloid. It can be used for the manufacture of a medicament useful for suppressing or stopping the progress of diseases caused by amyloid /? Protein such as cis, especially Alheimer-type dementia.
  • the compound of the present invention having an antioxidant effect is useful as an agent for treating and preventing diseases caused by radicals as described above, in addition to Alzheimer's disease type 1 dementia.
  • some of the compounds of the present invention can cross the blood-brain barrier and are therefore particularly useful for adaptation to central nervous system diseases.
  • the compound of the present invention having an antioxidant effect is used as a protective agent for stored substances such as blood and organs, as a cosmetic for treating and preventing acne and spots, and as an antioxidant for fats and oils contained in processed foods. You can also.
  • N-arylhydrazide compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof.
  • Means (8 5) the group consisting of Ariru group. )
  • R d 1 represents a hydrogen atom or a C- 6 alkyl group.
  • ( 25 ) a 5-membered or 1- to 3-hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with 1 to 3 substituents selected from the following group B or A 6-membered heteroaryl group, or
  • (2 ′ ′) means a group consisting of a C alkyl group which may be substituted with 1 to 3 substituents selected from the group A. ) ⁇
  • R 2 and R 3 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.
  • each symbol is as described in (1).
  • each symbol is as described in (1).
  • ⁇ And R. Is a meta-position or a para-position with respect to the substitution position of —NR 3 — on the benzene ring, the N-arylhydrazide compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (5). Acceptable salts thereof.
  • R al and R a2 are each the same or different and are a hydrogen atom, a C alkyl group which may be substituted with a halogen atom, a C i_ 6 alkoxy group, or a two-port group.
  • N-arylhydrazide compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7).
  • X is —NR dl —, and: R dl is a hydrogen atom, and ring A is further substituted with 1 to 3 substituents selected from group B of (1).
  • a pharmaceutical composition comprising the N-arylhydrazide compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (10), and a pharmaceutically acceptable carrier.
  • An amyloid /? Aggregation inhibitor comprising, as an active ingredient, the N-arylhydrazide compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (10).
  • a therapeutic agent for dementia and / or amnesia comprising the N-arylhydrazide compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient and / Or prophylactic agent.
  • a method for inhibiting amyloid /? Aggregation which comprises administering an effective amount of the N-arylhydrazide compound or the pharmaceutically acceptable salt thereof according to any of (1) to (10).
  • a method for treating or preventing dementia or amnesia comprising administering an effective amount of the N-arylhydrazide compound or the pharmaceutically acceptable salt thereof according to any of (1) to (10).
  • Halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a fluorine atom.
  • ( ⁇ _ 6 alkyl group) a linear or branched alkyl group having 1 to 6 carbon atoms, specifically a methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, Isopuchiru group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, hexyl group and the like.
  • alkyl group having 1 to 4 carbon atoms particularly preferably a methyl group or an ethyl group, and more preferably a methyl group.
  • the - 6 alkyl group may be substituted with 1 to 3 substituents selected from the following group A.
  • Group A means a halogen atom, a nitro group, an amino group, Shiano group, carboxyl group, C i-e alkoxy group, a guru Ichipu consisting C _ 6 alkoxycarbonyl group and Ariru group.
  • chloromethyl group Specifically, chloromethyl group, dichloromethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, trifluoromethyl group, nitromethyl group, aminomethyl group, cyanomethyl group, carboxymethyl group, methoxymethyl group And a methoxycarbonylmethyl group.
  • ( ⁇ -6 alkoxy group) refers to an alkyloxy group whose alkyl moiety is “( ⁇ alkyl group” as defined above. Specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropyl group Examples include a xy group, a butoxy group, an isobutyloxy group, a tert-butyloxy group, a pentyloxy group, a hexyloxy group, etc.
  • the alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms. It is an alkoxy group, particularly preferably a methoxy group or a small oxy group, and more preferably a methoxy group.
  • the alkoxy moiety is an alkoxycarbonyl group which is a linear or branched alkoxy group having 1 to 4 carbon atoms, particularly preferably a methoxycarbonyl group.
  • the “( ⁇ _ 4 alkylamino group” is a monoalkylamino group substituted with an alkyl group having 1 to 4 carbon atoms. Specifically, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a tert-butylamino group, etc. A methylamino group or an ethylamino group is preferred.
  • the “di (C i alkyl) amino group” is a di (alkyl) amino group which is disubstituted by an alkyl group having 1 to 4 carbon atoms. Specific examples include a dimethylamino group, a methylethylamino group, a getylamino group, a diisopropylamino group, and a di-tert-butylamino group. Preferably, it is a dimethylamino group or a getylamino group.
  • the “cyclic amino group” is a 5- or 6-membered cyclic group containing at least one nitrogen atom and substituting with the nitrogen atom. It is a saturated or unsaturated cyclic group which may further contain a hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom in addition to one nitrogen atom. Specific examples include a 1-pyrrolidinyl group, a 1-pyrrolinyl group, a 1-pyrrolyl group, a 1-imidazolidinyl group, a 1-imidazolyl group, a piperidino group, a 1-piperazinyl group, a morpholino group, and a thiomorpholino group.
  • the “cyclic amino group” in R a , als R a2 , R ”and R c2 is preferably a 1-pyrrolidinyl group, a piperidino group or a morpholino group.
  • Aryl group means a phenyl group or a naphthyl group, and is preferably a phenyl group.
  • the “aryl group” may be substituted with 1 to 3 and preferably 1 substituent selected from the following group B.
  • Group B a halogen atom, a nitro group, an amino group, Shiano group, carboxyl groups, C WINCH 6 alkoxy groups, C 6 alkoxycarbonyl group, 1 to 3 substituents selected from Ariru Moto ⁇ beauty the group A A group consisting of a C 6 alkyl group which may be substituted with a group.
  • Particularly preferred substituents are “C i -e alkyl group optionally substituted with 1 to 3 substituents selected from group A” or “r C i -e alkoxy group as defined
  • the “aryl group optionally substituted with 1 to 3 substituents selected from group B” is preferably a phenyl group, a 4-methylphenyl group or a 4-methoxyphenyl group, more preferably a 4-methylphenyl group. is there.
  • aryl alkyl group is an “alkyl group” substituted with an “aryl group”, wherein the “aryl group” has the same meaning as the above “aryl group”, and the “alkyl group” is ⁇ _ 6 alkyl group "as synonymous Specifically, benzyl group, Nafuchirume ethyl group, 2 -.. Fueniruechiru, 3-phenylpropyl group, 4-phenylbutyl group and the like preferably base Njiru group, 2 —Phenylethyl group or 3-phenylpropyl group, particularly preferably 3-phenylpropyl group.
  • the “aryl” in the “aryl alkyl group” may be substituted with one to three substituents selected from the above group B as in the case of the above “aryl group”.
  • 4-trifluoromethylbenzyl group, 2-trifluoromethylbenzyl group, 2- (4-trifluoromethylphenyl) ethyl group, 412 trobenzylyl group, 4-methoxy Examples include a benzyl group and a 4-tolylmethyl group.
  • arylamino group is an “amino group” substituted with an “aryl group”, wherein the “aryl group” has the same meaning as described above, and specific examples include a phenylamino group and a 2-naphthylamino group. . Preferably, it is a phenylamino group.
  • the “aryl group” is substituted with 1 to 3 substituents selected from the above group B. It may be. Specific examples include a 4-tolylamino group, a (4-trifluoromethylphenyl) amino group, and a (4-nitrophenyl) amino group.
  • arylalkylamino group is an “amino group” substituted with an “arylalkyl group”, wherein the “arylalkyl group” has the same meaning as described above. And a phenethylamino group. Preferably, it is a benzylamino group.
  • the “arylalkyl group” may be substituted with 1 to 3 substituents selected from the above group B, and specifically, (4-tolylmethyl) amino group, (4-trifluoromethylbenzyl) amino Group, a (412-benzyl) amino group and the like.
  • a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom refers to a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a virazinyl group, , 2,4 —triazinyl, 1,3,5 —triazinyl, piperyl, chenyl, furyl, pyrazolyl, imidazolyl, 1,2,4—triazolyl, 1,2,4 , 5-tetrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, etc., and preferably pyridyl group.
  • heteroaryl groups may be substituted with 1 to 3 substituents selected from the above group B, and specifically, 3-methyl-pyridine-2-yl group, 5-methyl-pyridine- 2-yl, 5-nitro-pyridine-12-yl, 6-methyl-1-pyridine-13-yl, 5-methyl-pyridine-13-yl and the like.
  • group a heteroaryl group which may be substituted with one to three substituents selected from B”, preferably a 5-methyl-pyridine-12-yl group or a 6-methyl-pyridine_3-y Group.
  • the - "C 3 7 cycloalkyl group” are cyclopropyl group, Shikuropuchiru group, consequent opening pentyl group, heptyl group a hexyl group or cycloalkyl cycloalkyl.
  • the "C 3 _ 7 consequent opening alkyl group", 1 to 3 may be substituted with a substituent, and specifically 4-methyl cyclohexyl group selected from the group B, 4 one triflumizole Ruo Russia methyl Shi And a chlorohexyl group and a 412 trocyclohexyl group.
  • - "cycloalkyl group may be substituted with 1 to 3 substituents selected from group B C 3 ' And preferably a cyclopentyl group or a cyclohexyl group.
  • R a preferably as R al and R a2, a hydrogen atom, may be substituted with a halogen atom "( ⁇ alkyl group” is a RCI-s alkoxy group "or a nitro group. Particularly preferably a methyl group as R al , An ethyl group or a trifluoromethyl group, more preferably a methyl group, and Ra 2 is particularly preferably a hydrogen atom.
  • the substitution position of R a1 is preferably an ortho position or a para position with respect to the hydrazine substitution position, and particularly preferably a para position.
  • R 1 is preferably a hydrogen atom or a methyl group, or is preferably taken together with R a to form — (CH 2 ) 2 — or —CH ⁇ ⁇ CH—, particularly preferably a hydrogen atom, Or, together with Ra , forms 1 (CH 2 ) 2 —, and more preferably, together with Ra , forms 1 (CH 2 ) 2 —.
  • R 2 and R 3 are preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.
  • R bl and R b2 are preferably a hydrogen atom or a phenylalkyl group such as a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, or a 4-phenylbutyl group, and particularly preferably a hydrogen atom or 3-phenyl.
  • R el and R e2 are preferably hydrogen atoms.
  • X is preferably one NR dl —, one NR dl C 0 — or one CONR dl —, particularly preferably one NR dl —, and R dl is preferably a hydrogen atom.
  • Ring A is preferably a phenyl group. Ring A may be substituted with a substituent selected from the group B, in this case, the preferred substituents are "(Bok 6 Al kill group” is a "( ⁇ _ 6 alkoxy group", particularly preferably It is a methyl group or a methoxy group, more preferably a methyl group, and the substituent position on the ring A is preferably a para position relative to 1X-.
  • the substituents are "(Bok 6 Al kill group” is a "( ⁇ _ 6 alkoxy group", particularly preferably It is a methyl group or a methoxy group, more preferably a methyl group, and the substituent position on the ring A is preferably a para position relative to 1X-.
  • the substitution position is preferably a meta position or a para position with respect to the hydrazide substitution position, and particularly preferably a para position.
  • R in the above substituents is preferably the amino or para position with respect to the —NR 3 — substitution position, and particularly preferably the para position.
  • Amyloid / Refers to the entire protein formed by processing or proteolysis from amyloid /? Precursor protein, and is mainly amyloid-4. And Amiguchi.
  • aggregation of amyloid refers to the formation of the above-described aggregate of only amyloid 5 and the formation of the aggregate of proteins mainly composed of amyloid.
  • the form of aggregation is not limited to the binding mode such as electrostatic interaction, ionic bond, covalent bond, and physical entanglement.
  • ementia and “amnesia”
  • the third edition of the American Manual of Diagnosis and Statistics by the American Psychiatric Association is now widely used as a general diagnostic standard for dementia.
  • a disease in which only memory impairment is observed is referred to as “amnesia”
  • a symptom in which some cognitive impairment is observed in addition to memory impairment is referred to as “dementia”.
  • the terms “dementia” and “amnesia” also follow this general definition.
  • the basic symptoms are memorization * memory impairment, disorientation about date and time, impairment in calculation, impairment in understanding, judgment,
  • Alzheimer's-type dementia Disability of daily life, disability of putting on and taking off clothes, disturbance of eating, disturbance of excretion (incontinence), disturbance of bathing, abnormal behavior 'wandering as a mental symptom', going out without permission, reversing day and night , Abuse, filthy acts (feeling stool), anorexia, hallucinations, excitement and delirium, depressive disabilities include dysarthria and gait disorders.
  • Alzheimer's-type dementia There are several definitions of “Alzheimer's dementia”, and the fourth edition of the diagnostic and statistical manual by the American Psychiatric Association is currently widely used as a diagnostic standard for Alzheimer's-type dementia.
  • the cognitive deficits cause significant impairment of social or occupational abilities and exhibit a marked decline from pre-illness functional levels
  • cognitive deficits are not due to any of the following, and are classified as other diseases.
  • systemic diseases known to cause dementia hyperthyroidism, bimin B12 or folate deficiency, nicotinic acid deficiency, hypercalcemia, neurosyphilis, HIV infection, etc.
  • Alzheimer's disease refers to a symptom in which no significant memory impairment is observed (eg, delusions, etc.). And senile plaques.
  • Alzheimer's disease refers to symptoms of the above-mentioned “dementia” in the Alzheimer's disease, including Alzheimer's type 1 dementia diagnosed by various criteria.
  • amyloid-aggregation inhibitor examples include the above-mentioned “dementia”, “amnesia”, “Alzheimer's disease”, and “Alzheimer-type dementia”. Diseases caused by amyloid?
  • amyloid / Specific diseases caused by amyloid /? include Alzheimer's dementia, Dunn's syndrome, cerebrovascular amyloidosis, and hereditary amyloid cerebral hemorrhage (particularly the Dutch type).
  • antioxidants include “dementia”, “amnesia”, “Alzheimer's disease” And “Alzheimer-type dementia", and further include the above-mentioned diseases caused by radicals.
  • diseases caused by radicals are ischemic brain disease, ischemic heart disease, ischemic liver disease, arteriosclerosis, hyperlipidemia, stroke, cerebral edema, Parkinson's disease, Huntington's disease, and amyotrophic side.
  • the indication of the compound of the present invention is preferably a symptom caused by amyloid / ?, specifically, dementia and Alzheimer's disease, particularly Alzheimer's type 1 dementia.
  • solvates, prodrugs and metabolites of each compound are also included.
  • a “prodrug” is a derivative of the compound of the present invention that has a group that can be chemically or metabolically degraded and that, after being administered to a living body, restores its original compound and exhibits its original drug effect, Conjugates and salts.
  • the compound of the present invention when used as a pharmaceutical preparation, it is usually known per se as a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring Agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and other additives, specifically water, vegetable oils, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactate Tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, etc.
  • a pharmaceutically acceptable carrier excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring Agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and other additives, specifically water, vegetable oils, alcohols such as ethanol or benzyl alcohol, poly
  • compositions such as starch, starch, etc., magnesium stearate, talc, lanolin, petrolatum, etc.
  • Formulation, aerosol, elixir, suspension, emulsion, syrup, etc. for systemic or topical It can be administered orally or parenterally.
  • the dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, etc., but in general, 0.1 to 1 mg to 1 g at a time, once to several times a day per adult .
  • the method for producing the compound of the present invention is not limited thereto.
  • the production may be carried out efficiently by introducing a protecting group into a functional group as necessary to perform deprotection in a subsequent step, or changing the order of each production method and step.
  • the post-reaction treatment may be performed by a usual method, and a commonly used method such as isolation and purification, crystallization, recrystallization, silica gel chromatography, and preparative HPLC is appropriately selected. , Or in combination.
  • This production method is a method for obtaining a carboxylic acid compound used in production method 3,
  • Hal is a halogen atom such as a bromine atom and a chlorine atom, and other symbols are as described above.
  • the compound [1] obtained by a conventional method or commercially available is converted into a solvent such as N, N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), toluene, etc. in potassium carbonate, triethylamine, potassium t- Salts such as butoxide
  • a solvent such as N, N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), toluene, etc.
  • potassium carbonate triethylamine, potassium t- Salts such as butoxide
  • the compound [3] can be obtained by reacting with a commercially available or commercially available amine compound [2] in the presence of the group at room temperature or under heating conditions.
  • Palladium catalysts such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, palladium acetate-triphenylphosphine, and nickel chloride, [1,3-bis (diphenylphosphine) chloride; ) Propane]
  • a catalyst such as a nickel catalyst such as nickel (II) may be used.
  • Compound [4] can be obtained by reducing the nitro group of compound [3] by a conventional method.
  • a hydrogenation catalyst such as palladium carbon, palladium hydroxide, palladium black, Raney nickel, platinum oxide, etc. What is necessary is just to reduce.
  • Compound [6] can be obtained by reacting compound [4] with a commercially available or commercially available nitrile compound [5] in the same manner as in the first step of production method 1.
  • the nitrile compound [7] obtained in the same manner as in the third step of the conventional method or the production method 1 may be used in a solvent such as ethylene glycol or glycerin, or a strong base such as potassium hydroxide or sodium hydroxide, or concentrated sulfuric acid or concentrated sulfuric acid.
  • a strong acid such as hydrochloric acid.
  • This production method is a method for obtaining an amine compound used in production method 3.
  • n 1 or 2
  • R P1 is an alkyl group such as a methyl group or an ethyl group
  • R P2 is an amine protecting group such as t-butoxycarbonyl, benzyloxycarbonyl, and other symbols. Is as described above.
  • the nitro compound obtained by a conventional method or commercially available [9] is added to a solvent such as DMF, acetonitrile, THF, and toluene in the presence of a base such as potassium carbonate, triethylamine, potassium t-butoxide, at room temperature or under cooling conditions.
  • a base such as potassium carbonate, triethylamine, potassium t-butoxide, at room temperature or under cooling conditions.
  • the compound [11] can be obtained by dropping the halogenated compound [10] little by little below.
  • the compound [12] can be obtained by reducing the carbonyl site of the compound [11] by a conventional method.
  • Compound [13] can be obtained by reducing the nitro group of compound [12] by a conventional method such as the second step of Production Method 1.
  • Compound [14] can be obtained by introducing a protecting group into the amino group of compound [13] by a conventional method.
  • the protecting group is a t-butoxycarbonyl group
  • a protecting group can be introduced.
  • Compound [15] can be obtained by treating compound [14] with an azodicarboxylic acid dialkyl rubonate such as getyl azodicarboxylate in a solvent such as DMF, acetonitrile, or THF in the presence of a phosphine such as triphenyl phosphine. it can.
  • Compound [16] can be obtained by removing the amine protecting group of compound [15] by a conventional method.
  • the protecting group when it is a t-butoxycarbonyl group, it can be deprotected by treating with 2N hydrochloric acid in THF or treating with trifluoroacetic acid in chloroform.
  • the compound [13] can also be obtained by cyclizing the compound [13] in the same manner as in the fifth step of Production Method 2.
  • Compound [18] is obtained by hydrogenating compound [17] in a conventional manner. Can be.
  • Step 6 or the compound obtained in the sixth step 5 of Preparation 2 [1 6] (a compound containing a [18].)
  • the compound [19] can be obtained by obtaining a more nitroso compound and then performing reduction by a conventional method.
  • the reduction method for example, treatment with a reducing agent such as lithium aluminum hydride or lithium borohydride in a solvent such as getyl ether, THF, 1,4-dioxane or the like, or under cooling, zinc powder and A method such as treatment with acetic acid may be used.
  • a reducing agent such as lithium aluminum hydride or lithium borohydride in a solvent such as getyl ether, THF, 1,4-dioxane or the like, or under cooling
  • a method such as treatment with acetic acid
  • an amide compound is obtained from an amine compound and a carboxylic acid compound, or a hydrazide compound is obtained from a hydrazine compound and a carboxylic acid compound.
  • Compound [20] which is commercially available or obtained by a conventional method or Production Method 2, was treated with dicyclohexylcarpoimide, 1-cyclohexane in a solvent such as DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, or toluene.
  • a solvent such as DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, or toluene.
  • Compound [I] can be obtained by condensation with acid compound [8].
  • the acid halide is obtained by reacting a carboxylic acid compound [8] with thionyl chloride, oxalyl chloride (oxalyl chloride), or the like, or is obtained by reacting with chloroethyl carbonate.
  • thionyl chloride oxalyl chloride (oxalyl chloride), or the like
  • chloroethyl carbonate for example, in the form of a mixed acid anhydride, and then in the presence of a base such as triethylamine, potassium carbonate, pyridine or the like, in a solvent such as chloroform, THF, DMF, or pyridine.
  • a base such as triethylamine, potassium carbonate, pyridine or the like
  • a solvent such as chloroform, THF, DMF, or pyridine.
  • Compound [I] can also be obtained by reacting in an amine solvent such as
  • an amide compound or hydrazide compound can also be obtained by introducing the amine protecting group, performing the condensation reaction, and then deprotecting. You.
  • Compound [21] can be obtained from compound [6,] in the same manner as in the fourth step of Production Method 2.
  • Compound [22] can be obtained from compound [21] in the same manner as in the fourth step of Production Method 1.
  • Compound [2] was prepared from compound [22] and compound [20] in the same manner as in Production method 3-1. 3] can be obtained.
  • Compound [ ⁇ ] can be obtained from compound [23] in the same manner as in Production Method 6, Step 6.
  • N- (4-Tolyl)-1,4-phenylenediamine (4.73g) in dimethylformamide (DMF, 100ml) solution of 4-bromobenzonitrile (4.84g), tetrakis (triphenylphosphine) palladium (1.38 g) and potassium carbonate (9.89 g) were added, and the mixture was stirred at 180 ° C for 2 hours. Then the mixture was cooled to room temperature and filtered. The filtrate was diluted with distilled water and extracted with ethyl acetate. Wash the extract with distilled water and saline and concentrate did. The residue was purified by chromatography to give the title compound (3.30 g).
  • Step (2) 4 — “[Penzyl [4- ⁇ benzyl (4-tolyl) amino ⁇ phenyl] amino ⁇ benzoic acid
  • Trifluoroacetic acid (20 ml) was added to (2.45 g) of chloroform (20 ml) at 0 ° C, and the mixture was heated to room temperature and stirred for 1 hour. The mixture was then quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with distilled water and brine, and concentrated. The residue was purified by chromatography to give the title compound (1.56 g).
  • Step (8) N- [2,3-dihydro-5- (trifluoromethyl) -1-H-indole-1-yl] -14- [benzyl (4- ⁇ benzyl (4-methylphenyl) amino ⁇ Phenyl) amino] Production of benzamide
  • Example 45 In the same manner as in Example 44, the compound of Example 45 was obtained. Table 12 shows the chemical structural formula and physical properties of this compound.
  • the following suspension was prepared as seed fibril, which is a seed for amyloid-aggregation.
  • Synthetic amyloid 5i— 4 A peptide (manufactured by American peptide company or a peptide laboratory, purity> 95%, hereinafter referred to as amyloid /?) was dissolved in hexafluoroisopropanol to obtain a 0.5 mg / mL amyloid solution. Then, the cells were completely dissolved by sonication (10 minutes) at room temperature, freeze-dried, and stored at a temperature of not more than 120 ° C to not more than 180 ° C. Deionized purified water was added to the lyophilized amyloid, and the whole was dissolved by sonication (5 minutes) at room temperature to obtain a 0.5 mg / mL amyloid solution.
  • the suspension was incubated at 37 ° C for 18 hours in a thermostatic shaking incubator to prepare a suspension of the target amyloid; quintuple fiber.
  • the Congo-Red binding concentration was measured by the Congo-Red method (Note 1).
  • Amyloid-fiber suspension (10 zL) was added to a phosphate buffer (90 L) containing 25 M Congo-Red, left at room temperature for 30 minutes, and the absorbance at 477 and 540 nm was measured.
  • the Congo-Red binding concentration was determined from the following formula.
  • a suspension (50 L / well) containing the 250 g / mL amyloid 5 solution prepared from the lyophilized amyloid and the 25 g / mL amyloid ⁇ seed fiber suspension, and the test compound (ImM ) Containing DMS0 solution (l ⁇ L / well) was dispensed into a 96-well plate. After the plate was covered, it was humidified and sealed in a plastic bag, and stirred (10 minutes) with a plate mixer to allow a natural agglutination reaction (37 ° C, 150 rpm, 18 hours) in a thermostatic shaking incubator.
  • Fluorescence intensity when amyloid? Aggregation inhibitory activity of the present compound (IC 5 0) is obtained by adding the fluorescence intensity cases plus test substance and 25 zg / mL amyloid /? Suspension (50 zL) Calculated from
  • the amount of lipid peroxide produced by incubating the above brain homogenate supernatant at 37 ° C for 0-120 minutes in a thermostatic incubator is used to detect N-methyl-2-phenylindole as a malondialdehyde-like substance. It was measured using a method kit (BI0XYTECH: LP0586TM).
  • test substance DMS0 solution 2 L
  • various concentrations of the test substance DMS0 solution (2 L) were added to the frozen brain homogenate supernatant (0.20 mL), and the mixture was incubated in a shaking incubator (37 ° C, 0 to 120 minutes).
  • An M Mix coloring solution (10.3 mM N-methyl-2-phenylindole / acetonitrile 25% methanol, 0.65 ml) and a 15.4 M methanesulfonic acid solution (0.15 mL) were added to the reaction solution, and the mixture was heated (45 ° C.). C, 40 minutes), and centrifuged (100 rpm, 15 minutes).
  • the resulting supernatant 0.8-0.3 mL was transferred to a microcut or 96-well plate, and the absorbance at 586 nm was measured.
  • the total amount of (a), (b) and (c) and 30 g of (d) are kneaded with water, dried in vacuo and granulated. This granulated powder is mixed with 14 (d) and lg (e) and made into tablets using a tableting machine to produce 1 000 tablets containing 1 Omg (a) per tablet. .
  • the compound of the present invention has an amyloid aggregation inhibiting effect and also has an antioxidant effect.
  • the compound of the present invention is useful as an amyloid /? Aggregation inhibitor or as an agent having both amyloid aggregation inhibitory activity and antioxidant activity, such as amnesia, dementia, Alheimer's disease, and especially Alheimer's disease Can be a therapeutic or prophylactic agent.
  • This application is based on patent application Nos. 2000-16157 and 2000-2264744 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

Cette invention, qui a trait à des composés à base de N-arylhydrazide correspondant à la formule générale (I), ou à leurs sels, acceptables du point de vue pharmaceutique, concerne également des médicaments les contenant et destinés à la prévention ainsi qu'au traitement de la démence. Dans cette formule, chaque symbole est tel que défini dans le descriptif. Ces composés et ces sels, qui font montre d'une action inhibitrice de l'agrégation de l'amyloïde-β, se révèlent des plus utiles comme agents prophylactiques et thérapeutiques de la démence, notamment de la démence du type maladie d'Alzheimer.
PCT/JP2001/000393 2000-01-25 2001-01-22 Composes a base de n-arylhydrazide et leur utilisation en tant que medicaments WO2001055093A1 (fr)

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JP2000016157 2000-01-25
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045923A1 (fr) * 2001-11-28 2003-06-05 Btg International Ltd. Agents preventifs ou remedes contre la maladie d'alzheimer ou inhibiteurs de la fibrose des proteines amyloides contenant des composes heteroaryle a teneur en azote
WO2008099210A2 (fr) 2007-02-12 2008-08-21 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
US8962677B2 (en) 2007-07-12 2015-02-24 Acumen Pharmaceuticals, Inc. Methods of restoring cognitive ability using non-peptidic compounds
US9006283B2 (en) 2007-07-12 2015-04-14 Acumen Pharmaceuticals, Inc. Methods of modifying amyloid β oligomers using non-peptidic compounds
US9150546B2 (en) 2009-02-13 2015-10-06 Shionogi & Co., Ltd. Triazine derivative and pharmaceutical composition comprising the same
US9212130B2 (en) 2010-08-10 2015-12-15 Shionogi & Co., Ltd. Heterocyclic derivative and pharmaceutical composition comprising the same
US9217024B2 (en) 2007-12-18 2015-12-22 Acumen Pharmaceuticals, Inc. ADDL receptor polypeptides, polynucleotides and host cells for recombinant production
AU2010307006B2 (en) * 2009-10-13 2016-08-11 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
US9550763B2 (en) 2012-02-09 2017-01-24 Shionogi & Co., Ltd. Heterocyclic ring and carbocyclic derivative
US9718790B2 (en) 2010-08-10 2017-08-01 Shionogi & Co., Ltd. Triazine derivative and pharmaceutical composition having an analgesic activity comprising the same
US9732060B2 (en) 2013-06-14 2017-08-15 Shionogi & Co., Ltd. Aminotriazine derivative and pharmaceutical composition comprising the same
EP3791870A1 (fr) * 2013-12-02 2021-03-17 The Trustees of Columbia University in the City of New York Modulation de la ferroptose et traitement des troubles excitotoxiques

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Publication number Priority date Publication date Assignee Title
JPS58124767A (ja) * 1982-01-21 1983-07-25 Mitsui Toatsu Chem Inc スルファモイル安息香酸誘導体
EP0753301A1 (fr) * 1993-06-07 1997-01-15 Takeda Chemical Industries, Ltd. Combinaison de benzimidazoles ayant une activité antagoniste de l'angiotensine-II avec des diurétiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58124767A (ja) * 1982-01-21 1983-07-25 Mitsui Toatsu Chem Inc スルファモイル安息香酸誘導体
EP0753301A1 (fr) * 1993-06-07 1997-01-15 Takeda Chemical Industries, Ltd. Combinaison de benzimidazoles ayant une activité antagoniste de l'angiotensine-II avec des diurétiques

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045923A1 (fr) * 2001-11-28 2003-06-05 Btg International Ltd. Agents preventifs ou remedes contre la maladie d'alzheimer ou inhibiteurs de la fibrose des proteines amyloides contenant des composes heteroaryle a teneur en azote
US7589105B2 (en) 2001-11-28 2009-09-15 Btg International Limited Preventives or remedies for alzheimer's disease, or amyloid protein fibril-formation inhibitors, which include a nitrogen-containing heteroaryl compound
KR101031720B1 (ko) * 2001-11-28 2011-04-29 비티지 인터내셔널 리미티드 질소함유 헤테로아릴 화합물을 함유하는 알츠하이머병의예방약 또는 치료약 또는 아밀로이드 단백질 섬유화억제제
US8003645B2 (en) 2001-11-28 2011-08-23 Btg International Ltd. Preventives or remedies for Alzheimer's disease, or amyloid protein fibril-formation inhibitors, which include a nitrogen-containing heteroaryl compound
WO2008099210A2 (fr) 2007-02-12 2008-08-21 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
US8962677B2 (en) 2007-07-12 2015-02-24 Acumen Pharmaceuticals, Inc. Methods of restoring cognitive ability using non-peptidic compounds
US9006283B2 (en) 2007-07-12 2015-04-14 Acumen Pharmaceuticals, Inc. Methods of modifying amyloid β oligomers using non-peptidic compounds
US9217024B2 (en) 2007-12-18 2015-12-22 Acumen Pharmaceuticals, Inc. ADDL receptor polypeptides, polynucleotides and host cells for recombinant production
US9150546B2 (en) 2009-02-13 2015-10-06 Shionogi & Co., Ltd. Triazine derivative and pharmaceutical composition comprising the same
US9688643B2 (en) 2009-02-13 2017-06-27 Shionogi & Co., Ltd. Triazine derivative and pharmaceutical composition comprising the same
US9622991B2 (en) 2009-10-13 2017-04-18 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
AU2010307006B2 (en) * 2009-10-13 2016-08-11 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
US9212130B2 (en) 2010-08-10 2015-12-15 Shionogi & Co., Ltd. Heterocyclic derivative and pharmaceutical composition comprising the same
US9718790B2 (en) 2010-08-10 2017-08-01 Shionogi & Co., Ltd. Triazine derivative and pharmaceutical composition having an analgesic activity comprising the same
US9550763B2 (en) 2012-02-09 2017-01-24 Shionogi & Co., Ltd. Heterocyclic ring and carbocyclic derivative
US9732060B2 (en) 2013-06-14 2017-08-15 Shionogi & Co., Ltd. Aminotriazine derivative and pharmaceutical composition comprising the same
US10065941B2 (en) 2013-06-14 2018-09-04 Shionogi & Co., Ltd. Aminotriazine derivative and pharmaceutical composition comprising the same
EP3791870A1 (fr) * 2013-12-02 2021-03-17 The Trustees of Columbia University in the City of New York Modulation de la ferroptose et traitement des troubles excitotoxiques
US11192849B2 (en) 2013-12-02 2021-12-07 The Trustees Of Columbia University In The City Of New York Compounds, compositions, and methods for modulating ferroptosis and treating excitotoxic disorders

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