JPH03204813A - Active oxygen-inactivating agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to an anti-active oxygen agent that has the effect of scavenging active oxygen generated within a living body.

Prior Art Conventionally, active oxygen such as superoxide, hydrogen peroxide, hydroxyl radicals, and stacked oxygen have been known to cause various pathologies,
It has been said that it is involved in the cause and progression of pathological conditions. For example, when arachidonic acid, which is an important component of biological membranes, is attacked by active oxygen, it induces the production of inflammatory factors such as lipid peroxide, and a chain reaction of peroxidation progresses in the body. Membrane dysfunction occurs and tissue damage is induced.

On the other hand, while living organisms have a system that generates active oxygen, they also have a system that eliminates (metabolically inactivates) the generated active oxygen as one of the oxidative metabolism or biological defense mechanisms.
Under normal conditions, active oxygen does not accumulate to the extent that it causes tissue damage. However, it is known that during pathological conditions, while the production of active oxygen is promoted, the function of its scavenging system tends to decline. For this reason, anti-reactive oxygen agents are considered to be useful as therapeutic agents for improving the functions of organs, tissues, etc. during pathological conditions or preventing the progression of damage, and various substances with anti-reactive oxygen effects are currently being researched. Proposed. Specific examples include α-tocopherol, phenylbutacin, D-penicillamine,
Clofibrate etc. are known [Japanese Pharmacological Journal (Fol.
ia pharmacol.

1apon), 83. 355-362 (198
4) ; Inflammation vat, 5 No, ] ] 37-40.
winter 1985; metabolism vol. 1.25. No
, 9831841 (198g), etc.), but their anti-active oxygen effects are still not satisfactory, and there is a demand in the art for a new anti-active oxygen agent to replace them.

Problems to be Solved by the Invention An object of the present invention is to provide a new anti-active oxygen agent that meets the needs of the above-mentioned industry.

As a result of intensive research for the above purpose, the present inventors have discovered a series of p-aminophenol derivatives that have therapeutic effects on diseases such as asthma, bronchitis, and psoriasis [Unexamined Japanese Patent Publication No. No. 64-25756] has been found to have an extremely excellent anti-active oxygen effect that meets the above-mentioned objective, regardless of the above-mentioned pharmacological action, and the present invention has now been completed.

Means for solving the problem, that is, the present invention is based on the general formula % [wherein R1 represents a lower alkyl group]. R2 represents a hydrogen atom or a lower alkyl group, R3 represents a hydrogen atom or a lower alkyl group, or R2 and R3 are combined to form a group (CH2
) 4 or the group Cl=CH-CH=CH-. α is an aromatic hetero 5- or 6-membered ring group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, or pyrimidine -N-oxide ring group, such aromatic heterocyclic groups are selected from lower alkyl groups, halogen atoms, phenyl groups, lower alkoxycarbonyl groups, amino groups, lower alkoxy groups and hydroxy lower alkyl groups. It may have 1 to 3 pieces.

However, the above-mentioned aromatic hetero 5- or 6-membered ring groups include thiazole ring groups, isothiazole ring groups, pyridine ring groups, and 1,3.
It must not be a 5-triazine ring group. ] The present invention relates to an anti-active oxygen agent characterized by containing as an active ingredient at least one selected from p-aminophenol derivatives represented by the following and salts thereof.

The anti-reactive oxygen agent of the present invention is effective as a therapeutic agent for autoimmune diseases such as Behçet's disease by utilizing its unique active oxygen scavenging action, and is also effective as a therapeutic agent for autoimmune diseases such as arteriosclerosis, ischemic heart disease, brain damage, and liver damage. It is useful as a therapeutic agent for various diseases involving active oxygen, such as renal failure, cataract, retinopathy, and various cancers.

Each group used in this specification is as follows.

Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as pentyl and hexyl groups.

Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, 1
Examples include straight chain or branched alkoxy groups having 1 to 6 carbon atoms such as ert-butoxy, pentyloxy, and hexyloxy groups.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

Lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, terl
Examples include alkoxycarbonyl groups in which the alkoxy moiety has 1 to 6 carbon atoms, such as -butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups.

Hydroxymethyl as a hydroxy lower alkyl group,
1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 5-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 1-methyl-2-hydroxyethyl, 1-methyl-2-hydroxypropyl, 1,
Examples include alkyl groups having 1 to 6 carbon atoms substituted with one hydroxyl group such as 1-dimethyl-2-hydroxyethyl group.

Examples of the hetero five- or six-membered ring group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms include pyrrole ring group, furan ring group, thiophene ring group, pyrazole ring group, imidazole ring group, isoxazole ring group, oxazole ring group, triazole ring group, thiadiazole ring group,
Examples include oxadiazole ring group, triazine ring group, pyrazine ring group, pyrimidine ring group, pyridazine ring group, etc. Specific representative examples thereof include 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrazolyl, 3-pyrazolyl, 4
-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2
-imidazolyl, 4-imidazolyl, 5-imidazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxasilyl, 4-oxasilyl, 5-
Oxacylyl, 1,2.3-4lyazol-1yl, 1
, 2.3-triazol-4-yl, 1°2.34 riazol-5-yl, 1.2.4 triazol-1-yl, 1,2.4-) riazol-3-yl, 1,2. 4-
1 lyazol-5-yl, 1. 2. 3-thiadiazol-4-yl, 1.2.3-thiadiazol-5-yl, 1,2°4-thiadiazol-3-yl, 1,2.
4-thiadiazol-5-yl, 1,3.4-thiadiazol-2-yl, 1. 2. 3-oxadiazol-4-yl, 1. 2. 3-oxadiazole-5-
yl, 1,2.4-oxadiazol-3yl, 1,2
．． 4-oxadiazol-5-yl, 1.3.4-oxadiazol-2-yl, 1゜2.4-triazine-3
-yl, 1,2.1-triazin-5-yl, 1. 2
．． 4-triazin-6-yl, 1,2.3-1 riazin-4-yl, 1.2.1 triazin-5-yl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4 -pyridazinyl group, etc. can be exemplified.

Representative examples of the pyrazine-N-oxide ring group, pyridazine-N-oxide ring group and pyrimidine-N-oxide ring group include pyrazine-1-oxide-2-yl, pyrazine-1-oxide-3-yl, pyrimidin-1-oxide-2-yl, pyrimidin-1-oxide-4-yl,
Pyrimidine 1-oxide-5-yl, pyrimidine-1-
Oxido-6-yl, pyridazine-1-oxide-3-
Examples include pyridazin-1-oxide-4-yl, pyridazin-1-oxide-5-yl, pyridazin-1-oxide-6-yl, and the like.

The above general formula (1) used as an active ingredient of the anti-active oxygen agent of the present invention
The p-aminophenol derivative represented by can be produced according to the method described in the above-mentioned publication, and can be isolated and purified by conventional separation means.

Further, the salts of the above derivatives include pharmaceutically acceptable acid addition salts obtained by subjecting the derivatives to an addition reaction with a suitable acidic compound according to a conventional method. Examples of acidic compounds that can form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and maleic acid, fumaric acid, malic acid,
Examples include organic acids such as tartaric acid, citric acid, benzoic acid, and benzenesulfonic acid.

The anti-oxidant agent of the present invention is used in the form of a parenteral pharmaceutical preparation. The pharmaceutical preparation contains commonly used fillers, extenders,
It is prepared using binders, humectants, disintegrants, surfactants, diluents such as lubricants, excipients, etc. Various forms can be selected as appropriate for this pharmaceutical preparation, and representative examples include tablets, emulsions, powders, solutions, suspensions, emulsions, granules, capsules, halves, and injections (solutions, suspensions). Examples include medicaments, ointments, etc.), ointments, etc. When molding into tablet form, carriers such as lactose, sucrose, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, potassium phosphate, silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose,
Binding agents such as hydroxypropyl cellulose, methyl cellulose, and polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid surfactants such as monoglycerides,
Disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin, bentonite, and colloidal silicon. Adsorbents such as acids, purified talc, stearates, boric acid powder, lubricants such as polyethylene glycol, etc. can be used. Furthermore, tablets may be coated with a normal coating if necessary.
For example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets, etc. can be used. When molding into an emulsion, carriers include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, laminaran,
A disintegrant such as agar can be used.

When molding into half pieces, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Capsules can be prepared by mixing the active ingredient compound of the anti-oxidant agent of the present invention with the various carriers exemplified above and filling them into hard gelatin capsules, soft gelatin capsules, etc. according to a conventional method. Injectables are preferably sterilized and isotonic with blood, and when molded into injectable forms such as solutions, emulsions, and suspensions, diluents such as water, ethyl alcohol, propylene glycol, and ethoxylated isostearyl are used. Alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, sufficient amounts of salt, glucose, glycerin, etc. to prepare an isotonic solution may be included in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can. Furthermore, the pharmaceutical preparation of the present invention may contain coloring agents, preservatives, perfumes, flavoring agents,
It may also contain sweeteners and other pharmaceuticals. paste,
When molding into cream and gel forms, diluents such as white petrolatum, paraffin, glycerin,
Cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used.

The amount of the compound of general formula (1) and/or its salt to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually 1 to 70% by weight based on the total composition. It is better to do so.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and it can be administered in accordance with various preparation forms, patient age, sex and other conditions, degree of disease, etc. For example, tablets, gunpowder, liquid,
Suspensions, emulsions, granules, capsules, etc. are administered orally. Injections are administered intravenously alone or mixed with conventional replacement fluids such as glucose and amino acids, and further intramuscularly, intradermally, subcutaneously or intraperitoneally, if necessary. In the case of halving, it is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
Usually the amount of active ingredient compound is about 0 per 1 kg of body weight per day.
．． It is preferable to use an amount of 5 to 500 cm, and the preparation has 1
It can be administered in 2 to 4 divided doses per day.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, formulation examples of the anti-active oxygen agent of the present invention will be given as examples, and then pharmacological test examples will be given.

Example 1 2.6-di-1ert-butyl-4-pyrazinylaminophenol 250g crystalline cellulose (Japanese Pharmacopoeia) 30g cornstarch (
Japanese Pharmacopoeia Crystal) 17g Talc (Japanese Pharmacopoeia Crystal)
2g magnesium stearate 2,6-tetf-butyl-4-pyrazinylaminophenol as active ingredient, 250% per capsule
Hard gelatin capsules (1000 pieces) containing mg
Prepared according to the above recipe.

That is, each component was finely powdered, thoroughly mixed to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions to prepare the desired capsules.

Example 2 2-N-(3,5-di-tert-butyl-4-hydroxyphenyl) 100g Aminopyrazine-4-oxide crystalline cellulose (Avicel pH 101, manufactured by Asahi Kasei ■) 40g Cornstarch 30g Magnesium stearate 2g Total amount
172g hydroxypropyl methylcellulose (rTC-5J, 8g manufactured by Shin-Etsu Chemical Co., Ltd.) Polyethylene glycol 6000 2. 4g pigment 0.6g titanium dioxide 4.0g2-N-
After mixing and polishing (3,5-di-tert-butyl-4-hydroxyphenyl)aminopyrazine-4-oxide, crystalline cellulose, cornstarch and magnesium stearate, the mixture is tableted using a sugar coater with a radius of 8 mm. The obtained tablets were treated with TC-5, polyethylene glycol 6000, pigment,
A film-coated tablet having the above composition was produced by coating with a film-coating agent consisting of titanium dioxide and water.

Pharmacological test I “Lipid peroxide production inhibition test” Shimamoto et al.’s method [Norio Shimamoto et al.: Free radical clinical practice, v.
ol, I, 91-95 (1987)], male Wistar rats (body weight 221-365 g) were exsanguinated under ether anesthesia, and the brains were removed. The brain tissue was homogenized in phosphate buffer (pH 7,4) under water cooling,
The 5 w/v% homogenate was incubated at 37°C for 1 hour, and the lipid peroxides generated by autoxidation were collected using the method of Ohkawa et al. [Ohkawa, H, et al.
Biochem, 95 351-358 (1
979)] according to thiobarbylic acid (T B
A) Measured by method.

Each p-aminophenol derivative (invention) shown in Table 1 below and BHA and BIT as controls were used as test samples, and these were dissolved in dimethyl sulfoxide (DMSO) and used at a final concentration of 2%.

, B HA...Butylated hydroxyanisole (manufactured by Tokyo Kasei Co., Ltd.) OBHT...Butylated hydroxytoluene (manufactured by Tokyo Kasei Co., Ltd.)
The lipid peroxide production inhibitory effect is expressed as a % inhibition rate for the TBA reaction product compared to the solvent addition group, and is based on the IC5o value of each test sample and the IC5o value of BHA (1
) is expressed as a relative value.

The results obtained are shown in Table 2 below.

Table 2 Pharmacological test ■ [1,1-diphenyl-2-picrylhydrazyl (DP
PH) Reduction Test” Method of Brois et al. [Brois, M.S.
Nature181, 1199-1200 (195
8) ] 0.1. Each test sample dissolved in ethanol (
Add a 0.5yl solution (dissolved in distilled water for OCA and 10% DMSO for CF) of the same symbol as in Pharmacology Test ■, and measure the absorbance at 510 nm after 20 minutes. The DPPH reducing effects of the samples were compared and examined.

This reduction action uses the decrease in absorbance as an indicator of DPPH radical scavenging activity, and IC5 of DPPH radical scavenging activity.
It is expressed as a relative value when the o value and the IC5o value of BHA are taken as the standard (1).

The results are shown in Table 3 below.

As is clear from the results in Table 3 and above, it can be seen that the active ingredient compound of the present invention exhibits extremely excellent effects as an anti-active oxygen agent.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [In the formula, R^1 represents a lower alkyl group. R^2 represents a hydrogen atom or a lower alkyl group, R^3 represents a hydrogen atom or a lower alkyl group, or R^2 and R^3 are combined to form a group ▲There is a mathematical formula, chemical formula, table, etc.▼ or Indicates the group -CH=CH-CH=CH-. α is an aromatic hetero 5- or 6-membered ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, or pyrazine-N
- oxide ring group, pyridazine-N-oxide ring group, or pyrimidine-N-oxide ring group, and these aromatic heterocyclic groups have as substituents lower alkyl groups, halogen atoms, phenyl groups, lower alkoxycarbonyl groups, It may have 1 to 3 groups selected from an amino group, a lower alkoxy group, and a hydroxy lower alkyl group. However, the aromatic hetero 5- or 6-membered ring group must not be a thiazole ring group, an isothiazole ring group, a pyridine ring group, or a 1,3,5-triazine ring group. An anti-active oxygen agent comprising at least one selected from the following p-aminophenol derivatives and salts thereof as an active ingredient.