JPH0717973A - 1,2-benzoisoxazole derivative or salt thereof - Google Patents

Abstract

PURPOSE:To obtain a novel compound having cerebral hypoxia protecting action, life-prolonging action on cerebral ischemic animal and anticonvulsive action and weak central nervous system depressing action and useful as an agent having excellent safety. CONSTITUTION:A compound of the formula I (R is H, halogen, etc.; R1 is H, lower alkyl, aralkyl, etc.; R2 is H, lower alkyl, etc.; R3 and R4 are H or lower alkyl or R3 and R4 together form lower alkylene, etc.; X is CH2, SO2, CHOR5, etc.; R5 is H, carbamoyl, etc.; (m) is 0 or 1), e.g. (S)-5-chloro-3-(2- pyrrolidinylmethoxy)-1,2-benzoisoxazole. The compound of the formula I can be produced by reacting a compound of the formula II (Z is halogen, lower alkylsulfonyloxy, etc.) with a compound of the formula III. It is useful as an agent for the treatment of not only cerebral vascular disorder of acute stage but also cerebral vascular disorder of chronic stage, posttraumatic syndrome after head injury and epilepsy.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (I)

[Chemical 3]

"In the formula, R is a hydrogen atom, a halogen atom,
At least one selected from optionally substituted lower alkyl, aralkyl, lower alkyloxy and aralkyloxy groups; R ₁ represents a hydrogen atom or an optionally substituted lower alkyl or aralkyl group; ₂ is a hydrogen atom or an optionally substituted lower alkyl, aralkyl, lower acyl or lower alkyloxycarbonyl group; R ₃ and R ₄ are the same or different and are a hydrogen atom or an optionally substituted lower alkyl. And R ₃ and R ₄ together represent a lower alkylene group; X represents CH ₂ , SO or SO ₂ or the formula CHOR ₅ (R ₅ represents a hydrogen atom or a lower alkyl or carbamoyl group. ) Or NR ₆ (R ₆
Represents a hydrogen atom or a lower alkyl group. Group represented by), oxygen atom, sulfur atom and formula

[Chemical 4] (Y represents an oxygen atom or a sulfur atom); m is 0 or 1; n is 2,
3 or 4 is shown, respectively. 1,2-
It relates to a benzisoxazole derivative or a salt thereof.

2. Description of the Related Art Conventionally, in the acute phase of cerebral circulatory disorders, the primary treatment is to save lives, and almost no treatment is performed to reduce the aftereffects. On the other hand, various drugs for improving cerebral circulation and metabolism are used in the chronic stage. However, because the symptoms have already been fixed,
The most desired neurological symptoms and activities of daily living have not been found to be improved in these cerebral circulation and metabolism improving agents.

Therefore, it is now considered that proper treatment in the acute phase can alleviate the sequelae, especially neurological sequelae.

[0004]

[Problems to be Solved by the Invention] Therefore, it has a brain protective effect of suppressing cell death in a cerebral ischemic state, and has a weak central inhibitory effect which makes systemic management of patients difficult,
Furthermore, the development of chemically stable compounds is desired.

[0005]

[Means for Solving the Problems] Under such circumstances,
As a result of earnest studies, the present inventors have found that the following formula was added to the 3-position of 1,2-benzisoxazole:

[Chemical 5] A compound having a group represented by "wherein R ₁ , R ₂ , R ₃ , R ₄ , X and m have the same meanings as described above," that is, the above-mentioned general formula (I ), A novel 1,2-benzisoxazole derivative or a salt thereof has an excellent cerebral protective effect of suppressing cell death in a cerebral ischemic state, and further has a weak central inhibitory effect. Not only in the acute phase, but also in the chronic phase of cerebral circulation,
The inventors have found that the compound is useful as a therapeutic agent for aftereffects of head trauma and epilepsy and is a chemically stable compound, and completed the present invention. Hereinafter, the present invention will be described in detail.

In the present specification, each term has the following meanings unless otherwise specified.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and the lower alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C _1-7 alkyl groups such as pentyl, hexyl and heptyl; lower alkyloxy groups include C _1-7 alkyl-O— groups such as methoxy, ethoxy, n-propoxy, n-butoxy and pentyloxy. An aryl group is phenyl, naphthyl and the like; an aralkyl group is an aryl-C _1-7 alkyl group such as benzyl, benzhydryl and trityl; an aralkyloxy group is benzyloxy and phenethyloxy and the like. And the lower alkylene group are, for example, ethylene, Pyrene, a C _2-7 alkylene group such as tetramethylene and pentamethylene; Lower acyl group, e.g., formyl, a C _1-7 acyl group such as acetyl and butyryl; and lower alkyloxycarbonyl groups, for example, C such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl
_1-7 alkyloxy-CO- group is shown.

Further, the substituents of optionally substituted lower alkyl, lower alkyloxy and aralkyloxy of R, R ₁ , R ₂ , R ₃ and R ₄ include, for example,
Examples thereof include a halogen atom, a hydroxyl group, a lower alkyloxy group, a lower alkyloxycarbonyl group, an aryl group, a cyano group and an amino group. Also, R, R
Examples of the substituent of the optionally substituted lower acyl, lower alkyloxycarbonyl and aralkyl group of ₁ and R ₂ include a halogen atom, a hydroxyl group,
Examples include lower alkyl groups and nitro groups. R,
Each of R ₁ , R ₂ , R ₃ and R ₄ may be substituted with one or more of the above-mentioned substituents.

The salt of the 1,2-benzisoxazole derivative of the general formula (I) may be any pharmaceutically acceptable salt, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. A salt with a carboxylic acid such as formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid and tartaric acid; a salt with an acidic amino acid such as aspartic acid and glutamic acid; and methanesulfonic acid, toluenesulfonic acid, Mention may be made of salts with inorganic acids and organic acids, such as salts with sulphonic acids such as hydroxybenzene sulphonic acid and naphthalene sulphonic acids.

In the 1,2-benzisoxazole derivative of the general formula (I), isomers (for example, optical isomers,
When a geometric isomer and a tautomer etc.) are present, the compound of the present invention includes all isomers thereof and also includes hydrates, solvates and all crystal forms.

Next, a method for producing the 1,2-benzisoxazole derivative of the general formula (I) or a salt thereof will be described.

The 1,2-benzisoxazole derivative of the general formula (I) or a salt thereof can be produced by a method known per se, for example, the following production method.

[0013]

[Formula 1] “In the formula, R, R ₁ , R ₂ , R ₃ , R ₄ , X and m each have the same meaning as described above, and Z is a halogen atom, methanesulfonyloxy, ethanesulfonyloxy or the like. It represents a leaving group such as a lower alkylsulfonyloxy group, a benzenesulfonyloxy group or an arylsulfonyloxy group such as p-toluenesulfonyloxy group. "

The compound of the general formula (II) can be obtained by the method described in Chemiste Berichte (Chem.Ber.) Vol. 100, 954-960 and 3326-3330 (1967), or a method known per se. It can be manufactured by the method described above.

The compound of the general formula (III) is, for example, a compound of the general formula (IV)

[Chemical 6] "In the formula, R ₁ , R ₂ , R ₃ , R ₄ , X and m each have the same meaning as described above, and R ₇ represents a hydrogen atom or a lower alkyl group." From the compound
For example, Tetrahedron Le
tters) 33, 5517-5518 (1992) or Chemical and Pharmaceutical Bulletin.
(Chem.Pharm.Bull.) Volume 30, Pages 1921-1924 (1982), or a method known per se. Next, a method for producing the compound of the present invention will be described based on the above production route.

The compound of the general formula (I) is reacted with an alkali metal salt such as sodium or potassium of the compound of the general formula (III) in the presence or absence of a solvent. Obtain the compound.

The solvent used in this reaction may be any solvent which does not adversely influence the reaction, for example, aromatic hydrocarbons such as benzene and toluene; methylene chloride, chloroform and 1,2-dichloroethane. Halogenated hydrocarbons; ethers such as tetrahydrofuran, dioxane, diethyl ether and 1,2-dimethoxyethane; esters such as ethyl acetate and butyl acetate; and acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , N
-Aprotic polar solvents such as methylpyrrolidone, dimethylsulfoxide, sulfolane and hexamethylphosphoric triamide, etc. may be mentioned, and these solvents may be used alone or in combination of two or more.

The amount of the alkali metal salt such as sodium or potassium of the compound of the general formula (III) used in this reaction is 1.0-3.0 with respect to the compound of the general formula (II).
It is twice the mole. Further, the reaction temperature and reaction conditions of this reaction are not particularly limited, but usually, it may be carried out at 0 to 150 ° C. for 10 minutes to 24 hours.

Further, the 1,2-benzisoxazole derivative of the general formula (I) or a salt thereof can be converted into, for example, substitution reaction, addition reaction, elimination reaction, reduction reaction, oxidation reaction, dehydration reaction and hydrolysis reaction itself. It is also possible to convert it into another 1,2-benzisoxazole derivative of the general formula (I) or a salt thereof by combining known reactions.

In the above-mentioned method for producing the compound of the present invention and the method for producing the starting compound, the compounds of the general formulas (I) and (III) and their salts are isomers (for example,
Optical isomers, geometric isomers, tautomers and the like), if they exist, they can also be used.

In the above-described method for producing the compound of the present invention and the method for producing the starting compound, when an active group such as an amino group and a hydroxyl group is present in addition to the reaction site,
These groups may be protected in advance by a conventional method, and after the reaction, they may be eliminated by a conventional method.

The reaction product can be isolated and purified by a conventional method such as extraction, crystallization and column chromatography.

When the compound of the present invention is used as a medicine, additives such as excipients, carriers and diluents which can be used pharmaceutically may be appropriately mixed, and these may be injections, tablets, capsules, suppositories. Alternatively, it can be administered orally or parenterally in the form of powder. In the case of parenteral administration, the dose is usually about 1 to 1000 mg per day for an adult, and is administered once or in several divided doses, which can be appropriately selected according to the age, weight and symptoms of the patient. .

Next, the pharmacological action of the representative compounds of the present invention (Table A and Table B) will be described. In addition, R and A in Table A and Table B are respectively represented by the following formulas.

[Chemical 7] The substituents of the compound represented by The test compound used in the following tests is the hydrochloride salt. The abbreviations used below have the following meanings.

Me group; methyl group Et group; ethyl group Further, the numerical value attached to each group of R in the table indicates the substitution position.

[0026]

[Table A]

[Table B]

[Cerebral hypoxia protective action] The test method is Archives International
Pharmaco Dynamies de Therapy (Arch.Int.Ph
armcodyn.) 139, 67-74 (1962). That is, 8 male ICR mice per group
(4 weeks old), 30 mg / kg of the test compound dissolved in distilled water or suspended in 0.5% (W / V) methylcellulose solution was orally administered, and 1 hour later, the mouse was placed in a glass container, and 4% thereof was added thereto.
A mixed gas consisting of oxygen and 96% nitrogen was aerated at 5 l / min, and the time until the mouse died was measured. The life-prolonging effect was calculated based on the time until death of a mouse that was orally administered with distilled water or a 0.5% (W / V) methylcellulose solution as 100. The results are shown in Table 1.

[0028]

[Table 1]

2. [Movement disorder effect] The test method is applied pharmacology, Volume 43, pp. 173-194 (1992).
It was performed according to the method described in. I of 3-4 animals per group
CR male mice (4 weeks old) dissolved in distilled water or 0.5%
(W / V) Test compound 100 suspended in methylcellulose solution
Oral administration of mg / kg was carried out, and after 30 minutes, the time until it was hung on a wire having a diameter of 1.6 mm and dropped was measured. When no fall was observed for 10 seconds, it was judged that there was no movement disorder effect. As a result, N
Compounds o.4, 8, 9, 11, 12 and 21 showed no motor impairment.

From the above results, it can be easily understood that the compound of the present invention has excellent cerebral hypoxia protective action, weak central nervous system depressing action, and high safety.

【The invention's effect】

The compound of the present invention is useful as a therapeutic agent for not only the acute phase of cerebral circulatory disorder but also the chronic stage of cerebral circulatory disorder, sequelae of head trauma and epilepsy.

【Example】

The following examples are provided to explain the present invention in detail, but the present invention is not limited thereto.
The mixing ratios of the mixed solvent and the eluent are all volume ratios, and the carrier in column chromatography is silica gel [silica gel 60, No.773 manufactured by Merck & Co., Inc.].
4] was used. The abbreviations used below have the following meanings. Me: Methyl group Et: Ethyl group

Example 1 (1) A suspension of 60% (W / W) sodium hydride (0.39 g) in tetrahydrofuran (10 ml) was added at 20-25 ° C. to (S) -2-pyrrolidinylmethanol (1.00 g) in tetrahydrofuran (10 ml). Add the solution and reflux for 2 hours. Then, under reflux, a solution of 3,5-dichloro-1,2-benzisoxazole (2.29 g) in tetrahydrofuran (10 ml) is added, and the mixture is further refluxed for 1 hour.
After cooling the reaction mixture, the solvent is distilled off under reduced pressure, ethyl acetate and water are added to the obtained residue, the mixture is shaken, and the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then subjected to silica gel column chromatography [eluent: chloroform: methanol = 15: 1].
The oily substance (S) -5-chloro-3- (2
1.45 g of -pyrrolidinylmethoxy) -1,2-benzisoxazole are obtained. (2) (S) -5-chloro-3- (2-pyrrolidinylmethoxy) -1,2-benzisoxazole 1.43 g of 2-
1.1 ml of 2-propanol solution (7.5N) of hydrogen chloride was added to 10 ml of propanol solution, and the precipitated solid was collected by filtration to obtain colorless crystals of (S) -5 having a melting point of 214.0-216.1 ° C.
Chloro-3- (2-pyrrolidinylmethoxy) -1,2-
1.36 g of benzisoxazole hydrochloride are obtained. No.1, IR (KBr) cm ^-1 ; 2915,2727,2498,1609,1540,1479,144
1,1362,1126,928,821,636,557

Examples 2-17 In the same manner as in Example 1, the compounds of Tables 2a-2c and their hydrochlorides are obtained. In addition, R and A in Tables 2a-2c are represented by the following formulas.

[Chemical 8] The substituents of the compound represented by Furthermore, R in the table
The numerical value attached to each group of indicates the substitution position.

[Table 2a]

[Table 2b]

[Table 2c]

The physical properties of the hydrochlorides of the compounds shown in Tables 2a-2c are shown below.

No. 2: IR (KBr) cm ^-1 ; 3442,2899,2731,2789,1
541,1477,1434,1361,926,822,639,559 Melting point; 207-210.8 ° C

No. 3: IR (KBr) cm ^-1 ; 3447,2942,2731,2699,1
536,1479,1440,1317,1012,935 Melting point; 256-260.5 ℃

No. 4: IR (KBr) cm ^-1 ; 3445,2934,2480,1540,1
478,1444,1369,1313,1107,950,828 Melting point; 235-240 ℃ (decomposition)

No. 5: IR (KBr) cm ^-1 ; 3077,2938,2709,2644,2
445,1610,1534,1476,1452,1368,1313,1126,938,823,69
2,556 Melting point; 207.6-209.0 ° C

No. 6: IR (KBr) cm ^-1 ; 3440,2981,2443,1531,1
478,1434,1370,1202,823,656,558 Melting point; 202-205 ° C

No. 7: IR (KBr) cm ^-1 ; 3448,1560,1536,1478,1
358,1079,928,815 Melting point; 164-165 ° C

No. 8: IR (KBr) cm ^-1 ; 3448,2856,2694,2491,2
440,1611,1551,1477,1438,1369,1103,989,814,698,555 Melting point; 220,6-223.8 ° C

No. 9: IR (KBr) cm ^-1 ; 3448,2895,2834,2734,1
552,1480,1376,1085,808,691,555 Melting point; 201.5-202.8 ° C (decomposition)

No. 10: IR (KBr) cm ^-1 ; 3448,2732,1551,1480,
1376,1085,808,668 Melting point; 201.5-202.8 ℃ (decomposition)

No. 11: IR (KBr) cm ^-1 ; 3447,2856,2691,2492,
2440,1611,1551,1477,1438,1370,1103,988,932,813 Melting point; 220.6-223.8 ° C (decomposition)

No. 12: IR (KBr) cm ^-1 ; 3446, 2887, 2685, 2590,
2770,1549,1476,1437,1370,1311,1152,995,816,697,556 Melting point; 215.3-216.8 ° C

No. 13: IR (KBr) cm ^-1 ; 3448,2926,1618,1542,
1474,1438,1364,1318,1054,820

No. 14: IR (KBr) cm ^-1 ; 3431,2865,2719,1710,
1614,1547,1448,1383,1065,756 Melting point; 210-213 ℃ (decomposition)

No. 15: IR (KBr) cm ^-1 ; 3440,2936,2778,2734,
1613,1539,1450,1383,1232,1007,924,773 Melting point; 255.5-256.8 ℃ (decomposition)

No. 16: IR (KBr) cm ^-1 ; 2942,2775,2783,1611,
1539,1316,1237,1014,816,560 Melting point; 249.9-251.0 ℃ (decomposition)

No. 17: IR (KBr) cm ^-1 ; 3445,2936,2778,2691,
2530,1614,1540,1498,1434,1343,1217,1101,1030,949,8
13 Melting point; 254.1-256.3 ° C (decomposition)

Example 18 (1) 0.4 g of (S) -5-chloro-3- (2-pyrrolidinylmethoxy) -1,2-benzisoxazole hydrochloride
To 5 ml of a methanol solution of 1), potassium tert-butoxide (0.62 g) and ethyl iodide (0.65 g) are added at 20 ° C, and the mixture is refluxed for 5 hours. After cooling the reaction mixture, the solvent is distilled off under reduced pressure, ethyl acetate and water are added to the obtained residue, the mixture is shaken, and the organic layer is separated. The separated organic layer was washed with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [eluent: chloroform: methanol = 50: 1].
Colorless oil (S) -5-chloro-3- (1-ethyl-
0.35 g of 2-pyrrolidinylmethoxy) -1,2-benzisoxazole is obtained.

(2) To a solution of 0.35 g of (S) -5-chloro-3- (1-ethyl-2-pyrrolidinylmethoxy) -1,2-benzisoxazole in 10 ml of 2-propanol was added hydrogen chloride. 2-Propanol solution (7.5N) (1.5 ml) was added, and the precipitated crystals were collected by filtration to give a melting point of 212.8-213.0 ° C.
Thus, 0.33 g of (S) -5-chloro-3- (1-ethyl-2-pyrrolidinylmethoxy) -1,2-benzisoxazole hydrochloride is obtained as colorless crystals. IR (KBr) cm ^-1 ; 3448,2927,2484,2363,1536,1475,1436,136
4,1312,937,819,693

Example 19 (1) To a solution of 2.0 g of (S) -5-chloro-3- (2-pyrrolidinylmethoxy) -1,2-benzisoxazole in 30 ml of methylene chloride was added 2.60 g of triethylamine at 20 ° C. And 1.50 g of ethyl bromoacetate are added, and the mixture is reacted at the same temperature for 18 hours. After the reaction, ethyl acetate and water are added to the reaction mixture, the mixture is shaken, and the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography [eluent: n-hexane: ethyl acetate = 3. : 1], a colorless oily substance (S) -5-chloro-3-
1.97 g of (1-ethoxycarbonylmethyl-2-pyrrolidinylmethoxy) -1,2-benzisoxazole are obtained.

(2) (S) -5-chloro-3- (1-ethoxycarbonylmethyl-2-pyrrolidinylmethoxy)
To a solution of 0.52 g of 1,2-benzisoxazole in 10 ml of 2-propanol, 0.53 ml of a 2-propanol solution of hydrogen chloride (4.4 N) was added at room temperature, and after reacting for 30 minutes, the solvent was distilled off under reduced pressure. . Ethyl acetate was added to the obtained residue, and the precipitated crystals were collected by filtration to give colorless crystals of (S) -5-chloro-3- (1-ethoxycarbonylmethyl-2-pyrrolid) having a melting point of 131.6-132.7 ° C. Dinylmethoxy) -1,2-
0.37 g of benzisoxazole hydrochloride is obtained. IR (KBr) cm ^-1 ; 3445,2932,1758,1532,1473,1360,1318,121
5,938,832,558

Example 20 (1) A suspension of 0.2 g of lithium aluminum hydride in 20 ml of tetrahydrofuran was added at 20 ° C. to (S) -5-chloro-3-.
A solution of (1-ethoxycarbonylmethyl-2-pyrrolidinylmethoxy) -1,2-benzisoxazole (1.5 g) in tetrahydrofuran (15 ml) was added dropwise over 10 minutes, and the mixture was reacted at the same temperature for 30 minutes. After the reaction, 0.38 g of water is added, the insoluble matter is filtered off, and the filtrate is distilled off under reduced pressure. Ethyl acetate and water are added to the obtained residue, and after shaking, the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography [eluent: chloroform: methanol = 20: 1]. The oily product (S) -5-chloro-3- [1- (2-hydroxyethyl) -2-pyrrolidinylmethoxy] -1,2-benzisoxazole (1.06 g) is obtained.

(2) (S) -5-chloro-3- [1-
To (2-hydroxyethyl) -2-pyrrolidinylmethoxy] -1,2-benzisoxazole (0.36 g) in 2-propanol (10 ml) was added hydrogen chloride in 2-propanol (6.2 N) (1.5 ml) to cause precipitation. If the collected crystals are collected by filtration,
0.22 g of colorless crystals of (S) -5-chloro-3- [1- (2-hydroxyethyl) -2-pyrrolidinylmethoxy] -1,2-benzisoxazole hydrochloride having a melting point of 178.5-178.9 ° C. obtain. IR (KBr) cm ^-1 ; 3356,2930,2645,1532,1480,1367,1320,81
8,692,558

Example 21 (1) (S) -5-chloro-3- [1- (2-hydroxyethyl) -2-pyrrolidinylmethoxy] -1,2-benzisoxazole 0.5 g of N, N -Dimethylformamide 6ml solution, potassium tert-butoxide 0.8g at 20 ℃
And 0.96 g of methyl iodide are added, and the mixture is reacted at the same temperature for 1 hour. After the reaction, ethyl acetate and water are added to the reaction mixture, the mixture is shaken, and the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography [eluent: chloroform: methanol = 30: 1].
The oily substance (S) -5-chloro-3- [1
0.23 g of-(2-methoxyethyl) -2-pyrrolidinylmethoxy] -1,2-benzisoxazole is obtained.

(2) (S) -5-chloro-3- [1-
(2-Methoxyethyl) -2-pyrrolidinylmethoxy]
To a solution of 0.23 g of 1,2-benzisoxazole in 10 ml of 2-propanol, 1.5 ml of a 2-propanol solution of hydrogen chloride (7.5 N) was added, and the precipitated crystals were collected by filtration to give a melting point of 184.6-185.8 ° C ( (S) -5 as colorless crystals showing (decomposition)
0.21 g of -chloro-3- [1- (2-methoxyethyl) -2-pyrrolidinylmethoxy] -1,2-benzisoxazole hydrochloride is obtained. IR (KBr) cm ^-1 ; 3448,2937,2591,2452,1535,1473,1435,136
2,1132,810,685,558

Example 22 (1) 0.80 g of (S) -5-chloro-3- (2-pyrrolidinylmethoxy) -1,2-benzisoxazole hydrochloride
10 ml suspension of methylene chloride in triethylamine at 20 ℃
Add 0.70 g and 0.40 g of bromoacetonitrile and react for 2 hours at the same temperature. After the reaction, ethyl acetate and water are added to the reaction mixture, the mixture is shaken, and the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography [eluent: n-hexane: ethyl acetate = 3. : 1], the colorless oily substance (S) -5-
0.61 g of chloro-3- (1-cyanomethyl-2-pyrrolidinylmethoxy) -1,2-benzisoxazole is obtained.

(2) A suspension of (S) -5-chloro-3- (1-cyanomethyl-2-pyrrolidinylmethoxy) -1,2-benzisoxazole (0.61 g) in 2-propanol (10 ml) was added with chloride. 2-propanol solution of hydrogen (6.2N) 0.
When 5 ml was added and the precipitated crystals were collected by filtration, the melting point was 180.0-18
Colorless crystals of (S) -5-chloro-3- (1 showing 2.9 ° C.
-Cyanomethyl-2-pyrrolidinylmethoxy) -1,2
0.62 g of benzisoxazole hydrochloride is obtained. IR (KBr) cm ^-1 ; 3459,2360,2339,1538,1477,1439,1364,105
6,934,829,694,561

Example 23 (1) (S) -5-chloro-3- (2-thiomorpholinylmethoxy) -1,2-benzisoxazole 0.50 g in methylene chloride 10 ml solution at 5 ° C. m- Chloroperbenzoic acid
(80%) 0.40 g is added and the reaction is allowed to proceed for 1 hour at the same temperature. After the reaction, water is added to the reaction mixture, the pH is adjusted to 9 with a 10% aqueous sodium hydroxide solution, the mixture is shaken, and the organic layer is separated. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography [eluent: chloroform: methanol = 50: 1]. The colorless oil (S) -5
0.24 g of -chloro-3- (S-oxo-2-thiomorpholinylmethoxy) -1,2-benzisoxazole is obtained.

(2) A solution of 0.24 g of (S) -5-chloro-3- (S-oxo-2-thiomorpholinylmethoxy) -1,2-benzisoxazole) in 5 ml of 2-propanol is added with chloride. 1.0 ml of 2-propanol solution of hydrogen (6.2N)
And the precipitated crystals are collected by filtration, and the melting point is 225.6-227 ° C.
Thus, 0.21 g of colorless crystals of (S) -5-chloro-3- (S-oxo-2-thiomorpholinylmethoxy) -1,2-benzisoxazole hydrochloride is obtained. IR (KBr) cm ^-1 ; 3426,2942,2698,2640,1610,1537,1477,144
1,1369,1318,1058,1022,936

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kuniichi Furuhata 160-3 Shiba, Namekawa, Toyama Prefecture (72) Inventor Tadakazu Takakura 26-2 Omachi, Toyama City, Toyama Prefecture (72) Makoto Takada Toda City, Saitama Prefecture Shinso 1417 (72) Inventor Hiroyo Kawabuchi 130 Sakaizawa, Tateyama-cho, Nakashinagawa-gun, Toyama Prefecture (72) Toru Hiraiwa 1-5-37 Nagaeshin-cho, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula: "In the formula, R represents at least one or more selected from a hydrogen atom, a halogen atom, an optionally substituted lower alkyl, an aralkyl, a lower alkyloxy and an aralkyloxy group; R ₁ represents a hydrogen atom or a substituted one. Optionally a lower alkyl or aralkyl group; R
₂ is a hydrogen atom or an optionally substituted lower alkyl, aralkyl, lower acyl or lower alkyloxycarbonyl group; R ₃ and R ₄ are the same or different and are a hydrogen atom or an optionally substituted lower alkyl. A group; or R ₃ and R ₄ together are a lower alkylene group; X is CH ₂ , SO or SO ₂ or a formula CH
A group represented by OR ₅ (R ₅ represents a hydrogen atom or a lower alkyl or carbamoyl group) or NR ₆ (R ₆ represents a hydrogen atom or a lower alkyl group), an oxygen atom, a sulfur atom and a group represented by the formula: Chemical 2] (Y represents an oxygen atom or a sulfur atom); m is 0 or 1; n is 2,
3 or 4 is shown, respectively. 1,2-
Benzisoxazole derivatives or salts thereof.