WO1999004786A1 - Nhibiteur et agent therapeutique contre le vieillissement cerebral - Google Patents

Nhibiteur et agent therapeutique contre le vieillissement cerebral Download PDF

Info

Publication number
WO1999004786A1
WO1999004786A1 PCT/JP1998/003287 JP9803287W WO9904786A1 WO 1999004786 A1 WO1999004786 A1 WO 1999004786A1 JP 9803287 W JP9803287 W JP 9803287W WO 9904786 A1 WO9904786 A1 WO 9904786A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
brain aging
therapeutic agent
active ingredient
disease
Prior art date
Application number
PCT/JP1998/003287
Other languages
English (en)
Japanese (ja)
Inventor
Kunie Nakamura
Norihiro Kakimoto
Mitsuo Akiba
Original Assignee
Biremo Science Co., Ltd.
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 Biremo Science Co., Ltd. filed Critical Biremo Science Co., Ltd.
Publication of WO1999004786A1 publication Critical patent/WO1999004786A1/fr

Links

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
    • A61K31/28—Compounds containing heavy metals
    • 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

Definitions

  • the present invention relates to an agent for inhibiting and treating brain aging, and more particularly, to an agent for inhibiting and treating brain aging, which comprises a specific organic germanium compound as an active ingredient and exhibits an excellent effect on brain aging such as Alzheimer's disease. It is about. Background art
  • the average life expectancy of the Japanese is over 75 years for both males and females, and as the population of the elderly increases, the number of elderly with dementia is also increasing rapidly. As of 1995, the number of elderly with dementia was about 12.6 It is estimated that the number will reach 156,000 in 2000 and 226,000 in 2010, and the diagnosis and treatment of senile dementia and the elderly with dementia The establishment of a nursing care and medical supply system is an important issue that must be addressed not only in the medical community but also in society.
  • Dementia is defined as an impairment of memory and intelligence that occurs in adults, the essence of which is impaired communication due to neuronal degeneration and death.
  • the cause of dementia is said to be 70, but cerebrovascular dementia and Alzheimer's disease are more common in the elderly, with both accounting for 80-90% of senile dementia.
  • the former is 55%
  • the latter is 22%
  • the former is 35% and the latter is 39% for women.
  • the above-mentioned cerebrovascular dementia is a condition caused by cerebral infarction occurring frequently in the elderly, that is, cerebrovascular dementia is considered to be secondary dementia which occurs through pathological aging of blood vessels. ing.
  • Alzheimer's disease is a degenerative disease associated with temporary aging of the brain.
  • Alzheimer's type dementia the type that develops early under 65 years Alzheimer's disease, a type that develops later in life, is called Alzheimer's disease, but since both have the same pathological characteristics, the name Alzheimer's disease is widely used. Used as a synonym for Ruthheimer-type dementia.
  • the pathological features of Alzheimer's disease are senile plaques and Alzheimer's neurofibrillary tangles (hereinafter referred to as neurofibrillary tangles).
  • the senile plaques are mainly due to extracellular deposition of / 3 amyloid protein.
  • the structure consists of the amyloid nucleus of 3) amyloid protein and the degenerating neurites surrounding it.
  • Vitek et al. (Proc. Natl. Acad. Sci. USA., 91: 4766, 1994) first suggested that the late stage product of the protein saccharification reaction (AGE) is involved in amyloid deposition in the brain. Since then, many researchers have reported that the immune response of antibodies to pentosidine, an AGE or a type of AGE whose structure has been elucidated, has been observed not only in amyloid deposition sites but also in senile plaques and neurofibrillary tangles Was done. These results point out that AGE may be involved not only in senile plaques but also in the formation of neurofibrillary tangles, indicating that AGE is involved in the pathogenesis of Alzheimer's disease.
  • AGE protein saccharification reaction
  • An object of the present invention is to solve the above-mentioned disadvantages of the prior art, and to provide an agent capable of suppressing aging of the brain such as Alzheimer's disease and treating it. Disclosure of the invention
  • composition of the brain aging inhibitory and therapeutic agent employed by the present invention is represented by the following formula (1) (Ge-C-CH-COX) 2 0 3 (1) R 2
  • R 1 to R 3 are a hydrogen atom, a lower alkyl group such as the same or different methyl group or ethyl group, or a substituted or unsubstituted phenyl group, and X is a hydroxyl group, an O-lower alkyl group, an amino group or OY.
  • Y represents a compound having a metal such as sodium or potassium, or a compound having a basic group such as lysozyme or basic amino acid), respectively.
  • the structures that characterize Alzheimer's disease are senile plaques and neurofibrillary tangles, and especially senile plaques are deposits of amyloid) 3 protein, which are thought to indicate essential abnormalities of Alzheimer's disease.
  • AGEs in the deposited amyloid was immunohistologically proved, and as a mechanism of the involvement of AGEs in the pathogenesis of Alzheimer's disease, neuronal damage due to active oxygen generated by AGEs, Two types of cytotoxicity due to various activated cytokines generated by AGE have been proposed.
  • the inventors of the present invention have been studying the bioactive effects of organic germanium compounds for many years, and as a result, organic germanium compounds can effectively suppress or improve protein saccharification reactions, and The drug was found to be highly safe during administration, and a patent application has already been filed (Japanese Patent Application No. 4-191685), but the inventors of the present invention have further investigated the use of organogermanium compounds. Further research focused on the inhibitory effect on protein saccharification reactions, and found that administration of a specific organic germanium significantly suppressed the development of senile plaques in the brain, and completed the present invention. That is what led to it. BEST MODE FOR CARRYING OUT THE INVENTION
  • the agent for inhibiting and treating aging of the brain of the present invention contains a specific organic germanium compound represented by the above formula (1) as an active ingredient.
  • R 3 may be the same or different and each represents a hydrogen atom, a so-called lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, or a substituted or unsubstituted phenyl group.
  • the group X represents a hydroxyl group, a 0-lower alkyl group, an amino group or a salt of a carboxylic acid represented by 0Y.
  • Y represents a metal such as sodium or potassium (however, it is not limited to monovalent ones, or a compound having basicity represented by a basic amino acid such as lysozyme or lysine).
  • the organogermanium compound having the above structure is a known compound and can be produced by various methods.
  • the substituents R i to R 3 are a hydrogen atom
  • the substituent X is a hydroxyl group.
  • trihalogermylpropionic acid such as trichlorogermylpropionic acid may be hydrolyzed as shown in the following reaction formula.
  • the organic germanium compound can also be represented by the formula below.
  • the agent for suppressing and treating aging of the brain of the present invention contains the above-mentioned organic germanium compound as an active ingredient, but the administration method is not particularly limited, and is orally, parenterally or It can be administered locally.
  • the dosage form is also not particularly limited, and may be used in combination with a known carrier, if necessary, for oral administration such as tablets, powders or capsules, or non-oral preparations such as injections, lotions, or the like. It is formulated into a topical application such as ointment.
  • the content of the organogermanium compound in the agent for suppressing and treating aging of the brain of the present invention may be, for example, about 5 to 50 mg / dosage unit as needed.
  • the concentration may be about 1 to 10 O mg / K g / day.
  • the agent for suppressing and treating brain aging of the present invention significantly suppresses the development of senile plaques, which are highly correlated with the degree of dementia in brain aging such as Alzheimer's disease. It has become.
  • the agent for suppressing and treating brain aging of the present invention significantly suppressed the production of fluorescent substances produced by the reaction between serum albumin and glucose.
  • the brain aging inhibitory and therapeutic agent of the present invention is dissolved in a reaction solution obtained by adding 250 mM glucose to 25 mg / m1 human serum albumin so that the concentration of the organic germanium compound as an active ingredient becomes 5 OmM. After culturing for 6 weeks at 37 ° C, the browning (two wavelengths: 415 nm Z 610 nm) was measured with a micro-mouthed plate reader and compared with the absorbance. The results are shown in Table 2.
  • a reaction solution of 25 mg / m1 human serum albumin or pepsin serum albumin and 25 OmM glucose was added to the brain aging inhibitor and therapeutic agent of the present invention, and the concentration of an organic germanium compound as an active ingredient was 5 OmM.
  • the cells were dissolved at 37 ° C. for 6 weeks.
  • the culture was hydrolyzed with 6 N hydrochloric acid, and the resulting pentosidine was measured by high performance liquid chromatography (excitation wavelength 335 nm, emission wavelength 385 ⁇ m). Table 3 shows the results.
  • OLET-F rats and LETO rats were bred up to 72 weeks of age, and lOOmgZkg (body weight) was administered from 25 weeks to 72 weeks of age of the brain aging inhibitory and therapeutic agent of the present invention.
  • a longitudinal section of the sacrificed rat brain was stained with a congolet, observed with a polarizing microscope, and evaluated for the range of senile plaques on a scale of 1, 1, 10, 10, +, + + + +
  • the expression frequency was represented by the number of expressed animals and the number of animals (%). The results are shown in Table 4. Table 4
  • the brain aging inhibitory and therapeutic agent of the present invention containing the organogermanium compound represented by the formula (1) as an active ingredient has a high correlation with the degree of dementia in brain aging such as Alzheimer's disease. It can significantly suppress the development of senile plaques that have been confirmed to have sex.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Médicament pouvant résoudre les problèmes existants et inhiber ou soigner le vieillissement cérébral lié à la maladie d'Alzheimer ou à une autre pathologie similaire. Ce médicament est caractérisé par le fait qu'il contient comme principe actif un composé à base de germanium organique, représenté par la formule générale (1), dans laquelle R1 à R3 représentent un atome d'hydrogène ou bien, étant identiques ou différents, représentent un groupe alkyle inférieur tel qu'un groupe méthyle ou éthyle, ou un groupe phényle substitué on non substitué; X représente un groupe hydroxyle, un groupe alkyle O-inférieur, un groupe amino ou un sel représenté par OY, où Y représente un métal tel que le sodium ou le potassium, ou bien un composé renfermant un groupe basique, tel qu'un lysozyme ou un acide aminé basique.
PCT/JP1998/003287 1997-07-25 1998-07-23 Nhibiteur et agent therapeutique contre le vieillissement cerebral WO1999004786A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9215618A JPH1143432A (ja) 1997-07-25 1997-07-25 脳の老化抑制及び治療剤
JP9/215618 1997-07-25

Publications (1)

Publication Number Publication Date
WO1999004786A1 true WO1999004786A1 (fr) 1999-02-04

Family

ID=16675396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003287 WO1999004786A1 (fr) 1997-07-25 1998-07-23 Nhibiteur et agent therapeutique contre le vieillissement cerebral

Country Status (2)

Country Link
JP (1) JPH1143432A (fr)
WO (1) WO1999004786A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2036552B1 (fr) 2006-07-05 2018-08-08 Kao Corporation Inhibiteur de la sénescence
JP7430867B2 (ja) * 2019-07-11 2024-02-14 学校法人近畿大学 有機ゲルマニウム化合物を有効成分として含むチオール基含有化合物の捕捉剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352815A (en) * 1992-03-16 1994-10-04 Asai Germanium Research Institute Co., Ltd. Agent for suppression and interception of mailard reaction
WO1995028151A1 (fr) * 1994-04-13 1995-10-26 Quadrant Holdings Cambridge Limited Utilisation d'inhibiteurs de la reaction de maillard dans le traitement des maladies amyloides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352815A (en) * 1992-03-16 1994-10-04 Asai Germanium Research Institute Co., Ltd. Agent for suppression and interception of mailard reaction
WO1995028151A1 (fr) * 1994-04-13 1995-10-26 Quadrant Holdings Cambridge Limited Utilisation d'inhibiteurs de la reaction de maillard dans le traitement des maladies amyloides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARRINGTON C. R., ET AL.: "INHIBITORS OF THE MAILLARD REACTION. POTENTIAL IN THE TREATMENT OF ALZHEIMER'S DISEASE.", CNS DRUGS, ADIS INTERNATIONAL, AUCKLAND, NZ, vol. 06., no. 03., 1 January 1996 (1996-01-01), AUCKLAND, NZ, pages 167 - 177., XP002912935, ISSN: 1172-7047 *

Also Published As

Publication number Publication date
JPH1143432A (ja) 1999-02-16

Similar Documents

Publication Publication Date Title
EP3407877B1 (fr) Inhibiteurs nlrp3 pour le traitement des pathologies cutanées inflammatoires
US20200062712A1 (en) Aldehyde trapping compounds and uses thereof
JP2854631B2 (ja) 糖尿病合併症および老化によって引き起こされる疾患の予防・治療剤
JP2021181471A (ja) ピペリジニルインドール誘導体の新規な使用
EP0474874B1 (fr) Compositions d'inhibiteur de la reaction de Maillard
US9150489B2 (en) 1-(2-fluorobiphenyl-4-yl)-alkyl carboxylic acid derivatives for the therapy of transthyretin amyloidosis
JP2018534343A (ja) ミトコンドリアの活性酸素種（ｒｏｓ）産生に関連する疾患の治療のための化合物
JP2003511369A (ja) 老化関連及び糖尿病性血管合併症の管理のためのピリジニウム誘導体、それらの製造方法並びにそれらの治療的使用
KR100609381B1 (ko) 인지 장애 치료방법
WO1999004786A1 (fr) Nhibiteur et agent therapeutique contre le vieillissement cerebral
JP2003511370A (ja) 糖尿病及び老化に関連する血管合併症の治療のための化合物
EP1623981A1 (fr) Agent anti-leishmania
EP2412705B1 (fr) Nouvel agent thérapeutique pour le déficit cognitif
JP4471141B2 (ja) 老化関連及び糖尿病脈管合併症の管理のための新規化合物、その製造方法及び治療的使用
HU199290B (en) Process for production of medical compositions against hyperurichemie containing derivatives of oxoquinasoline
JP4490536B2 (ja) 脳血管障害に基づく疾患の予防又は治療薬
JP7327788B2 (ja) 糖化産物生成抑制剤及び医薬組成物
CN111303161B (zh) 嘧啶并氮杂环类化合物及其用途
KR100851678B1 (ko) Ｐｐａｒ-감마 수용체의 활성화에 반응하는 질병의 치료에유용한 조성물
JP2008156313A (ja) アミロイド疾患の治療およびモニタリングのための薬剤
EP0308349B1 (fr) Nouveau derivé de choline, son procédé de préparation et nouveaux médicaments le contenant
TW202116297A (zh) 組合療法之方法、組成物與套組
Berni Imbimbo et al.
JPH05310565A (ja) 蛋白質の高度グリコシル化抑制組成物及び抑制方法
JP2023514236A (ja) ピラジン化合物およびその調製方法と使用

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase