WO2001013911A1 - Agents inhibiteurs des troubles d'hypertension arterielle - Google Patents

Agents inhibiteurs des troubles d'hypertension arterielle Download PDF

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Publication number
WO2001013911A1
WO2001013911A1 PCT/JP2000/004528 JP0004528W WO0113911A1 WO 2001013911 A1 WO2001013911 A1 WO 2001013911A1 JP 0004528 W JP0004528 W JP 0004528W WO 0113911 A1 WO0113911 A1 WO 0113911A1
Authority
WO
WIPO (PCT)
Prior art keywords
hypertensive
disorder
arteriole
arteriolar
tranilast
Prior art date
Application number
PCT/JP2000/004528
Other languages
English (en)
Japanese (ja)
Inventor
Yoichi Iwaki
Hiroshi Kusama
Atsutoshi Tsuji
Original Assignee
Kissei Pharmaceutical 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 Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to JP2001518049A priority Critical patent/JP4612981B2/ja
Publication of WO2001013911A1 publication Critical patent/WO2001013911A1/fr

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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
    • A61K31/185—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical composition useful as an agent for suppressing hypertensive arteriole damage.
  • a hypertensive arteriole comprising as an active ingredient N- (3,4-dimethoxycinnamoyl) antraninoleic acid (generic name: tranilast) or a pharmacologically acceptable salt thereof represented by the formula: It relates to a disorder inhibitor.
  • hypertension persists, vascular disorders occur in arterioles such as narrow arteries due to thickening of the peripheral basement membrane. If this hypertensive arteriole disorder develops in the retina, hypertensive fundus is observed, and progressing to hypertensive retinopathy. Since hypertensive retinopathy can progress to blindness if it worsens, it is necessary to control such arteriole disorders early.
  • hypertensive arteriolar dysfunction occurs in the brain, bleeding ⁇ lacunar infarction, a typical type of stroke, is observed, and hypertension is said to be the greatest risk factor for stroke.
  • a decrease in blood flow in the deep cerebrum due to cerebral arteriole disorder causes vascular dementia.
  • these cerebral blood vessels frequently occur in hypertension
  • disorders are controlled by antihypertensive treatment, it is a serious problem that needs improvement.
  • Tranilast represented by the above formula (I) is widely used as a therapeutic agent for bronchial asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis allergic diseases, and keloid 's hypertrophic scar skin diseases.
  • the action of suppressing the release of chemical mediators caused by the allergic reaction the action of suppressing the excessive synthesis of fibroblasts in skin tissue, the vascular smooth muscle of the coronary artery after PTCA administration It is known to have an action of suppressing the excessive proliferation of cells and the like.
  • tranilast suppresses hypertensive arteriole injury.
  • the present inventors have found a compound exhibiting an inhibitory effect on hypertensive arteriole disorders.
  • tranilast represented by the above formula U has been found to increase basement membrane thickening in arterioles caused by hypertension.
  • Of the present invention have been found to have an effect of remarkably suppressing the onset of cerebral apoplexy, and also have an effect of remarkably suppressing the occurrence of cerebral apoplexy in hypertension. Has been reached.
  • tranilast significantly suppressed the basal lamina hypertrophy, which is observed in the retinal arterioles. Make sure you do. This fact indicates that tranilast has an excellent inhibitory effect on arteriolar disorders that occur in hypertension.
  • tranila in an in vivo test using spontaneously stroke-prone spontaneously hypertensive rats (SHR-sp), It was confirmed that storage significantly reduced mortality from stroke. This fact indicates that tranilast has the effect of suppressing arteriolar dysfunction in the brain and preventing progression to stroke.
  • SHR-sp spontaneously stroke-prone spontaneously hypertensive rats
  • tranilast has an excellent inhibitory effect on hypertensive arteriole disorders and is a useful compound as an agent for suppressing hypertensive arteriole disorders. Therefore, it is effective in suppressing diseases caused by hypertensive arteriole disorders, such as stroke, vascular dementia, hypertensive fundus, and hypertensive retinopathy.
  • a pharmaceutical composition useful as an agent for suppressing hypertensive arteriole damage can be produced.
  • Examples of pharmacologically acceptable salts of tranilast include salts with inorganic bases such as sodium salt and potassium salt, and salts with organic amines such as morpholine, piperidine and pyrrolidine, and amino acids. it can.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, and the like. These pharmaceutical compositions can be used in the form of excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, etc., depending on the formulation used in the formulation. It can be produced by appropriately mixing, diluting and dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • the powder may be prepared by adding a suitable excipient, lubricant and the like to the tranilast represented by the formula (I) or a pharmacologically acceptable salt thereof, if necessary, to obtain a powder. You.
  • Tablets are prepared by adding appropriate excipients, disintegrants, binders, lubricants and the like, if necessary, to tranilast or a pharmacologically acceptable salt thereof, and compressing the tablets according to a conventional method.
  • the tablets can be coated, if necessary, to give film-coated tablets, sugar-coated tablets, enteric coated tablets and the like.
  • the capsenole preparation is prepared by adding appropriate excipients and lubricants to tranilast or a pharmacologically acceptable salt thereof as needed, and then mixing the resulting mixture into a suitable capsule to prepare a capsule. Further, after filling into granules or fine granules by a conventional method, it may be filled.
  • the dosage of the active ingredient tranilast or a pharmacologically acceptable salt thereof is appropriately determined according to the patient's body weight, age, and specific conditions.
  • oral administration it can be administered in the range of approximately 100 to 100 mg / day for adults, and in the case of parenteral administration, the range of approximately 20 ⁇ g to 30 O mg / day for adults Can be administered.
  • the contents of the present invention will be described in more detail with reference to the following examples.
  • the control group was fed a normal diet containing 4% NaC1 (CE-2, Kleane Japan: t), and the tranilast group was fed an additional diet containing the same NaC1 containing 1% tranilast. Started.
  • the eyes were excised and fixed in the control group and the tranilast group in the same manner as in the pre-treatment group.
  • the fixed eyeball is paraffin
  • 15 serial 4-micrometer sections were prepared per eye and stained with PAS. Each slice was photographed with a CCD camera and observed under a light microscope ( ⁇ 1,000). The area was measured and the average was calculated.
  • the comparison test between groups was performed by the t test. The results are shown in Table 1 below. Tranilast significantly reduced the basement membrane area of arterioles.
  • Example 2 the number of surviving spontaneously hypertensive rats (SHR-sp) at the time of enucleation was observed.
  • the comparison test between groups was performed based on the probability values calculated by Fisher's direct probability calculation method. The results are shown in Table 2 below. Tranilast significantly improved mortality and suppressed the onset of stroke. [Table 2]
  • Tranilast represented by the formula (I) and a pharmacologically acceptable salt thereof have a remarkable inhibitory effect on basement membrane thickening in arterioles due to hypertension, and frequently occur in hypertension.
  • the present invention has a remarkable inhibitory effect on the onset of cerebral apoplexy, and the present invention can provide an excellent agent for suppressing hypertensive arteriole damage.

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

Abstract

Ces agents inhibiteurs des troubles d'hypertension artérielle (apoplexie, démence vasculaire, hypertension du fond de l'oeil, rétinopathie hypertensive, etc.) contiennent comme ingrédient actif de l'acide anthranilique N-(3,4-diméthoxycinnamoyl), représenté par la formule suivante (I), ou ses sels acceptables du point de vue pharmaceutique. Cet ingrédient a pour effet d'inhiber de manière significative l'épaississement des membranes basales artérielles dû à l'hypertension, etc.
PCT/JP2000/004528 1999-08-19 2000-07-07 Agents inhibiteurs des troubles d'hypertension arterielle WO2001013911A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2001518049A JP4612981B2 (ja) 1999-08-19 2000-07-07 高血圧性細動脈障害抑制剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP23300899 1999-08-19
JP11/233008 1999-08-19

Publications (1)

Publication Number Publication Date
WO2001013911A1 true WO2001013911A1 (fr) 2001-03-01

Family

ID=16948379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/004528 WO2001013911A1 (fr) 1999-08-19 2000-07-07 Agents inhibiteurs des troubles d'hypertension arterielle

Country Status (2)

Country Link
JP (1) JP4612981B2 (fr)
WO (1) WO2001013911A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534815B2 (en) * 2001-06-05 2009-05-19 Kao Corporation Preventive or remedy for hypertension
WO2010147184A1 (fr) 2009-06-17 2010-12-23 国立大学法人熊本大学 Agent prophylactique et/ou thérapeutique pour dysménorrhée

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037650A1 (fr) * 1996-04-05 1997-10-16 Santen Pharmaceutical Co., Ltd. Medicaments contre les maladies retiniennes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037650A1 (fr) * 1996-04-05 1997-10-16 Santen Pharmaceutical Co., Ltd. Medicaments contre les maladies retiniennes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] AMERICAN CHEMICAL SOCIETY (ACS), COLUMBUS, OH, USA.; accession no. STN Database accession no. 131:295291 *
HONDA Y ET AL.: "Effect of tranilast on the retinal vessels in the hypertensive rat", ATARASHII GANKA, vol. 16, no. 9, September 1999 (1999-09-01), pages 1291 - 1294, XP002932535 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534815B2 (en) * 2001-06-05 2009-05-19 Kao Corporation Preventive or remedy for hypertension
WO2010147184A1 (fr) 2009-06-17 2010-12-23 国立大学法人熊本大学 Agent prophylactique et/ou thérapeutique pour dysménorrhée
US9592213B2 (en) 2009-06-17 2017-03-14 National University Corporation Kumamoto University Prophylactic and/or therapeutic agent for dysmenorrhea

Also Published As

Publication number Publication date
JP4612981B2 (ja) 2011-01-12

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