JP2000169388A - Vascularization inhibitor - Google Patents
Vascularization inhibitorInfo
- Publication number
- JP2000169388A JP2000169388A JP11272457A JP27245799A JP2000169388A JP 2000169388 A JP2000169388 A JP 2000169388A JP 11272457 A JP11272457 A JP 11272457A JP 27245799 A JP27245799 A JP 27245799A JP 2000169388 A JP2000169388 A JP 2000169388A
- Authority
- JP
- Japan
- Prior art keywords
- group
- active ingredient
- vascularization
- angiogenesis
- inhibitor
- Prior art date
- Legal status (The legal status 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 status listed.)
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Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、システイン誘導体
を有効成分とする血管新生阻害剤に関するものであっ
て、特に網膜疾患等の眼疾患の治療に有用な薬物を提供
するものである。TECHNICAL FIELD [0001] The present invention relates to an angiogenesis inhibitor containing a cysteine derivative as an active ingredient, and more particularly to a drug useful for treating eye diseases such as retinal diseases.
【0002】[0002]
【従来の技術】血管の恒常性は内皮細胞の有する多様な
機能によって保たれている。血管内皮細胞は、1)血液
中の栄養物などの必要な成分を組織へ輸送する仲介を
し、不必要に多量の成分が通過することを防ぐ作用、
2)血液が凝固しないで円滑に循環させる作用、3)血
管が離断したときに出血を阻止する作用、および4)血
管の緊張を一定に保つ調節作用を有している。2. Description of the Related Art Vascular homeostasis is maintained by various functions of endothelial cells. Vascular endothelial cells 1) mediate the transport of necessary components such as nutrients in the blood to tissues, and prevent the unnecessary passage of large amounts of components.
It has 2) the effect of circulating blood smoothly without coagulation, 3) the effect of preventing bleeding when a blood vessel is cut off, and 4) the regulating effect of keeping blood vessel tension constant.
【0003】血管内皮細胞に産生されたプロテアーゼに
よる基底膜の分解、血管内皮細胞の遊走・増殖、血管内
皮細胞の管腔形成、基底膜の形成と周辺細胞の取り囲み
という段階で血管新生が生じる。血管新生は種々の疾
患、特に糖尿病性網膜症、黄斑変性症、網膜静脈閉塞症
や網膜動脈閉塞症等の網膜疾患、血管新生緑内障または
血管腫などの腫瘍と密接なつながりがある。[0003] Angiogenesis occurs at the stage of degradation of the basement membrane by proteases produced in vascular endothelial cells, migration and proliferation of vascular endothelial cells, formation of vascular endothelial cell lumen, formation of basement membrane and surrounding cells. Angiogenesis is closely linked to various diseases, particularly diabetic retinopathy, macular degeneration, retinal diseases such as retinal vein occlusion and retinal artery occlusion, tumors such as neovascular glaucoma or hemangiomas.
【0004】一方、本発明の有効成分であるシステイン
誘導体(一般式[I])は、WO91/08199号公報
に免疫不全や自己免疫疾患などの治療剤として有用な化
合物であることが開示されている。しかしながら、血管
新生阻害効果または網膜症の治療効果に関する報告はな
い。On the other hand, a cysteine derivative (general formula [I]) as an active ingredient of the present invention is disclosed in WO91 / 08199 as a compound useful as a therapeutic agent for immunodeficiency and autoimmune diseases. I have. However, there is no report on an angiogenesis inhibitory effect or a therapeutic effect on retinopathy.
【0005】[0005]
【発明が解決しようとする課題】この医薬として有用な
システイン誘導体について、さらに新たな薬理作用を見
出すことは非常に興味のある課題である。It is a very interesting problem to find a new pharmacological action for this cysteine derivative useful as a medicament.
【0006】[0006]
【課題を解決するための手段】本発明者等はシステイン
誘導体の新たな薬理作用を見いだすために、血管新生に
対するシステイン誘導体の作用を検討した。その結果、
システイン誘導体が血管新生阻害作用を有しており、血
管新生が関与する疾患、特に、糖尿病性網膜症、黄斑変
性症、網膜静脈閉塞症、網膜動脈閉塞症等の網膜疾患、
血管新生緑内障および血管腫等の腫瘍の治療剤として有
用であることを見出した。Means for Solving the Problems The present inventors have studied the effects of cysteine derivatives on angiogenesis in order to find a new pharmacological action of the cysteine derivative. as a result,
Cysteine derivatives have angiogenesis inhibitory action, diseases involving angiogenesis, especially diabetic retinopathy, macular degeneration, retinal vein occlusion, retinal diseases such as retinal artery occlusion,
It has been found that it is useful as a therapeutic agent for tumors such as neovascular glaucoma and hemangiomas.
【0007】[0007]
【発明の実施の形態】本発明は下記一般式[I]で表わさ
れる化合物またはその塩類(以下、本化合物とする)を
有効成分とする血管新生阻害剤および網膜疾患治療剤を
提供するものである。BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides an angiogenesis inhibitor and a therapeutic agent for a retinal disease comprising a compound represented by the following general formula [I] or a salt thereof (hereinafter, referred to as the present compound) as an active ingredient. is there.
【0008】[0008]
【化2】 Embedded image
【0009】[式中、R1 およびR2 は同一かまたは異
なって、水素原子、低級アルキル基、低級アルカノイル
基、フェニルカルボニル基、フェニル低級アルキル基ま
たはフェニル低級アルコキシカルボニル基を示す。[Wherein R 1 and R 2 are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a phenylcarbonyl group, a phenyl lower alkyl group or a phenyl lower alkoxycarbonyl group.
【0010】R3 およびR4 は同一かまたは異なってヒ
ドロキシ基、低級アルコキシ基、アミノ基または低級ア
ルキルアミノ基を示す。R 3 and R 4 are the same or different and each represents a hydroxy group, a lower alkoxy group, an amino group or a lower alkylamino group.
【0011】A1 、A2 およびA3 は同一かまたは異な
って、直鎖または分枝の低級アルキレン基を示す。A 1 , A 2 and A 3 are the same or different and each represents a linear or branched lower alkylene group.
【0012】mは0または1を示す。] 上記で規定した基をさらに詳しく説明すると、低級アル
キル基とはメチル、エチル、プロピル、ヘキシル、イソ
プロピル、t−ブチル等の1〜6個の炭素原子を有する
直鎖または分枝のアルキル基を示し、低級アルカノイル
とは、アセチル、プロピオニル、ヘキサノイル、イソプ
ロピオニル、t−ブタノイル等の2〜6個の炭素原子を
有する直鎖または分枝のアルカノイルを示し、低級アル
コキシとは、メトキシ、エトキシ、プロポキシ、ヘキシ
ルオキシ、イソプロポキシ、t-ブトキシ等の1〜6個の
炭素原子を有する直鎖または分枝のアルコキシを示す。
特に好ましい化合物の具体例として下記式[II]で示され
るN1 −(6−アミノヘキシル)−N2 −(2,2−ジ
メチル−3−メルカプトプロピオニル)−L−システイ
ンアミドまたはその塩類が挙げられる。M represents 0 or 1. When the groups defined above are described in more detail, lower alkyl groups are straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, and t-butyl. And lower alkanoyl means a straight-chain or branched alkanoyl having 2 to 6 carbon atoms such as acetyl, propionyl, hexanoyl, isopropionyl, t-butanoyl, etc., and lower alkoxy means methoxy, ethoxy, propoxy. And straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as hexyloxy, isopropoxy and t-butoxy.
Specific examples of particularly preferred compounds include N 1- (6-aminohexyl) -N 2- (2,2-dimethyl-3-mercaptopropionyl) -L-cysteinamide represented by the following formula [II] and salts thereof. Can be
【0013】[0013]
【化3】 Embedded image
【0014】上記の塩類とは、医薬として許容される有
機または無機の酸もしくは塩基との塩類であればよく、
例えば、塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、乳
酸塩、マレイン酸塩、フマル酸塩、シュウ酸塩、メタン
スルホン酸塩、p−トルエンスルホン酸塩、ナトリウム
塩、カリウム塩、カルシウム塩、マグネシウム塩、亜鉛
塩、アンモニウム塩、トリエタノールアミン塩、ジシク
ロヘキシルアミン塩等が挙げられる。The above-mentioned salts may be salts with a pharmaceutically acceptable organic or inorganic acid or base.
For example, hydrochloride, hydrobromide, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt , Calcium salts, magnesium salts, zinc salts, ammonium salts, triethanolamine salts, dicyclohexylamine salts and the like.
【0015】本化合物には光学異性体が存在し、また場
合によってはジアステレオ異性体が存在するが、これら
を有効成分とするものも本発明に含まれる。また、本化
合物は溶媒和物、例えば水和物の形態をとっていてもよ
い。The present compound has optical isomers and, in some cases, diastereoisomers, and those containing these as an active ingredient are also included in the present invention. The compound may also be in the form of a solvate, for example, a hydrate.
【0016】一般式[I]で表わされるシステイン誘導体
の有用性を調べるべく、本化合物の血管新生阻害作用に
ついて検討した。詳細については後述の薬理試験の項で
示すが、本化合物は、in vivo の血管新生評価モデルで
ある鶏漿尿膜の血管新生に対して強い阻害作用を示すこ
とを見出した。この結果より、本化合物は、血管新生が
関与する疾患、特に、糖尿病性網膜症、黄斑変性症、網
膜静脈閉塞症、網膜動脈閉塞症等の網膜疾患、血管新生
緑内障および血管腫等の腫瘍の治療剤として有用である
ことが期待される。In order to examine the usefulness of the cysteine derivative represented by the general formula [I], the inhibitory effect of the present compound on angiogenesis was examined. Although the details will be described in the section of pharmacological test described below, the present compound was found to have a strong inhibitory effect on angiogenesis of chicken chorioallantoic membrane, which is a model for evaluating angiogenesis in vivo. From these results, the present compound is useful for diseases involving angiogenesis, particularly for retinal diseases such as diabetic retinopathy, macular degeneration, retinal vein occlusion, retinal artery occlusion, tumors such as neovascular glaucoma and hemangiomas. It is expected to be useful as a therapeutic agent.
【0017】本化合物の投与は経口でも非経口でも行う
ことができる。投与剤型としては、錠剤、カプセル剤、
散剤、顆粒剤、経皮吸収剤、注射剤、点眼剤、眼軟膏等
が挙げられ、汎用されている技術を用いて製剤化するこ
とができる。The compound can be administered orally or parenterally. Dosage forms include tablets, capsules,
Examples include powders, granules, transdermal absorbents, injections, eye drops, eye ointments, and the like, and can be formulated using commonly used techniques.
【0018】本化合物の投与量は症状、年齢、剤型等に
よって適宜選択できるが、経口剤であれば通常1日当り
0.1〜5000mg、好ましくは1〜1000mgを
1回または数回に分けて投与すればよい。The dose of the present compound can be appropriately selected depending on the condition, age, dosage form and the like. In the case of an oral preparation, the dose is usually 0.1 to 5000 mg, preferably 1 to 1000 mg per day, divided once or several times. It may be administered.
【0019】以下に薬理試験の結果を示すが、これは本
発明をよりよく理解するためのものであり、本発明の範
囲を限定するものではないThe results of the pharmacological test are shown below, which are for better understanding of the present invention and do not limit the scope of the present invention.
【0020】[0020]
【実施例】[1.受精卵胚漿尿膜法による血管新生阻害
効果]in vivo における血管新生評価モデルとして鶏漿
尿膜の血管新生に対する薬物の阻害効果を測定する受精
卵胚漿尿膜法がBiochem. Biophys. Res. Commun., 17 4,
1070-1076 (1991)に報告されている。そこで、上記文
献に記載された方法に準じて、システイン誘導体の血管
新生評価モデルに対する効果について検討した。Embodiments [1. Inhibition of Angiogenesis by the Fertilized Egg Embryonic Chorion Membrane Method] The fertilized egg embryo chorioallantoic membrane method, which measures the inhibitory effect of a drug on angiogenesis in chicken chorioallantoic membrane, is used as an in vivo angiogenesis evaluation model by Biochem. Biophys. Res. Commun., 17 4 ,
1070-1076 (1991). Therefore, the effect of a cysteine derivative on an angiogenesis evaluation model was examined according to the method described in the above-mentioned literature.
【0021】(投与用ペレットの調整) 1. メチルセルロース(0.1g)を滅菌精製水10
mlに溶解し1%メチルセルロース液とする。(Preparation of Pellet for Administration) Methylcellulose (0.1 g) is sterilized purified water 10
Dissolve in 1 ml to make 1% methylcellulose solution.
【0022】2. 被験化合物をエタノール/滅菌精製
水(1/1)で溶解し、24μmol/mlの溶液を調
製する。2. The test compound is dissolved in ethanol / sterile purified water (1/1) to prepare a 24 μmol / ml solution.
【0023】3. 24μmol/mlの被験化合物溶
液をエタノール/滅菌精製水(1/1)で希釈し、12
μmol/mlおよび6μmol/mlの被験化合物溶
液を調製する。3. A 24 μmol / ml test compound solution was diluted with ethanol / sterile purified water (1/1),
Prepare test compound solutions of μmol / ml and 6 μmol / ml.
【0024】4. 各濃度の被験化合物溶液0.20m
lと1%メチルセルロース液0.20mlを混合し、被
験化合物混合液とする。4. Test compound solution of each concentration 0.20m
and 0.20 ml of a 1% methylcellulose solution to prepare a test compound mixture.
【0025】5. 各濃度の被験化合物混合液10μl
を直径3mmのパラフィンフィルム上で約2時間風乾
し、被験化合物ペレットを得る。[5] Test compound mixture of each concentration 10μl
Is air-dried on a paraffin film having a diameter of 3 mm for about 2 hours to obtain a test compound pellet.
【0026】(実験方法)受精後3日齢の孵化卵(ホワ
イトレグホン)を空気相を上にして6穴の培養プレート
に3個づつ立て、CO2 インキュベーター(37℃、湿
度95%、CO2濃度5%)内で20分培養した。CO
2 インキュベーターから孵化卵を取り出し、クリーンベ
ンチ内で孵化卵の空気相上部の卵殻に約2cm四方の穴
をあけた。殻膜を卵黄膜から剥離した後、卵殻上の穴を
培養シャーレで覆い、孵化卵をCO2 インキュベーター
内で1日間培養した。その孵化卵の胚漿尿膜上(既存血
管の少ないところ)に被験化合物ペレットを胚漿尿膜に
接着させるように静置した。この孵化卵をCO2 インキ
ュベーター内で2日間培養した後、10%イントラリピ
ッド(血管造影剤)約2mlを胚漿尿膜内に注入し、実
体顕微鏡(×10)にてペレット周囲の血管形成を観察
した。血管新生が認められない場合を陽性とし、血管新
生阻害率を以下の式により算出した。(Experimental Method) Three eggs were hatched three days old after fertilization (White Leghorn) in a culture plate having 6 holes with the air phase facing upward, and placed in a CO 2 incubator (37 ° C., 95% humidity, CO 2 (Concentration: 5%) for 20 minutes. CO
2 The hatched eggs were taken out from the incubator, and a hole of about 2 cm square was made in the eggshell above the air phase of the hatched eggs in a clean bench. After peeling the shell membrane from the yolk membrane, the hole on the eggshell was covered with a culture dish, and the embryonated eggs were cultured in a CO 2 incubator for 1 day. The test compound pellet was allowed to stand on the embryo chorioallantoic membrane (where there are few existing blood vessels) so as to adhere to the embryo chorioallantoic membrane. After culturing the embryonated eggs in a CO 2 incubator for 2 days, about 2 ml of 10% intralipid (angiographic agent) is injected into the embryo chorioallantoic membrane, and angiogenesis around the pellet is observed by a stereoscopic microscope (× 10). Observed. The case where no neovascularization was observed was regarded as positive, and the angiogenesis inhibition rate was calculated by the following formula.
【0027】血管新生阻害率(%)=(陽性を示した孵化
卵数)/(試験に供した孵化卵数)×100Inhibition rate of angiogenesis (%) = (number of hatching eggs showing positive) / (number of hatching eggs subjected to test) × 100
【0028】(結果)被験化合物としてN1 −(6−ア
ミノヘキシル)−N2 −(2,2−ジメチル−3−メル
カプトプロピオニル)−L−システインアミド・塩酸塩
を用いた実験結果を表1に示す。(Results) Table 1 shows the results of experiments using N 1- (6-aminohexyl) -N 2- (2,2-dimethyl-3-mercaptopropionyl) -L-cysteinamide hydrochloride as the test compound. Shown in
【0029】[0029]
【表1】 [Table 1]
【0030】表1に示したように、本化合物は低投与量
であっても血管新生を顕著に阻害した。As shown in Table 1, this compound significantly inhibited angiogenesis even at a low dose.
【0031】[0031]
【発明の効果】上記の薬理試験の結果から明らかなよう
に、本化合物は優れた血管新生阻害作用を有し、血管新
生が関与する疾患、特に、糖尿病性網膜症、黄斑変性
症、網膜静脈閉塞症、網膜動脈閉塞症等の網膜疾患、血
管新生緑内障および血管腫等の腫瘍の治療剤として有用
であることが期待される。As is apparent from the results of the above pharmacological tests, the present compound has an excellent angiogenesis inhibitory effect, and particularly relates to diseases involving angiogenesis, particularly diabetic retinopathy, macular degeneration, retinal vein. It is expected to be useful as a therapeutic agent for retinal diseases such as obstruction and retinal artery occlusion, and tumors such as neovascular glaucoma and hemangiomas.
Claims (4)
その塩類を有効成分とする血管新生阻害剤。 【化1】 [式中、R1 およびR2 は同一かまたは異なって、水素
原子、低級アルキル基、低級アルカノイル基、フェニル
カルボニル基、フェニル低級アルキル基またはフェニル
低級アルコキシカルボニル基を示す。R3 およびR4 は
同一かまたは異なってヒドロキシ基、低級アルコキシ
基、アミノ基または低級アルキルアミノ基を示す。
A1 、A2 およびA3 は同一かまたは異なって、直鎖ま
たは分枝の低級アルキレン基を示す。mは0または1を
示す。]1. An angiogenesis inhibitor comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [Wherein R 1 and R 2 are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a phenylcarbonyl group, a phenyl lower alkyl group or a phenyl lower alkoxycarbonyl group. R 3 and R 4 are the same or different and each represents a hydroxy group, a lower alkoxy group, an amino group or a lower alkylamino group.
A 1 , A 2 and A 3 are the same or different and represent a linear or branched lower alkylene group. m represents 0 or 1. ]
載の阻害剤。2. The inhibitor according to claim 1, wherein the neovascularization is intraocular neovascularization.
物またはその塩類を有効成分とする網膜疾患治療剤。[3] A therapeutic agent for retinal diseases comprising the compound represented by the general formula [I] according to [1] or a salt thereof as an active ingredient.
(2,2−ジメチル−3−メルカプトプロピオニル)−
L−システインアミドまたはその塩類を有効成分とする
請求項1記載の血管新生阻害剤または請求項3記載の網
膜疾患治療剤。4. An N 1- (6-aminohexyl) -N 2-
(2,2-dimethyl-3-mercaptopropionyl)-
The angiogenesis inhibitor according to claim 1 or the therapeutic agent for retinal disease according to claim 3, comprising L-cysteinamide or a salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP27245799A JP3834710B2 (en) | 1998-10-02 | 1999-09-27 | Angiogenesis inhibitor |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP28065598 | 1998-10-02 | ||
JP10-280655 | 1998-10-02 | ||
JP27245799A JP3834710B2 (en) | 1998-10-02 | 1999-09-27 | Angiogenesis inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2000169388A true JP2000169388A (en) | 2000-06-20 |
JP3834710B2 JP3834710B2 (en) | 2006-10-18 |
Family
ID=26550213
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP27245799A Expired - Fee Related JP3834710B2 (en) | 1998-10-02 | 1999-09-27 | Angiogenesis inhibitor |
Country Status (1)
Country | Link |
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JP (1) | JP3834710B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2004090152A1 (en) * | 2003-04-08 | 2006-07-06 | 三菱瓦斯化学株式会社 | 2-alkylcysteine amides or salts thereof, and production methods and uses thereof |
-
1999
- 1999-09-27 JP JP27245799A patent/JP3834710B2/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2004090152A1 (en) * | 2003-04-08 | 2006-07-06 | 三菱瓦斯化学株式会社 | 2-alkylcysteine amides or salts thereof, and production methods and uses thereof |
JP4577513B2 (en) * | 2003-04-08 | 2010-11-10 | 三菱瓦斯化学株式会社 | 2-alkylcysteine amides or salts thereof, and production methods and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
JP3834710B2 (en) | 2006-10-18 |
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