JPS62135426A - Improver for hypoxia - Google Patents

Abstract

PURPOSE:An improver for hypoxia, containing a specific benzoazepine derivative or a salt thereof as an active ingredient, having improving action on hypoxia and useful as a cerebral activator, drug for consciousness disorder caused by cerebrovascular disorder, etc., drug for senile dementia, etc. CONSTITUTION:An improver for hypoxia containing a benzoazepine derivative expressed by formula I (R<1> is H, lower alkyl, etc.; R<2> is phenyl which may have 1-3 substituent groups, e.g. halogen, lower alkyl, etc.; A is lower alkylene). specifically the improver can be effectively used as a cerebral activator, improving drug for consciousness disorder caused by cerebrovascular disorder, encephalitis, metabolic disorder, etc., drug for senile dementia and preventing agent for arrhythmia or cardiac failure caused by oxygen shortage, etc. The compound expressed by the formula is capable of removing active oxygen species, has also preventing action on formation of peroxide lipid in the living body and is useful as an antiarteriosclerotic agent, anti-inflammatory agent, remedy for cataract, etc.

Description

[Detailed description of the invention] Top side of pot 1 The present invention relates to a hypoxia improving agent.

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

[In the formula, R1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R2 is a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxyl group.
Indicates a phenyl base that may have ~3. △ indicates a lower alkylene group. ] The benzazepine derivative represented by the above general formula (1) is a known compound as described, for example, in JP-A-57-193461.

However, the above-mentioned benzavipine derivatives are only known to have a middle-section nerve suppressing effect or an antihistamine effect.

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

The benzazepine derivative represented by the above general formula (1) has the effect of improving oxygen deficiency conditions and symptoms associated therewith, and is a drug that improves oxygen deficiency conditions and 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,
Medicines to treat or improve attention deficit, hyperactivity, speech disorders, and mental retardation, amnesia medicines, senile dementia medicines, medicines to improve respiratory arrest and hypoxia associated with potassium cyanide poisoning, arrhythmia and heart failure caused by lack of oxygen. It is effectively used as a preventive medicine.

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 droxy radicals through reactions in energy production systems, enzyme reactions, ultraviolet rays, radiation, and the like. While these reactive 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, etc., which exist abundantly in living organisms.
Promotes peroxidation of unsaturated fatty acids such as arachidonic acid that form phospholipids in biological membranes, forming lipid peroxides. This lipid peroxide causes generation of alkoxy radicals and hydroxyl radicals like the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes (metabolism,
1 branch (10).

(See 1978 Special Feature on Active Oxygen). However, in living organisms, for example, superoxide dismutase (S00), catalase, and glutathione peroxidase substances exist, and various vitamins with antioxidant ability, such as α-tocopherol (vitamin E), are present. However, for some reason, the appropriate defense mechanisms such as the enzymes and vitamins listed above may become defective, or the ability of the secondary defense mechanisms may be impaired. generation of reactive oxygen species and lipid peroxides,
It is often observed that accumulation occurs.

When a deficiency in such a defense mechanism occurs, the peroxidation reaction progresses in a chain reaction, resulting in serious disorders such as various diseases caused by platelet aggregation, inflammation, liver damage, arteriosclerosis, hemolysis, aging or 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 enzyme agents such as the above-mentioned SOD [Super Oxinide and Medicine, written by Yoshihiko Oyanagi, 1]
981, Imori Publishing, pp. 137-141, Latest Medicine, Special Feature: Active Oxygen and the Medical Role of Mo, Vol. 39, No. 7 (19
84), Inflammation, Yu, p699 (1981)
, ibid. 2, p367('l 982), c
current Therap, Rep, -20,
p62-69 (1976), “perSpeCtiV
e 1nIr+41amation” Red-Woo
d Burn, Ltd, p527-544 (
1977), Ala, Physio1. 5ca
nd, 4 9-2, 5ul) I) I 59-65 (1
980), Proc, Natt.

Acad, Sci, USA, 79. p7509
~7513 (1982), Pathology of
Oxygen Acad, Presspa 5-97
(1982), J, Clnic, Invest.

67, p983 (1981), J, C11ni
c. Invest.

70, p650-658 (1982), Pathol
ogy of Oxygen, p261-275 (1
982), Bioct+em, BiophysJct
a,,542.

f) 28-38 (1978), Bull, euro,
Physiopathol Re5p,, 17
, 5upl p287-288 (1981), Pa
thOIOCI'/of oxygen, D277
~302 (1982), Ministry of Health and Welfare Collection of Research Team's Research Team on Specified Diseases (1982), J, I
mmunol, 128. p2770 (1982), etc.], butylated hydroxytoluene (Bl-IT>, butylated hydroxyanisole (to BH), α-tocopherol (vitamin E), etc.) (Mishin, Hidetaka Tanaka, Pharmaceutical Journal, 19 (12).

D 2351-2359 (1983), Toshihiko Sueyasu, same magazine, 1U (5), p909-914 (1983)
,8rch,Biochem,Biophys,,2
27, p. 534-541 (1983), J
, Clnic, Invest, 57° p732-73
7 (1976), 8dv, Can5er, R.
os,,26. D197 (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 protective ul1 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 R/I, R2 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 linear or branched C2-C6 groups such as edynyl, 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. , 2-methyl-3-phenylpropyl group, etc., in which the alkyl moiety is a straight chain or branched alkyl having carbons v11 to 6, can be exemplified.

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

Lower alkoxy groups include methyl, ethoxy, propoxy, isopfoxy, butoxy, tert-71
Examples include straight-chain or branched alkoxy groups having 1 to 6 carbon atoms such as ~xy, pentyloxy, and hexyloxy groups.

Examples of phenyl bases that may have 1 to 3 substituents selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups, and hydroxyl groups include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-fluorophenyl, 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, 3,5-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-ethyl-1-xyphenyl,
3-ethyl-1-xyphenyl, 4-ethyl-1-xyphenyl, 4
-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-lame-1-xyphenyl, 3,4.5
-trimer-gysyphenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2-methoxy-3-chlorophenyl, 2-hydroxyphenyl, 3
-Halogen atom, straight chain or branched alkyl group having 1 to 6 carbon atoms, straight chain or branched alkoxy group having 1 to 6 carbon atoms on phenyl ring such as hydroxyphenyl and 3,4-dihydroxyphenyl ring Examples include phenyl haze, which may have 1 to 3 substituents selected from the group consisting of and hydroxyl groups.

Examples of lower alkylene groups include carbon groups such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2゜2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene groups. Examples include straight chain or branched alkylene groups of v11 to 6.

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

The benzazepine 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, tartaric acid, citric acid, malonic acid, and methanesulfonic acid. Organic acids such as 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, thickeners,
It is prepared using diluents or excipients such as 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, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, tablets, and injections (liquids). , suspensions, etc.), ointments, etc. When forming into a tablet, a wide variety of carriers known in this field can be used, such as lactose, sucrose, mono- to lithium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline xerulose, silicic acid, etc. excipients, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyhinylpyrrolidone, dry starch, storium alginate. , agar end, laminaran end, hydrogen carbonate 1.

disintegrants such as chlorine, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium bases , absorption enhancers such as sodium lauryl 5AM, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Examples include lubricants and the like. Zara tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into an emulsion, a wide variety of conventionally known carriers can be used, such as glucose, lactose,
Starch, cocoa butter, hydrogenated vegetable oil, kaolin, excipients such as talc, gum arabic powder, tragacanth powder, pyratin,
Examples include binders such as ethanol and disintegrants 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, gelatin, semi-synthetic glycerides, and the like. 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, propylene glycol, ethyl-oxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, sufficient salt, glucose, or glycerin may be included in the pharmaceutical preparation to prepare an isogenic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming pastes, creams, and gels, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone,
Examples include bentonite.

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 the case of injections, it may be used alone or with 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 method, patient's age, sex and other conditions, degree of disease, etc., but usually the amount of the compound of general formula (1), which is the active ingredient, is 1 kg (l) of body weight per day. The amount is preferably about 0.2 to 200 mg per serving.

Example Examples of pharmacological tests and formulations are listed below.

Pharmacological test (antioxidant deficiency effect)
rmacodyn, .

233.137 (1978).

ICR male mice (weight 20-30 g) were used. Four mice each were placed in a glass desiccator and the internal pressure was adjusted to 18.
Suction air with a vacuum pump until it reaches 0mm and 11g 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: 8-(3-(4-(3-methylphenyl)-1-piperazinyl]propoxy)-2,3,
4,5-tetrahydro-1 F+-1-benzazepin-2-one No. 2: 8- (3-(4-(3-chlorophenyl)-1-piperazinyl)propoxy)-2,3,
4,5-tetrahydro-1 H-l-benzazepine-2-one No. 3: Chlorpromacin (comparative compound) No. 1
Table Testing Dose Antioxidant Deficiency Compound No.
(m(]/kc+, oral) Effect (%) Formulation Example 1 8- (3-(4-(3-methylphenyl)-1-piperazinyl] propoxy)-,2,3,4,5-tetrahydro-1H -l-benzazepin-2-one 200m (] glucose 250m.

Distilled water for injection Suitable quantity
The compound of the present invention and glucose are dissolved in 5 ml of distilled water for injection, poured into 5 ml ampoules, replaced with nitrogen, and autoclaved at 121° C. for 15 minutes to obtain an injection with the above composition.

Formulation Example 2 8-(3-(4-(3-chlorophenyl)-1-piperazinyl) propoxy)-2,3,4,5-tetrahydro-1-day-1-benzazepin-2-one 100Q Avicel (trade name , Asahi Kasei flavor 40Cl cornstarch 30C] Magnesium stearate 2gTC-510g (Product name, Shin-Etsu Chemical Co., Ltd. (Tai-made, hydroxypropyl methylcellulose)) Polyethylene glycol-60003q Castor oil
40Q methanol
400 The compound of the present invention, Avicel, cornstarch and magnesium stearate were mixed and polished, followed by sugar coating R.
Compress the tablets with a 10 mm kine. Jqed tablets TC-5
, polyethylene glycol-6000, castor oil, and methanol to produce film-coated tablets having the above composition.

Formulation example 3 8-(3-(4=(3-methylphenyl)-1-piperazinyl]propoxy)-2,3,4,5-tetrahydro-11-1-1-benzazepin-2-one 2q purified lanolin 5q White beeswax 5g total amount 1
00CI White beeswax is heated to become liquid, then the compound of the present invention, purified lanolin and white petrolatum are added, heated until it becomes liquid, and then stirred until it begins to solidify to obtain an ointment having the above composition.

(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 halogen atom , represents a phenyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a hydroxyl group. A represents a lower alkylene group] or its benzazepine derivatives A hypoxia improving agent characterized by containing salt as an active ingredient.