JPH03206041A - Preventive and remedy for opacification of lens - Google Patents

Abstract

PURPOSE:To obtain a preventive and remedy for the opacification of lens exhibiting remarkable effect by using an organic germanium compound and a phenoxazine derivative as active components. CONSTITUTION:The objective agent contains a compound of formula I [R1 to R3 are H, lower alkyl such as methyl or ethyl or (substituted) phenyl; X is OH, O-lower alkyl, amino or O-Y<+> (Y is metal such as Na or K, lysozyme or a compound having basic group such as basic amino acid)] and a phenoxazine derivative such as 1-hydroxy-5-oxo-5H-pyrido(3,2-a)phenoxazine-3-carboxylic acid (metal salt) of formula II (M is H or metal such as Na or K) as active components. The agent can keep the transparency of lens over a long period and even clarify a lens exhibiting grave symptom caused by cortex opacification.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a therapeutic agent for preventing clouding of the crystalline lens in the eye, and more specifically, to a combination of a specific organic germanium compound and a specific phenoxazine derivative. The present invention relates to a therapeutic agent for preventing clouding of the crystalline lens that exhibits a more remarkable effect. (Prior art) The lens in the eyeball is mainly composed of approximately 65% water and approximately 35% protein, and compared to other tissues, It contains a high proportion of protein, and while this high concentration of protein is subject to various biological controls, it maintains its transparency by forming and maintaining a hydrocolloid state with intracellular water. When the crystalline lens, which should be transparent, becomes cloudy for some reason, the amount of light that should reach the retina decreases, and naturally, visual acuity decreases depending on the degree of cloudiness. A disease called cataract is known as a typical example of clouding of the crystalline lens.There are two types of cataract: congenital cataract and acquired cataract. It is classified,
The cause of this condition is a change in the contents of the aqueous humor that nourishes the crystalline lens, resulting in malnutrition in the lens capsule, etc.
Several theories have been proposed, including that the sac itself is damaged and cannot absorb nutrients, or that waste products cannot be excreted to the outside, so they accumulate inside. (Problems to be Solved by the Invention) However, there are still many unresolved problems with lens opacity, including the above-mentioned cataracts. There is no specific cure, and drugs are currently being used that are highly effective in restoring vision and preventing the progression of clouding. On the other hand, some of the inventors of the present invention have found that a drug based on a specific organic germanium compound can significantly prevent or treat lens opacity, and have already filed a patent application. He was conducting research to develop a drug that showed a certain effect. The present invention has been made against the background of the above-mentioned prior art, and aims to provide a drug that can effectively prevent and improve lens opacity. Another object of the present invention is to provide a therapeutic agent for preventing lens opacification that is free of toxicity and side effects, considering that this type of drug is administered over a relatively long period of time. (Means for Solving the Problems) The configuration adopted by the present invention to achieve the above object is based on the formula RI R3 11 (Ge-C-CH-COX)203 ・
...(1) -R2 (wherein R1 to R3 are a hydrogen atom or the same or different methyl group, a lower alkyl group such as an ethyl group, or a substituted or unsubstituted phenyl group, X is a hydroxyl group, 〇1 lower alkyl group , an amino group, or O-Y'' [Y represents a compound having a metal such as sodium or potassium or a basic group such as lysozyme or a basic amino acid], and a phenoxazine derivative. The present invention will be described in detail below.The agent for preventing and treating clouding of crystalline lenses of the present invention contains a specific organic germanium compound represented by the above formula (1) as an effective ingredient. First, we will explain this compound.It has a basic skeleton of germylprobionic acid in which a germanium atom is bonded to a probionic acid derivative having three substituents R1 to R3 and an oxygen functional group OX. Germanium atoms and oxygen atoms in the basic skeleton are bonded at a ratio of 2:3.
Here, the substituents R1 to R3 are hydrogen atoms, methyl groups, etc. It represents a so-called lower alkyl group such as an ethyl group, a probyl group, a butyl group, or a substituted or unsubstituted phenyl group, and the substituent X is a hydroxyl group. 〇 Mono-lower alkyl group,
Each shows a salt of an amino group or a carboxyl group represented by O-Y+. Y represents a metal such as sodium or potassium (however, it is not limited to a monovalent one) or a compound having basicity represented by a basic amino acid such as lysozyme or lysine. Also, substituents R1 and R2 is bonded to the α-position of the germanium atom, and the substituent R3 is also bonded to the β-position. Therefore, the following can be exemplified as the organic germanium compound used in the present invention agent. I (Ge-CH-CH2 -COOH)zosCH3 I (Ge-CHz-CH-COOH)zo3CH3 ■ (Ge-CH-CH-COOH)203謬CH3 CH3 1 (Ge-C-CH2-COOH)zo3CH3 (Ge-CH-CHz-COOH )20:s1 C6H5 ・・・・・・(1-2) ・・・・・・(1-3) ・・・・・・(1-4) ・・・・・・(1-5) ・...(1-6) CH3 1 (Ge-CH-CH-COOH)203 ...
・(1-7) Honey C6H5 (Ge-CHx-CH2-COOCH3〉20s' -
- (1-8) (Ge-CHz-CHz-CONHz
)zos---(1-9)(Ge-CH2-C
Hz-Coo-Na''')203 =- (1-
10) Organic germanium compounds having the above structure can be produced by various methods. That is, the above formula (
In 1), X-OH is obtained by hydrating trihalogenylprobionic acid such as trichlorogermylpropionic acid (a) into which substituents R1 to R3 have been introduced in advance, as shown in the reaction formula below, for example. All you have to do is disassemble it. Reaction formula On the other hand, in formula (1), a group such as X-〇-1 lower alkyl group is converted into the corresponding acid halide by, for example, reacting thionyl chloride or the like with the above compound (a),
This acid halide may be hydrolyzed after reacting with an alcohol corresponding to the lower alkyl group,
Further, in formula (1), the compound represented by X-NH2 may be hydrolyzed after, for example, ammonia is applied to the acid halide. Furthermore, in formula (1), X is coo-y+
The above compound (a) is represented by , and Y is a metal.
It is sufficient to react with a metal hydroxide, and even when Y is a compound having a basic group, a known acid-monobase reaction may be followed. The results of instrumental analysis such as nuclear magnetic resonance absorption (NMR) spectrum and infrared absorption (IR) spectrum of the organic germanium compound obtained as described above indicate that the above compound is represented by general formula (1). It supports something very well. The formulas representing the above organic germanium compounds correspond to the state in which they are isolated as crystals, and the germanium-oxygen bond undergoes hydrolysis in an aqueous solution, for example, the above compound (1-1).
It is known that it takes the structure (HO)s-Ge-CHz-CH2-COOH. Among the above compounds, compound (1-1) is preferred because it is relatively easily available. On the other hand, the phenoxazine derivatives used in the present invention are those represented by the basic structural formula, and especially the 1-
Hydroxy-5-oxo 5H-pyride (3,2-a
〉Phenoxazine-3-carboxylic acid (common name: bilenoxine)〉 or its salts with metals such as sodium and potassium are preferred. This compound has conventionally been used for the treatment of cataracts, and the results have been introduced in papers (e.g. Rinnin 11:272, 1957). Phenoxazine derivatives are disclosed in Japanese Patent Publication No. 55-10570. The therapeutic agent for preventing clouding of crystalline lenses of the present invention contains the above-mentioned organic germanium compound and the above-mentioned phenoxazine derivative as active ingredients, and preferably contains boric acid, ibusilone aminocaproic acid, It is administered in an ophthalmic solution together with known ingredients such as methyl roseoxyaminobenzoate and chlorobutanol. In this case, if the liquid is alkaline, the solubility of the organic germanium compound, etc., which is the active ingredient of the agent of the present invention described above, will be improved. The organic germanium compound, which is the active ingredient of the present invention, is characterized by extremely low toxicity and almost no side effects, and phenoxazine derivatives have also been used for a long time as cataract treatments and their safety has been proven. ．． In addition, since both active ingredients of the present invention agent have such characteristics, the usage amount can be determined relatively freely. However, when making eye drops, the organic germanium compound is
5 to 500 mg of the phenoxazine derivative, and about 0.05 to 15 mg of the phenoxazine derivative per ml.
It's fine if you can prepare it. It goes without saying that the agent of the present invention may be prepared separately into, for example, an agent containing an organic germanium compound and an agent containing a 7-enoxazine derivative, and the agents may be mixed and used when necessary. (Examples) Hereinafter, the present invention will be explained in more detail with reference to Examples. The experimental animals used were 1-month-old (12 mice) and 5-month-old (12 mice) accelerated aging mice. Both age groups were divided into three groups, and the first group received 1-hydroxy-5-oxo-5H-pyrido(3,2-a)phenoxazine-3-
Carboxylic acid (generic name: bilenoxine) in 1ml is 0.
A liquid containing 05 mg (hereinafter abbreviated as bilenoxine liquid),
The second group contains both a solution containing 4% of an organic germanium compound (1-1> (hereinafter referred to as Ge solution) and birenoxine solution, and the third group (target group) contains a surface activity inhibitor. Distilled water was used as a placebo solution, and each application was applied 4 times a day, 6 days a week.
Days later, 60 days later, 90 days later, and 120 days later, under anesthesia by intraperitoneal injection of 0.7 ml/Kg of sodium Nembutal (trade name), the pupils were dilated with Midrin P (trade name), and the crystalline lens was observed using a stereomicroscope. The lens findings of aging-accelerated mice can be roughly classified into four categories: transparency, striae formation, distortion, and cortical opacity.Clear here means that there is no abnormality in the lens and that the retinal blood vessels can be seen through. Okay, striation formation refers to the presence of 2-5 concentric rings in the crystalline lens.Also, distortion is
This is a case where the fundus image is distorted due to refractive error of the crystalline lens, and cortical opacification refers to a case where wedge-shaped or diffuse opacification occurs in the lens cortex. In addition, in some cases, the two symptoms of striation formation and distortion overlap, and in such cases, the one showing the stronger change was selected as the abnormal finding. 1 month old t* I month old eye drop initiation experiment When eye examination of young aging accelerated mice at 1 month old before eye drop was performed, the majority of mice, including the control group, had clear crystalline lenses with no abnormalities observed. However, mild cortical opacity and anophthalmia were observed in one individual in the first group (combined Ge solution and birenoxine solution group). On the 30th day after starting the eye drops, the cortical opacity that existed before the eye drops had disappeared. However, a ring-like pattern appeared on the crystalline lens in one eye in group 1 (birenoxine solution administration group) and in group 2 (Group 2).
(combined group with e solution and birenoxine solution), one eye, and the third
This occurred in two eyes in each group (target group). Also, eye drops 60
On the day of examination, lens abnormalities due to striae formation and distortion were observed in one eye of the first group and four eyes of the third group. In the examination on the 90th day of instillation, five eyes of the first group had clear crystalline lenses.
Stryform formation (5 eyes) or distortion (1 eye), resulting in early cataract [! It was noticed. In the 4 eyes of Group 3 with lens distortion, this examination was the same as the previous examination, and no changes were observed in the findings. On the other hand, the crystalline lenses of the second group were in good condition and were judged to be transparent even during this examination. In the examination on the 120th day after instillation, the distortion that was observed in the two eyes of the first group on the 90th day had disappeared. Also, the third
Among the four lenses in the group, the distortion disappeared in one eye, indicating that distortion is not necessarily a fixed change. On the other hand, in the second group, one animal died during the experiment, but all the remaining animals were determined to be transparent even in this test. The above results are shown in Table 1 below, and the ratios of symptoms in the lens of each group are shown in Figures 1 to 3. It can be said that this experiment confirmed the preventive effect of the inventive agent. 2 Start of eye drops at 5 months old Experimental newborn f & 5 month old aging accelerated mice received 1-
Two vestigial rings had begun to appear, but the fundus was still transparent, so I assumed that the eye was clear and started administering the eye drops. On the 30th day after the start of eye drops, clear patterns appeared in 2 eyes of the 2nd group and 4 eyes of the 3rd group, but no changes were observed in the 1st group. In the examination on the 60th day of instillation, both the first and second groups showed a good progress with clear results, but four eyes in the third group, which was the target group, showed not only streak formation but also distortion. It also occurred together. Examination on the 90th day after instillation revealed significant changes in both groups 1 and 2, resulting in striae formation (16 eyes) or distortion (2 eyes). At this time, all four eyes in the third group were judged to have distortion, and strong changes were observed in the crystalline lenses. In the examination on the 120th day of instillation, embedding formation was observed in all lenses (16 eyes) in Groups 1 and 2, and distortion (4 eyes) was observed in Group 1 (birenoxine solution administration group) in particular. On the other hand, in the third group, which was the target group,
Distortion disappeared in one of the four eyes, but skin opacity developed in another eye, and it was recognized that the cataract was progressing further. The above results are shown in Table 2 below, and the ratios of symptoms in the lens of each group are shown in Figures 4 to 6. It can be said that this experiment confirmed the preventive and therapeutic effects of the present agent. (Margins below this page) (Effects of the invention) As is clear from the above experiments, Groups 1 and 2 were more effective in preventing or stopping the progression of cataracts in aging-accelerated mice than Group 3. However, in the group where virenoxine solution was administered alone, a small number of individuals developed cataract progression, and it appears that it cannot necessarily be said to be absolutely effective. In the second group, that is, the combination group of Ge solution and pirenoxine solution, all crystalline lenses maintained their transparency for a long period of time, and even lenses with severe symptoms of cortical opacity became clear. It showed a remarkable improvement effect.It should be noted that even when compounds other than compound (1-1) were used,
Almost the same results were obtained. Therefore, the present invention can be said to be very excellent.

[Brief explanation of drawings]

All the drawings show the distribution of symptoms in each eye drop group as a percentage. Figures 1 to 3 show the results of the experiment in which the eye drops were started at 1 month of age, and Figures 4 to 6 show the results of the experiment when the eye drops were started at 5 months of age. Each represents the results of the starting experiment.

Claims (1)

[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼...(1) (In the formula, R1 to R3 are hydrogen atoms, the same or different lower alkyl groups such as methyl group or ethyl group, or substituted or unsubstituted The substituted phenyl group, 1. A preventive and therapeutic agent for lens opacification, which contains as active ingredients an organic germanium compound represented by the formula (respectively) and a phenoxazine derivative. 2 The organic germanium compound represented by formula (1) is
2. The agent for preventing and treating crystalline lens clouding according to claim 1, wherein R_1 to R_3 are hydrogen atoms and X is a hydroxyl group. 3. The phenoxazine derivative according to claim 1, wherein the phenoxazine derivative is represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, M represents a hydrogen atom or a metal such as sodium or potassium) A therapeutic agent to prevent clouding of the crystalline lens. 4. The agent for preventing and treating crystalline lens opacification according to claims 1 to 3, characterized in that the organic germanium compound and/or the phenoxazine derivative is contained in the form of a sodium salt. 5. The agent for preventing and treating lens clouding according to claims 1 to 4, which is formulated into an eye drop together with known ingredients such as boric acid, epsilon aminocaproic acid, methyl paraoxyaminobenzoate, and chlorobutanol. 6. The agent for preventing and treating crystalline lens opacification according to claims 1 to 5, wherein at least the organic germanium compound and the phenoxazine derivative are prepared separately and used as a mixture.