JPS62135425A - Improver for hypoxia - Google Patents

Abstract

PURPOSE:An improver for hypoxia, containing a specific benzoxazine derivative or a salt thereof as an active ingredient, having improving action on hypoxia and useful as a cerebral activator, improving drug for consciousness disorder caused by cerebrovascular disorder, etc., drug for senile dementia, etc. CONSTITUTION:An improver for hypoxia containing a benzoxazine derivative expressed by formula I (R<1> is H, lower alkyl or phenyl lower alkyl; R<2> is phenyl which may have 1-3 substituent groups, e.g. halogen or lower alkyl, etc.; A is lower alkylene; Z is O or S) or a salt thereof as an active ingredient. Specifically the improver can be effectively used as a drug for improving consciousness disorder caused by cerebrovascular disorder, encephalitis, cerebral tumor, metabolic disorder, mental diseases, etc., and improving agent for sequelae, deterioration in attentiveness, language disorder, etc., and drug for amnesia, senile dementia, arrhythmia caused by oxygen shortage, drug for cardiac failure, etc. The dose thereof is preferably about 0.2-200mg/kg/day.

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 contains a benzoxazine derivative represented by the following general formula (1) or its ``n'' as an active ingredient.

[In the formula, R1 does not represent a hydrogen atom, a lower alkyl group, or a lower alkyl group. R2 represents a phenyl group which must have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a low alkyl group. A
indicates a low-handling Alkylene base. Z represents an oxygen atom or a sulfur atom. ] The benzoxazine derivative represented by the above general formula (1) is a known compound as described, for example, in Chichimun Sho 59-70675.

However, the above benzoxazine derivatives are only known to have central nervous system depressant action or antihistamine action.

As a result of repeated research on the above-mentioned benzoxazine derivatives, the present inventors have discovered that the above-mentioned derivatives have hypoxia-improving effects that could not be expected from the above-mentioned central nervous system depressing effects and antihistamine effects. The present invention was completed based on this new knowledge.

The benzoxazine 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 deficiency state and the symptoms associated therewith [i.e., hypoxia ( [hypoxia) improving agent], more specifically (51 such as brain stimulant, cerebrovascular disorder (cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, hypertensive encephalopathy), encephalitis, brain tumor, trauma to the head and 1, psychosis, metabolic disorder, drug addiction,
l Of course, physical i: Improvement of consciousness disorders caused by φ harm, etc., and treatment or ameliorating drugs for after-effects of the above diseases, decreased attention, hyperactivity, speech disorders, mental retardation, amnesia drugs, senile dementia drugs It is effectively used as a medicine to improve respiratory arrest and hypoxia associated with potassium cyanide poisoning, and to prevent arrhythmia and heart failure caused by lack of oxygen.

For living organisms, oxygen is essential for maintaining 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, enzymatic reactions, ultraviolet rays, and reactions with q4 radiation. While these reactive oxygen species are useful for living organisms, such as oxygenation enzymes and white blood cell bactericidal action,
It promotes the peroxidation of unsaturated fatty acids that form the phospholipids of biological membranes, such as oleic acid, linoleic acid, linoleic acid, and arachidonic acid, which are abundantly present in living organisms, forming lipid peroxides. This lipid peroxide induces the production of alkoxy radicals in the same way as the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various M-components for 41 (B (metabolism, -1 mutual ( 10).

(See 1978 Special Feature on Active Oxygen). However, in living organisms, for example, superoxide dismutase (SOD), catalase, and glutathione peroxidase substances exist, as well as various vitamins with antioxidant ability such as α-tocopherol (vitamin E). However, for some reason, the enzymes, vitamins, etc. described above may lack the appropriate defense mechanisms, or the defense mechanisms such as these may occur. (It is often observed that the generation of active oxygen species and the production and accumulation of lipid peroxides exceed the capacity of Ill.

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. Disease, II! Some drug-induced heart and liver damage, ischemic vascular disease, etc. occur.

Compounds that scavenge active oxygen species (radicals), which are considered to be the main cause of the various disorders listed above, and that prevent or reduce the production and accumulation of lipid peroxides in living organisms are generally considered antioxidants. Called and actually that +
Numerous reports have been made on the preventive and therapeutic effects of the above-mentioned various diseases using the drug "1".

Reported antioxidants include enzyme agents such as the above-mentioned SOD [Superoxide and Medicine, Dai I111 Yoshihiko, 1981, Imori Publishing, 137-141 Shin, Latest Medicine, Special Feature Active Oxygen and its Medical Role Haj, Volume 39, 7
No. (1984), Inflammation, 1, p699 (198
1), ibid, 2, p367 (1982)
, current Dingherap, Re1),,
20. p62-69 (1976), “Pe
rSpeCtiVe inInflammation”
Red-Wood Burn, Ltd, p 52
7-544 (1977), Acta, Physio
l, 5cand, 492, 5uppl 59-65
(1980), prOc, Natt.

To Acad, Sci, US, 79. p750
9-7513 ('l 9 F32 > , PathOI
O(11/ of oxygen ACad, PreS
Sp85-97 (1982), J, Clnic,
Invest.

67, p983 (1981), J, Cl1ni
c. Invest.

70, D650-658 (1982), Pathol
ogy of Oxygen, p261-275 (1
982), Biochem, Biophys, octa, 542゜p28-38 (1978), B
Ull, euro.

111ysiopath0+ RC3l), , F.
5uDr) I 1) 287-288 (1981)
, Pathology of Oxyquen, p2
77-302 (1982), Ministry of Health and Welfare, Ministry of Health and Welfare, Specified Disease Bechut's Disease Investigation Research Team Collection (1980, 1982), J
, Immunol, 128. p2770 (1982)
[etc.] Yabutylhydroxytoluene (BHT), butylhydroxyanisole (B)-IA), α-1~cophyerol (vitamin E), etc. (Makoto Mino, Hidetaka Tanaka, Pharmaceutical Journal, 19 (12).

D 2351-2359 (1983), Toshihiko Suematsu, same issue, ■(5), p909-914 (1983
), 8rch, Biochcm, Biophys,...
227, p534-541 (1983), J
, Clnic, Invest, 57° p732-73
7 (1976), 8dv, cancer, R
O3, 26, p197 (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 preventive and therapeutic agents for various disorders and diseases caused by excessive generation of active oxygen species, bioaccumulation of lipid peroxides, or deficiencies in the IL1 mechanism, such as anti-arteriosclerotic agents. It is also useful as a medicine, such as an anti-inflammatory agent, an analgesic, a therapeutic agent for autoimmune diseases, a platelet aggregation inhibitor, an antihypertensive agent, a hyperlipidemic agent, and an agent for preventing and treating retinopathy of prematurity and cataracts. 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 and A can be more specifically exemplified by the respective methods.

Illustrative examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as alkyllopyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

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.

As the lower alkoxy group,
Examples include linear or branched alkoxy groups having 1 to 6 carbon atoms such as propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyl suboxy groups.

Examples of phenyl groups that may have 1 to 3 substituents selected from the group consisting of halogen atoms, lower alkyl groups, and lower alkoxy groups include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and 2-fluorophenyl. Phenyl, 3-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, 3.4.5-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. 5-1~
Rimedylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,
4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-thume-1-xyphenyl, 3,4.
5-Trime1-xypheni/L/, 3-1 thyl-4-chlorophenyl, 2-'70 rho-6-methylphenyl, 2
- From a halogen on the phenyl ring such as a me1-xy3-chlorophenyl group, a straight chain or branched alkyl group having 1 to 6 carbon atoms, and a straight chain or branched alkoxy group having 1 to 6 carbon atoms. Examples include phenyl groups which may have 1 to 3 substituents (from the group consisting of phenyl groups).

Examples of lower alkylene groups include methylene, ethylene, trimethylene, 2-methyltrimethylene, and 2.

2-dimethyl 1-rimethylene, ]-methyl 1-rimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene group, etc. having 1 to 6 carbon atoms
Examples include straight chain or branched alkylene groups.

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

The benzoxazine 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, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid,
Organic acids such as tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzoic acid, etc. 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 diluents or excipients such as binders, wetting agents, disintegrants, surface active agents, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, solutions, suspensions,
Examples include emulsions, granules, capsules, fixatives, injections (solutions, suspensions, etc.), ointments, etc. When forming tablets, 10 types of λD are widely used in this field. Excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac,
Binders such as medyl cellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid Disintegrants such as monoglycerides, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil;
Absorption enhancers such as grade ammonium bases and sodium lauryl sulfate, moisturizing agents such as glycerin and starch, starches,
Examples include adsorbents such as lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets can be made into tablets with conventional coatings, such as sugar-coated tablets, viradine-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-handed tablets, or multilayer tablets, if necessary. When forming into an emulsion, a wide variety 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, powdered tragacanth, and gelatin. , a binder such as ethanol, and a disintegrant such as laminaran agar. When molding into the form of an inhibitor, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, pyratine, semi-synthetic glycerides, and the like. When prepared as injectables, solutions and suspensions are preferably sterile and isotonic with blood; these solutions, emulsions and! J! When forming into a clouding agent, any diluent commonly used in this field can be used, such as water, alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples include polyoxyethylene sorbitan fatty acid esters. In this case, the pharmaceutical preparation may contain a sufficient amount of dietary supplements, glycerin, or glycerin to prepare an isobiotic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, etc. may be added. Furthermore, if necessary, colorants, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceuticals may be included in the pharmaceutical preparation. When forming into paste, cream and gel forms,
As the diluent, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose G9, polyethylene glycol, silicone, and Pen 1-Nite.

The amount of the compound of general formula (1) contained in the pharmaceutical formulation of the present invention is not particularly limited and may be appropriately selected from 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 the case of injections, it may be used alone or with glucose,
It is administered intravenously in a mixture with a conventional replacement fluid such as amino acids, and if necessary, it is administered alone intramuscularly, intracranially, 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, the age, sex and other conditions of the patient, the severity of the disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually 11 (g) per day. The amount is preferably about 0.2 to 200 mg per serving.

Example The mulberry embedding test and formulation examples are listed below.

Pharmacological test [antioxygen deficiency effect] The antioxygen deficiency effect was determined by Arch, int, Ph
armacodyn, .

233.137 (1978). .

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

Place four mice at a time in a glass dessicator and reduce the internal pressure to 1.
Suction air with a vacuum pump until it reaches 80 mm and 11 g, and close the cock. The time period from when the vacuum pump was activated to when each mouse stopped breathing was measured and defined as the survival time. The test compound was administered orally 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: 6- (3-(4-(3-methylphenylation)-1-piperazinyl)propoxy)-2H-
1,4-penzoxazine-3(41-1>-one No., 2:6-(3-(4-(3-methylphenyl)-1-piperazinyl]propoxy)-2H-1
, 4-Benzothiazin-5 (4 days)-one No. 3: 8- (3-(4-(3-methylphenyl)-1-piperazinyl]propoxy)-2H-1,
4-Benzoxazine-3(4H>-one No. 4: 6-(3-(4-phenyl-1-piperazinyl)propoxy)-2H-1゜4-benzoxazine-3(4H)-one No. 5 : 6-(3-(4-(2,3-dimethylphenyl>-1-piperazinyl)propoxy)-2H-1,4-benzoxalan-3(4H)-one No. 5: Rilorpromazine (comparative compound ) Table 1 Testing role!=j amount Antioxygen deficient preparation example 1 6- (3-(4-(3-methylphenyl)-1-piperazinyl]propoxy)-2H-1,4-benzoxazine-3 (4H>-on 200mg grapes, 250mg pouring distilled water for fish, suitable for sling quantity
The compound of the present invention and glucose are dissolved in distilled water for IJ injection, poured into a 5 mQ ampoule, and autoclaved under nitrogen at 121°C for 15 minutes to obtain an injection having the above composition.

Formulation Example 2 6-(3-(4-(2,3-dimethylphenyl)-1
-Piperazinyl]-21-1-1,4-benzoxazin-5(4to1)-one 100Q Avicel (trade name, Asahi Kasei Shinri 40C) Cornstarch 30g Stearin-brown magnesium 2qTC-510g (Product name , Shin-Etsu Chemical Co., Ltd., Hydroxypropyl methylcellulose) Polyethylene glycol - 60003Ω Castor oil
40q methanol
40q The compound of the present invention, Avicel, cornstarch and magnesium stearate are mixed and polished, followed by sugar coating R1.
Compress the tablets with a 0mm kine. The obtained tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol-6000, castor oil and methanol to produce film-coated tablets having the above composition.

Formulation Example 3 6-(3-(4-(3-methylphenyl)-1-piperazinyl)propoxy)-2H-1,4-benzokylyzin-3(4H)-one 2g purified lanolin 5q white beeswax 5g white petrolatum
88Q total amount 100Q Heat beeswax to make it liquid, then add the compound of the present invention, purified lanolin and white petrolatum, heat until it becomes liquid, stir until it starts to solidify, and make an ointment with the above composition. 1 q.

(that's all)

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group. R^2 represents a phenyl group that may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group. A represents a lower alkylene group. Z represents an oxygen atom or a sulfur atom. ] A hypoxia improving agent characterized by containing a benzoxazine derivative or a salt thereof as an active ingredient.