JPS60142919A - Antioxidant - Google Patents

Abstract

NEW MATERIAL:An indane derivative expressed by formula I a or I b (R<2> and R<3> are H, lower alkyl or halogen, provided that R<2> and R<3> in formula I a are not H at the same time) and a salt thereof. EXAMPLE:7-Hydroxy-4-methyl-1-indanone oxime. USE:An antioxidant, having the ability to remove active oxygen species and prevent the formation of lipoperoxides in the living body, and specifically useful as an antiarteriosclerotic agent, carcinogenic preventing agent, carcinostatic agent, anti-inflammatory agent, analgesic agent and remedy for autoimmune diseases, etc. PREPARATION:A compound expressed by formula 2 is reacted with a compound expressed by formula 3 in the presence or absence of a basic compound, e.g. NaOH, in an inert solvent, e.g. methanol or dioxane, to afford the aimed compound expressed by formula I a, which is then catalytically hydrogenated in the presence of a catalyst, e.g. Pd, to give the compound expressed by formula I b.

Description

[Detailed description of the invention] The present invention relates to antioxidants.

Oxygen is essential for living organisms to maintain life, such as energy production and metabolism. The oxygen is converted into so-called active oxygen species such as oxygen aniosil radicals, sulfur peroxide radicals, and hydrodic radicals through reactions with energy-generating fibers, enzymatic reactions, reactions with purple rays, radiation, and the like. These reactive oxygen species are useful for living organisms, such as oxygenation enzymes and white blood cell bactericidal action, but they also contain oleic acid, linoleic acid, dilucic acid, etc., which are abundantly present in living organisms.
Promotes peroxidation of unsaturated fatty acids, such as ara+tonic acid, which form lysilipids in biological membranes, forming lipid peroxides. This lipid peroxide causes the generation of alco+diradicals and 0+diradicals like the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes [metabolism,
1 scarcity (10).

(See 1978 Special Feature on Active Oxygen). However, enzymes involved in the metabolic deactivation of the above-mentioned reactive oxygen species, such as superoxidase dismutase C3OD) and catalase% curtathiosybelositase, are present in living organisms, and α-tocopherol (Pita-3) is present in living organisms. , 7E), etc., which have various antioxidant abilities, exist, and the normal living body is normally maintained by the action of these.
For some reason, there may be a deficiency in the appropriate defense mechanisms such as the enzymes, pita-tris, etc., or the generation of reactive oxygen species or the production and accumulation of lipid peroxides that exceed the ability of the appropriate defense mechanisms. It is often recognized that When a deficiency in such a defense mechanism occurs, the peroxidation reaction progresses in a chain reaction, leading to serious disorders such as various diseases caused by platelet aggregation, inflammation,
Liver damage, arteriosclerosis, hemolysis, aging or senile dementia, retinopathy, lung damage, heart and lung damage caused by certain drugs, ischemic vascular disease, etc. occur.

Compounds that have the effect of removing active oxygen species (radicals), which are considered to be the main cause of the various disorders listed above, and preventing or reducing the production and accumulation of lipid peroxides in the body are generally known as antioxidants. In fact, there have been many reports on the preventive and therapeutic effects of each of the above-mentioned f[liE diseases due to its use.

Antioxidants that have been reported include the above-mentioned SOD and other topical agents [Superoxide and Medicine, written by Yoshihiko Oyanagi, 1
981, Kyoritsu Shuppansha, pp. 137-141], Butyl Shidoro + Citrueshi (BHT), Butyl Shidoro + Cyanisole (BHA), α-Tokovyori Hill (Pip.l Niji E), etc. [Makoto Mino, Hide Tanaka. High, Pharmaceutical, Yarnal, +9 (
+2), 1983, p.2351-2359 and Toshihiko Suematsu, Ibid., 19 (5).

1983, p.909-914].

The present inventors have discovered that a series of Ishitashi derivatives newly produced by the present inventors have an antioxidant effect similar to that of the above-mentioned conventionally known antioxidants, and have hereby completed the present invention. I ended up doing it.

That is, the present invention relates to the general formula [wherein R1 is an amino group or a human
2 and R3 are the same or different and each represents a hydrogen atom, a lower alkyl group or a bald atom. However, when R1 is a group, R2 and R3 must not both be hydrogen atoms. ] The present invention relates to an antioxidant containing the Ishita derivative represented by the following and its salt as an active ingredient.

The antioxidant active ingredient compound of the present invention has the effect of removing active oxygen species and preventing or reducing lipid peroxide production in the body. Therefore, the antioxidant of the present invention can be used as a prophylactic and therapeutic agent for various disorders and diseases caused by excessive generation of active oxygen species, bioaccumulation of lipid peroxides, or lack of defense mechanism against these, for example, as an anti-arteriosclerotic agent. As a pharmaceutical agent, carcinogenesis prevention agent, anti-cancer agent, anti-inflammatory agent, analgesic agent, autoimmune disease treatment agent, platelet aggregation inhibitor, antihypertensive agent, antihyperlipidemia agent, retinopathy of prematurity and cataract prevention and treatment agent, etc. Useful. Furthermore, the antioxidant of the present invention is effective not only as the above-mentioned medicine, but also as an antioxidant for fats and oils contained in processed foods, etc.

In the Ishitashi derivative represented by the above general formula f1) used as an active ingredient of the antioxidant of the present invention, R□, R2 and R3
The lower alkyl groups represented by include methyl, ethyl,
Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as zuOFf:, ru, isozutyl, butyl, tert-butyl, besityl, and hesyl groups. Further, examples of the hydrogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The intane rust conductor represented by the above general formula +1+ is a new compound that has not been published in any literature, and is produced, for example, by the method shown in the following reaction scheme-1.

[Reaction equation-! ]

(2) (Ia) 1R' (1b) [In the formula, R2 and R3 are the same as above. ] Known compound of general formula (2)
The reaction with 3) can be carried out in a suitable inert solvent in the presence or absence of a basic compound.

The basic compounds used in this case include, for example, inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.; Azapishik [1 [4
,3,O]]nonene-5DBN), 1.5-diazadicycloC5,4,01UshidececciCDBU),
;Azapisik O[2,2,2]octa,7(DABCO
) and the like can be exemplified.

Any inert solvent may be used as long as it does not adversely affect the reaction, but examples include lower alcohols such as methanol, ethanol, and isopropyl alcohol, dioxychloride, tetrahydrophylazine, and alcohol. Ethers such as ethyl ether and ethylesidilycol 7-methyl ether, Beshit! Aromatic hydrocarbons such as citric acid, tornizi, and beef citrus, hydrocarbons such as chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfo+side, hexamethyllisic acid triamide, etc. can be mentioned. Human 0 + Silua E, 7 (3)
The amount used is usually at least equal to the amount of the compound of general formula (2), preferably from equal to 7 to 5 times the amount. The reaction temperature is usually room temperature to 200°C, preferably 50 to 150°C, and the reaction is generally completed in about 1 to 10 hours.

The reduction of the compound of general formula (1a) can be carried out by catalytic hydrogenation in a suitable solvent in the presence of a catalyst. Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isodurobanol, hydrocarbons such as hexane and cyclohexane, diethyle, 7-glycol dimethyl ether, dioxic acid, and tetrahedron. Examples include ethers such as 0-furan and ethyl ether, esters such as ethyl acetate and methyl acetate, and non-50% polar polar solvents such as dimethylformamide.

Examples of catalysts include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite,
Raney nickel or the like is used. The amount of catalyst to be used is generally 0.02 to 1 for the compound of general formula (la).
It is best to double the amount.

The reaction temperature is usually -20°C to around room temperature, preferably 0°C to
It is best to set the hydrogen pressure to around room temperature and usually 1 to 10 atm.
The reaction generally takes about 0.5 to 10 hours to complete.

Further, the Ishita derivative represented by the general formula +1) can also be produced by the method shown in the following reaction scheme-2.

[Reaction Scheme-2] (IC) (Id) [In the formula, R1 is the same as above. R2' and R3' are the same or different and represent a hydrogen atom or a lower alkyl group. However, R2'
and R'' are not both lower alkyl groups.R2
"and R3" are the same or different and represent a hydrogen atom, a lower alkyl group or a hydrogen atom. However, R2" and R3" are both lower alkyl groups, and R2" and R
At least one of 3'' shall represent a herogesi atom.] The helogesylation reaction of the compound of general formula (1c) is carried out in the presence of a conventional halogenating agent. A wide variety of known halogenating agents can be used.
halogenating agents such as bromine, chlorine or -iodine chloride,
N- such as sulfuryl chloride, thiodiluk D-lide, N-bromosuccinimide, N-lyD-succinimide, etc.
Examples include halogenating agents such as halogenoic acid imide and the like. The amount of the halogenating agent to be used is usually about equimolar to 10 times the molar amount of the compound of general formula (IC),
Preferably, the amount is equimolar to 5 times the molar amount. Examples of the solvent used in the reaction include dioxyhydrocarbons such as dichloride, dichloromethane, dichloroform, and carbon tetrachloride, acetic acid, dihyosic acid, and water. In this reaction, the reaction temperature is usually 0°C to the boiling point of the reaction solvent, preferably 0 to 40°C, and usually 1-1
The reaction is completed in about 0 hours.

The target products obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and thin layer chromatography.

Incidentally, the compound of the general formula ([) naturally includes optical isomers.

The A:J4y derivative represented by the general formula (RI) can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and in the present invention, this acid addition salt can also be used as an active ingredient. In the above, examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, ricic acid, and hydrobromic acid, acetic acid,
Oxalic acid, succinic acid, maleic acid, fumaric acid, Rishi 1
Acid, tartaric acid, quesic acid, ma0. ．． Organic acids such as I acid, metacisulfosic acid, benzoic acid, etc. can be used.

The antioxidant of the present invention is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pre-splits, powders, liquids, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.)
, ointments, etc. When forming into a tablet, a wide variety of carriers known in the art can be used, such as lactose, sucrose, sodium chloride, glucose, urea, di, I, calcium carbonate, kaori, crystalline cellulose, silicone, etc. Excipients such as acids, water, ethanol, dipanol, simple syrup, sucrose solution, desiccant solution, gelatin solution, carboxylic dimethylcellulose, shellac, methylcellulose, potassium ricinate, and binders such as polyvinylpyrrolidone. , dried deciJJ'J1 alf sodium sinate,
Kashiteshi powder, Laminaran powder, sodium bicarbonate, calcium carbonate, polyester fatty acid esters, sodium lauryl sulfate, heptanoglyceride stearate, decomposition agents such as lactose, white sugar, stearin, cocoa butter, Disintegration inhibitor for hydrogenated oil, etc., No. 4
Absorption enhancers such as grade A, I monium base, sodium lauryl sulfate, moisturizing agents such as glyceric acid, dindushi, adsorbents such as desi-dushi, lactose, kaorishi, besitonite, colloidal silicic acid, purified talc, stearic acid, etc. acid salt, boric acid powder,
Polyethylene: Examples include lubricants such as J Klicol.

Furthermore, the tablets may be provided with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets.

When forming into split pieces, a wide range of conventionally known carriers can be used, such as excipients such as glucose, lactose, desiccant, cacao butter, hydrogenated vegetable oil, kaorishi, talc, powdered gum arabic, and talc. Examples include binders such as sword powder, gelatin, and ethanol, and disintegrants such as laminar acid. When molding into the form of a suppository, a wide range of conventionally known carriers can be used, such as polyethylene, 7-crystalline, cacao butter, high alcohols, esters of higher alcohols, gelatin, 1% and 1/2% Synthetic lycerides and the like can be mentioned. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions, and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, such as water, ethyl alcohol, dipropylene glycol, ethyl + isostearyl silicide, polyol + isostearyl silyl alcohol, polyiodecethylecysolpitan fatty acid. Examples include esters.

In this case, a sufficient amount of salt, glucose, or chrycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraphyte, chrycerin, cellulose derivatives, polyethylene glycol, silifushi, besitonite and the like.

The amount of the compound of the general formula fl) and its salt to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected from a wide range, but usually ranges from 1 to 70% by weight in the pharmaceutical preparation. It is good to be treated.

The method of administering the above pharmaceutical preparation is not particularly limited, and is appropriately determined depending on the various preparation forms, age, sex and other conditions of the patient, the severity of the disease, and the like. For example, tablets, tablets, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and further, if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the compound of general formula f11 and its salt, which is the active ingredient, is 1.
It is preferable to set the amount to about 0.2 to 200 W9 per kg of body weight per day.

Examples of the production of the Ishitashi Rui conductor represented by the general formula (1) and formulation examples of the antioxidant of the present invention containing the same are listed below, followed by pharmacological test examples.

Manufacturing example! Human 0+ Silamici Hydrochloride 28F and Potassium Carbonate 56
Add F to 400ff/methanol and heat under reflux for 30 minutes. After cooling, the supernatant is collected and a human-0-bovine-dylamine methanol solution is prepared. 6.29 g of 7-silica 4-methyl-1-ishitanosi I was added to this solution of human and dimetathur, and the mixture was heated under reflux for 5 hours with stirring. The reaction mixture is concentrated to dryness under reduced pressure. Add 200 ml of ethyl acetate to the residue, and remove insoluble matter. The filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized from methanol to obtain colorless needle crystals of 7-hydro+cy 4-methyl-1-internosio shim 17.6F.

mp, 148-149-5°C Using appropriate starting materials, Production Example 2 was prepared in the same manner as in Production Example 1.
Obtain the compound ◎ Production Example 2 4.6-, Methyl-7-hydro+Shi l-Intanosio+Shim mp, 155-156°C Colorless needle crystals Production Example 3 7-HydoD-4-Methyl- 1-Ishitanoshio 15. Dissolve OF in 200d acetic acid and add platinum oxide catalyst 1
．． 02 was added and catalytic reduction was carried out at room temperature for 8 hours under a hydrogen pressure of 5 atm. After removing the catalyst, the filtrate is concentrated to dryness under reduced pressure. Add 200 ml of ethanol to the residue to dissolve it, and saturated it by blowing in hydrochloric acid gas.

The solvent was concentrated to dryness under reduced pressure, and the residue was recrystallized from ethanol to give colorless needle-like crystals of 1-a3-7-hydro-4-
3.30y of methyl ishitashi hydrochloride is obtained.

*zp, 221-223°C Using appropriate starting materials, the following 1st
The compounds listed in the table are obtained.

Table 1 Production Example 8 1-Amino-7-shidoroshi 4-methylishitashi hydrochloride 11 was dissolved in 20 g of water, stirred vigorously at room temperature, and then mixed with a 3N hydrochloric acid solution containing 0.85 y of iodine monochloride 5 m
Add 1 dropwise. After stirring at the same temperature for 2 hours, cool on ice.

The precipitated crystals are filtered and converted into hydrochloride, then washed with ether and dried. Yellow needle crystals of 1-amino-7-hydrochloride 6-B-4-methylhydrochloride 0.70
Get y.

mp, decomposed at 200 DEG C. or above.Production Example 9 1-Amino-7-hydrohydrochloride 1-Oy is dissolved in 60 m of acetic acid, and 1.53 p of sulfuryl chloride is added dropwise with stirring while cooling with water. After stirring at the same temperature for 3 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid residue in saturated ethanol 50%
After dissolving in 11 Ll, the solution was dried under reduced pressure. iso-50
Colorless prismatic crystals recrystallized from panol-ether
-Asanno 4.6-'-/R00-7-Hydo0+C, 0.43y of Itan hydrochloride is obtained.

mp, 238-239°C (decomposed) Formulation example l Compound of Production Example 1 200 Tq Glucose 250 mq Smoked distilled water for injection Appropriate amount Total amount 5 tnl Nl Water for injection Preparation The compound obtained in Example I and glucose were dissolved. After that, it was injected into Uba's Ashizuru, and after nitrogen replacement, 121
Autoclaving is performed at ℃ for 15 minutes to obtain an injection having the above composition.

Formulation Example 2 Compound of Production Example 3 100y Avicel (trade name, manufactured by Asahi Kasei ■) 40y Cocystarch 302 Magnesium stearicate 22 Polyethylene sidilycol-60003y Mustard oil 40
y The compound obtained in Production Example 3, Avicel, cornstarch, and magnesium stearicate were mixed and polished, followed by sugar coating A'1O.
Compress the tablets with +ne of rul. The tablets thus obtained are coated with a film-coating agent consisting of TC-5, polyethylene, 7Cryolue 6000, castor oil, and methanol to produce film-coated tablets having the above composition.

Formulation Example 3 Compound of Production Example 7 2゜Purified lanolin 5y Sarashimitsu D 5y White petrolatum, 7 88y Total amount 100y Heat the Sarashi Mitsuwa to make it liquid, then Production Example 7
Add the compound obtained in , purified lanolin and white petrolatum,
After heating until it becomes liquid, it is stirred until it begins to solidify to obtain an ointment having the above composition.

Pharmacological Tests It is well known that luminol is a luminescent reagent that emits more intense light than lipid peroxide in the presence of a hemisi catalyst.

This test uses linoleic acid hydride, which is known as a strong oxidizing agent like hydrogen peroxide, to evaluate the oxidation of luminol by this peroxide, and to determine the extent to which the compound (antioxidant) to be tested is The antioxidative ability of the compound was evaluated by measuring the inhibition. In addition, the control drug (antioxidant), Jiri Sanshi E (VE'), has been shown to be effective against allo+ in vivo (in viυ0) based on its antioxidant ability.
It is known to reduce blood peroxidized lipids caused by Saku, and it is recognized that compounds having similar antioxidant ability can similarly reduce blood peroxidized lipids. The test method is as follows.

(1) Test method The test compound was measured at 1 to 1 x lo W/ml, and the linoleic acid hydroperoxide side was measured at 1. OX 10-97ru/
Prepare a methanol solution containing me concentration (hereinafter referred to as test solution). Also, prepare a 0.1M sodium carbonate buffer containing lXl0#L minol and TC8 (fetal bovine serum, manufactured by 4zuko) at a concentration of 1-25xlOy/ml.

These prepared solutions were automatically inhaled and mixed in 0.4 ml portions in the order of test solution, TC5 solution, and luminol solution using the flow system shown in Figure 1. After mixing the final luminol solution, the photo counter was 7?649S: Hamamatsu Photonics Co., Ltd.) to measure the amount of luminescence. In addition, in Figure 1,
n> is the photo counter, (2) is the cell, (3) is the mixer, (4) is the test solution, (5) is the luminescent reagent (luminol solution), and (6) is the catalyst (, FC, S liquid),
(7) is a washing buffer (0.1M sodium carbonate buffer), (8) is a syringe, (9) is a washing buffer, (1
0) indicates pulp.

Each of the compounds shown in Table 2 was used as a test compound at a predetermined concentration, and the results of measuring the luminescence amount at each @&~ concentration are also shown in Table 2. Each luminescence amount was expressed by calculating the ratio (H) to this amount according to the following formula, with the luminescence amount when using the above-mentioned test solution not containing the test compound as 1, and the value was shown.

A: Number of mustards when no test compound is added and lipid peroxide is added B: Number of mustards when neither the test compound nor lipid peroxide is added C: Number of mustards when both the test compound and lipid peroxide are added The test compounds in Table 2 are as follows.

Present invention I......Produced in Production Example 3 [general formula (
1), R□=N112. R2=H, R=C113
) Present invention II・・・・・・・・・Production example 4 [
General formula (1), R□=NH2, R2=Cll3. R
,=CH3] Unexploded I of the present invention... Obtained in Production Example 6 [General formula (I).

R□=NH2, R2=I, R3=CH3) Present invention ■...... Obtained in Production Example 7 [For general formula, R□
=NH2, R2=C1, R3=C1) vs. [BIIT ・
=-=Butyl human D beef Citruue υ vs. [v E-=-=-
・Vitamin E (2) In addition, in the same test as above, the 50% inhibition rate against 50 μt of linoleic acid hydride O pero+side 1 x 7 l/ml (i.e., the oxidation ability of the pero+ side was
Concentration of each test compound that inhibits antioxidative activity (IL5o)
The results for each test compound are shown in Table 3 below.

Table 3 From Tables 2 and 3 above, it can be seen that all of the Ishita derivatives used in the present invention (inventions ① to ①) have strong antioxidant ability. Furthermore, each of the above compounds was found to exhibit strong activity in vivo as well as BHT and VE. This indicates that the antioxidant of the present invention is useful as a prophylactic and therapeutic agent for various diseases caused by lipid peroxides and active oxygen species.

[Brief explanation of the drawing]

FIG. 1 shows a flow path diagram of an apparatus for measuring the antioxidant ability of the active ingredient compound of the antioxidant of the present invention. (That's all) Figure 1

Claims (1)

[Claims] ■ General formula [wherein R1 is an amino group or a human
2 and R3 are the same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom. However, when R1 is a human group, R2 and R3 must not both be hydrogen atoms. ] An antioxidant containing an Ishitashi derivative represented by the following and its salt as an active ingredient.