WO2001013911A1 - Agents inhibiting hypertensive arteriolar disorder - Google Patents
Agents inhibiting hypertensive arteriolar disorder Download PDFInfo
- 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
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
- A61K31/185—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.
Abstract
Agents inhibiting diseases concerning hypertensive arteriolar disorder (cerebral stroke, vascular dementia, hypertensive eyeground, hypertensive retinopathy, etc.) containing as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by formula (I), which has effects of remarkably inhibiting arteriolar basement membrane thickening caused by hypertension etc., or pharmacologically acceptable salts thereof.
Description
明細書 高血圧' 14細動脈障害抑制剤 〔技術分野〕 Description Hypertension'14 Arteriolar Artery Disorder Inhibitor [Technical Field]
本発明は、 高血圧性細動脈障害抑制剤として有用な医薬品組成物に関するも のである。 The present invention relates to a pharmaceutical composition useful as an agent for suppressing hypertensive arteriole damage.
さらに詳しく述べれば本発明は、 式 More specifically, the present invention provides the following formula:
〔背景技術〕 (Background technology)
高血圧症が持続した場合、 全周性の基底膜肥厚化による狭細など細動脈にお いて血管障害が発生する。 この高血圧性細動脈障害が網膜において発現した場 合、 高血圧性眼底が認められ、 進行すると高血圧性網膜症に至る。 高血圧性網 膜症は悪化すると失明に進展することがあるため、 このような細動脈障害を早 期に抑制する必要がある。 If 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.
高血圧性細動脈障害が脳内で発現した場合、 脳卒中の代表的な病型である月 出血ゃラクナ梗塞が認められ、 高血圧症が脳卒中における最大のリスク因子で あると言われている。 また、 脳細動脈障害により大脳深部が血流量低下を来す と、 血管性痴呆の原因となる。 現在、 高血圧症において頻発するこれら脳血管
障害に対し降圧治療により抑制が図られているが、 依然改善が要請される重大 な問題である。 When hypertensive arteriolar dysfunction occurs in the brain, bleeding 月 lacunar infarction, a typical type of stroke, is observed, and hypertension is said to be the greatest risk factor for stroke. In addition, a decrease in blood flow in the deep cerebrum due to cerebral arteriole disorder causes vascular dementia. Currently, these cerebral blood vessels frequently occur in hypertension Although disorders are controlled by antihypertensive treatment, it is a serious problem that needs improvement.
前記式 （ I ) で表されるトラニラス トは、 気管支喘息、 アレルギー性鼻炎、 ァトピー性皮膚炎及びァレルギ一性結膜炎のァレルギ一性疾患、 ケロイド '肥 厚性瘢痕の皮膚疾患の治療剤として広く用いられている薬剤であり、 例えば、 ァレルギ一反応に起因するケミカルメディエーターの遊離を抑制する作用、 皮 膚組織における線維芽細胞のコラーゲン過剰合成を抑制する作用、 P T C A施 行後における冠動脈の血管平滑筋細胞の過剰増殖を抑制する作用等を有するこ とが知られている。 しかしながら、 トラニラストが高血圧性細動脈障害を抑制 することは何ら知られていない。 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. For example, 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. However, it is not known that tranilast suppresses hypertensive arteriole injury.
現在、 高血圧性細動脈障害に係わる疾患を予防治療する薬剤は知られておら ず、 高血圧性細動脈障害を抑制する薬剤の早期開発が待望されている。 At present, there is no known drug for preventing or treating diseases related to hypertensive arteriole disorders, and early development of drugs for suppressing hypertensive arteriole disorders is expected.
〔発明の開示〕 [Disclosure of the Invention]
本発明者らは、 高血圧性細動脈障害に対して抑制効果を示す化合物を見出す ベく鋭意研究した結果、 前記式 U ) で表されるトラニラストが、 高血圧に起 因する細動脈における基底膜肥厚を顕著に抑制する作用を有し、 また高血圧症 において頻発する脳卒中の発現を顕著に抑制する作用を有することを見出し、 高血圧性細動脈障害抑制剤として極めて有用であるという知見を得、 本発明を なすに至った。 The present inventors have found a compound exhibiting an inhibitory effect on hypertensive arteriole disorders. As a result of intensive studies, 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.
第一に、本発明者らは、脳卒中易発症高血圧自然発症ラット （S HR—s p ) を用いた i n v i v o試験において、 トラニラストが網膜の細動脈において 全周的に認められる基底膜肥厚を有意に抑制することを確認した。この事実は、 トラニラス トが高血圧症において発症する細動脈障害に対して優れた抑制効果 を有していることを示している。 First, the present inventors found that in an in vivo test using stroke-prone spontaneously hypertensive rats (S HR-sp), 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.
更に、 本発明者らは、 食塩摂取により脳卒中に至る脳卒中易発症高血圧自然 発症ラット （S H R— s p ) を用いた i n v i v o試験において、 トラニラ
ス卜が脳卒中による死亡率を有意に低下させることを確認した。 この事実は、 トラニラストが脳内の細動脈障害を抑制し、 脳卒中への進展を予防する効果を 有していることを示している。 Furthermore, the present inventors have found that 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.
このように、 トラニラストは高血圧性細動脈障害に対して優れた抑制効果を 有するものであり、 高血圧性細動脈障害抑制剤として有用な化合物である。 そ れ故、 高血圧性細動脈障害に起因する発症する疾患、 例えば、 脳卒中、 血管性 痴呆、 高血圧性眼底、 高血圧性網膜症等の抑制に有効である。 Thus, 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.
従って、 トラニラストまたはその薬理学的に許容される塩を有効成分として 用いることにより、 高血圧性細動脈障害抑制剤として有用な医薬品組成物を製 造することができる。 Therefore, by using tranilast or a pharmacologically acceptable salt thereof as an active ingredient, a pharmaceutical composition useful as an agent for suppressing hypertensive arteriole damage can be produced.
有効成分であるトラニラストおよびその塩の製法は種々知られており、 文献 記載の方法等により容易に製造することができる（特公昭 56— 40710号、 特公昭 57— 36905号、 特公昭 58— 17186号、 特公昭 58— 485 45号、 特公昭 58— 55138号、 特公昭 58— 55139号、 特公平 1― 28013号、 特公平 1一 50219号、 特公平 3-37539号他)。 Various methods for producing the active ingredient tranilast and its salts are known and can be easily produced by the methods described in the literature (Japanese Patent Publication No. 56-40710, Japanese Patent Publication No. 57-36905, Japanese Patent Publication No. 58-17186). No. 58-48545, No. 58-55138, No. 58-55139, No. 1-28013, No. 1-150219, No. 3-37539, etc.).
トラニラストの薬理学的に許容される塩としては、 例えば、 ナトリウム塩、 力リゥム塩等の無機塩基との塩、 モルホリン、 ピぺリジン、 ピロリジン等の有 機ァミン、 アミノ酸との塩を挙げることができる。 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.
本発明の医薬品組成物を実際の治療に用いる場合、 用法に応じ種々の剤型の ものが使用される。 このような剤型としては、例えば、 散剤、 顆粒剤、細粒剤、 ドライシロップ剤、 錠剤、 カプセル剤、 注射剤などを挙げることができる。 これらの医薬品組成物は、 その剤型に応じ調剤学上使用される手法により適 当な賦形剤、 崩壊剤、 結合剤、 滑沢剤、 希釈剤、 緩衝剤、 等張化剤、 防腐剤、 湿潤剤、 乳化剤、 分散剤、 安定化剤、 溶解補助剤などの医薬品添加物と適宜混 合または希釈 ·溶解し、常法に従い調剤することにより製造することができる。 例えば、 散剤は式 （I) で表されるトラニラストまたはその薬理学的に許容 される塩に必要に応じ、 適当な賦形剤、 滑沢剤等を加えよく混和して散剤とす
る。 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. For example, 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.
錠剤は、 トラニラストまたはその薬理学的に許容される塩に必要に応じ適当 な賦形剤、 崩壊剤、 結合剤、 滑沢剤等を加え常法に従い打錠して錠剤とする。 錠剤はまた必要に応じ、 コーティングを施し、 フィルムコート錠、 糖衣錠、 腸 溶性皮錠等にすることができる。 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.
カプセノレ剤は、 トラニラストまたはその薬理学的に許容される塩に必要に じ適当な賦形剤、 滑沢剤等を加えよく混和した後、 適当なカプセルに充填して カプセル剤とする。 さらに常法により顆粒あるいは細粒とした後充填してもよ レヽ。 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.
本発明の医薬品組成物を実際の治療に用いる場合、 その有効成分であるトラ 二ラストまたはその薬理学的に許容される塩の投与量は患者の体重、 年齢、 †¾ 別等により適宜決定されるが経口投与の場合成人 1日当たり概ね 1 0 0〜 1 0 0 O m gの範囲で投与することができ、 非経口投与の場合は、 成人 1日当たり 概ね 2 0 μ g〜 3 0 O m gの範囲で投与することができる。 本発明の内容を以下の実施例によりさらに詳細に説明する。 When the pharmaceutical composition of the present invention is used for actual treatment, 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. However, in the case of 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 μg 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.
実施例 1 Example 1
網膜の細動脈における基底膜肥厚抑制作用確認試験 Confirmation test of inhibitory effect on basement membrane thickening in retinal arterioles
雄性 1 0週齢脳卒中易発症高血圧自然発症ラット （S H R— s p， 1 2 0〜 2 3 0グラム， 清水実験材料株式会社製） 5 0匹を使用して 5群に分け、 1群 を治療前群とし、 両眼を摘出し、 4 %ダルタルアルデヒド Z P B S中で固定し て網膜基底膜面積測定のための組織切片を作製した。。残り 4群を対照群および トラニラスト群に分け、 更にそれぞれ 4週飼育群と 8週飼育群に分けた。対照 群には 4 %N a C 1を含む普通飼料 （C E— 2， 日本クレアネ: t ) を、 トラニ ラスト群には更に 1 %トラニラストを含む同 N a C 1含有普通飼料を与えて飼 育を開始した。 飼育開始 4週および 8週後に対照群およびトラニラスト群にお いても治療前群と同様にして眼球を摘出し、 固定した。 固定した眼球はパラフ
イン包埋後、 4マイクロメートルの連続薄切切片を 1眼あたり 15枚作製し、 PAS染色した。 各繊切片を CCDカメラにより撮影後、 光学顕微鏡下 （1 000倍） で観察し、 細動脈の横断面像が得られた血管について画像解析ソフ ト （N IH ima g e) を用いてその基底膜面積を測定し、 その平均値を算出 した。 群間の比較検定は t検定にて行った。 その結果は以下の表 1に示す通り であり、 トラニラストは細動脈の基底膜面積を有意に減少させた。 Male 10-week-old spontaneously stroke-prone spontaneously hypertensive rats (SHR-sp, 120-230 g, manufactured by Shimizu Experimental Materials Co., Ltd.) Using 50 rats, divided into 5 groups, 1 group before treatment As a group, both eyes were enucleated and fixed in 4% dataraldehyde ZPBS to prepare tissue sections for measurement of retinal basement membrane area. . The remaining four groups were divided into a control group and a tranilast group, and further divided into a 4-week rearing group and an 8-week rearing group, respectively. 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. Four and eight weeks after the start of breeding, 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 After in-embedding, 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.
[表 1] [table 1]
脳卒中の発症抑制作用確認試験 Confirmation of inhibitory effect of stroke onset
実施例 1において眼球摘出時における脳卒中易発症高血圧自然発症ラット (SHR- s p) の生存数を観察した。 群間の比較検定は f i s h e rの直接 確率計算法にて計算した確率値を基に行った。 その結果は以下の表 2に示す通 りであり、 トラニラストは有意に死亡率を改善し、 脳卒中の発症を抑制した。
[表 2 ] In Example 1, 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]
〔産業上の利用可能性〕 [Industrial applicability]
前記式（ I )で表されるトラニラストおよびその薬理学的に許容される塩は、 高血圧に起因する細動脈における基底膜肥厚に対して顕著な抑制効果を有して おり、 また高血圧症において頻発する脳卒中の発現に対して顕著な抑制効果を 有しており、 本発明により優れた高血圧性細動脈障害抑制剤を提供することが できる。
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.
Claims
:請求の範囲 式 : Claim expression
で表される N— ( 3， 4ージメ トキシシンナモイル） アントラニル酸またはそ の薬理学的に許容される塩を有効成分として含有することを特徴とする高血圧 性細動脈障害抑制剤。 An antihypertensive arteriole disorder inhibitor comprising as an active ingredient N- (3,4-dimethoxycinnamoyl) anthranilic acid or a pharmacologically acceptable salt thereof represented by the formula:
2 . 高血圧性細動脈障害に係わる疾患が高血圧性眼底又は高血圧性網膜症 であることを特徴とする請求項 1記載の高血圧性細動脈障害抑制剤。 2. The agent for suppressing hypertensive arteriole disorder according to claim 1, wherein the disease relating to hypertensive arteriole disorder is hypertensive fundus or hypertensive retinopathy.
3 . 高血圧性細動脈障害に係わる疾患が脳卒中であることを特徴とする請 求項 1記載の高血圧性細動脈障害抑制剤。 3. The hypertensive arteriole disorder inhibitor according to claim 1, wherein the disease associated with hypertensive arteriole disorder is stroke.
4 . 高血圧性細動脈障害に係わる疾患が血管性痴呆であることを特徴とす る請求項 1記載の高血圧性細動脈障害抑制剤。
4. The agent for suppressing hypertensive arteriole disorder according to claim 1, wherein the disease associated with hypertensive arteriole disorder is vascular dementia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001518049A JP4612981B2 (en) | 1999-08-19 | 2000-07-07 | Hypertensive arteriopathy inhibitor |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11/233008 | 1999-08-19 | ||
| JP23300899 | 1999-08-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001013911A1 true WO2001013911A1 (en) | 2001-03-01 |
Family
ID=16948379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2000/004528 WO2001013911A1 (en) | 1999-08-19 | 2000-07-07 | Agents inhibiting hypertensive arteriolar disorder |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP4612981B2 (en) |
| WO (1) | WO2001013911A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7534815B2 (en) * | 2001-06-05 | 2009-05-19 | Kao Corporation | Preventive or remedy for hypertension |
| WO2010147184A1 (en) | 2009-06-17 | 2010-12-23 | 国立大学法人熊本大学 | Prophylactic and/or therapeutic agent for dysmenorrhea |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997037650A1 (en) * | 1996-04-05 | 1997-10-16 | Santen Pharmaceutical Co., Ltd. | Remedies for retinal diseases |
-
2000
- 2000-07-07 JP JP2001518049A patent/JP4612981B2/en not_active Expired - Lifetime
- 2000-07-07 WO PCT/JP2000/004528 patent/WO2001013911A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997037650A1 (en) * | 1996-04-05 | 1997-10-16 | Santen Pharmaceutical Co., Ltd. | Remedies for retinal diseases |
Non-Patent Citations (2)
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7534815B2 (en) * | 2001-06-05 | 2009-05-19 | Kao Corporation | Preventive or remedy for hypertension |
| WO2010147184A1 (en) | 2009-06-17 | 2010-12-23 | 国立大学法人熊本大学 | Prophylactic and/or therapeutic agent for dysmenorrhea |
| 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 (en) | 2011-01-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2020045354A (en) | Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid | |
| WO2010113753A1 (en) | Prophylactic or therapeutic agent for retinal diseases and method for preventing or treating retinal diseases, each comprising jnk (c-jun n-terminal kinase)-inhibiting peptide, and use of the peptide | |
| JP2008308489A (en) | Prophylactic or therapeutic agent for posterior ocular disease comprising ropinirole or salt thereof as active ingredient | |
| JP2009137971A (en) | Medicine and medicinal kit | |
| JP2021503449A (en) | Compositions and Methods for the Treatment of Eye Disorders | |
| JP2011529958A (en) | Use of dronedarone to prepare drugs to prevent stroke or transient ischemic attack | |
| JPH05194209A (en) | Hemangioendothelial cell function improver | |
| WO2016171152A1 (en) | Therapeutic agent, improving agent, and preventative agent for corneal disorders | |
| JP2021500377A (en) | Delayed release deferiprone tablets and their usage | |
| JPWO2005079792A1 (en) | Preventive or therapeutic agent for severe diabetic retinopathy | |
| KR100471351B1 (en) | Preventives·remedies for complications of diabetes | |
| JP5566521B1 (en) | Bladder / urethral coordination disorder improving agent | |
| WO2001013911A1 (en) | Agents inhibiting hypertensive arteriolar disorder | |
| JP6328856B2 (en) | Depressant detrusor overactivity improving agent with reduced contractile force | |
| EP2968227B1 (en) | S-enantiomerically enriched compositions of beta blockers for treating amyotrophic lateral sclerosis | |
| JPH11269171A (en) | Therapeutic agent for fat metabolic disorder comprising 5-(1,2-dithiolan-3-yl-)valeric acid (alpha-lipoic acid) or its physiologically acceptable salt as active ingredient | |
| WO2023176720A1 (en) | Retinal vasodilator and pharmaceutical composition | |
| CN113975276B (en) | Application of cobicistinib in preparation of medicines for treating ischemia/reperfusion injury and cytoprotective medicines | |
| JP4843313B2 (en) | Pharmaceutical composition for prevention or treatment of diseases associated with esophageal movement disorders | |
| KR20090035448A (en) | Combination therapy for neuroprotection | |
| JP6850730B2 (en) | Glaucoma preventive treatment | |
| JPH09227371A (en) | Atherosclerosis inhibitor | |
| JP5978472B2 (en) | Drugs for the treatment of tinnitus patients | |
| CN114681470A (en) | Method of treating pain | |
| WO2011052628A1 (en) | Angiogenesis promoter |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): JP 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 |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 122 | Ep: pct application non-entry in european phase |