JP2835545B2 - Cataract prevention and treatment agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for preventing and treating cataracts,
More specifically, the present invention relates to a cataract preventive and therapeutic agent containing a specific carboxylic acid amide derivative as an active ingredient.

[0002]

2. Description of the Related Art Cataract is commonly referred to as "shiragahi" and is a disease in which the lens is generally opaque. The diseases are mainly 1) senile cataract, 2) traumatic cataract due to trauma such as bruise, sting, cut, etc. 3) concurrent cataract secondary to non-traumatic disease of the eyeball, 4) diabetic cataract seen in diabetic patients And 5) are classified as congenital cataracts, but the cause has not yet been elucidated.

At present, as therapeutic agents for such diseases, there are cineraria eye drops containing two kinds of herbs as main ingredients, catalin eye drops, facollidine eye drops having an action of preventing lens protein denaturing action, and redox system. In addition to tathione, glutathione, etc., which regulates salivary gland hormones such as parotin and thiobronine as oral medicines, there are still problems that should be improved as cataract treatment drugs, There is a need for a new alternative cataract treatment.

[0004]

Means for Solving the Problems In view of the above situation, the present inventors have conducted intensive studies, and as a result, specific carboxylic acid amide derivatives represented by the following general formulas (1) and (2) have been obtained. They have found that they are effective for the prevention and treatment of cataracts, and have now provided a novel agent for preventing and treating cataracts of the present invention.

That is, the present invention relates to the general formula

[0006]

Embedded image

[Wherein R ¹ and R ² are each a hydrogen atom,
Alkyl group, cycloalkyl group, diphenyl lower alkyl group or group

[0008]

Embedded image

Is shown. In the group, R ⁵ , R ⁶ and R ⁷
Each represents a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group, a halogen-substituted lower alkyl group, a cyano group, a carboxyl group or a hydroxyl group, A represents a lower alkylene group, l represents 0 or 1 is shown. R ¹ and R ² may form a heterocyclic group together with or without a nitrogen atom to which they are bonded via a nitrogen atom or an oxygen atom, and the heterocyclic group may be a lower alkyl group. Or a phenyl lower alkyl group or a phenyl group which may have a lower alkyl group, a lower alkoxy group, a halogen atom or a halogen-substituted lower alkyl group as a substituent. R ³ represents a hydrogen atom, an alkyl group or a phenyl lower alkyl group. R ⁴ represents a lower alkyl group or a phenyl group. X represents an oxygen atom or a sulfur atom. ] The present invention relates to a cataract preventive and therapeutic agent comprising the carboxylic acid amide derivative represented by the formula (1) as an active ingredient.

Among the compounds of the above general formula (1) used as an active ingredient in the cataract preventive and therapeutic agents of the present invention, preferred compounds are represented by the following general formula (2).
Diethoxyphosphinoylmethyl-N- (4-bromo-
2-Cyanophenyl) benzamide is optimal.

[0011]

Embedded image

The present inventors have already developed a carboxylic acid amide derivative represented by the above general formula (1) as a compound effective for pharmacological uses such as anti-inflammatory agents (Japanese Patent Application Laid-Open No. 61-1519).
No. 9), and subsequently a known compound developed as an active ingredient of a therapeutic agent for hyperlipidemia (see JP-A-63-264421), which can be obtained by the method described in the publication.

The carboxylic acid amide derivative represented by the general formula (2) has also been previously developed by the present inventors as an active ingredient of a therapeutic agent for hyperlipidemia (Japanese Patent Application No. 2-11).
No. 6525), and the details of its production are as described below.

However, there is no description in the above publications that the carboxylic acid amide derivative is effective for the prevention and treatment of cataract, and the carboxylic acid amide derivative other than the above publications has some pharmacological uses. There is no report on this matter, and of course, there is no example in which its application to the ophthalmic field has been proposed.

Thus, the present invention has been completed by finding that each of the derivatives represented by the above general formulas (1) and (2) has a preventive and therapeutic effect on cataract which is completely unrelated to conventionally known pharmacological uses. In particular, the preventive and therapeutic effects seen with these derivatives are observed for cataracts belonging to any of the above classifications, and are particularly remarkable for diabetic cataracts.

The agent for preventing and treating cataract of the present invention comprises at least one of the above-mentioned general formulas (1) and (2).
It is an essential requirement that a compound of a certain type is contained as an active ingredient. Generally, the compound is prepared into various formulations depending on the administration method using a commonly used nontoxic pharmaceutical carrier together with the compound. It is applied to cataract patients as a prophylactic and therapeutic agent for and is used as a prophylactic agent for the disease.
Here, the pharmaceutical carrier includes various diluents or solvents, fillers, extenders, binders, suspending agents, disintegrants, surfactants, lubricants, excipients, which are generally used depending on the form of the pharmaceutical preparation to be prepared. Excipients and wetting agents can be exemplified. In addition, the above-mentioned preparations may optionally contain, if necessary, commonly used solubilizers, buffers, preservatives, coloring agents, flavors, flavors and the like.

The above-mentioned preparation form of the therapeutic agent of the present invention is not particularly limited and can be determined as appropriate. For example, oral administration preparations such as tablets, capsules, granules, pills, syrups, solutions, emulsions, suspensions, etc. Various forms of parenteral administration agents such as injections (subcutaneous, intravenous, intramuscular, intraperitoneal injections, etc.) and eye drops can be employed.

The various forms of the drug of the present invention are prepared by a usual method. For example, tablets, capsules, granules,
Oral preparations such as pills include excipients such as sucrose, lactose, glucose, starch, mannitol; syrup, gum arabic,
Binders such as sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose,
It is prepared according to a conventional method using a disintegrant such as polyethylene glycol; a lubricant such as talc, magnesium stearate, calcium stearate and silica; a wetting agent such as sodium laurate and glycerol. Injections,
Solutions, emulsions, suspensions, syrups and the like include, for example, solvents for dissolving active ingredients such as ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, sesame oil, etc .; Surfactants such as oxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil and lecithin; cellulose derivatives such as sodium carboxymethylcellulose and methylcellulose; and natural rubbers such as tragacanth and gum arabic. A suspending agent is prepared according to a conventional method using a preservative such as an ester of paraoxybenzoic acid, benzalkonium chloride, and sorbitan salt as appropriate. Eye drops are based on sterile distilled water.
Buffers such as sodium dihydrogen phosphate and sodium monohydrogen phosphate, isotonic agents such as sodium chloride, benzathonium chloride, preservatives such as chlorobutanol, etc., as appropriate,
It is prepared by a usual method.

The dosage of the cataract preventive and therapeutic agent of the present invention depends on the form of preparation, administration route, age, weight, sensitivity,
Although it can be arbitrarily determined according to the degree of the disease and the like, and is not particularly limited, the amount of the active ingredient usually contained in each preparation in an oral administration preparation is about 0.05 per 1 kg of body weight per day. ~ 80mg, preferably about 0.1 ~ 50m
It is appropriate that the amount is in the range of g, and it is needless to say that this can be appropriately increased or decreased as needed. In the case of eye drops, an effective dose is generally about 0.3 to 2 times.
It is preferable to select from the range of about μg.

Hereinafter, the production of the compound of the general formula (2) used as an active ingredient in the present invention will be described in detail. The compound can be produced by the method shown in the following reaction formula-1.

[0021]

Embedded image

Wherein R ^{4 ′} , R ^{5 ′} , R ^{6 ′} and R ^{7 ′} are the same as above. According to the method shown in Reaction Formula-1, by reacting the carboxylic acid chloride derivative (A) with the amines (B),
The compound of the general formula (2) can be obtained.

The above reaction is generally carried out in a suitable solvent in the presence of a deoxidizing agent. As the deoxidizing agent used here, any of various known agents that do not adversely affect the reaction can be used. Specific examples thereof include preferably tertiary amines such as triethylamine, diethylaniline, N-methylmorpholine, pyridine, and 4-dimethylaminopyridine. Examples of the solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether, chain or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF) and 1,4-dioxane, and acetone. , Methyl ethyl ketone, acetophenone and the like, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like.

The proportion of the carboxylic acid chloride derivative (A) and the amine (B) used in the above reaction is not particularly limited, but it is usually preferred to use the former in an equimolar amount to an excess amount with respect to the latter. The deoxidizing agent is preferably used in an equimolar amount to a small excess with respect to the carboxylic acid chloride derivative (A). The reaction proceeds under cooling, at room temperature and under heating, but it is usually preferable to employ a temperature condition in the range of around room temperature to the reflux temperature of the solvent, and generally in about 0.5 to 10 hours. finish.

The target compound obtained by the method shown in the above-mentioned reaction formula-1 can be isolated from the reaction system or purified by a conventional separation means. As the above isolation and purification means, a solvent extraction method, a distillation method, a recrystallization method, column chromatography, preparative thin-layer chromatography, and the like can be employed.

[0026]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, a production example of an active ingredient compound for preventing and treating cataract of the present invention will be described, and then a preparation example of a preparation of the present invention will be described as a prescription example.

[0027]

Production Example 1 3.94 g (20 mmol) of 2-amino-5-bromobenzonitrile, 2.2 of triethylamine
2 g (22 mmol) and 0.49 g (4 mmol) of 4-dimethylaminopyridine are added to dry dichloromethane 4
0 ml, and the mixture was stirred under ice-cooling and stirred under ice-cooling with 4-diethoxyphosphinoylmethylbenzoyl chloride 5.81.
g (20 mmol) in 40 ml of dry dichloromethane was slowly added dropwise. After stirring at room temperature for 10 hours, 50 ml of water was added to the reaction mixture, and extracted with chloroform.
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform: ethyl acetate = 1: 2) and recrystallized from benzene-n-hexane to give colorless crystals of 4-diethoxyphosphinoylmethyl-N- (4- Bromo-2-cyanophenyl)
2.94 g of benzamide were obtained. Melting point: 165-166
° C (recrystallized from benzene-n-hexane)

[0028]

Production Examples 2 to 7 The compounds shown in Table 1 were obtained in the same manner as in Production Example 1.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

Formulation Example 1 Preparation of Tablets 4-Diethoxyphosphinoylmethyl- as an active ingredient
Tablets containing 250 mg of N- (4-chlorophenyl) benzamide (referred to as “Compound A”) per tablet (10
00 tablets) were prepared according to the following formulation:

Component A (g) Compound A 250 Lactose (Japanese Pharmacopoeia) 33.3 Corn starch (Japanese Pharmacopoeia) 16.4 Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 12.8 Methylcellulose (Japanese Pharmacopoeia) 6.0 Magnesium stearate (Japanese Pharmacopoeia product) 1.5 Total amount 320 Compound A, lactose, corn starch and carboxymethylcellulose calcium were thoroughly mixed in accordance with the above formula,
Granulated using an aqueous methylcellulose solution, passed through a 24-mesh sieve, mixed with magnesium stearate, and pressed into tablets.

[0033]

[Formulation Example 2] Preparation of capsules 4-diethoxyphosphinoylmethyl- as an active ingredient
Hard gelatin capsules (1000 pieces) containing N- (4-bromo-2-cyanophenyl) benzamide (referred to as "Compound B") at 250 mg per capsule were prepared according to the following formula.

Ingredient (g) Compound B 250 Microcrystalline cellulose (Japanese Pharmacopoeia) 30 Corn starch (Japanese Pharmacopoeia) 17 Talc (Japanese Pharmacopoeia) 2 Magnesium stearate (Japanese Pharmacopoeia) 1 Total amount 300 Each component was finely powdered according to the above-mentioned formula, thoroughly mixed so as to form a uniform mixture, and filled into a gelatin capsule for oral administration having a desired size to obtain a desired capsule.

[0035]

Formulation Example 3 Preparation of Granules 4-Diethoxyphosphinoylmethyl-as an active ingredient
N-phenylbenzamide (referred to as "Compound C")
Granules containing 500 mg / g (1000 g) were prepared according to the following formula.

Ingredient (g) Compound C 500 Corn starch (Japanese Pharmacopoeia) 250 Lactose (Japanese Pharmacopoeia) 100 Microcrystalline cellulose (Japanese Pharmacopoeia) 100 Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 40 Hydroxypropylcellulose (Product of the Japanese Pharmacopoeia) 10 Total 1000 After mixing Compound C, corn starch, lactose, crystalline cellulose and calcium carboxymethylcellulose according to the above formula, add an aqueous solution of hydroxypropylcellulose to the mixture, knead the mixture, and granulate with an extrusion granulator. And 50 ℃
For 2 hours to obtain the desired granules.

Examples of pharmacological tests conducted on the active ingredient compound of the drug of the present invention are described below.

[0038]

[Pharmacological Test Example 1] Wistar rats (male, 6 weeks old,
Group = 25), streptozotocin 65mg / kg
Was intravenously administered to produce diabetic rats, and 5
From the day after, diabetic rats are fed a cholesterol diet (cholesterol 0.25%, sodium cholate 0.40).
% And a diet containing 2.50% of olive oil) were allowed to freely ingest and were kept (control group). To the experimental group, 30 mg / kg / day of the compound of Production Example 1 as a test substance was orally administered for 12 weeks together with the free intake of the cholesterol diet.

FIG. 1 shows the obtained results.

In the figure, the vertical axis indicates the number (rats) and the incidence (%) of cataract-induced rats, and the horizontal axis indicates the number of elapsed days (weeks) with the fifth day of streptozotocin administration as the reference day (day 0). In the figure, (1) shows a control group (no administration of a test substance), and (2) shows an experimental group (administration group of a test substance).

As shown in FIG. 1, the cataract incidence rate was significantly suppressed in the experimental group to which the carboxylic acid amide derivative, which is the active ingredient compound of the cataract preventive and therapeutic agent of the present invention, was administered as compared with the non-administered control group. From this, it is clear that the therapeutic agent of the present invention can exert an excellent effect on the prevention and treatment of cataract.

[0042]

[Pharmacological test example 2] The same test as in pharmacological test example 1 was repeated using the following compounds as test reagents.

The results of counting the number of cataract-induced rats 8 weeks later are shown in Table 2 below, using the number of test rats as the denominator. Table 2 also shows the results of the control group (without administration of the test substance).

Test compounds A: 4-diethoxyphosphinylmethyl-N-phenylbenzamide B: 4-diethoxyphosphinylmethyl-N- (p-chlorophenyl) benzamide C: 4-diethoxyphosphinylmethyl -N-benzyl-N- (m, p-dichlorophenyl) benzamide D ... 4-diethoxyphosphinylmethyl-N- (p-trifluoromethylphenyl) benzamide

[0045]

[Table 3]

As can be seen from Table 2, the incidence of cataract was suppressed in the experimental group to which each of the above compounds (carboxylic acid amide derivatives) was administered, indicating that the therapeutic agent of the present invention is excellent in preventing and treating cataract. I understand.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of a test conducted in accordance with Pharmacological Test Example 1 for elucidating the cataract preventive effects of the active ingredient compounds for preventing and treating cataract of the present invention.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-264421 (JP, A) JP-A-62-12776 (JP, A) JP-A-62-238286 (JP, A) JP-A-1- 156965 (JP, A) (58) Fields studied (Int. Cl. ⁶ , DB name) A61K 31/66 ABL

Claims (3)

(57) [Claims] 1. A compound of the general formula [Wherein R ¹ and R ² each represent a hydrogen atom, an alkyl group,
Cycloalkyl group, diphenyl lower alkyl group or group Is shown. In the group, R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group,
A lower alkoxycarbonyl group, a lower alkyl group, a halogen-substituted lower alkyl group, a cyano group, a carboxyl group or a hydroxyl group, A represents a lower alkylene group, and l represents 0 or 1. R ¹ and R ² may form a heterocyclic group together with or without a nitrogen atom to which they are bonded via a nitrogen atom or an oxygen atom, and the heterocyclic group may be a lower alkyl group. Or a phenyl lower alkyl group or a phenyl group which may have a lower alkyl group, a lower alkoxy group, a halogen atom or a halogen-substituted lower alkyl group as a substituent. R ³ represents a hydrogen atom, an alkyl group or a phenyl lower alkyl group.
R ⁴ represents a lower alkyl group or a phenyl group. X represents an oxygen atom or a sulfur atom. ] A cataract preventive and therapeutic agent comprising the carboxylic acid amide derivative represented by the formula [1] as an active ingredient. 2. An active ingredient represented by the general formula: [Wherein R ^{4 ′} represents a lower alkyl group, R ^{5 ′} represents a cyano group,
^{6 ′} represents a halogen atom, and R ^{7 ′} represents a hydrogen atom or a halogen atom, respectively. The cataract preventive and therapeutic agent according to claim 1, which is selected from carboxylic acid amide derivatives represented by the formula: 3. The agent for preventing and treating cataract according to claim 2, wherein the active ingredient is 4-diethoxyphosphinoylmethyl-N- (4-bromo-2-cyanophenyl) benzamide.