JPH09227524A - Phenylpyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new phenylpyrazole derivative, having suppressing actions on the contraction of smooth muscles of blood vessels, prostate glands, urethras, etc., due to the blocking of an α1-adrenergic receptor and useful as a hypotensive agent or an improver for dysuria. SOLUTION: This phenylpyrazole derivative is represented by formula I [R<1> is H, a lower alkyl, a lower hydroxyalkyl or phenyl (substitutable with a halogen); R<2> is phenyl (substitutable with a halogen, an alkyl or OH); R<3> is phenyl (substitutable with a halogen, an alkyl or an alkoxy); (m) is 1-3] or its pharmaceutically permissible acid addition salt, e.g. 4-[2-[4-(2- methoxyphenyl)piperazino]ethyl]-1-methyl-5-phenylpyrazole. The compound represented by formula I is obtained by reacting, e.g. a compound represented by formula II with a compound represented by formula III, providing a compound represented by formula I, then reacting the resultant compound represented by formula IV with a compound represented by the formula, (R<5> ) R<4> NCH(OR<6> )2 (R<4> and R<5> are each an alkyl, etc.; R<6> is an alkyl), affording a compound represented by formula V and finally reacting the prepared compound represented by formula V with a compound represented by the formula, R<1> HNNH2 .

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a phenylpyrazole 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 As a result of intensive studies to achieve the above-mentioned objects, the present inventors have found that certain phenylpyrazole derivatives block α1-adrenoceptors to cause hypotensive action or dysuria. The inventors have found that it has an improving effect and completed the present invention. That is, the present invention provides a compound of the formula (I)

[0005]

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(In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkyl group or a “phenyl group optionally substituted by 1 to 3 halogen atoms”,
R ² represents a phenyl group which may be substituted with 1 to 3 of groups selected from “halogen atom, lower alkoxy group and hydroxyl group”, and R ³ represents “halogen atom, lower alkyl group and lower alkoxy group”. 1-3 of the groups selected
Represents a phenyl group that may be substituted with m, and m represents an integer of 1 to 3. ) Is a phenylpyrazole 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 lower hydroxyalkyl group refers to a linear or branched chain having 1 to 4 carbon atoms, and examples thereof include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group and the like. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The pharmaceutically acceptable acid addition salt of the compound of formula (I) means a salt to which an inorganic acid or an organic acid is added, and for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propione. Acid, glycolic acid, fumaric acid, succinic acid, tartaric acid,
Examples thereof include ascorbic acid, salicylic acid, lactic acid, malic acid, methanesulfonic acid, and paratoluenesulfonic acid. When the phenyl group defined by R ¹ , R ² and R ³ has two or three substituents, the substituents may be the same or different.

The compound of the present invention can be produced, for example, according to the method shown below.

That is, the formula

[0011]

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(Wherein R ² and m have the same meanings as described above, and X represents a halogen atom) and a compound represented by the formula

[0013]

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(Wherein R ³ is as defined above) is reacted in a solvent to give a compound of the formula

[0015]

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A compound represented by the formula (wherein R ² , R ³ and m are as defined above) is obtained. Here, as the solvent, a benzene-based solvent (eg, 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 optionally a metal iodide (eg, sodium iodide, potassium iodide, etc.) can be used.

When R ² is a phenyl group substituted with a hydroxyl group, the hydroxyl group can be protected in advance. Examples of the protective group include a benzyl group, a trialkylsilyl group such as t-butyldimethylsilyl group, and a methoxymethyl group.

Next, the compound obtained above and the formula

[0019]

[Chemical 6]

(Wherein R ⁴ and R ⁵ represent a lower alkyl group, or R ⁴ and R ⁵ together represent a heterocycle with an adjacent nitrogen atom. R ⁶ represents a lower alkyl group. By reacting a compound represented by the formula

[0021]

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A compound represented by the formula (wherein R ² , R ³ , R ⁴ , R ⁵ and m have the same meanings as described above, and includes both E-form and Z-form). 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, a compound represented by the formula R ¹ HNNH ₂ (wherein R ¹ has the same meaning as described above) or an acid addition salt is reacted with the compound obtained above to give a compound of the formula ( The compounds of I) can be obtained.

Here, an alcohol solvent (methanol, ethanol, etc.) can be used as the solvent. In addition, acetic acid or sodium acetate can be used if necessary. The reaction temperature is 0 ° C to 100 ° C, and the reaction time is 10 minutes to 24 hours. When R ² is a phenyl group substituted with a hydroxyl group and a protecting group is introduced into the hydroxyl group, deprotection can be performed by hydrolysis, hydrogenation or the like following the above reaction. The substitution position of R ¹ (excluding hydrogen atom) of this reaction product has been confirmed by various instrumental analyzes such as NMR-NOE, and it is clear that the compound represented by the formula (I) can be selectively obtained. Has become.

[0025]

EFFECTS OF THE INVENTION The compound of the present invention has an inhibitory effect on smooth muscle (blood vessel, prostate, urethra, etc.) contraction by blocking α1-adrenoceptor, as will be apparent from the test examples described below. It is useful as an agent for improving urination disorders.

[0026]

The present invention will be described below in more detail with reference to examples and test examples. (Example 1) 4- [2- [4- (2-methoxyphenyl) piperazino] ethyl] -1-methyl-5-phenylpyrazole (1) 11.4 g of 4-chlorobutyrophenone and 2-methoxyphenylpiperazine 14. 4 g of toluene 200 m
It is dissolved in 1 l, 22.0 ml of triethylamine and 12.4 g of potassium iodide are added, and the mixture is heated under reflux for 15 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel chromatography (developing solvent: hexane: ethyl acetate = 1: 9) to obtain 14.6 g of 4- [4- (2-methoxyphenyl) piperazino] -1-phenyl-1-butanone.

(2) 4- [4- (2-) obtained in (1)
Methoxyphenyl) piperazino] -1-phenyl-1-
A solution of 13.5 g of butanone in 105 ml of dimethylformamide dimethylacetal was heated under reflux for 42 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 is dried over magnesium sulfate, filtered, and concentrated to give 2-dimethylaminomethylene-4- [4- (2-methoxyphenyl) piperazino].
17.8 g of -1-phenyl-1-butanone was obtained.

(3) To a solution of 1.9 g of 2-dimethylaminomethylene-4- [4- (2-methoxyphenyl) piperazino] -1-phenyl-1-butanone obtained in (2) in 18 ml of ethanol, methyl was added. Hydrazine sulfate 0.
85 g and 0.48 g of sodium acetate were added, and the mixture was stirred at room temperature for 5.5.
Stirred for hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. Then, it was dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate) to obtain 1.29 g of the title compound. ¹ H-NMR (CDCl ₃ ) δppm; 2.48-2.
76 (8H, m), 2.97-3.18 (4H, m),
3.74 (3H, s), 3.84 (3H, s), 6.8
1 to 7.05 (4H, m), 7.25 to 7.53 (6
H, m).

The following compounds were synthesized in the same manner. 1- (2-hydroxyethyl) -4- [2- [4- (2
- methoxyphenyl) piperazino] ethyl] -5-phenyl-pyrazole _{^{1 H-NMR (CDCl 3)}} δppm; 2.45~2.
74 (8H, m), 2.98 to 3.15 (4H, m),
3.84 (3H, s), 3.86 to 4.22 (4H,
m), 6.80 to 7.06 (4H, m), 7.24 to
7.54 (6H, m). 1,5-Diphenyl-4- [2- [4- (2-methoxyphenyl) piperazino] ethyl] pyrazole (Compound 1) ¹ H-NMR (CDCl ₃ ) δppm; 2.55-2.
81 (8H, m), 2.98 to 3.19 (4H, m),
3.84 (3H, s), 6.73 to 7.42 (14H,
m), 7.69 (1H, s).

5- (4-fluorophenyl) -4- [2
-[4- (2-Methoxyphenyl) piperazino] ethyl] -1-methylpyrazole (Compound 2) ¹ H-NMR (CDCl ₃ ) δppm; 2.45-2.
76 (8H, m), 2.94-3.18 (4H, m),
3.72 (3H, s), 3.84 (3H, s), 6.8
1 to 7.37 (8H, m), 7.46 (1H, s). 5- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- [2- [4- (2-methoxyphenyl)
Piperazino] ethyl] pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.46-2.
70 (8H, m), 2.98 to 3.15 (4H, m),
3.84 (3H, s), 3.88 to 4.08 (4H,
m), 6.80 to 7.38 (8H, m), 7.51 (1
H, s). 1,5-bis (4-fluorophenyl) -4- [2-
[4- (2-Methoxyphenyl) piperazino] ethyl]
Pyrazole ¹ H-NMR (CDCl ₃ ) δ ppm; 2.54 to 2.
78 (8H, m), 2.99 to 3.17 (4H, m),
3.85 (3H, s), 6.81 to 7.28 (12H,
m), 7.67 (1H, s).

Example 2 5- (4-hydroxyphenyl) -4- [2- [4-
(2-Methoxyphenyl) piperazino] ethyl] -1-
Methylpyrazole (1) 7.52 g of 4-chloro-4′-hydroxybutyrophenone was dissolved in 50 ml of dimethylformamide,
8.57 g of t-butyldimethylsilyl chloride and 5.16 g of imidazole were added, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into ethyl acetate, and the organic layer was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate 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 obtain 11.86 g of 4-chloro-4 ′-(t-butyldimethylsiloxy) butyrophenone.

(2) 11.86 g of 4-chloro-4 '-(t-butyldimethylsiloxy) butyrophenone was dissolved in 100 ml of toluene, 11.50 g of 2-methoxyphenylpiperazine and 13.2 ml of triethylamine were added, and 13.5 g was added. Heated to reflux for hours. The reaction mixture was poured into ethyl acetate, washed twice with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate), and 1- (4-t-butyldimethylsiloxy) phenyl-4- [4- (2-methoxyphenyl) piperazino] -1-butanone 10.07.
g was obtained.

(3) 1- (4-t-butyldimethylsiloxy) phenyl-4- [4- (2-methoxyphenyl)
To a solution of 3.15 g of piperazino] -1-butanone in 3.1 ml of dimethylformamide, 5.4 ml of dimethylformamide dimethylacetal and 3.4 ml of pyrrolidine were added, and the mixture was heated under reflux for 6 hours. Pour the reaction solution into ethyl acetate,
The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to give 1- (4-t-butyldimethylsiloxy) phenyl-4- [4- (2-methoxyphenyl).
2.97 g of piperazino] -2-pyrrolidinomethylene-1-butanone was obtained.

(4) 1- (4-t-butyldimethylsiloxy) phenyl-4- [4- (2-methoxyphenyl)
2.97 g of piperazino] -2-pyrrolidinomethylene-1-butanone was dissolved in 20 ml of ethanol, 0.36 ml of methylhydrazine and 0.38 ml of acetic acid were added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate = 4: 1) to obtain 0.38 g of the title compound. ¹ H-NMR (CDCl ₃ ) δppm; 2.53 to 2.
89 (8H, m), 3.01 to 3.23 (4H, m),
3.70 (3H, s), 3.84 (3H, s), 6.6
2 to 7.13 (8H, m), 7.43 (1H, s).

The following compounds were synthesized in the same manner. 1- (2-hydroxyethyl) -5- (4-hydroxyphenyl) -4- [2- [4- (2-methoxyphenyl) piperazino] ethyl] pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.53 ~ 2.
87 (8H, m), 3.00 to 3.21 (4H, m),
3.85 (3H, s), 3.80 to 4.11 (4H,
m), 6.63 to 6.75 (2H, m), 6.80 to
7.14 (6H, m), 7.46 (1H, s). 4- [2- [4- (5-chloro-2-methoxyphenyl) piperazino] ethyl] -3- (4-hydroxyphenyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.56-2.
94 (8H, m), 3.00 to 3.21 (4H, m),
3.84 (3H, s), 6.65 to 7.02 (5H,
m), 7.21 to 7.35 (2H, m), 7.50 (1
H, s).

4- [2- [4- (5-chloro-2-methoxyphenyl) piperazino] ethyl] -1- (2-hydroxyethyl) -5- (4-hydroxyphenyl) pyrazole ¹ H-NMR (CDCl ₃ ) δppm; 2.53-2.
85 (8H, m), 3.00 to 3.18 (4H, m),
3.83 (3H, s), 3.86 to 3.97 (2H,
m), 4.00 to 4.11 (2H, m), 6.68 to
6.99 (5H, m), 7.02 to 7.13 (2H,
m), 7.46 (1H, s) 4- [2- [4- (4-fluoro-2-methoxyphenyl) piperazino] ethyl] -1- (2-hydroxyethyl) -5- (4-hydroxyphenyl) ) Pyrazole ¹
_{H-NMR (CDCl 3) δppm} ; 2.51~2.
86 (8H, m), 2.96 to 3.18 (4H, m),
3.83 (3H, s), 3.85 to 3.96 (2H,
m), 3.98 to 4.11 (2H, m), 6.50 to
6.92 (5H, m), 7.07 (2H, d, J = 8H
z), 7.46 (1H, s).

(Example 3) 5- (4-hydroxyphenyl) -4- [2- [4-
(2-Methoxyphenyl) piperazino] ethyl] -1-
Methylpyrazole dihydrochloride (Compound 3) [UF-642] 5- (4-hydroxyphenyl) -4- [2- [4-
(2-Methoxyphenyl) piperazino] ethyl] -1-
0.38 g of methylpyrazole was dissolved in 20 ml of 17% hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and the precipitate was recrystallized (ethanol) to obtain 0.26 g of the title compound. m. p. 206.5-207.5 ° C. ¹ H-NMR (DMSO-d ₆ ) δppm; 2.74-
3.60 (12H, m), 3.67 (3H, s), 3.
78 (3H, s), 6.81 to 7.09 (6H, m),
7.18 to 7.30 (2H, m), 7.45 (1H,
s).

4- [2- [4- (5-chloro-2-methoxyphenyl) piperazino] ethyl] -3- (4-hydroxyphenyl) pyrazole dihydrochloride m.p. p. 216 to 218 ° C. ¹ H-NMR (DMSO-d ₆ ) δ ppm; 2.97 to
3.67 (12H, m), 3.80 (3H, s), 6.
83 to 7.11 (5H, m), 7.40 to 7.52 (2
H, m), 7.75 (1 H, s). 4- [2- [4- (5-chloro-2-methoxyphenyl) piperazino] ethyl] -1- (2-hydroxyethyl) -5- (4-hydroxyphenyl) pyrazole dihydrochloride m.p. p. 149-152 ° C ¹ H-NMR (DMSO-d ₆ ) δppm; 2.70-
2.90 (2H, m), 2.95 to 3.61 (10H,
m) 3.62 to 3.75 (2H, br t, J = 6H
z), 3.78 (3H, s), 3.91 to 4.03 (2
H, br t, J = 6 Hz), 6.87 to 7.11 (5
H, m), 7.22 to 7.34 (2H, m), 7.51
(1H, s).

Example 4 4- [2- [4- (4-Fluoro-2-methoxyphenyl) piperazino] ethyl] -1- (2-hydroxyethyl) -5- (4-hydroxyphenyl) pyrazole fumar Acid salt (compound 6) 4- [2- [4- (4-fluoro-2-methoxyphenyl) piperazino] ethyl] -1- (2-hydroxyethyl) -5- (4-hydroxyphenyl) pyrazole.
To a solution of 64 g of ethanol in 10 ml, 0.17 of fumaric acid
g and stirred for 30 minutes. The solvent was distilled off under reduced pressure to obtain 0.81 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δppm; 2.38-
2.60 (8H, m), 2.80-2.96 (4H,
m), 3.59 to 3.71 (2H, m), 3.78 (3
H, s), 3.83 to 3.98 (2H, m), 6.59.
.About.6.72 (1H, m), 6.61 (2H, s), 6.
78 to 6.93 (4H, m), 7.22 (2H, d, J
= 8 Hz), 7.41 (1 H, s).

Test Example 1 [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-hydrochloric acid 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.

[0041]

[Table 1]

(Test Example 2) [Extracted prostate contraction inhibitory action test] The isolated bladder contraction inhibitory action test was conducted by Couldwell et al. [J. Pharm.
Pharmacol., Vol 45: 922-924 (1993)]. . The prostate was extracted from a beagle dog under anesthesia, the connective tissue was removed, and the urethra was also divided into two along the urethra.
The prostate smooth muscle tissue was cut in the longitudinal direction to a thickness of about 1 mm to prepare a prostate smooth muscle tissue specimen having a width of 4 to 6 mm and a length of about 10 to 15 mm. The sample was a Krebs-Henseleit solution (KH) at 37 ° C, which was aerated with a mixed gas of 95% O ₂ and 5% CO _2.
In S), a static tension of 1 g was loaded and suspended, and the KHS was exchanged at intervals of 20 minutes, and after stabilizing for about 40 minutes, the isometric tension was measured. The contractile inhibitory effect was examined by phenylephrine-induced contraction. That is, cumulative administration of phenylephrine (10 ^{-10 to} 3 × 10 ^-4 M) was used as a control, after which the specimen was thoroughly washed, and then the sample was administered 15 minutes before cumulative administration of phenylephrine, at which time phenylephrine contraction occurred. Was compared with the control to determine the pA ₂ or pD ₂ 'value. The results are shown below.

[0043]

[Table 2]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomoki Ota 3-24-1 Takada, Toshima-ku, Tokyo Within Taisho Pharmaceutical Co., Ltd. (72) Inventor Ikyuki Tomizawa 3-24-1 Takada, Toshima-ku, Tokyo Within Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (1) Formula (1) (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkyl group or a “phenyl group which may be substituted with 1 to 3 halogen atoms”, and R ² represents a “halogen atom, a lower alkoxy group”. And a hydroxyl group, which represents a phenyl group which may be substituted with 1 to 3 of a group selected from R, and R ³ is substituted with 1 to 3 of a group selected from a “halogen atom, a lower alkyl group and a lower alkoxy group”. Represents a phenyl group which may be represented, and m represents an integer of 1 to 3.)
The phenylpyrazole derivative represented by or a pharmaceutically acceptable acid addition salt thereof.