JPS62135423A - Improver for hypoxia - Google Patents

Abstract

PURPOSE:An improver for hypoxia, containing a specific carbostyril derivative or salt thereof as an active ingredient, capable of improving the oxygen shortage state or symptoms accompanying the state and effective as an improving drug, e.g. cerebral activator, cerebrovascular disorder, etc. CONSTITUTION:An improver for hypoxia containing a carbostyril derivative expressed by formula I (R<1> is H, lower alkyl, etc.; R<2> is H or lower alkyl; R<3> is pyridyl or phenyl having 1-3 substituent groups, e.g. halogen, lower alkyl, etc.; formula II is a group expressed by formula III or IV; A is lower alkylene; the broken line indicates single bond or double bond, provided that R<3> is not pyridyl when the group expressed by formula II is a group expressed by formula IV) or a salt thereof as an active ingredient. Specifically the improver can be collectively used as a cerebral activator, consciousness disorder improving agent for cerebrovascular disorder, encephalitis, cerebral tumor, etc., drug for senile dementia, etc. The improver may be used as a drug for arrhythmia or preventing agent for cardiac failure, etc., caused by oxygen shortage.

Description

[Detailed description of the invention] Industrial applications The present invention relates to a hypoxia improving agent.

Disclosure of the Invention The hypoxia improving agent of the present invention necessarily contains a carbostyril derivative represented by the following general formula (1) or a salt thereof as an active ingredient.

R (in the formula, R1 represents a hydrogen atom, a lower argyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R2 represents a hydrogen atom or a lower alkyl group. R3
represents a pyridyl group or a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxyl group. The carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are single bonds or double bonds, R3
must not be a phenyl group substituted with at least one pyridyl group or hydroxyl group. ) Calfostyryl derivatives represented by the above general formula (1) are described, for example, in JP-A-54-160389 and JP-A-55.
-2693 publication, JP-A-55-124766 publication,
JP-A-55-'l 29268, JP-A-56-4
9359, JP-A-56-49361 @ JP, JP-A-56-164'186 @, JP-A-57-'145
It is a known compound as described in Japanese Patent No. 872 and the like. However, the above carbostyril derivatives are only known to have central nervous system depressant action or antihistamine action.

As a result of extensive research on the above-mentioned carbostyril derivatives, the present inventors have discovered that this derivative has a hypoxia-improving effect that was completely unexpected from the above-mentioned central nervous system depressing effect and antihistamine effect. The present invention was completed based on such new knowledge.

The carbostyril derivative represented by the above general formula (1) has the effect of improving the oxygen instability state and the symptoms associated therewith, and is a drug that improves the oxygen instability state and the symptoms associated therewith [i.e., hypoxia]. (hypoxia) improving agent],
More specifically, for example, brain stimulants, cerebrovascular disorders (cerebral hemorrhage,
cerebral infarction, subarachnoid hemorrhage, hypertensive encephalopathy), encephalitis, brain tumor,
Improvement of consciousness disorders caused by head trauma, psychosis, metabolic disorders, drug addiction, physical disorders, etc., and sequelae of the above diseases,
Medications for treating or improving attention deficit, hyperactivity, speech disorders, mental retardation 2HH, amnesia medicine, senile dementia medicine, medicine for improving respiratory arrest and hypoxia due to potassium cyanide poisoning, arrhythmia caused by lack of oxygen, It is effectively used as a heart failure preventive drug.

Oxygen is essential for living organisms to maintain life, such as energy production and metabolism. The oxygen becomes so-called active oxygen species such as oxygen anion radicals, peroxide ions, and hydroxyl radicals through reactions in energy production systems, enzyme reactions, ultraviolet rays, radiation, and the like. While these active oxygen species are useful for living organisms, such as oxygenating enzymes and bactericidal effects on white blood cells, they are also useful for living organisms, such as oleic acid, linoleic acid, lylunic acid, and arachidonic acid, which are abundant in living organisms and form phospholipids in biological membranes. Promotes peroxidation of saturated fatty acids and forms lipid peroxides. This lipid peroxide causes the generation of alkoxy radicals and hydroxyl radicals similar to the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes (metabolism, (10).

(See 1978 Special Feature on Active Oxygen). However, enzymes involved in the metabolic deactivation of the above-mentioned reactive oxygen species, such as superoxide dismutase (SOD), catalase, and glutathione peroxygase, exist in living organisms, and enzymes such as α-tocopherol (vitamin E) and others exist. There are various vitamins and other substances that have anti-oxidant properties, and these effects normally maintain the body's normal body. However, for some reason, the enzymes, vitamins, etc. mentioned above do not provide adequate protection. It is often observed that defects occur in other systems, or that the generation of reactive oxygen species and the production and accumulation of lipid peroxides exceed the capabilities of secondary defense mechanisms.

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 and senile dementia, and retina. symptoms, lung damage, heart and lung damage caused by certain drugs, and ischemic vascular disease.

Compounds that scavenge active oxygen species (radicals), which have traditionally been thought to be the main mechanisms of the various disorders listed above, and prevent or reduce the production and accumulation of lipid peroxides in living organisms are generally considered antioxidants. In fact, there have been many reports on the preventive and therapeutic effects of the various diseases mentioned above due to its use.

Reported antioxidants include the above-mentioned SOD and other arranging agents [Superoxide and Medicine, written by Yoshihiko Oyanagi, 1
981, Imori Publishing, pp. 137-141, R-New Medicine, special feature on active oxygen and its medical role, vol. 39, no. 7 (19
84), Inflammation, Yu, p699 (Ko981), 1b
id, 2, p367 (1982), Curren
t Therap, Rep,, 20. I) 62~
69 (1976), “Perspective in
Inflammation” Red-Wood Bur
n, Ltd, p527-544 (1977)
, Acta, Physiol, 5cand, Dan 2,
5uppl 59-65 (1980), Proc.
Natt.

Acad, Sci, USA, 79. p7509-7
513 (19R32>, Pathology of
Oxygen Acad, Pressp85-97 (
19B 2 ), J, C11nic, Invest.

67, p983 (1981), J, Clnic.
, Invest.

70, p650-658 (1982), 'Patho
logy of Oxygen, p261-275 (
1982>, Biochem, Biophys, Ac
ta,, 542°p2B ~38 (197B>, B
Ull, euro.

Physiopathol Re5p, 17, 5
uppl p 287-288 (1981), Pa
thology of Oxygen, p277-3
02 (1982), Ministry of Health and Welfare, Ministry of Health and Welfare Specified Disease Behchut's Disease Investigation Research Group Achievements (1980, 1981), J, Imm.
unol, 128. p2770 (1982), etc.), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BH△), α-tocopherol (vitamin E), etc. (Minogu, Hidetaka Tanaka, Pharmaceutical Journal, 19
(12>.

p. 2351-2359 (1983), Toshihiko Suematsu, same as above, ■(5), p.909-914 (1983)
, Arch, Biochem, Biophys, 2
27. p534-541 (1983), J, Cl
1nic, Invest, 57゜p732-737 (
1976), Adv, Can5er, Rosl, Zdan, p'197 (1978), etc.).

The compounds of the present invention also have the effect of removing active oxygen species and preventing or reducing lipid peroxide production in vivo.

Therefore, the compounds of the present invention can be used as prophylactic and therapeutic agents for various disorders and diseases caused by excessive generation of reactive oxygen species, in vivo accumulation of lipid peroxides, or deficiencies in defense mechanisms against the above.
For example, it is useful as a medicine such as an anti-arteriosclerotic agent, an anti-inflammatory agent, an analgesic, an autoimmune disease treatment agent, a platelet aggregation inhibitor, an antihypertensive agent, a hyperlipidemic agent, and an agent for preventing and treating retinopathy of prematurity and cataracts. I'll go. Furthermore, the compounds of the present invention are effective not only as the above-mentioned pharmaceuticals, but also as antioxidants for oils and fats contained in processed foods and the like.

In this specification, each group represented by R1, R2, R3 and A can be more specifically exemplified by the following groups.

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

Examples of lower alkenyl groups include linear or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl groups. can.

Examples of lower alkynyl groups include straight chain or branched carbon atoms having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, and 2-hexynyl groups. Examples include alkynyl groups such as

Examples of phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, Examples include phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 2-methyl-3-phenylpropyl group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-71~
1 carbon number such as xy, pentyloxy, hexyloxy group, etc.
-6 linear or branched alkoxy groups can be exemplified.

Examples of phenyl groups having 1 to 3 substituents selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups, and hydroxyl groups include 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, -fluorophenyl, 4-fluorophenyl, 2-
Bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, 3゜5-dichlorophenyl, 2.6-dichlorophenyl, 3
, 4-dichlorophenyl, 3,4゛-difluorophenyl, 3.5-dibromophenyl, 3゜4.5-trichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3 -ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2,3-dimethylphenyl, 3,4.5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxy Phenyl, 3.4-jethoxyphenyl, 2.5-dimethoxyphenyl, 3,4.5-trimethoxyphenyl, 3
-Methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2-methoxy-3-chlorophenyl, 2-
Hydroxyphenyl, 3-hydroxyphenyl, 3.4
- selected from the group consisting of a halogen atom, a straight chain or branched alkyl group having 1 to 6 carbon atoms, a straight chain or branched alkoxy group having 1 to 6 carbon atoms, and a hydroxyl group on a phenyl ring such as a dihydroxyphenyl group. An example is a phenyl group having 1 to 3 substituents.

Examples of lower alkylene groups include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2゜2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, 1-ramethylene, pentamethylene, and hexamethylene groups. Examples include linear or branched alkylene groups having 1 to 6 carbon atoms.

The carbostyryl derivative of the above general formula (1) can be produced by various methods, but a preferred method is, for example, yA-manufactured according to the method shown in the reaction formula below.

Reaction formula The carbon-carbon bonds between the 3rd and 4th positions of the carbostyril skeleton are the same as above. X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. ] The carbostyril derivative of general formula (1) is represented by general formula (2)
It is produced by reacting the compound represented by formula (3) with the compound represented by formula (3).

The compound of general formula (2) and the compound of general formula (3) used as starting materials are both known compounds.

In the compound of general formula (2), the lower alkanesulfonyloxy group represented by Examples include oxy, pentanesulfonyloxy, hexanesulfonyloxy groups, and arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, and 4-nitrophenylsulfonyloxy. ,
Examples include substituted or unsubstituted arylsulfonyloxy groups such as 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and examples of aralkylsulfonyloxy groups include benzylsulfonyloxy , 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as -methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy.

The reaction between the compound of general formula (2) and the compound of general formula (3) can be carried out without a solvent or in a common inert solvent at room temperature to 200°C.
C1 Preferably, the process is completed in several hours to about 24 hours under a temperature condition of 60 to 120'C. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol, and dimethyl needles, aromatic hydrocarbons such as benzene, 1-helene, and xylene, methanol,
Lower alcohols such as ethanol and isopropanol,
Polar solvents such as dimethylformamide, dimethylsulfoside, acetone, acetonyl-lyl, N-methylpyrrolidone, and hexamethylphosphoric triamide can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride,
Examples include tertiary amines such as 1°8-diazabicyclo(5,4,0)-7-undecene, 1-ethylamine, tripropylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary. General formula (2) in the above reaction
) and the compound of general formula (3) are usually an equimolar excess of the latter relative to the former, preferably equimolar to 5 times the molar amount, more preferably 1 to 1.2 (8 It is better to use moles.

The compound of general formula (1) thus obtained can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Incidentally, the compound of the general formula (1) above naturally includes stereoisomers and optical isomers.

The carbostyryl derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by acting with a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. . In the above, examples of acids include inorganic acids such as hydrochloric acid, ffA acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, Organic acids such as methanesulfonic acid and benzoic acid can be used.

The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders,
It is prepared using a diluent such as a binder, wetting agent, disintegrant, surfactant, lubricant, or excipient (11). Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquid , suspensions, etc.), ointments, etc. When forming tablets, a wide variety of carriers known in this field can be used, such as lactose, sucrose, sodium chloride to thulium glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl 1iAa, stearic acid monoglyceride, starch, Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc, stearate, and boron. Examples include lubricants such as acid-terminated polyethylene glycol.

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

When forming an emulsion, a wide range of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, tragacanth ethanol, etc. Examples include binders such as , disintegrants such as laminalan agar, and the like. When forming into a suppository, a wide range of conventionally known carriers can be used, such as polyethylene glycol, cacao moonban, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic polylyceride, etc. . 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, alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, sufficient salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and conventional solubilizing agents, buffers, soothing agents, etc. may be added. In addition, coloring agents, preservatives, fragrances, flavoring agents,
Sweeteners and other pharmaceutical agents may also be included in the pharmaceutical formulation. When molding paste 1~ into a cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can.

The amount of the compound of general formula (1) to be contained in the pharmaceutical formulation of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight in the pharmaceutical formulation.

There are no particular restrictions on the method of administering the above pharmaceutical preparations, and the administration method is determined depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally. In addition, in the case of injections, it is used alone or glucose,
It is administered intravenously in a mixture with a normal replacement fluid such as an amino acid, and if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. In the case of a depressant, it is 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 (1), which is the active ingredient, is
The amount is preferably about 0.2 to 200 mg per f11kc+.

Example Reference examples, pharmacological tests, and formulation examples are listed below.

Reference Example 1 2.0 CI of 7-(3-chloropropoxy)-3,'4-dihydrocarbostyryl and 1.6 g of sodium iodide were mixed in 60 mQ of acetone and heated at 40 to 50°C for 2 hours.
After stirring, 60 mQ of dimethylformamide was added, and acetone was distilled off under reduced pressure. To this reaction solution were added 1.74 g of 4-(3-methylphenyl)-1,2,5°6-titrahydropyridine and 2 mQ of triethylamine, and
Stir at 60'C for 6 hours. Concentrate under reduced pressure and add 5% to the residue.
When 80 mQ of sodium hydrogen carbonate aqueous solution is added and stirred, the organic matter crystallizes. The precipitate was washed with water, dried, and recrystallized from ethanol-water to give 7-(3-(4-(
1.8 g of 3-methylphenyl)-1,2,5,6-titrahydro-1-pyridyl)propoxy)-3,4-dihydrocarbostyryl are obtained.

Colorless scaly crystals Melting point 143-145°C Reference example 2 4.8 g of 7-(3-chloropropoxy)-3,4-dihydrocarbostyryl and 3.5 g of sodium iodide are added to 50 ml of acetone and heated under reflux for 3 hours. . Then add dimethylformamide i40mQ and heat at 40-45°C.
Acetone was distilled off under reduced pressure. Add 4-(
4-methylphenyl)-piperazine 3゜9q and triethylamine 3. Add Oq and stir at 70-80'C for 7 hours. After evaporating the solvent, 60 n12 of a 5% aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. After washing the chloroform layer twice with water and drying it? 8. The solvent is distilled off.

The obtained residue was recrystallized from ethanol to give 7-(3-(
4-(4-methylphenyl)-1-piperazinyl]propoxy)-3,4-dihydrocarbostyryl 6.0CI
get.

Yellow needle crystals Melting point: 149-150'C Using appropriate starting materials, the following compound is obtained in the same manner as in Reference Example 2.

7- (3-(4-(3-chlorophenyl)-1-piperazinyl)propoxy)-3,4-dihydrocarbostyryl colorless needle crystals (recrystallized from ethanol) Melting point 156-158°C 7- (3-(4 -(4-chlorophenyl)-1-piperazinyl]propoxy)-3,4-dihydrocarbostyryl pale yellow prismatic product (recrystallized from ethanol) Melting point 2
00-202°C Pharmacological test (antioxidant deficiency effect) Antioxidant deficiency effect was determined by arch. int. Ph ha
rmacodyn. .

233, 137 (1978).

ICR male mice (body weight 20-30Cl) were used.

Place four mice at a time in a glass desiccator and reduce the internal pressure to 1.
Suction air with a vacuum pump until the volume reaches 80 mm/1 g and close the cock. The time from when the vacuum pump was activated to when each mouse stopped breathing was measured and used as the survival time. The test compound was orally administered 15 minutes before the start of suction. The survival time of control mice was set as 100, and the percentage of survival time when the test compound was administered is shown, and the results are shown in Table 1 below.

The test compounds are as follows.

Test compound no. 1 : 7 - (3 - (4 - (3
-Medylphenyl)-1-piperazinyl]propoxy)-3,4-dihydrocarbostyryl No. 2: 7-(3-(4-(4-methylphenyl)-1-piperazinyl)propoxy)-3,
4-dihydrocarbostyryl No. 3: 7 - (3 - (4 - (2.
3-dimethylphenyl)-1-piperazinyl]propoxy)carbostyryl No. 4: 7 - (3 - (4 - (3.
4-dimethylphenyl>-1-piperazinyl]propoxy)-3,4-dihydrocarbostyryl No. 5 : 7 - (3 - (4 - (3-
Chloro-4-methylphenyl)-1-piperazinyl)propoxy)-3,4-dihydrocarbostyryl No. 6: 7-(3-(4-(3-chlorophenyl)-1-piperazinyl]propoxy)-3,
4-dihydrocarbostyryl No. 7 : 7 - (3 - (4 - (3-
Chlorophenyl)-1-piperazinyl)propoxy)carbostyryl No. 8: 7-(3-(4-(4-chlorophenyl)-1-piperazinyl]propoxy)-3,
4-dihydrocarbostyryl No. 9: 7-(3-(4-(3-)
Hydroxyphenyl>-1-piperazinyl)
xy)-3,4-dihydrocarbostyryl No. 10: 7 - (3 - (4 - (4-
Hydroxyphenyl)-1-piperazinyl]propoxy)-3,4-dihydrocarbostyryl No. 11 : 7 - (3 - (4 - (3
-methylphenyl)-1.2,5.6-tel-lahydro-1-pyridyl)propoxy)-3.

4-Dihydrocarpostili J Shi No. 12: 7 - (3 - (4 - (2.
3-dimethylphenyl)-1-piperazinyl]propoxy)-3,4-dihydrocarbostyryl No. 13: 7-(3-(4-(pyridyl-2-yl)-1-piperazinyl)propoxy)=3.
4-dihydrocarbostyryl No. 14: 5-(3-(4-(3-methylphenyl)-1-piperazinyl)propoxy)-3,
4-dihydrocarbostyryl NO,15: 7-(3-(4-(4-methylphenyl)-1,2,5,6-te1-lahydro-1-pyridyl)propoxy)-3゜4-dihydrocarbostyryl No. 16: Chlorpromacin (comparative compound) Table 1 Testing Period of administration Antioxidant deficiency testing
Dose Antioxygen deficiency 10 30'
11811, 30 6
47 Formulation Example 1 7- (3- (4- (4-methylphenyl)-1-piperazinyl propoxy)-3,4-dihydrocarbostyryl glucose 250 mg゛ River fish reservoir water appropriate amount total amount
5+nQ Dissolve the compound of the present invention and glucose in distilled water for injection, inject into a 5mf2 ampoule, and replace with nitrogen i%121
Autoclaving is performed at ℃ for 15 minutes to obtain an injection having the above composition.

Formulation example 2 7- (3- (4- (3-chlorophenyl)-1-piperazinyl propoxy)-3.4-dihydrocarbostyryl 100 g Avicel (trade name, manufactured by Asahi Kasei) 40cx cornstarch 30Q magnesium stearate 2qTC- 5
10q (trade name, manufactured by Shin-Etsu Chemical (2), hydroxypropyl methylcellulose) polyethylene glycol-6000 3Cl castor oil
40g methanol
40 g of the compound of the present invention, Avicel, cornstarch, and magnesium stearate were mixed, polished, and then tableted using a machine with a radius of 10 mm. The obtained tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, mustard oil, and methanol to produce film-coated tablets having the above composition.

Formulation Example 3 7-(3-(4-(4-riopphenyl)-1-piperazinyl)propoxy)-3,4-dihydrocarbostyryl 2g purified lanolin 5q white beeswax 5q white petrolatum
88Q quantity
100 and heated J white beeswax to form 1), then added the compound of the present invention, purified lanolin and white petrolatum, heated until it became liquid, stirred until it started to solidify, and obtained the above composition. Get the ointment.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R^2 is a hydrogen atom or a lower alkyl group. R^3 represents a pyridyl group or a phenyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxyl group. ▲ Numerical formula, chemical formula , tables, etc. ▼ is ▲ mathematical formula, chemical formula,
Indicates ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. A represents a lower alkylene group. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. However, if ▲There are mathematical formulas, chemical formulas, tables, etc.▼ indicates ▲There are mathematical formulas, chemical formulas, tables, etc.▼,
R^3 must not be a pyridyl group or a phenyl group substituted with at least one hydroxyl group. ] A hypoxia improving agent characterized by containing a carbostyril derivative or a salt thereof as an active ingredient.