JPH0881365A - Inhibitor for oxidation stress - Google Patents

Abstract

PURPOSE: To obtain an inhibitor for oxidation stress inhibiting edema, inflammation, blood circulation disorder, liver cirrhosis, etc., caused by the oxidation of a living cell without adverse effects and containing a specific hydro-condensed ring hydrocarbon as an effective ingredient. CONSTITUTION: This oxidation stress inhibitor contains in its molecular structure a two ring- and/or three ring-hydro-condensed ring hydrocarbon having at least one condensed benzene ring and containing 4 to 8 membered ring correspondent to a hydrogenated condensed ring compound as an effective ingredient. As the hydro-condensed ring hydrocarbon, a hydrogenated phenanthrene, a hydrogenated anthracene, a hydrogenated naphthalene, etc., are cited as examples. The inhibitor is formulated into a liquid or solid form by a usual method by suitably adding various other additives. The effective amount of administration is 10-800mg/kg/day.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oxidative stress inhibitor having an inhibitory effect on edema, inflammation, blood circulation disorder, liver cirrhosis and the like caused by the oxidation of living cells.

[0002]

2. Description of the Related Art With the recent discovery of an unexpectedly large number of diseases caused by oxidative stress in the living body, that is, oxidative deterioration of cells induced by some physiological stimulus, measures against it have been started to be searched. Oxidative depolymerization of the lubricating component (sodium hyaluronate) occurs by adding an oxygen anion radical (superoxide) that induces biological oxidation to the synovial fluid. This depolymerization is certainly slightly suppressed by the coexistence of hydrogen peroxide inactivating enzyme (catalase) or oxygen anion / radical inactivating enzyme (SOD) in the joint fluid [JM Cord; Science, 185 , 529]. (1974)]. Alcohol poisoning (cirrhosis) also increases liver tissue oxides [Satoshi Watanabe; Proc. Hoshi Univ., (34), 23 (1992)]. In addition, since various oxidative reactions in cells have been considerably elucidated, as the diseases deeply involved in oxidative stress, in addition to the above arthritis, alcoholic liver cirrhosis, retinopathy of prematurity, uveitis of the eye, and retinal iron rust. , Senile cataract, side effect disorder due to radiation treatment, asbestos (asbestos)
Disease, silicosis (pneumoconiosis), smoking bronchial injury, and at least some side effects of anti-cancer drug, arteriosclerosis, cerebral edema, pulmonary edema, foot edema, cerebral infarction (cerebral softening), hemolytic anemia Progeria, epilepsy, Alzheimer's disease (senile dementia), Down's syndrome (Morghalis), Parkinson's disease (tremor paralysis), Behcet's disease, Crohn's disease (terminal ileum). Flame), Weber Christian disease (non-suppurative subcutaneous panniculitis nodosa), Kawasaki disease, collagen disease, progressive systemic sclerosis, herpes dermatitis (IgA bullous dermatitis) , Endotoxin shock due to antigen toxin, immunodeficiency syndrome, nephritis, diabetes, etc. are also included.

Regarding prevention measures against these various diseases, vitamin E, vitamin C as antioxidants (radical scavengers),
Hydrocortisone (11β, 17α, 21-trihydroxy-4-pregnene-3,20-dione.cortisol), β-carotene, BHT (2,6-di-t-butyl-4-methylphenol), BHA (2 .6-di-t-
Butyl-4-methoxyphenol), 7,8-benzoflavone, copper (II) 3,5-diisopropyl salicylate and the like have been tested in animal experiments [Mino Makoto; Modern Medicine, 25 (10), 27 (19).
93)], the effect is uncertain, and many questions remain, and serious side effects have been pointed out even when a large amount of these is administered to obtain a temporary effect. For example, the above-mentioned antioxidant vitamin E is used for the treatment / prevention of retinopathy of prematurity, cerebral infarction, epilepsy, Parkinson's disease, Weber-Christian disease, carcinogenesis, cataract, cerebral edema, endotoxin shock, or wounds (burns). ) Although it was reported to be useful for promoting healing, in many clinical trials later, the results were ineffective and halfway effective [Tadahisa Hiramitsu; Hyundai Medical, 25 (10), 143 (1993)] and many newborns died. ,
The American Newborn Commission has come to the end of the recommendation of large dose administration of vitamin E (1985). The side effects of this oral administration (sepsis, necrotizing colitis) are excessive vitamin E.
It is considered that the adverse effect of the dispersant (surfactant) used for suspending vitamin E in water was further added during the intravenous injection [Committe
e of Fetus and Newborn Pediatrics, 76 , 315 (1985), D.
L. Phelps; Amer. J. Clin. Nutr., 46 , 187 (1987)]. BHT and BH that are effective in preventing the oxidation of cell membrane lipids (suppressing aging)
There is suspicion in A as well, and the result of re-examination that it is completely ineffective in preventing aging [AM Michaelson et al .; Biochem.Biophys.Res.Commun., 5
8 , 1079 (1974), Kunihiko Kato, Experimental Medicine, 4 , 1116 (1986)] is also famous. There are also doubts about vitamin C and vitamin A [Y.Oy
anagi; Biochem.Pharmacol., 25 , 1473 (1976), Kunihiko Kato, Experimental Medicine, 4 , 1116 (1986)], side effects (nausea, hair loss, headache,
Itching) has been pointed out. In addition, hydrocortisone warps in rats and mice, causing cataracts, and the actual situation is not simple (H. Nishigori et al .; Exp. Eye Res., 36 , 617 (198
3), H. Nishigori et al .; Investigative Ophthalmol. Visual
Sci., 25 , 1051 (1984)]. As described above, a safe, reliable, and useful method for suppressing pathological oxidation of biological tissues has not been established.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an oxidative stress inhibitor capable of inhibiting oxidative deterioration of living cells without causing side effects.

[0005]

DISCLOSURE OF THE INVENTION In the present invention, a two-ring and / or three-ring having at least one condensed benzene ring in its molecular structure and containing a 4- to 8-membered ring corresponding to a condensed ring hydride. There is provided an oxidative stress inhibitor containing the hydro-condensed ring hydrocarbon as an active ingredient.

The present invention will be described in more detail below. The oxidative stress inhibitor of the present invention has at least one condensed benzene ring in terms of molecular structure, and has 4 equivalent to a condensed ring hydride.
A two- and / or three-ring hydrocondensed ring hydrocarbon containing an 8-membered ring is used as an active ingredient. Examples of the specific hydro-condensed ring hydrocarbon used as an active ingredient in the present invention include phenanthrene hydride, anthracene hydride, and naphthalene hydride. In addition, an alkyl group such as a methyl group, an ethyl group or a propyl group may be introduced into these hydro-condensed ring hydrocarbon skeletons. For example, 1-position, 2-position, 4-position of hydrophenanthrenes described later
Position, 4a-position, 7-position, 9-position, 10-position, 10a-position is an alkyl-substituted product in which an alkyl group is introduced (hereinafter abbreviated as "-position-substituted product"). May be.

The phenanthrene hydride can be obtained, for example, by catalytic hydrogenation of phenanthrene.
2,3,4,5,6,7,8-octahydrophenanthrene, 1,2,3,4,4a, 9,10,10a-octahydrophenanthrene, 1,2,3,4-tetrahydrophenanthrene, 9 , 10-dihydrophenanthrene and the like. Further, 1,4-dihydrophenanthrene, 1,2,3,4, which is synthesized by another known method,
5,6-hexahydrophenanthrene, 1,2,3
4,9,10-hexahydrophenanthrene, 1,2,
Examples include 3,4,4a, 10a-hexahydrophenanthrene and the like. 1, 2, 3, 4, 5, 6-
Hexahydrophenanthrene is 1, 2, 3, 4, 5,
It can be based on the Schroeter method of blowing an oxygen-containing gas into 6,7,8-octahydrophenanthrene. The 1,4-dihydrophenanthrene can be obtained by reducing phenanthrene with metallic lithium. Further, the 9,10-dihydrophenanthrene is
It can also be obtained by reacting 2,2-bisbromomethylbiphenyl with sodium metal. Phenanthrene, sodium metal, and ethanol are heated to produce the above 1, 2,
It is also possible to obtain 3,4-tetrahydrophenanthrene and 9,10-dihydrophenanthrene. 1, 2,
3,4,5,6,7,8-octahydroanthracene via isomerization via aluminum chloride or molybdenum disulfide, or benzene, 1-bromo-4-chlorobutane (or 1,2-dichlorobutane) and Depending on the method of reacting the three members of aluminum chloride,
It is also possible to obtain 2,3,4,5,6,7,8-octahydrophenanthrene.

As the anthracene hydride, 1,2-dihydroanthracene, 1,4-dihydroanthracene, 9,10-dihydroanthracene, 1,2,3,4-tetrahydroanthracene corresponding to a partial hydride of anthracene, 1 , 2,3,4,5,6-hexahydroanthracene, 1,2,3,4,9,9a-hexahydroanthracene, 1,2,3,4,5,6,7,8-octahydroanthracene , 1, 2, 3, 4, 4a, 9, 9
a, 10-octahydroanthracene and their 1-
The 2-position, 3-position, 4-position, 5-position, 8-position, 9-position or 10-position substitution product and the like can be exemplified.

As the naphthalene hydride, 1,2-dihydronaphthalene, 1,4-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene which is a partial hydride of naphthalene, and their 1-position, 2- Place, 3
The -position, 4-position, 5-position, 6-position, 7-position, 8-position substitution product and the like can be exemplified. On the other hand, for example, 1, 4,
Although 5,8-tetrahydronaphthalene has three carbon-carbon double bonds in the molecule, it lacks a condensed benzene ring and is not an active ingredient in the present invention.

Further, as an active ingredient in the present invention, a condensed benzene ring is possessed and 4 equivalent to a condensed ring hydride is obtained.
As long as it is a two- and / or three-ring hydro-condensed ring hydrocarbon containing an 8-membered ring, for example, indene (that is, benzene and 5
Condensate with member ring), 5H-benzocycloheptene, 7H
-Benzocycloheptene (that is, a condensation product of benzene and a 7-membered ring), benzocyclooctene (that is, a condensation product of benzene and an 8-membered ring), cyclobutabenzene (that is, benzene and a 4-membered ring).
Membered ring), cyclopenta [a] indene, cyclopenta [cd] indene (that is, a condensed product of benzene and two 5-membered rings), 1H-cyclopenta [a] naphthalene,
3H-cyclopenta [a] naphthalene, cyclopenta [b] naphthalene, fluorene, further acenaphthylene (condensation product of two benzene rings and five-membered ring), benzo [a]
Azulene, benzo [e] azulene, benzo [f] azulene, benzo [cd] azulene (benzene ring, 5-membered ring, 7
Membered ring condensation product), cyclohepta [a] naphthalene, cyclohepta [de] naphthalene (condensation product of two benzene rings and a 7-membered ring), cyclohepta [f] indene (7-membered ring,
6-membered ring, 5-membered ring condensate), phenalene (condensate of 3 6-membered rings), as-indacene, s-indacene (condensate of benzene ring and 2 5-membered rings), benzo [1, 2: 3
4] dicycloheptene, benzo [1,2: 4,5] dicycloheptene (condensation product of benzene ring and two 7-membered rings),
A hydro-condensed ring hydrocarbon compound corresponding to a hydride such as benzo [1,2,3,4] dicyclooctene (condensation product of a benzene ring and two 8-membered rings) can also be mentioned. Specifically, 2,3,6,7,8,9-hexahydro-1H
-Cyclopenta [a] naphthalene, 2,3,3a, 4
5,9b-Hexahydro-1H-cyclopenta [a] naphthalene and their 2-position, 3-position, 5-position, 6-position
Position, 7-position or 9b-position substitution product; 2, 3, 5, 6, 7,
8-hexahydro-1H-cyclopenta [b] naphthalene and its 1-position, 2-position, 4-position, 5-position, 6-position,
8-position or 9-position substitution product; 2,3,4,5-tetrahydro-1H-cyclopenta [a] naphthalene, 2,3,3
4,9-Tetrahydro-1H-cyclopenta [b] naphthalene, 2,3,5,6-tetrahydro-1H-cyclopenta [b] naphthalene and 5-, 6- or 8-position substitution products thereof; 2,3 -Dihydro-1H-cyclopenta [a] naphthalene, 2,3-dihydro-1H-cyclopenta [b] naphthalene and their 1-position, 5-position or 6-position substitutions; 1,2,3,3a, 8, 8a-hexahydrocyclopenta [a] indene, 2,2a, 3,4
-Tetrahydro-1H-cyclopenta [cd] indene, 1,2-dihydrocyclopenta [a] indene and 1-position, 2-position, 3-position or 8-position substitution products thereof;
2,3-dihydroindene, 3a, 7a-dihydroindene and their 1-position, 2-position, 3-position, 4-position, 5
-Position, 6-position or 7-position substitution product; 5, 6, 7, 8, 9,
10-hexahydrobenzocyclooctene, 5,6
7,8-Tetrahydrobenzocyclooctene, 7,8-
Dihydrobenzocyclooctene, 6,7,8,9-tetrahydro-5H-benzocycloheptene and one of these
-Position, 4-position or 5-position substitution product; 6,7-dihydro-5
H-benzocycloheptene, 6,9-dihydro-5H-
Benzocycloheptene, 8,9-dihydro-5H-benzocycloheptene and their 2-position, 3-position, 5-
Position, 7-position, 8-position or 9-position substitution product; dihydrocyclobutabenzene and its 1-position, 2-position, 3-position, 4-
Position, 5-position or 6-position substitution product; 1,2,3,4,4a,
9a-hexahydrofluorene and its 7-position or 9-
Position substitution product; 1,2,3,4-tetrahydrofluorene,
1,4,4a, 9a-tetrahydrofluorene and 4-position, 6-position, 7-position or 8-position substitution products thereof;
2,2a, 3,4,5-hexahydroacenaphthylene,
1,2,4,5-tetrahydroacenaphthylene, 1,2
-Dihydroacenaphthylene, 1,2,3,6,7,8-
Hexahydro-as-indacene, 1,6-dihydro-
as-indacene, 1,7-dihydro-s-indacene and their 1-position, 2-position, 3-position, 4-position, 5-
Position, 6-position, 7-position or 8-position substitution product; 1, 2, 3,
4,5,6,9,10,11,12,13,14-dodecahydrobenzo [1,2: 3,4] dicyclooctene,
1,2,3,3a, 4,9,10,10a-octahydrobenzo [f] azulene, 5,6,7,8,9,10-
Hexahydrobenzo [a] azulene, 1,2,3,3
a, 4,10b-hexahydrobenzo [e] azulene,
1,2,3,3a, 4,10a-hexahydrobenzo [f] azulene, 7,8,9,9a-tetrahydro-6
H-benzo [cd] azulene, 2,6,7,8,9,9
a-hexahydro-1H-benzo [cd] azulene,
2,3,4,7,8,9,10,11-octahydro-
1H-cyclohepta [a] naphthalene, 1,2,3
7,8,9,10,10a-octahydrocyclohepta [de] naphthalene, 6,6a, 7,8,9,10,1
1,11a-octahydro-5H-cyclohepta [a]
Naphthalene, 6,7,8,9,10,11-hexahydro-5H-cyclohepta [a] naphthalene, 1,2,
3,9,10,10a-hexahydrocyclohepta [d
e] naphthalene, 8,9,10,11-tetrahydro-
7H-cyclohepta [a] naphthalene, 7,8,9,1
0-tetrahydrocyclohepta [de] naphthalene,
6,6a-dihydro-5H-cyclohepta [a] naphthalene, 7,8-dihydrocyclohepta [de] naphthalene, 1,2,3,5,6,7,8,9-octahydrocyclohepta [f] indene , 1, 2, 3, 5, 6, 7-
Hexahydrocyclohepta [f] indene, 2,3,3
a, 4,5,6-hexahydro-1H-phenalene and 1-position, 4-position or 7-position substitution products thereof; 2,3-dihydro-1H-phenalene and its 1-position, 2-position, 3
-Position, 4-position, 5-position, 6-position, 7-position, 8-position or 9
A -position substitution product and the like can be mentioned.

Hydrocarbons rich in condensed ring numbers such as aceanthrylene, acephenanthrylene, benzo [a] anthracene, chrysene, fluoranthene, indeno [2,1-a] indene, naphthacene, pleiadene,
Pyrene, triphenylene (four rings or more), 1H-benzo [a] cyclopenta [j] anthracene, 6H-benzo [cd] pyrene, dibenzo [b, g] phenanthrene,
Hydrocondensed ring hydrocarbons corresponding to partial hydrides such as dibenzo [c, g] phenanthrene, pentacene, pentaphene, perylene, picene (above 5 rings) have similar effects to those of the active ingredient of the present invention, Therefore, in the present invention, the above-mentioned two-ring and / or three-ring hydro-condensed ring hydrocarbon is used as an active ingredient because of the problem of harmfulness.

Further, 3H-3-benzazepine, benzimidazole, benzofuran, isobenzofuran having heteroatoms (nitrogen, oxygen, sulfur, silicon) as ring-constituting atoms,
4H-1-benzopyran-4H-chromene, 4H-1-
Benzopyran-2H-chromene, 4H-1-benzopyran-1H-chromene, 2H-1-benzopyran-2H-
Chromene, 2H-1-benzopyran-4H-chromene,
2H-1-benzopyran-1H-chromene, 1H-2-
Benzopyran-1H-chromene, 1H-2-benzopyran-2H-chromene, 1H-2-benzopyran-4H-
Chromene, benzopyran, 4,1-benzothiazine, 1
-Benzothiophene, 2-benzothiophene, 4H-
3,1-benzoxazine, 1,4-benzoxazine, 3-benzoxepin, shinoline, dithianaphthalene, indole, isoindole, 1H-indole,
Phthalazine, quinazoline, conoxaline, quinoline, 1
-A similar effect to the active ingredient of the present invention is also observed in hydroheterocyclic compounds corresponding to partial hydrides such as silanaphthalene, but side effects associated with long-term regular use are feared, so these are the active ingredients in the present invention. It is not subject to.

The oxidative stress inhibitor of the present invention may contain various pharmaceutically acceptable additives in addition to the above active ingredients.

The dosage form of the oxidative stress inhibitor of the present invention may be liquid or solid, and the method of administration may be oral administration, that is, it may be added to an oral dose or a diet. In addition, alkyl sulfate / sodium, alkyl naphthalene sulfonic acid / sodium, halogenated trimethylaminoethyl alkylamide, polyoxyethylene alkyl ether, surfactant such as alkyl trimethyl amino acetic acid, or a solvent such as dimethyl sulfoxide or bile acid is used in combination, Subcutaneous injection, intravenous injection, and intraperitoneal injection are not impossible, but oral administration of the active ingredient is most preferable in order to prevent adverse effects due to surfactants, solvents and the like, and to prevent side effects and the like. The effective dosage of the oxidative stress inhibitor of the present invention is preferably 10 to 800 mg / kg body weight of the living body in terms of the active ingredient. Within this dose range, there is no need to worry about chronic toxicity, carcinogenicity, etc., even if daily administration is performed.

The specific hydro-condensed ring hydrocarbon which is the active ingredient in the present invention is required to avoid air (oxygen) modification, that is, auto-oxidation (degradation) of the hydro-condensed ring hydrocarbon itself.
It is preferable to synthesize and purify in a nitrogen or carbon dioxide atmosphere, then seal in a deaeration container, and ingest within a day or two after opening.

[0016]

EFFECTS OF THE INVENTION Since the oxidative stress inhibitor of the present invention contains a hydrocondensed ring hydrocarbon having a specific structure as an active ingredient, it can inhibit oxidative deterioration of living cells without causing side effects.

[0017]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[0018]

Example 1 A well-known simple method for inducing oxidative stress type edema by applying physiological stimulation to muscle (FM Veromese et al .: J. Pha
rmacol., 35 , 757 (1983)], and carrageenan (agar-like polysaccharide) was used as a stimulant. That is, 0.1 ml of a 1% aqueous solution of carrageenan was injected into the rat right hind plantar muscle (tendon) membrane, and as a result, redness was observed after 3 to 4 hours, and edema was subsequently exhibited (Table 1 No. 1 to 5). . On the other hand, a standard solid feed (commercial product, starch 70, protein 20, soybean oil 5, salt 4, vitamins 0.5 (wt%)) was added to 1,2,3,4 as the hydro-condensed ring hydrocarbon of the present invention. , 5,6,7,8-Octahydrophenanthrene (abbreviated OHP) 0.2 wt% was added to the rats, which were orally administered with 7 g daily for 3 days, the same carrageenan aqueous solution was injected. ~ 12
Over the time, almost no redness was observed and edema was only slight (Table 1, Nos. 6 to 10). Also this LD _{50 of} OHP
Was 10 g / kg or more (oral rat), and no bioaccumulation was observed. That is, edema (inflammation) prevention (suppression) due to OHP pre-administration (70 mg / Kg day)
The effect was clear.

[0019]

[Table 1]

[0020]

Example 2 Hypoxanthine (abbreviation HX) -as a biochemical oxidizing agent (oxygen anion / radical generator) was added to an aqueous solution of sodium hyaluronate known as a synovial fluid component.
Immediately after the addition of xanthine oxidase (abbreviation XO), changes in aqueous solution viscosity were traced. That is, potassium phosphate buffer
(50 mM, pH 7.5) 1.5 ml, sodium hyaluronate (0.9 g / l) and HX (0.7 n)
M) is dissolved and the room temperature viscosity is measured, and XO (15
(Unit / liter) was added, and the viscosity after shaking for a predetermined time was measured. In this case, 1 ml of the reaction system aqueous solution was sampled in a syringe barrel, and the relative viscosity was displayed depending on the 0.6 ml spontaneous fall required time (seconds). Unless XO was added, the viscosity of the reaction system did not change for 60 minutes or more, but the decrease in viscosity after addition of XO was remarkable (Table 2, Nos. 1 to 5).

However, 0.1 ml of a solution (10 mg / liter, dimethylsulfoxide as a solvent) of 1,2-dihydronaphthalene (abbreviation DHN) as a hydro-condensed ring hydrocarbon of the present invention was previously allowed to coexist in the reaction system. After addition of XO and XO, the viscosity was almost unchanged (Table 2, Nos. 6 to 10). The LD ₅₀ of this DHN is 10 g / kg.
It was confirmed that the above (rat oral) did not show bioaccumulation. That is, oxidative deterioration due to DHN (depolymerization)
The inhibitory effect was obvious.

[0022]

[Table 2]

[0023]

[Example 3] Ethanol was injected into the abdominal cavity of a mouse, and after 24 hours, the liver was isolated and subjected to the thiobarbituric acid method [CG Sidw
ell et al .; J. Amer. oil Chemist's Soc., 31 , 603 (1954), M.Ta
niguchi et al .; J. Nutr. Sci. Vitaminol., 29 , 283 (1983)], and the oxidative deterioration (peroxide) content of this organ was determined. As a result, peroxide increased by about 15% (Table 3 No.6-10).
However, along with the standard feed, 5-methyl-8,9,10,11-tetrahydro-7H-cyclohepta [a] naphthalene (abbreviation M as the hydro-condensed ring hydrocarbon of the present invention) was used.
TH) 19 mg daily for 4 days (700 mg /
Similarly, administration of ethanol did not lead to liver hypertrophy and did not produce peroxide accumulation in the mice (kg)) (Table 3, Nos. 11 to 15). Moreover, it was confirmed that the LD ₅₀ of MTH was 10 g / kg or more (orally in mice), and bioaccumulation was not observed. That is, the inhibitory effect of MTH on liver tissue oxidation was clear.

[0024]

[Table 3]

[0025]

Example 4 12-O-tetradecanoyl phorbol-13-acetate (phorbol myristate acetate, abbreviation TDP, 0.01% dimethyl sulfoxide solution) as a physiological stimulant (oxygen anion / radical generation).
After intravenously injecting 25 ml into the rat, the mean blood pressure was traced for 45 minutes. As a result, it was found that the blood pressure after intravenous injection was reduced by 30% (Table 4, Nos. 6 to 10). The blood pressure measurement in this case was based on a direct method using a rat left ventricular insertion cannula under pentobarbital anesthesia and artificial respiration.

However, MTH was added to the standard feed in advance.
It was confirmed that the blood pressure was scarcely lowered even when TDP was intravenously administered to a rat to which 190 mg (760 mg / kg) was administered daily for 4 days (Table 4, Nos. 11 to 15). Physiological stimulants [FAKuehl et al; Nature, 265 , 170 (197
7), JH Jackson et al .; J. Appl. Physiol., 61 , 353 (1986), J.
E. Heffner et al .; An. Rev. Resp. Dis., 140 , 531 (1989)] was found to be effective in suppressing the decrease in blood pressure, which is considered to be a myocardial injury scale.

[0027]

[Table 4]

Claims (1)

[Claims] 1. A two- and / or three-ring hydrocondensed ring hydrocarbon having at least one condensed benzene ring in the molecular structure and containing a 4- to 8-membered ring corresponding to a condensed ring hydride as an active ingredient. And an oxidative stress inhibitor.