JPH03184914A - Active oxygen-resistant agent - Google Patents

Abstract

PURPOSE:To provide an anti-acitve oxygen agent having an activity to remove the active oxygen generated in living bodies by using a p-aminophenol derivative as an active ingredient. CONSTITUTION:An anti-active oxygen agent contains a compound of the formula (R<1> and R<2> are H or lower alkyl; Ar is pyrayine ring, pyrayine N-oxide ring, thiazole ring, benzene ring, pyridine ring, pyridazine ring, pyrimidine ring or triazine ring; R<3> is H, lower alkyl, lower alkoxycarbonyl lower alkoxy, halogen or carboxy lower alkyl; A is lower alkylene; B is lower alkyl) or a salt thereof, e.g. 2-(1,1-dimethylethyl)-6-(1,1-dimethyl-2-hydroxyethyl)-4-pyrazinylamino phenol. The agent is useful for treating autoimmune diseases such as Behcet disease, arterial sclerosis, ischemic heart diseases, encephalopathia, hepatic insufficiency, renal insufficiency, cataract, retinopathy, various cancers, etc.

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.

Conventional technology It has been known that active oxygen such as superoxide, hydrogen peroxide, hydroxyl radicals, and heavy ring oxygen have been associated with 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 pharmac.

1apon) 83. 355-362 (1984)
Inflammation Vol. 5 No. 137-40.
winter 1985 metabolism vol. 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 by the present inventors for the above-mentioned purpose, a novel p-aminophenol derivative [Patent Application No. 144728], which the present inventors previously researched and developed and applied for a patent for, has been found to be extremely suitable for the above-mentioned purpose. It was discovered that it has an excellent anti-active oxygen effect, and the present invention has now been completed.

Means for solving the problems, that is, the present invention is based on the general formula % [wherein R1 and R2 each independently represent a hydrogen atom or a lower acyl group]. Ar is a pyrazine ring group, pyrazine N-
It represents an oxide ring group, a thiazole ring group, a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrimidine ring group, or a triazine ring group.

R3 represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy group, a halogen atom, or a carboxy lower alkyl group. Further, A represents a lower alkylene group, and B represents a lower alkyl group. The present invention relates to an anti-active f/l oxygen agent characterized by containing as an active ingredient at least one selected from p-amine phenol 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.

In this specification, pyrazine N-oxide ring groups defined by Ar include pyrazine 1-oxybe-2-yl and pyrazine 1-oxide-3-yl groups, and thiazole ring groups include 2-thiazolyl and 4- Thiazolyl, 5-thiazolyl groups, pyridine ring groups include 2-pyridyl, 3-
Pyridyl, 4 pyridyl group, 3 as pyridazine ring group
-pyridazinyl, 4-pyridazinyl group, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl group as pyrimidine ring group.
pyrimidinyl group, triazine ring group: 1.2.4
- triazin-3-yl, 1,2.4 triazin-5
-yl, 1,2.1-)riazin-6-yl, 1.3.
5-triazin-2-yl, 1,2.1-)riazine-
Examples include 4-yl and 1,2°3-triazin-5-yl groups.

Examples of lower acyl groups include straight or branched acyl groups having 1 to 6 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, trimethylacetyl, and hexanoyl groups.

Examples of lower alkyl groups include straight or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1erl butyl, pentyl, and hexyl groups.

Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 5ec-butoxy,
Examples include straight-chain or branched alkoxy groups having 1 to 6 carbon atoms such as 1erl-butoxy, pentyloxy, and hexyloxy groups.

Lower alkoxycarbonyl Lower alkyl groups include ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 1-methyl-1-
Methoxycarbonylethyl, 4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, 6-medoxycarbonylhexyl, 1-ethoxycarbonylethyl,
Examples include straight-chain or branched alkoxycarbonyl alkyl groups having 1 to 6 carbon atoms, such as butoxycarbonylmethyl, 2-1ef-butoxycarbonylethyl, pentyloxycarbonylmethyl, and hexyloxycarbonylmethyl groups.

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

Carboxy lower alkyl groups include carboxymethyl,
1-carboxyethyl, 2-carboxyethyl, 1-carboxy-1-methylethyl, 3carboxypropyl,
Examples include straight-chain or branched carboxyalkyl groups having 1 to 6 carbon atoms, such as 4-carboxybutyl, 2-carboxy-1,1-dimethylethyl, 5-carboxypentyl, and 6-carboxyhexyl groups.

Lower alkylene groups include methylene, ethylene, trimethylene, 1-methylmethylene, tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene,
(2) A linear or branched alkylene group having 1 to 6 carbon atoms such as a 1-dimethylethylene group can be exemplified.

The p-aminophenol derivative represented by the above formula (1) can be produced by various methods, specific examples of which are shown in the reaction scheme below.

<Reaction Scheme-1> (2) (4) [In the formula, Ar, A and B are the same as above. R3a represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy group, or a halogen atom. ] According to the method shown in the above reaction scheme-1, a known benzoquinone derivative (2) and a known aromatic amine derivative (3)
The target compound (1a) can be produced by a condensation reaction with and a subsequent reduction reaction.

The above condensation reaction is carried out in the presence of a halide Lewis acid such as titanium tetrachloride, aluminum chloride, ferric chloride, tin chloride, or zinc chloride, using the benzoquinone derivative (2) and an aromatic compound that also serves as a deoxidizing agent. The reaction can be carried out by reacting the group amine derivative (3) in an inert organic solvent at a temperature of room temperature to about 120'C. Examples of inert organic solvents include 1,2-dichloroethane, chloroform, benzene, and toluene. In the above reaction ζ, an inert organic base such as pyridine or triethylamine may be added as a deoxidizing agent. The ratio of the aromatic amine derivative (3) to the benzoquinone derivative (2) is usually about 1 to 10 times the molar amount, preferably about 2 to 4 times the molar amount. The above reaction using titanium tetrachloride is described in, for example, Journal of Organic Chemistry C.
I, Org, Chem,, 32. 324
6 (1967)).
It can be carried out according to the method of Ngarlen et al. Compound (4) obtained above may be isolated from the reaction system and subjected to the subsequent reduction reaction 6, or may be subjected to the subsequent reaction without being isolated.

The subsequent reduction reaction of compound (4) can be carried out using hydrogen gas in the presence of a catalyst such as palladium-carbon or platinum, and thus the target compound (1a) can be obtained.

Incidentally, the above reduction reaction can also be carried out by a method using, for example, sodium hydrosulfide, N,N-diethylhydroxylamine, zinc and acetic acid.

<Reaction scheme-2> 1-I O-A 1 (5) (1b) (1C) (1a) 2 and R2a are the same or different and represent a lower acyl group.

] According to Reaction Scheme-2, the target compound (1b) can be produced via the compound (5) by the O-acylation reaction of the compound (4) and the subsequent reduction reaction, and the compound (1b)
N-acylation reaction of compound (1a) or N, O of compound (1a)
- The target compound (1c) can be produced by diacylation reaction.

The O-acylation reaction of compound (4) shown in the above formula-2 is carried out by adding acetic anhydride, propionic anhydride to the starting material compound (4) without a solvent or in an appropriate solvent such as pyridine, lutidine, collidine, acetic acid, etc. The process can be carried out using a suitable linear lower alkanoic acid anhydride such as, for example, at temperatures from room temperature to about 120'C.

The ratio of acid anhydride to compound (4) is usually about 1 to
The amount may be selected from a range of 10 times the molar amount.

The compound (5) obtained above can be isolated from the reaction system or can be subjected to the subsequent reduction degree 3 reaction without isolation, and the reduction reaction is the same as the reduction reaction shown in the reaction scheme-1 above. It can be carried out under the same conditions.

Also, N-acylation reaction of compound (1b) and compound (1b)
N,O-diacylated carbon ↓L in a) is the above compound (4) using a chain lower alkanoic acid anhydride in a 2 to 20 times molar amount.
The reaction can be carried out under the same conditions as the O-acylation of antisilo, and thus the target compound (1c) can be obtained.

<Reaction scheme-3> F(0-A (1d) 4 [In the formula, Ar, A, B and R2 are the same as above.

R3b represents a lower alkyl group, and E represents a lower alkylene group. ] The hydrolysis reaction shown in the above formula-3 is carried out in a solvent in which water is mixed with an appropriate inert organic solvent such as methanol, ethanol, tetrahydrofuran (TTIF), dioxane, etc., with respect to compound (1d). The reaction can be carried out by reacting with ~20 times the molar amount of sodium hydroxide, potassium hydroxide, etc. at a temperature of 0°C to the boiling point temperature of the solvent, preferably around 0°C to room temperature, and the reaction results in Compound 1e) can be obtained.

The target compounds obtained by the reactions shown in each of the above-mentioned reaction schemes can be easily isolated and purified by conventional separation means such as solvent extraction method, recrystallization method, column chromatography, etc.

The target compound of general formula (1) thus obtained can be converted into a pharmaceutically acceptable acid addition salt by addition reaction with an appropriate acidic compound according to a conventional method, and in the present invention 5, such acid addition salts are also effective. Can be used as an ingredient. 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, tartaric acid, citric acid, methanesulfonic acid, and benzenesulfonic acid. Examples include organic acids such as acids.

Furthermore, some of the compounds of the above formula (1) can be made into pharmaceutically acceptable salts by reacting with basic compounds according to conventional methods, and such salts can also be used as active ingredients in the present invention.

The salts include alkali metal salts such as lithium salts, sodium salts, potassium salts, etc., alkaline earth metal salts such as calcium salts, magnesium salts, etc., and other metal salts such as copper salts.

The anti-active oxygen agent of the present invention is used in the form of a general 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 appropriate6 for this pharmaceutical preparation, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, serious drugs, and injections (liquids, suspensions, etc.). (cloudy agents, etc.), ointments, etc. When molding into tablet form, carriers such as lactose,
Excipients such as white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, potassium phosphate, silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, Binders such as carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate , surfactants such as stearic acid monoglyceride, white sugar, stearin,
Disintegration inhibitors such as cocoa butter and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbents, purified talc, stearates, boric acid powder, lubricants such as polyethylene glycol, etc. can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets, etc. When molding into an emulsion, carriers such as glucose, lactose,
Starch, cocoa butter, hydrogenated vegetable oil, kaolin, excipients such as talc, gum arabic powder, tragacanth powder, gelatin,
Binders such as ethanol, disintegrants such as laminaran, agar, etc. can be used.

When molding into the form of heavy punishment, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Capsule preparations 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. in accordance with a conventional method. Injectables are preferably sterilized and isotonic with blood, and when molded into injectable forms such as solutions, emulsions, and suspensions,
As a diluent, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl 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 isodominant 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, fragrances, flavoring agents, sweeteners, etc. and other pharmaceuticals as required. When molding into a paste, cream or gel form, 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 in the total composition. %
It is better to

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, emulsions, liquids,
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 if necessary, administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. As a single drug, it is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the patient's age, sex and other conditions, the severity of the disease, etc., but the amount of the active ingredient compound is usually about The amount is preferably 15 to 500 mg O, and the preparation can be administered in 2 to 4 divided doses per day.

Examples Hereinafter, in order to explain the present invention in more detail, examples of production of raw material compounds (reference examples) for producing the active ingredient compound of the anti-active oxygen agent of the present invention, production examples of the active ingredient compound, and examples of the production of the anti-active ingredient compound of the present invention will be given. An example of an oxygen agent formulation will be given, followed by a pharmacological test example.

Reference example 1- 2-(1,1-dimethylethyl) -6-(1-, 1-
Production of dimethyl-2-hydroxyethyl)-1,4benzoquinone 400 g of 2-(1,1-dimethylethyl)-4-methoxyphenol, 360 g of 40% glyoxal solution and 36% hydrochloric acid 2011 were dissolved in acetic acid 160011 and stirred. The mixture was heated at 120°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting solid was washed with diethyl ether to give 105 g of 7(1,1-dimethylethyl)-5-methoxy-2(3H)-benzofuranone as a pale red solid. Obtained.

Water was added to the above solution, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated brine, dried over magnesium sulfate, and concentrated. The crude product thus obtained was
Crystallization from diethyl ether-hexane (1:1) further yielded 90 g of 7-(1,,]-dimethylethyl)-5-methoxy-2(3LT)benzofuranone as pale red crystals.

Melting point: 117-118°C 'H-NMR (CDCl2): δ 1°37 (s, 9H), 3.69 (s, 2IO3
, 79 (s, 3H) 6.68 (d, J=2.6Hz, 1H) 6.79 (
d, J = 2.6 Hz, IT-1)2 60.7 g of 60% sodium hydride was suspended in 400 yl of N,N-dimethylformamide (DMF), and 7-(1,1- A solution of 160g of dimethylethylfuranone in DMF1000z!! was added dropwise and stirred for 30 minutes.Next, 230g of iodomethane was added.
DMF 1. 00 ml solution was added and stirred at room temperature for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane = 1:10).
), further washed with cold hexane, and purified with 3,3-dimethyl-7-(1.1-dimethylethyl)-5-methoxy-2.
(3TI)-benzofuranone 1. Obtained 0.4 g as a pale yellow solid.

Melting point: 63.5-64.5°C H-NMR (CDC/3): δ 1, 39 (s. 9 D
, 1. 49 (s, 6Tl)
3 3, 81 (s, 3H) 6, 59 (d, J=2. 611z,
IH) 6, 77 (d, J=2.6H
z, IT () 18 g of lithium aluminum hydride was suspended in 500 yA' of diethyl ether, and 3.3-dimethyl-7-(1.1-dimethylethyl)-5-methoxy-2 was added to this while stirring at room temperature. A solution of 104 g of (3H)-benzofuranone in 400 x 1 liter of diethyl ether was added over 1 hour, and the mixture was further stirred at room temperature for 1 hour. While cooling the reaction mixture in a water bath, add 60 r# of ethyl acetate and 1 ml of water.
00zA' and 10% hydrochloric acid 90011 were sequentially added and the liquids were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over magnesilla sulfate, and then concentrated. The crude product obtained was crystallized from hexane to give l-(1,
I-dimethylethyl) -6- (1,1-dimethyl-
2-hydroxyethyl)-4-methoxyphenol 100
g was obtained as colorless crystals.

4 Melting point: 102.5-1.03.5°C 'TI-NMR (CDCI13): δ]
．． ．． 42 (s. 9H), 1. , 44
(s, 6H,)2, 56 (t, J
=4. 3T-Tz. ITT) 3, 77
(s. 3H) 3, 80 (d. J=4. 311z,
2TI) 6, 7]. (d.l=3.OT
Iz. IH)6. 81. (d, J=3.
Oilz, iTT) 8, 74 (s. I
H) 2-(1.1-dimethylethyl)-6-(1..

55g of 1,-dimethyl-2-hydroxyethyl)-4-methoxyphenol was added to 275111 of acetonitrile and 1111 of water.
．． 6 5 yl! Dissolve 50% of 297 g of dicerium ammonium nitrate while cooling in a water bath.
440xll of acetonitrile aqueous solution was added over 10 minutes. After stirring the reaction mixture for 30 minutes, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated. The crude product obtained was crystallized from hexane,
49 g of the target compound was obtained as yellow crystals.

Melting point = 92~94°C' H-NMR (CD CI!3)
: δ1,, 26 (s, 6H), 1. ,
28 (s, 9H) 1, 81 (t, J=5.6H
z, LH) 3, 80 (d, J=5.6H
z, 2II) 6, 53 (d, J=2.
6Hz. 1.11) 6, 58 (d, J
=2. 6Hz, IT-T) Production Example 1 Production process 1 of 2-(1,1-dimethylethyl)-6-(1.1dimethyl-2-hydroxyethyl)-4-pyrazinylaminophenol [Compound 1] Pyridine ]. 3.4g of dichloroethane 80011! 8.1 g of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 15 minutes. Next, 10.0 g of 2-(1.,]-dimethylethyl)-6-(1.1-dimethyl-26 hydroxyethyl)-1,4-benzoquinone
and 1-2.1-g of aminopyrazine and stirred for 15 minutes.
The mixture was heated and stirred at 5°C. After the mixture was cooled to room temperature, it was filtered through Celite, and the insoluble matter was washed with chloroform. The furnace solution was washed with saturated brine, dried over magnesium sulfate, and then concentrated. The obtained crude product was subjected to silica gel column chromatography (chloroform:ethyl acetate-6=1
→ 31) to produce 2-(1,,]-dimethylethyl)-6-(1,1-dimethyl-2-hydroxyethyl)
8.3 g of -4-pyrazinylimino-2,5-cyclohexadien-1-one [Compound 1a] was obtained as a pale red solid.

In addition, 2-(],,]1-dimethylethyl-6(1,1
-dimethyl-2-hydroxyethyl)J, 3.7 g of 4-benzoquinone was thinned.

Structure and physical properties (melting point and ITI'NM) of the obtained compound
R value) are shown in Table 2.

7 Step 2 Compound 1. 2.5 g of a was dissolved in ethyl acetate 4503FA', and 10% palladium-carbon was added as a catalyst.
After adding 30 g of the mixture and purging the inside of the container with hydrogen gas, the mixture was stirred at room temperature. Hydrogen], 80 xi! After consumption, the catalyst was removed by filtration through Celite, washed with ethyl acetate, and the liquid was concentrated under reduced pressure. The obtained crude product was washed with diethyl ether to obtain 2.3 g of the target compound as a colorless solid.

The structure and physical properties of the obtained compound are shown in Table 2.

Production Examples 2 to 11 Production of Compounds 2 to 11 In the same manner as in Step 1 of Production Example 1, 1-(1,1 dimethylethyl)-6-(],,]1-dimethyl-2-hydroxyethyl-1, 4-benzoquinone, 3-aminopyrazine 1-oxide, 2-aminothiazole, 2-amino-4
-Methylthiazole, 2-amino-4-thiazole ethyl acetate, aniline, 4-fluoroaniline, 3-aminopyridine,
3-amino-6-medoxypyridazine, 2-aminopyrimidine and 3-amino-], 2. From each compound selected from 4 triazines, the target compound [Compound 2
a~Compound 11a'' were produced, respectively.

The structure and physical properties of the obtained compound are shown in Table 1.

In addition, from each compound obtained above, Step 2 of Production Example 1
The target compounds [Compound 2 to Compound 11] were produced in the same manner as above.

Their structures and physical properties are shown in Table 2.

Production example l-2 2-(2-acetoxy-J, 1-dimethylethyl)6-
Manufacturing process 1 of (1,i~dimethylethyl)-4-pyrazinylaminophenol [Compound 12] Compound], a (produced in Step 1 of Production Example 1)2.
2g, acetic anhydride 1. ．． 711! and pyridine 50xl1
The mixture of 9 was stirred at room temperature for 8 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (diethyl ether:hexane-1=3→1.2) to give 2-(2-acetoxy-1,1-dimethylethyl)-
6-(],.

]l-dimethylethyl-4-pyrazinylimino 2.5-
Cyclohexadien-1-one [Compound: +-2a]
1-, 6 g were obtained as a red oil.

The structure and physical properties of the obtained compound are shown in Table 1.

Step 2 Compound 12a was hydrogenated in the presence of palladium-carbon in the same manner as Step 2 of Production Example J to obtain the target compound.

The structure and physical properties of the compound are shown in Table 2.

Production Example 13 2-(2-acetoxy-1,1-dimethylethyl)0 6-(1,,1-dimethylethyl)-4-(2thiazolyl amino)phenol [Compound 13] Manufacturing process] - Production Example 12 In the same manner as in Step 1, the target compound [Compound 13a] was produced from Compound 3a (produced in Step 1 of Production Example 3) and acetic anhydride.

The structure and physical properties of the obtained compound are shown in Table 1.

Step 2 Dissolve 1.3 g of compound 1.3a in 50 rl of THF,
Add to this 6.5 g of sodium hydrosulfide and 1 water.
After adding 50yA' solution and stirring at room temperature for 10 minutes, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was washed with diethyl ether hexane to obtain the target compound 1. og
was obtained as a colorless solid.

The structure and physical properties of the obtained compound are shown in Table 2.

1 Production Example 14 2-(2-acetoxy-1,1-dimethylethyl)6-
(1,1-dimethylethyl)-4-[N-acetyl-N-
(2-thiazolyl)aminocophenol [Compound 14]
A mixture of 0.50 g of Compound 13 (produced in Production Example 13) and acetic anhydride 611 was heated at 1-'OO'C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (diethyl ether:hexane-1:2) to obtain 0.50 g of the target compound as a colorless solid.

The structure and physical properties of the obtained compound are shown in Table 2.

Production Example 15 1-[3-(t+ 1-dimethylethyl)-5(1
, 1-dimethyl-2-hydroxyethyl) 4-hydroxyphenylaminoco-4-thiazoleacetic acid [compound 1-
5] Production 2 3.2 g of compound 5 (produced in Production Example 5) was added to T H
Dissolve in a mixture of F 407/ and ethanol 8011 and add 5 g of sodium hydrosulfide to 5 g of water at room temperature.
0rI! solution, then 2N aqueous sodium hydroxide solution 30
yll was added and stirred for 1 hour. Cool the reaction mixture on ice;
iN Hydrochloric acid 5011 was added and extracted with methylene chloride.

The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated at about 0°C.

The obtained crude product was crystallized from methylene chloride and further washed with diethyl ether to obtain 0.80 g of the target compound as colorless crystals.

The structure and physical properties of the obtained compound are shown in Table 2.

3 Table CI-I 3 3 H3 (approximately 1:1 mixture of syn, H3 anti isomers) z 7 38 1- 42 Table 2 CI-13 3 CI-(3R2 CI (3 5 6 9 50 51 Formulation example) 1 2-(1°, 1 6-(1,10 xyethyl) Minophenol crystalline cellulose (101, manufactured by Asahi Kaei) Cornstarch magnesium stearate dimethylethyl) Dimethyl-2-human "Avicel p T-( - 4-Biradinylar i-00g 0g 0g 2g Total amount 72g Hydroxypropyl methyl cellulose (rTc-5J, manufactured by Shin-Etsu Chemical Co., Ltd.) 2g Polyethylene glycol 6000 Dye titanium dioxide 2.4g 0.6g 4.0g 2 2-(1, , 1-dimethylethyl)-6-(1゜1-dimethyl-2-hydroxyethyl)-4-pyrazinylaminophenol, crystalline cellulose, cornstarch, and magnesium stearate were mixed and polished, followed by sugar coating R8111.
Compress the tablets with a 111 kine. The obtained tablets were heated to T(, -5,
The tablets were coated with a film coating agent consisting of polyethylene glycol 6000, pigment, titanium dioxide, and water to produce film-coated tablets having the above composition.

Pharmacological test ■ "Lip peroxide production inhibition test" Shimamoto et al.'s method [Norio Shimamoto et al.: Free radical clinical practice, v.
ol, 1. 91-95 (+987) ], H
fI 1/C Wistar rats (weight 221-365
g) After blood was removed under ether anesthesia, the brain was removed. The brain tissue was homogenized in phosphate buffer (p 117, 4) under water cooling, the 5v#% homogenate was incubated at 37°C for 1 hour, and the lipid peroxides generated by autoxidation were purified using the method of Okawa et al. Ohkawa, II.
el at.

^na1. Biochem, 95. 351
-358 (1979)), it was measured by the thiobarbic acid (TDA) method.

The compounds obtained in each of the above reference examples [indicated by compound numbers in Table 2 above] and the following compound as a control were used as test samples and dissolved in dimethyl sulfoxide (DM SO) at a final concentration of 2%. Using.

<Control sample> oBHA...butyl hydroxyanisole (manufactured by Tokyo Kasei Co., Ltd.) oBHT...butylated hydroxytoluene (manufactured by Tokyo Kasei Co., Ltd.)
The inhibitory effect on lipid peroxide production is expressed as a % inhibition rate for TBA-reactive rawhide compared to the solvent addition group, and is based on the IC50 value of each test sample and the rc5o value of BHA.
1) is expressed as a relative figure.

The results obtained are shown in Table 1.

4 Table 1 Pharmacological test ■ “1.1-diphenyl-2-picrylhydrazyl (DP
PH) reduction effect test” method by Preuss et al.
NatuIe181, 1199-1200 (+95
According to CF was dissolved in 10% DMSO) was added to distilled water, and after 20 minutes, the absorbance at 510 nm was measured to compare and examine the DPPH reducing effect of each test sample.

This reduction effect was expressed using the decrease in absorbance as an indicator of D P P H radical scavenging activity, and the relative value when the IC value of D P P H radical scavenging activity and the IC5o value of BHA were set as the standard 0 (1). .

The results are shown in Table 2 below.

Table 2 Table 6 Table (Continued) As is clear from the above results, it can be seen that the active ingredient compound of the present invention exhibits extremely excellent effects as an anti-slip oxygen agent.

(hereinafter “2)” 7

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 each independently represent a hydrogen atom or a lower acyl group. Ar represents a pyrazine ring group, a pyrazine N-oxide ring group, a thiazole ring group, a benzene ring group, a pyridine ring group, a pyridazine ring group, a pyrimidine ring group, or a triazine ring group. R^3 represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy group, a halogen atom, or a carboxy lower alkyl group. Further, A represents a lower alkylene group, and B represents a lower alkyl group. ] 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.