JP2000169388A - Vascularization inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a vascularization inhibitor that has the vascularization inhibitory action and is useful for treatment of the diseases to which the vascularization participates, particularly diabetic retinopathy, retina vein occlusion, acoustic macula degeneration, vascularizing glaucoma and the like by using a specific cysteine derivative as an active ingredient. SOLUTION: This vascularization inhibitor contains, as an active ingredient, a compound represented by the formula (R1 and R2 are each H, a lower alkyl, a lower alkanoyl or the like; R3 and R4 are each OH, a lower alkoxy, amino or the like; A1-A3 are each a lower alkylene; (m) is 0 or 1) or its salts, typically N1-(6-aminohexyl)-N2-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine amide. A daily dose of this inhibitor is usually 0.1-5,000 mg, preferably 1-1,000 mg in a single dose or in several portions when it is orally given.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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]

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] 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.

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]

It is a very interesting problem to find a new pharmacological action for this cysteine derivative useful as a medicament.

[0006]

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]

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]

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[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 each represents a linear or branched lower alkylene group.

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]

Embedded image

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.

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.

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.

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.

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.

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]

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.

(Preparation of Pellet for Administration) Methylcellulose (0.1 g) is sterilized purified water 10
Dissolve in 1 ml to make 1% methylcellulose solution.

2. The test compound is dissolved in ethanol / sterile purified water (1/1) to prepare a 24 μmol / ml solution.

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.

4. Test compound solution of each concentration 0.20m
and 0.20 ml of a 1% methylcellulose solution to prepare a test compound mixture.

[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.

(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.

Inhibition rate of angiogenesis (%) = (number of hatching eggs showing positive) / (number of hatching eggs subjected to test) × 100

(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]

[Table 1]

As shown in Table 1, this compound significantly inhibited angiogenesis even at a low dose.

[0031]

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)

[Claims] 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. ] 2. The inhibitor according to claim 1, wherein the neovascularization is intraocular neovascularization. [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. 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.