JPH09227557A - Thienyloxazole derivative and thienylpyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a thienyloxazole derivative and a thienylpyrazole derivative useful as an antihypertensive medicine, a therapeutic agent for urinary disturbance, etc., having antihypertensive action or improving action on urinary disturbance, by blocking an α 1-adrenaline receptor. SOLUTION: This thienyloxazole derivative is shown by formula I [R<1> is a (substituted)2-thienyl or a (substituted)3-thienyl; R<2> is H, a halogen, a lower alkyl or a lower alkoxy; R<3> us a halogen, a lower alkyl or a lower alkoxy; (m) is 1-3] and this thienylpyrazole derivative is shown by formula II (R<4> is H, a halogen, a lower alkyl or a lower alkoxy; R<6> is a lower alkyl; (n) is 1-3). The derivatives have antihypertensive action or action on urinary disturbance and are useful as an antihypertensive medicine, a therapeutic agent for urinary disturbance, etc. The compound of formula I is obtained by reacting an oxazole derivative of formula III (X<1> is a halogen, a methanesulfonic acid ester, etc.) with an N-phenylpiperazine of formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a thienyloxazole derivative and a thienylpyrazole derivative having an antihypertensive action or a dysuria improving action by blocking α1-adrenoceptors.

[0002]

2. Description of the Related Art α1-adrenoceptor blockers are mainly used as antihypertensive agents and do not reduce cardiac output or organ perfusion, so they are not suitable for patients with reduced cardiac function or renal function. It is characterized in that it can be used even in cases of impaired function. Further, in recent years, it has been used as an agent for improving urinary disorders. Known antihypertensive agents are prazosin, doxazosin, urapidil, etc., and tamsulosin, prazosin are known as therapeutic agents for dysuria, but none are structurally similar to the compounds of the present invention.

[0003]

The object of the present invention is to provide α1
-To provide a compound which exhibits an antihypertensive effect or an dysuria improving effect by blocking an adrenergic receptor.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to achieve the above-mentioned object, and as a result, certain thienyloxazole derivatives and thienylpyrazole derivatives block the α1-adrenoceptor to lower blood pressure. Found to have an action or a dysuria-improving action,
The present invention has been completed. That is, the present invention uses the formula

[0005]

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(In the formula, R ¹ represents a 2-thienyl group or a 3-thienyl group which may be substituted with a methyl group, and R ²
Represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ³ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and m represents an integer of 1 to 3. And a pharmaceutically acceptable acid addition salt thereof, represented by the formula:

[0007]

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(In the formula, R ⁴ is a hydrogen atom, a halogen atom,
A lower alkyl group or a lower alkoxy group, R ⁵ represents a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁶ represents a lower alkyl group, and n represents an integer of 1 to 3. ) Is a thienylpyrazole derivative or a pharmaceutically acceptable acid addition salt thereof.

In the present invention, the lower alkyl group means a straight or branched chain having 1 to 4 carbon atoms,
For example, it is a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group or a t-butyl group. The lower alkoxy group refers to a linear or branched chain having 1 to 4 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, an isobutoxy group or t-butoxy group. It is a base. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The substituent R ¹ in the compound of formula (I) substitutes the 3- or 4-position of the oxazole ring, and the substituent R ¹ in the compound of formula (II) is
⁶ replaces either one of the two nitrogens of the pyrazole ring.

The acid addition salt of the compound of formula (I) means a salt to which an inorganic acid or an organic acid is added, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, Fumaric acid, succinic acid, tartaric acid, ascorbic acid,
Mention may be made of salicylic acid, lactic acid, malic acid, methanesulfonic acid, paratoluenesulfonic acid.

The compound of the present invention can be produced, for example, according to the method shown below. (1) Of the compounds of formula (I), the formula

[0012]

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(In the formula, R ¹ represents a 2-thienyl group or a 3-thienyl group which may be substituted with a methyl group, and R ²
Represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ³ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and m represents an integer of 1 to 3. ). formula

[0014]

[Chemical 6]

(Wherein R ¹ and m have the same meanings as described above, and R ⁷ represents a methyl group or an ethyl group).

[0016]

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A compound represented by the formula (wherein R ¹ and m are as defined above) is obtained. Here, lithium aluminum hydride, diisobutylaluminum hydride, or the like can be used as the reducing agent. As the solvent, diethyl ether or tetrahydrofuran can be used. The reaction temperature is -75 ° C to 100 ° C, and the reaction time is 10 minutes to 24 hours.

Next, the compound obtained above is halogenated or sulfonated to give a compound of the formula

[0019]

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(Wherein R ¹ and m have the same meanings as described above, and X ¹ represents a halogen atom, a methanesulfonic acid ester or a toluenesulfonic acid ester). Here, phosphorus tribromide, thionyl chloride or the like can be used as the halogenating agent,
As the sulfonic acid esterifying agent, chloromethanesulfonic acid, chlorotoluenesulfonic acid, or the like can be used. As the solvent, a halogen-based solvent (for example, dichloromethane or carbon tetrachloride), a benzene-based solvent such as toluene, or a basic solvent such as pyridine can be used, and a solvent may not be used. Reaction temperature is 0
The reaction temperature is 10 minutes to 48 hours. In this reaction, a base (eg, potassium carbonate, triethylamine, etc.) can be used if necessary.

Next, the compound obtained above and the formula

[0022]

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A compound of formula (III) can be obtained by reacting a compound represented by the formula (wherein R ² and R ³ have the same meanings as described above). Here, as the solvent, a benzene solvent (toluene, benzene), dimethylformamide, acetonitrile, or the like can be used. The reaction temperature is 0 to 150 ° C., and the reaction time is 10 minutes to 48 hours. In this reaction, a base (eg, potassium carbonate, triethylamine, etc.) and, if necessary, a metal iodide (eg, sodium iodide, potassium iodide, etc.) can be used.

(2) A compound of formula (II). It can be manufactured in the same manner as in (1).

(3) Of the compounds of formula (I), those of formula

[0026]

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(In the formula, R ¹ represents a 2-thienyl group or a 3-thienyl group which may be substituted with a methyl group, and R ²
Represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ³ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and m represents an integer of 1 to 3. ). formula

[0028]

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(Wherein R ¹ and m have the same meanings as described above, X ² represents a halogen atom, a methanesulfonic acid ester or a toluenesulfonic acid ester) and a compound of the formula (IV) By reacting
formula

[0030]

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A compound represented by the formula (wherein R ¹ , R ² , R ³ and m are as defined above) is obtained. here,
As the solvent, a benzene solvent (toluene, benzene), dimethylformamide, acetonitrile or the like can be used. The reaction temperature is 0 to 150 ° C., and the reaction time is 10 minutes to 48 hours. In this reaction, a base (eg, potassium carbonate, triethylamine, etc.) and, if necessary, a metal iodide (eg, sodium iodide, potassium iodide, etc.) can be used.

Next, the compound obtained above and the formula

[0033]

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(In the formula, R ⁸ and R ⁹ each represent a lower alkyl group, or R ⁸ and R ⁹ together represent a heterocycle with an adjacent nitrogen atom, and R ¹⁰ represents a lower alkyl group. .) By reacting a compound represented by the formula

[0035]

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(Wherein R ¹ , R ² , R ³ , m, R ⁸ and R
⁹ has the same meaning as described above and includes both E-form and Z-form. ) Is obtained. This reaction may be solvent-free or may use dimethylformamide as a solvent. The reaction temperature is room temperature to 250 ° C., and the reaction time is 10 minutes to 48 hours.

Next, the compound obtained above is reacted with a hydroxyamine acid addition salt (acid has the same meaning as described above) in the presence of sodium acetate or sodium hydroxide, and then treated with an acid to give a compound of the formula (V ). Here, an alcohol solvent (methanol, ethanol, etc.) can be used as the solvent. As the acid, hydrochloric acid, sulfuric acid, acetic acid or the like can be used. The reaction temperature is 0 ° C to 100 ° C, and the reaction time is 10 minutes to
24 hours.

[0038]

EFFECTS OF THE INVENTION The compound of the present invention has an inhibitory effect on smooth muscle contraction by blocking the α1-adrenoceptor, as will be apparent from the test examples described below, and is therefore useful as an antihypertensive agent and a dysuria improving agent. .

[0039]

The present invention will be described below in more detail with reference to examples and test examples. (Example 1) 3- [4- (2-methoxyphenyl) piperazino] methyl-5- (2-thienyl) isoxazole (1) A suspension of 1.70 g of lithium aluminum hydride in 30 ml of tetrahydrofuran under ice cooling. A solution of 5.0 g of 3-ethoxycarbonyl-5- (2-thienyl) isoxazole in 20 ml of tetrahydrofuran was added dropwise,
The mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, the insoluble matter was filtered through Celite, washed with ethyl acetate, and the solvent was evaporated. Add ethyl acetate to the residue and 10%
The extract was washed successively with aqueous sodium hydroxide solution and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 2) to give 3-hydroxymethyl-5- (2-
2.43 g of thienyl) isoxazole was obtained.

(2) 1.0 g of 3-hydroxyethyl-5- (2-thienyl) isoxazole obtained in (1)
0.19 ml of phosphorus tribromide was added to a 20 ml solution of carbon tetrachloride and heated under reflux for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1) to give 3-bromomethyl-5- (2-thienyl) isoxazole 1.
06 g were obtained.

(3) 0.95 g of 3-bromomethyl-5- (2-thienyl) isoxazole obtained in (2) and 0.81 g of 2-methoxyphenylpiperazine were dissolved in 20 ml of acetonitrile to give 0.62 m of triethylamine.
1 was added and the mixture was heated under reflux for 1 hour. The solvent of the reaction solution was evaporated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain 1.43 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm;
2.68 to 2.82 (4H, m), 3.03 to 3.19
(4H, m), 3.71 (2H, s), 3.85 (3
H, s), 6.47 (1H, s), 6.82 to 7.07
(4H, m), 7.12 (1H, dd, J = 4,5H
z), 7.43 (1H, dd, J = 1, 5 Hz), 7.
51 (1H, dd, J = 1, 4 Hz).

The following compounds were synthesized in the same manner. 3- [4- (2-Methoxyphenyl) piperazino] methyl-5- (3-thienyl) isoxazole ¹ H-NMR (DMSO-d ₆ ) δppm; 2.51
2.68 (4H, m), 2.88 to 3.07 (4H,
m), 3.63 (2H, s), 3.77 (3H, s),
6.80 to 7.02 (4H, m), 6.89 (1H,
s), 7.59 (1H, dd, J = 1, 5 Hz), 7.
75 (1H, dd, J = 4,5Hz), 8.17 (1
H, dd, J = 1,4 Hz). 3- [4- (2-methoxyphenyl) piperazino] methyl-5- [2- (3-methylthienyl)] isoxazole m.p. p. 146-148 ° C. ¹ H-NMR (DMSO-d ₆ ) δ ppm; 2.41
(3H, s), 2.50 to 2.67 (4H, m), 2.
88 to 3.04 (4H, m), 3.64 (2H, s),
3.75 (3H, s), 6.63 (1H, s), 6.7
9 to 6.98 (4H, m), 7.08 (1H, d, J =
5 Hz), 7.69 (1 H, d, J = 5 Hz).

3- [4- (2-methoxyphenyl) piperazino] methyl-1-methyl-5- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.68-2.
83 (4H, m), 3.02 to 3.22 (4H, m),
3.63 (2H, s), 3.85 (3H, s), 3.9
6 (3H, s), 6.38 (1H, s), 6.80-
7.05 (4H, m), 7.08 to 7.18 (2H,
m), 7.38 (1H, dd, J = 1, 5 Hz). 5- [4- (4-fluorophenyl) piperazino] methyl-1-methyl-3- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.56-2.
68 (4H, m), 3.04 to 3.15 (4H, m),
3.55 (2H, s), 3.92 (3H, s), 6.3
7 (1H, s), 6.97 to 7.07 (5H, m),
7.18-7.31 (2H, m).

3- [4- (4-Fluorophenyl) piperazino] methyl-1-methyl-5- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.65-2.
77 (4H, m), 3.09 to 3.20 (4H, m),
3.12 (2H, s), 3.96 (3H, s), 6.3
9 (1H, s), 6.82 to 7.03 (4H, m),
7.08 to 7.20 (2H, m), 7.40 (1H,
m). 5- [4- (2-chlorophenyl) piperazino] methyl-1-methyl-3- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.55-2.
74 (4H, m), 2.95 to 3.13 (4H, m),
3.57 (2H, s), 3.93 (3H, s), 6.3
8 (1H, s), 6.90 to 7.40 (7H, m).

3- [4- (2-chlorophenyl) piperazino] methyl-1-methyl-5- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.67-2.
82 (4H, m), 3.03 to 3.18 (4H, m),
3.63 (2H, s), 3.95 (3H, s), 6.3
9 (1H, s), 6.90 to 7.42 (7H, m). 5- [4- (2,3-dimethylphenyl) piperazino]
Methyl-1-methyl-3- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.22 (3
H, s), 2.26 (3H, s), 2.53 to 2.71.
(4H, m), 2.82 to 2.95 (4H, m), 3.
57 (2H, s), 3.94 (3H, s), 6.38
(1H, s), 6.85 to 7.32 (6H, m).

3- [4- (2,3-dimethylphenyl)
Piperazino] methyl-1-methyl-5- (2-thienyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.21 (3
H, s), 2.25 (3H, s), 2.62 to 2.80.
(4H, m), 2.88 to 3.00 (4H, m), 3.
62 (2H, s), 3.96 (3H, s), 6.40
(1H, s), 6.84 to 6.96 (2H, m), 7.
02 to 7.20 (3H, m), 7.38 (1H, dd,
J = 1,5 Hz).

Example 2 4- [2- [4- (4-fluorophenyl) piperazino] ethyl] -5- (2-thienyl) isoxazole (1) 10 g of 4-chloro-2-butyrothienone and 4- Fluorophenylpiperazine 3.4 g toluene 200 m
26 ml of triethylamine was added, and the mixture was heated under reflux for 16 hours. The solvent is distilled off from the reaction solution under reduced pressure, water is added to the residue, the mixture is extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography (developing solvent: hexane:
Ethyl acetate = 4: 1 to 3: 1), 4- [4- (4-fluorophenyl) piperazino] -1- (2-thienyl)-
5.4 g of 1-butanone was obtained.

(2) 4- [4- (4-
A solution of 5.0 g of fluorophenyl) piperazino] -1- (2-thienyl) -1-butanone in 40 ml of dimethylformamide dimethylacetal was heated under reflux for 38 hours. The solvent of the reaction solution was evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine. Then, it was dried over magnesium sulfate, filtered, and concentrated to give 2-dimethylaminomethylene-4- [4- (4-fluorophenyl) piperazino] -1- (2-thienyl) -1-butanone 6.0.
g was obtained.

(3) 2-Dimethylaminomethylene-4- [4- (4-fluorophenyl) piperazino] -1- (2-thienyl) -1-butanone 2.0 obtained in (2)
To a solution of g in 20 ml of ethanol, 0.45 g of hydroxyamine hydrochloride and 0.53 g of sodium acetate were added, and the mixture was heated under reflux for 7 hours. The solvent was evaporated from the reaction solution under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Next, the residue was dissolved in 10 ml of ethanol, 1 ml of 10% hydrochloric acid was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and then saturated aqueous sodium hydrogen carbonate was added for neutralization, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine. The extract was dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (developing solvent: ethyl acetate) to obtain 0.63 g of the title compound. ¹ H-NMR (CDCl ₃ ) δppm; 2.60-3.
21 (12H, m), 6.81 to 7.04 (4H,
m), 7.17 (1H, m), 7.44 to 7.56 (2
H, m), 8.28 (1 H, s).

Similarly, the following compounds were synthesized. 4- [2- [4- (2-Methoxyphenyl) piperazino] ethyl] -5- (2-thienyl) isoxazole; 4- [2- [4- (2-chlorophenyl) piperazino] ethyl] -5- ( 2-thienyl) isoxazole; 4- [2- [4- (2,3-dimethylphenyl) piperazino] ethyl] -5- (2-thienyl) isoxazole; m. p. 85-87 ° C ¹ H-NMR (CDCl ₃ ) δppm; 2.22 (3
H, s), 2.27 (3H, s), 2.65 to 2.76
(6H, m), 2.85 to 2.97 (6H, m), 6.
89-6.96 (2H, m), 7.06 (1H, d, J
= 8 Hz), 7.02 (1H, dd, J = 1,5H
z), 7.18 (1H, dd, J = 4,5 Hz), 7.
49 (1H, dd, J = 1, 5 Hz), 8.29 (1
H, s).

(Example 3) 3- [4- (2-methoxyphenyl) piperazino] methyl-5- (2-thienyl) isoxazole dihydrochloride 3- [4- (2-methoxyphenyl) piperazino] methyl- 1.43 g of 5- (2-thienyl) isoxazole
4N hydrogen chloride / ethyl acetate solution was added to a 10 ml solution of ethanol in 1., and the precipitate was collected by filtration and recrystallized from methanol to obtain 0.90 g of the title compound. m. p. 215 to 218 ° C. ¹ H-NMR (DMSO-d ₆ ) δppm; 3.00
3.64 (8H, m), 3.79 (3H, s), 4.5
7 (2H, s), 6.83 to 7.09 (4H, m),
7.27 (1H, s), 7.28 (1H, dd, J =
4,5Hz), 7.73 (1H, dd, J = 1,4H
z), 7.79 (1H, dd, J = 1, 5 Hz).

Similarly, the following compounds were synthesized. 3- [4- (2-methoxyphenyl) piperazino] methyl-5- (2-thienyl) pyrazole dihydrochloride m.p. p. 195-199 ° C ¹ H-NMR (DMSO-d ₆ ) δppm; 2.82-
3.35 (4H, m), 3.40 to 3.60 (4H,
m), 3.78 (3H, s), 3.98 (3H, s),
4.30-4.40 (2H, br), 6.81 (1H,
s), 6.88 to 7.05 (4H, m), 7.25 (1
H, dd, J = 4,5 Hz), 7.47 (1H, dd,
J = 1,4 Hz), 7.76 (1H, dd, J = 1,5)
Hz).

4- [2- [4- (2-methoxyphenyl) piperazino] ethyl] -5- (2-thienyl) isoxazole dihydrochloride (Compound 1) m.p. p. 205-207 ° C ¹ H-NMR (DMSO-d ₆ ) δppm; 3.02-
3.76 (12H, m), 3.80 (3H, s), 6.
87 to 7.12 (4H, m), 7.32 (1H, dd,
J = 4,5 Hz), 7.83 (1H, dd, J = 2,4
Hz), 7.92 (1H, dd, J = 2.5 Hz),
8.69 (1H, s).

4- [2- [4- (2-chlorophenyl)
Piperazino] ethyl] -5- (2-thienyl) isoxazole dihydrochloride m.p. p. 188 to 191 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δppm; 3.08 to
3.58 (10H, m), 3.62 to 3.82 (2H,
m), 7.12 (1H, dt, J = 2, 7 Hz), 7.
24 (1H, dt, J = 2, 7 Hz), 7.28 to 7.
41 (2H, m), 7.47 (1H, dd, J = 2, 7)
Hz), 7.79 (1H, dd, J = 1, 4Hz),
7.92 (1H, dd, J = 1, 5Hz), 8.69
(1H, s).

Test Example [α1 Receptor Binding Test] The α1 receptor binding reaction was carried out by Greengrass, Bremner [Eur. J. P.
harmacol., vol55, 323 (1979)]. After decapitating the wistar rat, the whole brain except the cerebellum was removed and homogenized with 10 times the volume of Tris-hydrochloride buffer (pH 7.4). This was centrifuged at 1,000 xg for 5 minutes, and the supernatant was further centrifuged at 48,000 xg for 20 minutes,
A precipitate was obtained. Precipitate the 50 mM Tris-HCl buffer (p
H7.4) and suspended again at 48,000 xg for 20 minutes. 50 mM Tris-HCl buffer (pH 7.
The sample was suspended in 7) to prepare a standard α1 receptor. 0.2 nM [ ³ H] prazosin and various concentrations of specimens were added to 1.0 ml of the receptor preparation, and the mixture was reacted at 25 ° C. for 60 minutes.
After completion of the reaction, suction filtration was carried out using a glass filter (Whatman GF / B), and the filter was washed 3 times with 3 ml of 50 mM Tris-hydrochloric acid buffer solution (pH 7.4). Radioactivity on the filter was measured by liquid scintillation counter. 10 μM from radioactivity without addition of sample
Was subtracted from the radioactivity obtained in the presence of prazosin, and this was used as the specific binding of the control. Calculate the ratio to the control from the radioactivity obtained when adding the sample,
Plotted against analyte concentration. The 50% inhibitory concentration (I
The _C50 value) was calculated. The results are shown in Table 1.

[0057]

[Table 1]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Yuichi Hatada, 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Tomomi Ota, 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceuticals Co., Ltd. (72) Inventor Ichiyuki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (2)

[Claims] (1) Formula (1) (In the formula, R ¹ represents a 2-thienyl group or a 3-thienyl group which may be substituted with a methyl group, R ² represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and R ³ represents A thienyloxazole derivative represented by a halogen atom, a lower alkyl group or a lower alkoxy group, and m is an integer of 1 to 3, or a pharmaceutically acceptable acid addition salt thereof. 2. The formula: (In the formula, R ⁴ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁵ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and R
⁶ represents a lower alkyl group, and n represents an integer of 1 to 3. ) A thienylpyrazole derivative represented by the formula) or a pharmaceutically acceptable acid addition salt thereof.