JPH0466568A - Central antioxidant compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 and R3 are H, (substituted) hydrocarbon residue, heterocyclic group or acyl provided that when R1 and R2 are not H, R1 and R2 may form a cyclic amino together with adjacent N; R4 to R6 are H, lower alkyl or lower alkoxy; m is 2-4] or salt thereof. EXAMPLE:1-Ethyl-5-(4-methyl)pentylindoline-dihydrochloride. USE:A medicine. An active ingredient of central antioxidant, brain cell degeneration-suppressing agent and brain cell necrosis suppressing agent. The aimed compound has action suppressing a cell necrosis owing to glutamic acid and is used in prevention and treatment for cerebral ischemia, anoxia, etc., produced from cerebral infarction, temporary stop of heart stroke, etc., lung operation or cerebral injury, etc. PREPARATION:For example, a compound expressed by formula II is reacted with a compound expressed by formula III (R3, is R3 excluding H; Y is halogen) and the resultant compound expressed by formula V is subjected to catalytic reduction to provide the compound expressed by formula I wherein R2 is H; R2 is R5; R3 is R3.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a compound represented by the following formula (1) or a salt thereof, and a central antioxidant containing the same.

(Prior art and problems to be solved by the invention) Degeneration and necrosis of brain nerve cells caused by cerebral infarction, stroke, temporary cessation of heartbeat, lung surgery, cerebral ischemia caused by brain injury, oxygen deficiency, etc. It is thought that the glutamic acid and aspartic acid, which are sexual amino acids, are the cause, but much of the mechanism is still unknown. Although many efforts have been made to date to find antagonists of glutamate as a means of suppressing the degeneration and necrosis of these brain neurons, the current situation is that no satisfactory and effective drug has yet been found. It is.

The purpose of the present invention is to search for compounds that suppress cell necrosis caused by the addition of glutamic acid, to create these effective compounds,
Its purpose is to serve as a central antioxidant.

N-18-RE-105 cell line (Neuroblast
oma primary retina hybrid
The addition of glutamic acid to cells) inhibits the intracellular uptake of cystine and decreases the intracellular concentration of glutathione, resulting in cellular oxidative stress, that is, the accumulation of intracellular active oxygen and peroxide. , which is thought to result in cell degeneration and necrosis (Neuron, 2.1547 (19
89), JP Pharmaeol, Exp, The
r., 250.1132 (1989)). Using this evaluation system, we searched for a compound that suppresses cell necrosis caused by glutamic acid, and as a result, we found that a compound represented by the following formula (1) has the effect of suppressing cell necrosis.After further investigation, we developed the present invention. completed.

That is, the present invention provides formula (1), in which R3, R2, and R3 are independently hydrogen atoms or hydrocarbon residues, heterocyclic groups, or alkyl groups each having a substituent and -C. (However, R and R2 are not hydrogen atoms at the same time), but R1 and R7 may form a cyclic amine group together with the adjacent nitrogen atom, and R,...
R5, R6 independently represent a hydrogen atom, a lower alkyl group or a lower alkoxy group, and m represents 2.3 or 4] or a salt thereof; and central antioxidants containing these as active ingredients; Brain cell degeneration inhibitor, brain cell necrosis inhibitor (hereinafter sometimes referred to as central antioxidant)
Regarding.

In formula (1), R, , R2 and R1 represent "
The hydrocarbon residue is preferably a hydrocarbon residue having 1 to 8 carbon atoms, such as alkyl having 1 to 8 carbon atoms (e.g., methyl, ethyl, furoyl butyl, hequinyl,
4-methylpentyl, octyl), vinyl, allyl, 2
Examples thereof include alkenyl having 2 to 8 carbon atoms such as -butenyl and 3-methyl-2-buteno, alkynyl having 2 to 8 carbon atoms such as propalkyl, 2-butynyl and 3-octynyl, and aralkyl such as phenyl and hennol.

These alkyl, alkenyl, and alkynyl have one substituent.
-4, preferably 1 to 3, and examples of these substituents include norogen (eg, iodine, bromine, fluorine, chlorine), and amine groups.

Cyan group, alkoxy group having 1 to 3 carbon atoms, hydroxyl group, primary or secondary amino group having an alkyl group having 1 to 6 carbon atoms (for example, methyl, ethyl, butyl, hexyl), 4 carbon atoms
-6 cyclic amine groups, and the like. Furthermore, aralkyl groups such as phenyl and benzyl may have 1 to 3 substituents on the ring, and examples of the substituents include carbon atoms with 1 to 3 substituents.
~3 alkoxy groups (e.g., methquin, ethoxy), alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), cyan group, ami 7 groups, mono- or cyC6 alkylami 7 groups, 5 to 7 7-membered cyclic amine hydroxyl group, nitro group, norogen (e.g., chlorine atom).

bromine atom, bromine atom), etc.

The "anru group" of the "anol group which may have a substituent" represented by R-R3 is carboxylic acid acyl (eg, acetyl, propionyl).

alkylcarbonyl having 2 to 8 carbon atoms such as butyryl),
itmoxycarbonyl (for example, alkyl or aralkyloxycarbonyl having 2 to 8 carbon atoms, such as methyloquinecarunyl, tert-butyloki/carbonylbenneluoquinecarphonyl, etc.). Examples of substituents that these a/r groups may have include \rokene (e.g., iodine, bromine, fluorine, chlorine), ami7 group, alkyl MUI having 1 to 6 carbon atoms, such as methyl, ethyl, and 70-biru. , hexyl), etc., and may have 1 to 3, preferably 1 to 2 of these groups.

Cyclic amide formed with R, R, or adjacent nitrogen atoms 7
Examples of the group include a nitrogen-containing 5- to 7-membered heterocyclic group. Here, S is O, ], 2, t is 1, 2, and R7
represents a substituent or hydrogen that the cyclic amine 7 group formed by these R, , R, and the substituent includes, for example, an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl,
propyl) oxo, hydroxy, phenyl, benzyl,
Indicates a substituent such as an amine group. R8 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms as described above.

The heterocyclic group represented by R8-R3 is N.

1 to 4 hetero atoms selected from O7S, preferably 1 to 4
Two saturated or unsaturated 5- to 8-membered, preferably 5- to 6-membered heterocyclic groups are suitable. Particularly preferred are nitrogen-containing saturated heterocyclic groups such as pyrrolidinyl and pipery7nyl, and it is desirable that the group is bonded to N at a ring-constituting carbon atom. These heterocyclic groups have 1 to 3 substituents, preferably 1 to 2 substituents similar to the phenyl and benzyl groups represented by R3-R3 above.
It may be owned individually.

As the lower alkyl group represented by R,, R5, R,
An alkyl group having 1 to 6 carbon atoms (eg, methyl.

(ethyl, propyl, butyl, hexyl, 4-methylpentyl), or as a lower alkoxy group, carbon number 1 to 4
Alcoquine groups (eg, metquine, ethoxy, propoxy, butoxy, t-butquine), and the like.

Preferred embodiments of the compound represented by formula (1) include the following. RR't, R3
is a hydrogen atom or an alkyl having 4 to 7 carbon atoms,
Alkenyl is preferable, and the group substituting the alkyl or alkenyl is preferably a primary or secondary amine group or a cyclic amine group having 4 to 6 carbon atoms. Furthermore, R,,R,
When neither of are hydrogen, it is preferable that R3 is hydrogen, and when R3 is not hydrogen, it is preferable that one of R, , R, and R is hydrogen.

As R4, R5, and R6, a hydrogen atom or a lower alkyl group is preferable, and a hydrogen atom or an alkyl group having 1 to 3 carbon atoms is particularly preferable.

The compound (I) may form acid addition salts, especially physiologically acceptable acid addition salts, such as inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g. acetic acid,
Propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).

The compound represented by the formula (I) can be produced, for example, by the following method.

That is, a compound represented by formula (II) [wherein m+Ra+Rs+Ra has the same meaning as above] is converted into a compound represented by formula (III) R,'-Y (m) [wherein R
3' represents R3 without hydrogen, and Y represents halogen (e.g., chlorine, bromine, iodine)] to produce a compound represented by formula (IV). , this is expressed as formula (V) [wherein,
m, R3', R4, Rs, Re have the same meanings as above].

The reaction between the compounds represented by formula (II) and formula (III) is usually carried out using a hydrocarbon solvent (eg, pentane, hexane).

benzene, toluene), halogenated hydrocarbon solvents (e.g., dichloromethane, chloroform, chloroethane, carbon tetrachloride), ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxanosimethoquinethane), amide solvents (e.g., dimethylformamide, hexachloride), It is best to use an organic solvent such as methylphosphonotriamido) or methylsulfokinoto. The reaction is carried out from -10°C to 100°C.
It may be carried out at 9°C, preferably 10°C to 40'C. Furthermore, this reaction may be carried out as necessary, for example, with pyrin, 4
Dimethylamine/pyrylamine triethylamine [where m, R3' + R41R5+ R6 are the same as above] diethylene/amine, tetramethylethylene/
Organic bases such as amines, e.g. sodium bicarbonate, potassium bicarbonate, thorium carbonate, potassium carbonate,
The reaction can be carried out in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide, sodium hydride, potassium hydride, n-butyllithium, or the like.

For 1 mole of the compound represented by formula (H), formula (II
The amount of the compound represented by I) is usually about 1 to 5 mol, preferably about 1 to 2 mol.

The compound represented by formula (IV) can be converted to the compound represented by formula (V) by a method known per se in which the nitro group of the compound represented by formula (IV) is reduced to an amino group. That is, the compound represented by formula (IV) can be produced by catalytic hydrogen reduction in a solvent in the presence of a catalyst. As a solvent, any solvent commonly used in chemical reactions may be used as long as it does not interfere with the reaction, such as water, methanol, ethanol/methylformamide 1-, and tetrahydrofuran.
In a solvent such as nooxane, in the presence of a palladium-based catalyst, a platinum-based catalyst, or a fluorine-based catalyst, -
It can be carried out at a temperature of 10° C. to 100° C., preferably about 200° C. to 50° C., a hydrogen pressure of 1 atm to 100 atm, preferably 1 atm to 5 atm, and if necessary in the presence of an acid. The acids used include mineral acids (e.g. hydrochloric acid, nitric acid,
phosphoric acid, hydrobromic acid) or organic acids (e.g. acetic acid,
Examples include propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, and toluenesulfonic acid).

The compound represented by the formula (V) is represented by the formula (■) [wherein,
R,'i;! R, 'C or i; LR, 'CH2 is the above R0
Indicates that it has the same meaning as Y has the same meaning as above] to form a compound represented by the formula (1-1,) rLR+', R
3', R4, R5+ Re, and m have the same meanings as above] can be produced.

The compound a represented by the formula (1-1) is a compound represented by the formula (1-2) and the compound represented by the formula (1-3) is a compound represented by the formula (I1, where R,
', R3', R, , R5, Rtt, m have the same meanings as above], and furthermore, the compound represented by formula (+ -2) is obtained by formula (■) 1, where R2' is R,'C
Or R, 'CH2 has the same meaning as R7 above. By reacting with a compound represented by the same meanings as above, Y can be converted to the formula (I [wherein R+', R7', R3', R
4, R5, R,, m have the same meanings as above], [wherein R1', R1', R3'
, R4+ R5+ Re1m has the same meaning as above]
This can lead to the compound represented by

The reaction of the compound represented by the formula (V) and the formula (Vl) and the reaction of the compound represented by the formula (1-2) and the formula (■) are usually carried out using a hydrocarbon solvent (e.g. pentane), Hensen, toluene), halokene hydrocarbon solvents (e.g. dichloromethane, chloropormcycloethane, carbon tetrachloride), ether solvents (e.g. ethyl ether, tetrahydrofuran dioxane, nomethoxy/ethane), amide solvents (e.g. dimethyl Organic solvents such as formamide, methylphosphonotonoamyl-), and methylsulfoquinide may be used. The reaction is from -10'C to 1
The temperature is preferably from 10'C to 40'C. Furthermore, this reaction may be carried out using an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethyleneamine, tetramethylethylenediamine, etc. Inorganic bases such as sodium, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, n
- It can be carried out in the presence of butyllithium or the like.

The amount of the compounds represented by formulas (■) and (■), respectively, is usually about 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compounds represented by formula (V) and formula (I-2). The quantity is good.

Known methods for reducing compounds represented by formulas (1-1) and (1-3) include hydrocarbon solvents (e.g., hentane, hexane, benzene, toluene), halogen solvents (e.g., dichloromethane), , chloroform, dichloroethane), preferably in an ethereal medium (e.g., diethyl ether, diethyl ether, tetrahydrofuran, dioxane), and the reaction temperature is from -30°C to 200°C, preferably from 0°C to 60°C (hydrogen). This can be carried out by using lithium aluminum oxide, sodium aluminum hydride, or the like.

Compound represented by formula (V) and formula (■) R, -Y
(■) In the formula (I5) 2 formula (1-6) 1, R+, R3', R4 , R, Re and m have the same meanings as above].

In addition, a compound represented by formula (1-5) and formula (rX)R,
-Y (IX) In formula 1, R2
, Y has the same meaning as defined above.
31R41R51R'L m has the same meaning as above] can be produced.

A compound represented by formula (V) and a compound represented by formula (■), or a compound represented by formula (1-5) and formula (I
The reaction with the compound represented by
Halogenated hydrocarbon solvents (e.g. dichloromethane, chloroform, dichloroethane carbon tetrachloride), ether solvents (e.g. ethyl ether, tetrahydrofuran, dioxane, methane), amide solvents (e.g. dimethylformamide, hexamethylphosphonotriamide)
It is preferable to use an organic solvent such as trimethyl sulfoxide. The reaction is carried out at -10°C to 100°C2, preferably at 10°C.
It is best to do it at 'C to 40'C. In general, this reaction may be carried out using organic bases such as pyridine, 4-methylaminopyridine, triethylamine/isoflobilamine, triethyleneamine, and tetramethylethylenediamine, as well as sodium bicarbonate, potassium bicarbonate, sodium carbonate, The reaction can be carried out in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, 1-potassium oxide, sodium hydride, potassium hydride, n-butyllithium, or the like.

Compounds represented by formula (Xl) and formula (IX) for 1 mole of the compound represented by formula ()7 formula (1-5): usually about 1 to 5 moles, preferably 1 to 2 moles f (Y degree is good.

By reacting a compound represented by the formula (V) with a compound represented by the formula (X)RY (X) and j, where R and -Y have the same meanings as above, the compound represented by the formula ([8)] A compound represented by can be produced.

The reaction between the compounds represented by formula (V) and formula (X) is usually carried out using a hydrocarbon solvent (e.g., pentane, hexane, henzene toluene), a halogenated hydrocarbon solvent (e.g., cyclomethane, chloroform, /chloroethane, carbon chloride),
Ether solvents (e.g., ethyl ether, tetrahydrofuran, methoxyethane), amide solvents (e.g., methylformamide, methylformamide)
It is better to use an organic solvent such as heliamide methyl sulfoxide. The reaction is from -10°C to 100°C1
Preferably, it is carried out at 10'C to 40°C. Furthermore, this reaction can be carried out using organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethyleneamine, and tetramethylethylenediamine, as well as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and water. The reaction can be carried out in the presence of an inorganic base such as sodium oxide, potassium hydroxide, sodium hydride, potassium hydride, n-butyllithium, or the like.

The amount of the compound represented by formula (X) is usually about 1 to 5 moles, preferably 1 to 1 mole of the compound represented by formula (V).
~2 molar amount is sufficient.

Further, a compound represented by the formula (V) and a compound represented by the formula (Xl)○ (XI) R'CH [wherein R3' is a compound represented by the same meaning as above, or a compound represented by the formula (X■) \ -O / (Xl ) (1-9), a compound represented by formula (I-10) [wherein each symbol has the same meaning as above] can be produced.

The reaction between formula (V) and the compound represented by formula (Kari) or formula (Xll) may be carried out using any solvent commonly used in chemical reactions, as long as it does not interfere with the reaction.
In solvents such as methanol, ethanol, propatool, etc.
This can be carried out by reduction using lithium anoborohydride, lithium aluminum hydride, phosphorane, or the like. The reaction temperature can be from 30°C to 100°C2, preferably from 10°C to 30'C. The represented compound is usually used in an amount of about 1 to 10 moles, preferably about 1 to 2 moles. The reaction time is usually about 0.5 to 10 hours, preferably about 1 to 4 hours.

Formula (1-4) (1-2) (1-3) (1-4) (1-5
) (1-6XI7) (1-8) (1-9) (1-10)
To produce a compound represented by formula (bi) [wherein R,, R2, R,, R5, R, and m have the same meanings as above] by removing R3' from the compound represented by can. For example, when R3' is an anru group, hydrolysis is effective, and when R3' is a hennol group, hennluoki/carbonyl group, etc., catalytic hydrogen reduction is effective. Hydrolysis can be carried out by methods known per se, for example, alkali metal hydroxide (e.g. hydroxide, lithium hydroxide, potassium hydroxide),
0°C to 200'C in alkali metal carbonate compounds (e.g., potassium carbonate, sodium carbonate, lithium carbonate) or mineral acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, phosphoiodic acid)
, preferably from 50°C to 100°C. 10 to 100 equivalents of acid or base, preferably 20 to 4
Use 0 equivalents. The strength of the acid and base is preferably about 1N to 10N, preferably 4N to 10N. The reaction time depends on the reaction temperature, but is usually 1 hour to 24 hours, preferably 2 hours to 10 hours.
It takes about an hour.

Catalytic hydrogen reduction can be produced by a method known per se, for example, by catalytic hydrogen reduction in a solvent in the presence of a catalyst. As the solvent, any solvent commonly used in chemical reactions may be used as long as it does not interfere with the reaction.
For example, in a solvent such as water, methanol, ethanol, dimethyl fluoramide, or tetrahydrofuran, in the presence of a palladium-based, rhodium-based, platinum-based, or silica-based catalyst, -10'C-100°C2 is preferred. At about 20°C to 50°C, hydrogen pressure is 1 atm to 1 atm.
00 atm, preferably 1 atm to 5 atm, if necessary,
It can be carried out in the presence of acid. Examples of acids used include mineral acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g., acetic acid, propionic acid, distartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid). .

In addition, if the obtained target product is a free product, it can be converted into an acid addition salt as described above according to a conventional method, and if the target product is obtained as a salt, it can be converted into a free compound according to a conventional technique. .

The reaction product can be isolated and purified by known means, such as solvent extraction, liquid conversion, dissolution, salting out, crystallization, recrystallization, and chromatography.

The compound (1) of the present invention can be used to treat cerebral hypoxia, cerebral infarction, and stroke.
Symptoms associated with cerebral ischemia caused by temporary cessation of heartbeat 2
Protects brain nerve cells against symptoms associated with head trauma 1 during surgery.

It is recognized that it exhibits a central antioxidant effect and can be used for the prevention or treatment of these diseases.

When the compound of the present invention is used for the prevention, treatment, etc. of the above-mentioned symptoms, it may be administered orally or parenterally in the form of a bulk powder or in the form usually prepared with a pharmaceutical carrier.

The dosage form of the administration preparation is not particularly limited, and includes, for example, tablets,
Various dosage forms include powders, granules, capsules, injections, and skewers.

The formulation of compound (I) or a salt thereof of the present invention is prepared according to a conventional method. As carriers for oral preparations, substances commonly used in the pharmaceutical field, such as starch, mannitol, crystalline cellulose, and sodium carboxydimethylcellulose, are used. Distilled water, physiological saline, glucose solution, infusion, etc. are used as carriers for injection.

Does the dosage vary depending on the type of disease, symptoms, etc.? - In the case of injection administration in adults for boat fishing, - 0.1+ng to 3g per day, preferably 0.3mr-300
mg, most preferably 3 mg to 50 mg. For oral administration, preferably 1 mg to 1 g, most preferably 10 mg to 300 mg per day.

EXAMPLES The present invention will be explained in more detail with reference to Examples, Formulation Examples, and Test Examples, but it goes without saying that the present invention is not limited thereto.

Example 1 CI (3 1-acetyl-5-(pyrrolinon-1-yl)indoline (1) 5-nitroindoline was dissolved in acetic anhydride (30 rotations) and heated and stirred at 100'C for 1 hour. After the reaction was completed. ,
Excess acetic anhydride was distilled off, ethyl ether was added to the residue, and the solid was collected for one month to obtain 9.2 g of ■-acetyl-5-nitroindoline.

(2) l-acetyl-5-nitroindoline (9.0g
) in methanol (20 M) with concentrated hydrochloric acid (6 mfl).
was added, and catalytic reduction was carried out at room temperature and pressure using 10% palladium/carbon as a catalyst. The catalyst was removed, the solvent was distilled off, ethyl ether was added to the residue, and the precipitate was collected in July (
From this, 1-acetyl-5-aminoindoline hydrochloride 8
2g was obtained.

(3) To a solution of 1-acetyl-5-aminoindoline hydrochloride (2.55 g) in dimethylformamide (20 turns), potassium carbonate (6.6 g) and 1,4-dibromobutane (1.43 centimeters) were added. The mixture was heated and stirred at 100°C for 3 hours. Add ethylester acetate (50 pieces) and water (5 pieces) to it.
0+J) was added thereto, and the organic layer was further washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the remaining residue was recrystallized from ethanol to obtain 1.3 g of colorless crystals with a melting point of 209-210°C.

Elemental analysis value C,, H, 8N, old 1 calculation value C as ○
73,01,t(7,88,N +216 experimental value C7
310, l-(7,70, N12.14 Example 2 Acid salt Example 1 1-acetyl-5-(pyro r nonone-1
-) Dissolve indoline (1.15 g) in a mixture of water (5 ml), ethanol (5 ml), and concentrated hydrochloric acid (5 ml),
After heating and stirring at C for 5 hours, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 0.5 g of colorless crystals with a melting point of 235-238°C.

Elemental analysis value CI21-(+ec LN? Calculated value C55,18I"6.95: N 10.72
Experimental value C55,311 (6,95; N 10.4
8 Example 3 ゛CCO OH3 1-acetyl-5-aminoindoline hydrochloride (213 g) obtained in Example 1 and triethylamine (4,2+J
) was dissolved in dichloroform (30d), acetyl chloride (1,6yffl) was added at room temperature, and the mixture was stirred for 2 hours. After washing with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to FT+ crystallization from ethanol, and the melting point was 2.
18 g of colorless crystals of 09-211'C were obtained.

Elemental analysis value C, H, N, O, calculated value C6
6,04; l(6,47,\1284 experimental value C
65,81; t(6,47; 5ami/in1
Linohydrochloride (2,13g) and isocaproic acid chloride (2,13g)
melting point 53-0g) using the same procedure as in Example 3.
7 g of colorless crystals at 55°C were obtained.

Elemental analysis value: Calculated value as C,,H,,N,0,
C70,04: H8,08: N 10.2+Experimental value C70,12,H813: N 1003 Example 5 ■ I-1,000-5-1,000 ruaminoyl/doline dihydrochloride actual F= 5 obtained from Example 3 -acetamide/-1 acetylin I. phosphorus (], 11g with tetrahydrofurano (30d)
suspended in 7-d lithium t-aluminum (0
．． 6g) was heated to T+ and stirred at 60°C for 30 minutes. A 10% aqueous solution of hydrogen chloride (076&"l) was added to the solution and stirred at room temperature for 30 minutes. The precipitate was removed.
An oki→nan solution (3 J) was added, the solvent was distilled off, and the residue was recrystallized from ethanol-acetic acid ethyl ester to obtain 1.0 g of colorless crystals with a melting point of 144-147°C.

Elemental analysis value CItH'! . Calculated value as CQtN:
C54,76; H7,66; N 10.64 Experimental value: C54,94; H758; N 10.
82 Example 6 An oxane solution (1.5%) was added and the solvent was distilled off.

The residue was recrystallized from ethyl ether and the melting point was 158159.
0.5 g of colorless crystals were obtained.

Elemental analysis value C,, H2,, C (calculated value as N20: C64,74; H8,49; N9.44 Experimental value: C64,88; H8,27N9J5 Example 7 1- obtained in Example 4 Acetyl-5-(4-methyl)pentanoylindoline (1.7 g) was suspended in tetrahydrofuran (30 g), and lithium aluminum hydride (0.7 g) was suspended in tetrahydrofuran (30 g).
, 37 g) was added thereto, and the mixture was stirred for 1 hour in the chamber. Water (0,
6d), 10% aqueous sodium hydroxide solution (0.49%)
After stirring at room temperature for 30 minutes, the precipitate was removed, and the mother liquor was added with 6N hydrogen chloride. 1-Acetyl-5 obtained in Example 4
-(4-methyl)pentanoylindoline (1,7g)
was suspended in tetrahydrofuran (37g), lithium aluminum hydride (0.74g) was added, and the mixture was heated and stirred at 60°C for 2 hours. Water (1.2d) and 10% aqueous sodium hydroxide solution (1.0d) were added. After stirring at room temperature for 30 minutes, the precipitate was removed, a 6N hydrogen chloride dioxane solution (5 am) was added to the mother liquor, the solvent was distilled off, and the residue was recrystallized from ethanol-ethyl acetate. Melting point 145-14
1.4 g of colorless crystals at 9°C were obtained.

Elemental analysis values: C, H, CN, N, calculated values:
C60, 18, H8, 84; N 8.77 Experimental value: C60, 25, Hg, 9o; was distilled off, and the residue was recrystallized from ethyl acetate to obtain 1.9 g of a colorless solid. This solid (0,7 g) and fumaric acid (0
, 23g) in methanol, and after distilling off the solvent,
Recrystallization from ethanol gave 0.8 g of colorless crystals with a melting point of 194-195°C.

Elemental analysis value C,, N3. Calculated value as N305: C6
7,08・H6,71・N903 experimental value: C66,
87:H6,68,N 9.19 Example 9 1-acetyl-5-aminoindoline hydrochloride (2.12 g) obtained in Example 1 and N-hensyl-4piperidone (2
,08g) in methanol (10g) was added sodium cyanoborate (0.63g), and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (30d) in the reaction solution
and water (30d) were added to C-O R3. 1 acetyl~5-(1 hene/lupiperinyl)aminointhrin (1,26 g) obtained in Example 8 was mixed with ethanol (10 bottles) and water (10 g).
) It was dissolved in a mixed solvent of concentrated hydrochloric acid (1 store), and catalytic hydrogen reduction was carried out at room temperature and pressure using 10% radium/carbon as a catalyst. After the reaction was completed, the catalyst was removed, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 0.9 g of colorless crystals with a melting point of 300'C or higher.

Elemental analysis value C, sH-sCQtN Calculated value as 30: C54,22: H6,9g, N 12.6
5 Experimental values: C54,13; H6,36; N1
2,81 Formulation Example 1 (1) 1-Ethyl-5-(4-methyl)pentylindoline dihydrochloride (compound of Example 7) 5
09(2) Lactose 19
8゜(3) Corn starch
509(4) Magnenium stearate
2! ? (1,) (2) and 20g of 1-Umorofun starch were mixed, and 159 Umorofun starch and 25 mQ
Granulate it with a paste made from water, add 15
9 of corn starch and (4) were added, and the mixture was compressed to form a tablet with a diameter of 5π containing 50 mg of (1) per tablet.
1000 tablets of m were manufactured.

Formulation example 2 1-ethyl-5-(4-methyl)pentylindoline
After dissolving dihydrochloride 29 and mannitol 1259 in water, the pH was adjusted to 5 to 7 with Q, IN-Na○1], and the total amount was adjusted to 100 ρ. This solution was filtered to remove bacteria through a 02 μm filter. Add this to 1r (1 ampoule for!
It was dispensed into 00 bottles.

Protective effect against glutamate-induced cell death in N18-RE-105 cells High concentrations of glutamate (1
10mM), the intracellular uptake of nostin
Cell death is observed due to oxidative stress caused by
'). The effects of compounds on this glutamate-induced cell death were investigated. Approximately 10,000 cells were seeded in a 3bii diameter culture tube containing 11 DME M medium, and after culturing for 2.4 hours, glutamic acid and the compound were added. After converting to DMEM medium in which compounds of various intensities were dissolved, 10 mM glutamic acid was added. After adding glutamic acid, an additional 244
After culturing for an hour, surviving cells were collected and the lactate dehydrogenase (L I H) activity contained in the cells and medium was measured. Cell lethality was calculated using the following formula.

Table 1 shows the minimum concentration (IC5,) that suppresses the cell lethality to 50% or less for typical example compounds.

Table 1 Effect of glutamate on cytotoxicity Example number ■0. . (μM) 20.5 52.0 62.0 (1) Neuron 2. 1547 (+989) (
2) J, Pharmacol, Exp, The
r, 250. 1132 (1989) (Effects of the Invention) The central antioxidant (1) of the present invention and its salts exhibited the effect of strongly suppressing cell necrosis caused by glutamic acid, as is clear from the above test examples.

Diseases for which the central antioxidant (+) and its salts of the present invention are useful include, for example, cerebral infarction, temporary cessation of heartbeat caused by stroke, cerebral ischemia resulting from lung surgery or brain injury, and diseases caused by oxygen deficiency. symptoms.

Symptoms associated with increased intracranial pressure due to intracranial neoplasms and traumatic pressure, as well as diseases such as cerebral edema and dementia, and the central antioxidant (1) and its salts of the present invention are effective against these diseases. It can be used to prevent or treat cancer.

Therefore, the present invention provides a useful therapeutic agent for post-stroke IE, a neuroprotective agent, and a central antioxidant.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1, R_2 and R_3 are independently a hydrogen atom or a hydrocarbon residue which may each have a substituent,
Indicates a heterocyclic group or acyl group (however, R_1 and R_
2 are not hydrogen atoms at the same time), R_1 and R_2 may form a cyclic amino group together with adjacent nitrogen atoms, and R_4, R_5, and R_6 independently represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group. , m represents 2, 3 or 4] or a salt thereof. 2. A central antioxidant characterized by containing the compound according to claim 1 or a salt thereof.