JPS59181267A - Novel 5-methylamino-3-substituted phenylisoxazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R1 is m- or p-chloro, lower alkyl, or lower alkoxy; D is group shown by the formula II (R2 and R3 are lower alkyl), pyrrolidino, piperidino] and its nontoxic salt. EXAMPLE:5-[ N-Methyl-N-( 3-piperidino-2-methyl-1-propionyl ) ]amino-3-( 2-chlorophenyl)isoxazole. USE:A central muscle relaxant, or an anticonvulsant. PREPARATION:A compound shown by the formula III is reacted with methacrylic acid chloride in a solvent such as a halogenated hydrocarbon, ketone,etc. in the presence of 2-5 equivalent triethylamine or pyridine at 0-30 deg.C to give a compound shown by the formula IV, which is then reacted with an amine shown by the formula HD at 20-80 deg.C to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) C, where R+ is m- or p-chloro, lower alkyl group,
Lower alkoxy group, D is -N'1mo2 (also \l).

where R2, R: + represents a lower alkyl group] or a pyrrolidino group, a piperidino group]
-Methylamino-3-4% phenyl isoxazole derivative.

5-methylamino-3- represented by the above general formula (I)
Although substituted phenyl isoxazole derivatives have strong central muscle relaxant and anticonvulsant effects, they have weak effects on the motor center and are expected to be highly selective central muscle relaxants.

It has been reported that it has some physiological effects as a 5-aminoisoxazole derivative. Namely, Kaoru Hori et al. synthesized 5-(2-diethylamino-1-acetyl)amino-3,4-dimethylisoxazole, investigated its uterine contraction effect, and reported that it had no effect [Pharmacy Journal, 11 .636-6
39 (j961)]. Takahashi Gazo et al. reported that 2-dialkylaminoacetylamino type derivatives of 5-amino-3゜4-dimethylisoxazole [Pharmaceutical Journal 82.474-4
80 (1962)] and] 2-dialkylaminoacetylamino derivatives of 5-amino-3-alkoxyethyl isoxazo [Pharmaceutical Journal, Kaisei 481-486 (
1962)] and investigated and reported its analgesic activity. In addition, Shojibe Ageo et al. synthesized a 2-dialkylaminoacetylamino type derivative of 5-amino-3-methylisoxazole [Pharmaceutical Journal, 83゜198-2.00 (1
963)] investigated and reported its analgesic activity. Also, A
ndre' Luven Pon5 et al. synthesized [F
Lance Demand 2.068,418In
[nothera] has been reported to have anticonvulsant and anti-inflammatory effects. Furthermore, J, P, Triv
synthesized a 2-dialkylaminoacetylamino type derivative of 5-amino-3,4-dimethylisoxazole derivative [Indian J, J'harma et al.
cc-utical 5science411)28-3
1 (1979)] investigated its anti-inflammatory and anticonvulsant effects and reported that it had no effect.

The compound of the present invention is a 3-dialkylaminopropionylamino derivative of the 2-dialkylaminoacetylamino derivative of 5-aminoisoxazole, which has been reported so far, and is the conventionally known 5-aminoisoxazole derivative. It has a stronger anticonvulsant effect than oxazole derivatives, as well as a strong muscle relaxing effect, but it has a weaker motor-suppressing effect and is highly selective.

In the general formula (I), the lower alkyl groups in R, R2, R3 include methyl group, ethyl group, propyl group, butyl group, etc., and the lower alkoxy groups in R1 include methyl group, ethyl group, propyl group, Examples include butyl group.

The substitution position of the lower alkyl group in R1 is 0-.

Either In+p- may be used.

Among the compounds of the present invention, R1 is preferably 〇-
Among them, 0-chloro compounds are particularly preferred.

Typical compounds represented by the general formula (I) of the present invention are as follows.

Compound N Compound 1.5
-(N-methyl-N-(3piperidino-2-methyl-1
-propionyl)]]]amino-3-2-chlorophenyl)isoxazole 2,5-(N-methyl-N-(3-pyrrolidino-
2-methyl-1-propionyl)]]amino-3-2-
chlorophenyl)isoxazole 3.5-CN-methyl-N-(3-diethylamino-2
-methyl-1-propionyl)]]]amino-3-2-chlorophenyl)isoxazole 4,'5-1:N-methyl-N-(3-piperidino-2-methyl-1-propionyl)]]amino-3- (3 -chlorophenyl)inoxazole 5.5-CN-methyl-N-(3-diethylamino-2
-methyl-1-propionyl)]]amino-3-3-chlorophenyl)inoxazole6.5-(N-methyl-N-(3-diethylamine-2-・methyl-1-propionyl)]]amino-3-2- methylphenyl)isoxazole 7.5-[N-methyl-N-(3-diethylamino-2-methyl-1-propionyl)]]amino-3-3-methylphenyl)isoxazole 8.5-
[N-methyl-N-(3-diethylamine-2-methyl-1-propionyl)]]amino-3-2-methoxyphenyl)isoxazole 9.5-(N-methyl-N-
(3-diethylamino-2-meth-1-globionyl)]]amino-3-3-methoxyphe,nyl)isoxazole The compound of the present invention represented by the above general formula (I) is produced according to the following formula.

(II) Mark J) ・・・・・・
...111 [In the formula, R1 and D are the same as above] That is, halogenated hydrocarbons such as 5-methylaminothane represented by general formula I, aromatic hydrocarbons such as benzene and toluene, acetone, methyl ethyl ketone, etc. Using a ketone solvent of
A 5-acylamino derivative represented by the general formula (I) is obtained by reacting at a temperature of 1000°C, preferably 0°C to 30°C, and then this compound (III) is mixed with a m solvent or a lower alcohol such as methanol, ethanol, or glopanol. , acetone, ketones such as methyl ethyl ketone, acetic acid lower alkyl esters such as methyl acetate and ethyl acetate, and amines represented by general formula (IV) at O℃.
The compound of the present invention represented by general formula (I) can be obtained by reacting at a temperature of 100°C to 100°C, preferably 20 to 80°C.

The compounds obtained by this production method can be used as pharmacologically acceptable acid addition salts, such as salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or organic acids such as maleic acid, fumaric acid, malonic acid, tartaric acid, and citric acid. can do.

In addition, among the compounds of the present invention, in the case of those having at least one asymmetric carbon in the molecule, those compounds theoretically have a
At least two optical isomers exist, and in such cases, the present invention includes both the ramid and the optical isomer. For optical isomers, for example, a salt with an optically active acid is generated from a racemate by a known method, and then the two diastereomer salts generated are separated and the optical isomer is isolated from each diastereomer salt. It can be obtained by

Next, the pharmacological action and acute toxicity of representative compounds of the present invention will be described.

1) Muscle relaxing effect (5) As an indicator of muscle relaxing effect, the method of Fukuda et al. [Hideomi Fukuda, Ito, Hashimoto, Kudo, Japanese Journal o
fPbarmacology+ 24 + 810 (
Anemic decerebrate swab specimens were prepared and used according to (1974).

Specifically, using male Wistar rats, a tracheal cannula was inserted under ether anesthesia, the carotid arteries on both sides were ligated, the base arteries were cauterized with a bipolar coagulator to stop blood flow, and the specimen was fixed. Create. Recording of hard cotton was carried out as described in 2 below. The rat was fixed in the dorsal position on a fixed table, and its forelimbs were attached to one end of a celluloid plate with strain gauges attached to both sides. The change in resistance produced in response to the force pushing up the cicelloid plate by the stiff cotton of the forelimb was recorded as tension through a bridge circuit on an automatic balance recorder. The tension before administering the test compound is (a), and the tension at the maximum reaction after intravenous administration (iV) of the test compound is (b), and the inhibition rate of the cotton is -'-'X 1
00 (calculated with @.

The value of each test compound at which the inhibition rate was 50% was determined in my/ky (ED50). Results 7 are shown in Table 1.

2) Anticonvulsant effect (Yoshio Ban et al., Pharmaceutical Research Methods, page 258, Breakfast Shoten) (B) Bentetrazole 170 in mice (I CR strain, male)
m9/kV was administered intraperitoneally to examine the effect on the onset of tonic convulsions in the hind limbs.

Each compound was administered intraperitoneally, and 370 minutes later, bentetrazole was administered intraperitoneally, and those in which tonic extensor spasms of the hind limbs disappeared were considered to have anticonvulsant effects. 50% effective dose E
Dso (me/kP) was calculated by the van der Weerden method (co-authored by Keiji Takagi and Obama, Pharmacological Experiments, 3rd edition, Nanzando), and the results are shown in Table 1.

3) The 50% lethal dose upon intravenous administration was determined using acute toxicity test (LDsom9/kfj). The results are shown in Table 1.

Table 1 Pharmacological action and acute toxicity of the compounds of the present invention 4) Central depressant action (C) As an indicator of central depressant action, mice (ICR
1) was used to investigate the inhibitory effect on spontaneous movement. All test compounds were dissolved in fresh J1ρ saline and injected intraperitoneally. Immediately after administration, place it in a rotating basket device, and immediately after that,
The number of rotations for 0 minutes was measured (for baclofen, for 10 minutes from 20 minutes to 30 minutes after administration).

Physiological saline was administered to the control group, and the number of rotations for 10 minutes was similarly measured. The number of rotations for 10 minutes in the control group was 135 ± 55
(standard deviation above the average, number of cases 31), and those that were 165 times the standard deviation from the average, ie, 45 rotations or less, were considered to have locomotor inhibition.

50% effective dose (EDsol'V/Ni#) is Vandc
r Calculated by Wacrden method. Table 2 shows representative compounds.

Further, Table 2 shows the results showing the selectivity of representative compounds of the present invention. As an index of central depressant effect, locomotor inhibitory effect using the rotating cage method was used. or,
N, IN, 5hare et al.'s method (N, N, 5h
are and C, S, McFarlane, N
europharma-cology, 14, 67
5-684 (1975)), the ratio of the ED5o value (C1 and the EDSo value for muscle relaxant action) and the ED5o value for anticonvulsant action (B) was used as an index of the selectivity of the compound (PI value). That is, the larger the value of this ratio, the higher the selectivity.

The results are also shown in Table 2.

As is clear from this table, the LI value of tolperisone, which has been conventionally recognized as a relatively highly selective anti-spasmodic drug, is 126 for muscle relaxant action and 2.2 for anticonvulsant action.
0, whereas in compound 1 of the present invention, each 57
．． 9.4.1, and 25.4.1 for compound 2, respectively.
3.1, indicating that the selectivity of the compound of the present invention is extremely high compared to tolperisone in terms of both muscle relaxant action and anticonvulsant action.

General formula (LI
) The 5-methylaminoisoxazole derivative represented by
■] 0110 [II] [In the formula, R1 is the same as above] That is, the method of D. N. Ridge et al. [J, Med,
Chem, 22(11), 1385 (19
79) ], the benzonitrile and acetonitrile represented by the formula [■] can be converted into benzene, toluene, xylene,
In an aprotic solvent such as ethyl ether, tetrahydrofuran or hexane, preferably benzene, toluene, ethyl ether or hexane, in the presence of a base such as sodium hytrite, sodium amide or sodium. By reacting at a temperature of 0° C. to 200° C., preferably 00° C. to 80° C., a 3-iminopropioniol derivative of the general formula CVD is obtained. Next, this compound is treated with hydroxylamine or an inorganic salt thereof at a temperature of 0°C to 100°C, preferably 20 to 50°C, in water, a lower alcohol such as methanol, ethanol, and proponol, or a mixture thereof. are reacted to obtain a 5-aminoisoxazole derivative represented by the general formula [1] in Table 6. Subsequently, formic acid is added to this compound in the presence or absence of acetic anhydride at 0-100°C, preferably 20-100°C.
The reaction was carried out at 30°C to form 5-formylaminoisoxazole represented by the general formula [■], and finally, this compound was reacted with O in a solvent such as ether, tetrahydrofuran, or dioxane using lithium aluminum rhamnohydride.
The desired 5-methylaminoisoxazole derivative I can be obtained by reacting at a temperature of 100°C to 100°C.

The desired 5-aminoisoxazole derivative can also be obtained by reacting it with formalin in an alcohol such as methanol, ethanol, propatool, or butanol at a temperature of 0 to 30°C, and then reducing it with sodium boronohydride. Methylaminoisoxazole Derivatives (Co., Ltd.) can be obtained.

Next, the method for producing the compound of the present invention will be specifically described with reference to Examples.

Example 1.5-(N-methyl-N-(3-pyrrolidino-
2-methyl-1-globionyl)]]amino-3-2-
Chlorophenyl) Inoxazole (Compound Part 2) (1) 5-Methylamino-3-phenylisoxazole40. Dissolve Ogr in 600 rnl of chloroform and add 53.5 ml of triethylamine.

To this mixture, under water cooling, a solution of 37.5 me of methacrylic acid chloride obtained by fresh distillation in anhydrous chloroform was added.
Drop 00m6. After dropping, the mixture is allowed to react at room temperature for 3 hours.

After completion of the reaction, the chloroform layer was washed twice with water and dried over anhydrous magnesium sulfate, and after removing the desiccant from F, it was concentrated under reduced pressure. The resulting oily residue was purified by silica gel chromatography.
-inoxazole)-N-methylmethacrylic acid amide is obtained.

Yield 46.7 gr, yield 813.1% 46.7 gr of this compound was dissolved in 250 m13 of toluene, and then 169 ml of pyrrolidine and all of vinegar were added.
Add A and react at 60°C for 24 hours. After the reaction is complete,
Concentrate under reduced pressure to obtain an oily residue. This residual fragrance is dissolved in ether, washed with water, and then extracted from the ether layer using Q, 5-41 hydrochloric acid. After washing the hydrochloric acid layer twice with ether, the hydrochloric acid layer is made alkaline with concentrated aqueous ammonia and extracted with ether again. After washing the ether layer with water and drying with anhydrous magnesium sulfate, the desiccant was removed separately and the ether was distilled off to give crude 5-[
N-methyl-N-(3-pyrrolidino-2-methyl-1-
propionyl)]]amino-3-2-chlorophenyl)
Inoxazole is obtained as an oil. Yield 44.
7 gr6 is distilled off and the total volume is concentrated to 200ml1K. When this acetone solution is left to cool, crystals are obtained. These crystals are separated from each other, heated and dissolved in acetone, and recrystallized to obtain fumarate. Yield 47.7 gr Yield 79.9
%, mpHl-112℃ (acetone) elemental analysis value C
2□H26CI N30b (C+s H2□0□N3
C1-C4H404) Calculated value C:56.9611:5
．． 65 N+9. o6 actual value C: 56.7511: to 47 N: 8.832.05 to 2.65 (6I-1,
m), 2.65-3.25 (1N, l71)
, 3.42 (3I-i,s).

The following compound is obtained in the same manner as in this example using the corresponding raw materials.

Compound Nn 1. ．． 5- (N-methyl-N-(3-
piperidino-2-methyl-1-propionyl)]]amino-3-2-10lophenyl)inoxazole yield 86% 77-/L/acid acid mp83-88℃ (
61-1, rn), 2.5-3.3 (IH, m)
.

3.41 (3H, s), 6.61 (In, S).

7.2~7.53 (3Fl, Iη), 7.53~7
,80(IH,m) Mass (C,,H24CIN302); M+3
61 + 363 compound Nn4. 5-[N-methyl-
N-(3-piperidino-2-methyl-1-propionyl)]]amino-3-3-chlorophenyl)isoxazole 2.1-2.5 (6I-1,m), 2.5-3
．． 2 (IH.

m), 3.45 (3H,s), 6.55 (I
H,s).

7.3-7.5 (2H, m), 7.5-7.
9 (21-1゜m) Mass (Ct9H24CIN302) :M" 3
61,363 Example 2.5-(N-methyl-N-(3
-diethylamino-2-methyl-1-propionyl)]]]amino-3-2-chlorophenyl)isoxazole (compound 3) Example 1-(
N-[3-(2-chlorophenyl)-5 obtained in 1)
-Isoxazole]-N'-Methyl-methacrylic acid amide (1.4 gr) and diethylamide (750 ml) are mixed, and a few drops of acetic acid are added to the mixture and heated under reflux for 48 hours. After the reaction is completed, excess diethylamine is distilled off, and water and methylene chloride are added to the resulting oily residue, followed by extraction with methylene chloride. After washing the methylene chloride layer with water, it is dried over anhydrous magnesium sulfate, and after the desiccant is removed from each house, it is concentrated under reduced pressure. The resulting residual aroma is purified by silica gel chromatography to obtain the desired 5-
[N-Methyl-N-(3-diethylamino-2-methyl-1-propionyl)]amino-3-2-chlorophenyl)isoxazole is obtained. Yield 1.61gr
, yield 91.0%.

(7H, m), 3.4.3 (31-1, s), 6.
66 (11-1, s), 7.3-7.6 (3f (, m
).

7.6-7.9 (II-1,m) Mass (Cu
+l-12+cIN, Oz); M 349, 35
1 Using the corresponding raw materials, the following compounds are obtained in the same manner as in this example.

Compound 1b5. 5-[N-methyl-N-(3-diethylamino-2-methyl-1-propionyl)]7mi,'
-3-(3-chlorophenyl)isoxazole yield 497% (7H, m), 3.44 (3H, s), 6.54 (
IH,s), 7.3 Hair, 9 (4f-1,m
)Mass(Cl8H24CIN302); M
349, 351 compound Nn6. 5-[N-methyl-
N-(3-diethylamino-2-methyl-1-propioni) l/)]]amino-3-2-methylphenyl)inoxazole Yield 79% NMR (CDC13, IM8) ppm; 0.95
(3H, t, J=8.0Hz).

1.13 (3B, a J=8.0Hz), 2.50
(31(.

s), 2.0-'3.2 (7H,m)', 3
．． 41 (3H.

S), 6.40 (IH,s), 7.1-7.7 (
4H.

m) Compound 1'lki 7. 5-[: N-Methyl-(3-diethylamino-2-methyl-1-propionyl)]]amino-3-3-methylphenyl)inoxazole Yield 57% NMR (CDCl2.TMS) pp+η; 0.
90 (3fI, d, J = 7.8l-1z).

1.08 (6H, J=7.I Hz), 2.
2-2.57 (6I-I, m), 2.43 (31
1,s), 2.57~3.1 (IH,m), 3
．． 42(3]1.s).

6.49 (If-1,s), 7.16-7.3
(2H, m).

73~7.7 (2H, m) Mass (C19H27N30:+): M 32
9 Compound Nci8. 5-CN-methyl-N-(3-diethylamino-2-methyl-1-propionyl)]]amino-3-2-methoxyphenyl)iboxazole NMR (CDCl2.TMS) ppm; 0.9 +
(3H, d, J=7.811z) 1.09 (6H
,t, J=7.2l-Lz)2.2~3.1 (7H
, m), 3.38 (3r-t, s) 3.9
1 (5H, S), 6.65 (11, S) 6.8-7.2
(2H, m), 7.2-7.6 (IH, m)7
．． 88 (IH, d, a, J=8.4Hz, , H=
2. QH2) Mas8 (C49H2703N3) i
M+345 compound shop 9.5-(N-methyl-N-(3
-diethylamino-2-methyl-1-propionyl)]]]amino-5-3-methoxyphenyl)isoxazole Yield 27% NMR (CDC15+ TMS) ppm; 0.
89 (3H, a, J near, 8H2) 1.11 (6H,
t, J=7.2H2)2.2-3.1 (7I(,m
) + 3.41 (3H, S ) 3.8 s (3H, 8)
6.5 (I H,B) 6.8-7.2 (IM,
m).

7.3'1 (2H, m) 7.37' (1H, s) Mas
s (C,9H2703N3); M” 545 Reference Example 1. Synthesis of s-methylamino-3-(2-chlorophenyl)isoxazole After washing 76.5 gr of 50% sodium hydride with anhydrous ether, the ether was decanted. after,
Pour into a flask, add anhydrous ether 600.1 and stir. 4 element air flow middle and lower acetonium) IJ Le 9L 7m
Add 13 and reflux for 40 minutes. Thereafter, 400 ml of an anhydrous ether solution containing 120.8 g of 2-chlorobenzonitrile was added dropwise, and further 5 d of tertiary butyl alcohol was added, followed by heating under reflux for 2 hours. After the reaction is complete, the mixture is poured into a mixture of ice and 1N HCI to stop the reaction, and then extracted with ether. After washing the ether layer with water, drying with anhydrous magnesium sulfate, filtering off the desiccant, and distilling off the ether, a crystal residual aroma is obtained.N-hexane is added to the residual aroma, and the crystals are separated and dried under reduced pressure to obtain the desired 3. -Imino-3'-(2-lylorophenyl)propionitrile 90.2 gr was obtained. Yield 57.4%, mp 102-104℃ This compound 8501
Anhydrous ethanol 600 shoulder/! 'iC add. Aqueous solutions fj of hydroxylamine hydrochloride so, o, y are added to the mixture.
, 200 rn, l were added and allowed to react at room temperature for 15 hours. After the reaction is complete, ethanol is distilled off under reduced pressure and then extracted with ethyl acetate. After washing the ethyl acetate layer with water, it was dried over anhydrous magnesium sulfate, the desiccant was removed, and the mixture was concentrated under reduced pressure to obtain crude 3-amino-5.
After adding 30 ml of acetic anhydride and stirring at room temperature for 24 hours, the reaction solution was poured into ice-water to precipitate crystals.

The crystals are filtered with suction and washed with water. The wet crystals are added to ether and dissolved, then dried over anhydrous magnesium sulfate, the desiccant is removed in an oven, and the ether is distilled off. N-hexane is added to the resulting residue, and the precipitated crystals are filtered and dried under reduced pressure. Yield 81.2 gr Yield 802%, mp 104-1
07℃.

Pour 600 me of anhydrous ether into a flask, and add 15.0 me of lithium aluminum hydride there. Add Ogr.

While stirring, 60.0 gr of 5-methylamino-3-(2-chlorophenyl)isoxazole was added little by little to the suspension. After the addition, the mixture was heated under reflux for 2 hours. After the reaction was completed. Cool at room temperature, carefully add water to treat excess lithium aluminum hydride, add anhydrous magnesium sulfate, dry, suction filtrate, and concentrate P719 under reduced pressure.
]-1 After adding xane, separate the precipitated crystals by P. When the obtained crystals are dried under reduced pressure, 5-methylamino-
3-(2-chlorophenyl)isoxazole is obtained. Yield: 53.9gr, yield: 915, mp73-76
°c.

5-methylamino-3-(2-methylphenyl)isoxazole is obtained in the same manner.

Reference Example 2. 5-Methylamino-3-(2-methoxyphenyl)isoxazole 17 gr of 50% sodium hydride is placed in a 7 flask, 200 ml of anhydrous ether is added thereto, and 2 Q m of acetonitrile is added dropwise. , 15 minutes after the completion of the addition, 25.1 gr of 2-methoxybenzonitrile was added dropwise, and the mixture was heated to reflux. After 30 minutes, tertiary Frisol 10
Add m1 and react for an additional 2.5 hours.

After the reaction is completed, the reaction solution is poured into ice water containing concentrated hydrochloric acid.

Add ethyl acetate and extract. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the desiccant was removed from the p side, and concentrated under reduced pressure to obtain crude 3-(2-methoxyphenyl)-3-imino-
Propionitrile deer is obtained. Dissolve this in 200rnt3 of ethanol, add 50rnl of water, and then add 20g of hydroxylamine hydrochloride to make 18.
Allow time to react. After the reaction is completed, ethanol is distilled off, and ethyl acetate is added for extraction. Ethyl acetate is dried over anhydrous magnesium sulfate, the desiccant is removed from the p side, and ethyl acetate is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-amino-3-(2-methoxyphenyl)inoxazole in a yield of 11%.

The obtained 5-amino-3-(3-methylphenyl)inoxazole 6, Ogr was added to 200 r of ethanol.
Add 20 c of formalin to the solution dissolved in nt, and allow to react at room temperature for 3 hours. Then, while cooling with ice water, add 2.8 g of sodium boronohydrite (Na B H4).
After adding r, let it react at room temperature for 2 hours. After the reaction is complete, ethanol is distilled off, methylene chloride and water are added to the remaining food, and the mixture is extracted with methylene chloride. The methylene chloride layer is dried over anhydrous magnesium sulfate, and after removing the desiccant from P, the methylene chloride is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain 5-methylamino-3-(2-methoxyphenyl)isoxazole. i car==
Discharge yield rate 31%.

Patent applicant: Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] (1) General formula [In the formula, R1 represents m- or p-chloro, lower alkyl group, lower alkoxy group, D represents -N group (here, R2 and R3 each represent a lower alkyl group) or pyrrolidino group or A 5-methylamino-3-substituted phenyl isoxazole derivative represented by the following formula (representing a piperidino group) and a non-toxic salt thereof.