JPH0358343B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to phenylpiperazine derivatives represented by the general formula ().

(In the formula, R ₁ is a linear or branched saturated or unsaturated alkyl group having 1 to 8 carbon atoms, which may be substituted at any position with a hydroxyl group, carboxyl group, lower alkoxycarbonyl group, or oxo group) The compound represented by the general formula () of the present invention is α-
It can be used as a strong, long-lasting antihypertensive agent with protubercular action and antiserotonin activity, and as a peripheral vasodilator, such as a cerebral vasodilator and a renal vasodilator.

The compound represented by the general formula () of the present invention is a new compound, and can be obtained, for example, by the method shown below.

(In the formula, X represents a halogen atom, and R ₁ has the same meaning as above.) In the above reaction formula, the compound represented by the general formula () is (a) 1-(2-methoxyphenyl)piperazine. As a starting material, a compound represented by the general formula () obtained according to the description in Japanese Patent Publication No. 45-19065 is mixed with trifluoromethylchloroformate in an inert organic solvent in the presence of a base such as sodium hydrogen carbonate or triethylamine. (b) A 3-(2-halogen compound of the general formula ethyl)-2,4-(1H,
3H) Quinazolinedione derivative with potassium carbonate,
It is produced by adding and heating 1-(2-methoxyphenyl)piperazine in dimethylformamide in the presence of a catalyst such as sodium iodide. Next, the compound () of the present invention is produced by reacting this compound () with an alkyl halide. At this time, the reaction is carried out by heating in an organic solvent such as ethanol or dimethylformamide in the presence of a catalyst such as sodium hydride or sodium iodide. In addition, in this reaction to obtain compound () from (), the general formula () is
When the alkyl group represented by R ₁ contains a hydroxyl group, the hydroxyl group is preferably subjected to this reaction in another form, for example, in the form of an acyloxy group such as an oxo group or an acetoxy group. The oxo group of the obtained compound is then subjected to a reduction reaction, for example using a metal hydride such as sodium borohydride, and the acyloxy group such as an acetoxy group is subjected to a conventional hydrolysis reaction, for example, an alcoholic It can be easily converted into a hydroxyl group by using an aqueous sodium hydroxide solution or a potassium hydroxide aqueous solution. Also R ₁
When the alkyl group represented by contains a carboxyl group, it is preferable to protect it once as in the case of a hydroxyl group and then subject it to this reaction. For example, after subjecting it to this reaction in an esterified form, the resulting compound is It is preferable to convert it into a carboxyl group by hydrolysis.

In these series of reactions, the target compound can be isolated from the reaction mixture by a conventional method, for example, by adding water to the reaction solution and collecting the precipitated crystals and recrystallizing them, or by adding water to the reaction solution and then adding methylene chloride, This can be easily carried out by extracting with an organic solvent such as chloroform, distilling off the solvent, and subjecting it to methods such as recrystallization or column chromatography.

The compounds () of the present invention form salts with organic or inorganic acids. The acid is preferably a pharmaceutically acceptable one, and examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as fumaric acid, maleic acid, tartaric acid, and succinic acid. . Salts can be easily produced according to conventional methods.

Example 1 0.44 g of 60% sodium hydride was suspended in 50 ml of dimethylformamide and 3-[2-[4-
(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione
Add 3.80g little by little and leave at room temperature for 30 minutes, then 50g
Stir for 10 min at °C. After cooling to room temperature, a solution of 2.37 g of ethyl 7-bromoheptanoate dissolved in 20 ml of dimethylformamide is added and stirred overnight at room temperature. The solvent is distilled off under reduced pressure, and the resulting residue is extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was subjected to silica gel column chromatography (solvent, chloroform:ethanol =
25:1) to give a pale yellow oil, 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
3.62 g of 2,4-(1H,3H)quinazolinedione are obtained. This was dissolved in 50 ml of ethanol, hydrogen chloride gas was introduced for about 5 minutes, the solvent was distilled off, and the resulting crystalline residue was recrystallized from ethanol-n-hexane to give colorless needle-shaped crystals with a melting point of 109-111°C. 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2
3.45 g of quinazolinedione dihydrochloride are obtained.

Elemental analysis value C ₃₀ H ₄₀ N ₄ O ₅・2HCl・1/2H ₂ O C H N Calculated value (%) 58.25 7.01 9.06 Actual value (%) 58.48 6.91 9.09 Example 2 Conducted using the corresponding raw material compound The following compounds (a to k) were obtained by processing in the same manner as in Example 1. In addition,
Compounds (i) to (k) were isolated without converting them into hydrochlorides.

(a) 1-(5-ethoxycarbonylbentyl)-3
-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride, melting point 101°C (recrystallized from ethanol-ether) Elemental analysis Value C ₂₉ H ₃₈ N ₄ O As ₅・2HCl C H N Calculated value (%) 58.48 6.77 9.41 Actual value (%) 58.76 6.80 9.97 (b) 1-(4-Ethoxycarbonylbutyl)-3-
[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride, melting point 140°C (recrystallized from ethanol-ether) Elemental analysis value C ₂₈ H ₃₆ N ₄ O ₅・2HCl・1/2H ₂ O C H N Calculated value (%) 56.95 6.66 9.49 Actual value (%) 57.12 6.53 9.48 (c) 1-(3-ethoxycarbonylpropyl)-3
-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride, melting point 184°C (decomposition,
Recrystallized from ethanol-n-hexane) Elemental analysis value C ₂₇ H ₃₄ N ₄ O ₅・2HCl・1/2H ₂ O C H N Calculated value (%) 56.25 6.47 9.72 Actual value (%) 55.95 6.13 10.02 (d ) 1-(6-1methoxycarbonyl-2-hexynyl)3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-
(1H,3H)quinazolinedione dihydrochloride, melting point
128℃ (decomposition, recrystallization from methanol-n-hexane) Elemental analysis value C ₂₉ H ₃₄ N ₄ O ₅・2HCl・1/2H ₂ O as C H N Calculated value (%) 58.00 6.21 9.33 Actual value (%) 57.81 5.91 9.23 (e) 1-heptyl-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
2,4-(1H,3H)quinazolinedione dihydrochloride, melting point 114°C to 116°C (recrystallized from ethanol-n-hexane) Elemental analysis value C ₂₈ H ₃₈ N ₄ O As ₃・2HCl C H N Calculated value (%) 60.97 7.31 10.16 Actual value (%) 61.36 7.31 10.68 (f) 1-pentyl-3[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,
4-(1H,3H)quinazolinedione dihydrochloride,
Melting point 148℃ (recrystallized from methanol-ether) Elemental analysis value C ₂₆ H ₃₄ N ₄ O as ₃・2HCl C H N Calculated value (%) 59.65 6.93 10.70 Actual value (%) 59.94 6.88 10.41 (g) 1-( 3-butenyl)-3-[2-[4-(2-
methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione 2
Hydrochloride, melting point 157℃ (recrystallized from methanol-ether) Elemental analysis value C ₂₅ H ₃₀ N ₄ O ₃・2HCl・1/2H ₂ O C H N Calculated value (%) 58.14 6.44 10.85 Actual value (%) 58.61 6.35 10.62 (h) 1-isopropyl-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]
-2,4-(1H,3H)quinazolinedione dihydrochloride, melting point 178℃ (recrystallized from ethanol-n-hexane) Elemental analysis value C ₂₄ H ₃₀ N ₄ O ₃・2HCl・1/2H ₂ O as C H N Calculated value (%) 57.14 6.59 11.11 Actual value (%) 57.10 6.35 10.92 (i) 1-Methyl-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,
4-(1H,3H)quinazolinedione dihydrochloride,
Melting point: 154°C to 155°C (recrystallized from ethanol-ether) Elemental analysis value As C ₂₂ H ₂₆ N ₄ O ₃ C H N Calculated value (%) 66.99 6.64 14.20 Actual value (%) 66.91 6.66 14.17 (j) 1− (3-oxo-trans-1-octenyl)-3-[2-[4-(2-methoxyphenyl)
-1-piperazinyl]ethyl]-2,4-(1H,
3H) Quinazolinedione, oil elemental analysis value C ₂₉ H ₃₆ N ₄ O ₄ C H N Calculated value (%) 69.02 7.19 11.10 Actual value (%) 68.72 7.21 10.98 (k) 1-(5-oxo-hexyl) 3-[2-[4
-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione, oil elemental analysis value C ₂₇ H ₃₄ N ₄ O ₄ C H N Calculated value (%) 67.76 7.16 11.71 Actual value (%) 67.46 6.90 11.41 Example 3 1-(3-ethoxycarbonylpropyl)-3-[2-[4-(2-methoxyphenyl)-1] obtained in Example 2(c) -piperazinyl]ethyl]-2,4-
(1H, 3H) Dissolve 4.53 g of quinazolinedione in 40 ml of ethanol and add 2N aqueous sodium hydroxide solution.
Add 10 ml under ice-cooling and stir at room temperature for 3 hours.
The residue obtained by distilling off the solvent under reduced pressure is dissolved in 20 ml of water, and the pH is adjusted to 7 with 10% hydrochloric acid. After collecting the precipitated crystals, they are recrystallized from ethanol-n-hexane. 1- pale yellow needle crystals with a melting point of 182℃ (decomposed)
(3-carboxypropyl)-3-[2-[4-(2
-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione 2.52
get g.

Elemental analysis value C ₂₅ H ₃₀ N ₄ O ₅ C H N Calculated value (%) 64.36 6.48 12.01 Actual value (%) 64.11 6.48 11.87 Example 4 1-(3-oxo obtained in Example 2-(j)) -trans-1-oxtenyl)3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
Dissolve 1.80 g of 2,4-(1H,3H) quinazolinedione in 20 ml of ethanol and add sodium borohydride.
After adding 163 mg of the mixture and stirring at room temperature for 2 hours, the pH was adjusted to 7 with 10% hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, the chloroform layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
Purify by TLC (silica gel, solvent, chloroform:ethanol = 20:1). The obtained crystals were recrystallized from benzene-n-hexane to a melting point of 118~
1-(3-hydroxy-trans-1-octel)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- in colorless needle-like crystals at 119°C.
350 mg of 2,4-(1H,3H)quinazolinedione was obtained.

Elemental analysis value C ₂₉ H ₃₈ N ₄ O ₄ C H N Calculated value (%) 68.75 7.56 11.06 Actual value (%) 69.02 7.58 11.02 Example 5 0.44 g of 60% sodium hydride was suspended in 50 ml of dimethylformamide, and nitrogen Under air flow, 3-[2-[4
-(2-methoxyphenyl)-1-piperazinyl]
Ethyl]-2,4-(1H,3H)quinazolinedione
Add 3.80g little by little at room temperature for 30 minutes, then at 80℃.
Stir for 10 minutes. After cooling to room temperature, a solution of 1.98 g of 1-acetoxy-5-chloropentane dissolved in 10 ml of dimethylformamide and 1.8 g of sodium iodide are added and reacted at 80° C. for 2 hours. After the reaction, 30 ml of water is added and the solvent is distilled off under reduced pressure, and the resulting residue is extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was subjected to silica gel column chromatography (solvent: chloroform:methanol = 100:1) to obtain a pale yellow oil. (5-
acetoxypentyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
2,4-(1H,3H)quinazolinedione is obtained.
Dissolve this in 50 ml of methanol, add a large excess of sodium hydroxide solution, and stir at room temperature for 1 hour. After the reaction, the solvent is distilled off under reduced indigo, and the resulting residue is extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow oily substance, 1-(5-hydroxypentyl)-3-
[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione is obtained. Dissolve this in about 50 ml of methanol, introduce hydrogen chloride gas for about 5 minutes, and then distill off the solvent under reduced pressure.
Recrystallized from diethyl ether, melting point 154-156℃,
Colorless needle-like crystals of 1-(5-hydroxypentyl)-3
2.1 g of -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride is obtained.

Elemental analysis value C ₂₆ H ₃₄ N ₄ O ₄・2HCl・1/2H ₂ O C H N Calculated value (%) 56.93 6.80 10.21 Actual value (%) 57.35 6.73 10.37 Example 6 Conducted using the corresponding raw material compound The following compound was obtained by processing in the same manner as in Example 5.

1-(2-hydroxyethyl)-3-[2-[4-
(2-Methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione 2
Hydrochloride, melting point 210℃ (recrystallized from water-ethanol-ether) Elemental analysis value C ₂₃ H ₂₈ N ₄ O ₄・2HCl・1/2H ₂ O C H N Calculated value (%) 54.55 6.17 11.06 Actual value ( %) 54.43 6.17 10.79 Reference example 7-chloro-6-sulfamoylisatoic anhydride 7.45g, 1-(2-aminoethyl)-4-(2-
Dissolve 6.64 g of methoxyphenyl)piperazine in 100 ml of methanol and reflux at boiling point for 3 hours under a nitrogen stream. After the reaction, the solvent is distilled off under reduced pressure, recrystallized from methanol-acetone, and dried. 2-amino-4-chloro-5-sulfamoyl-N-[2-
[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]benzamide is obtained. Phosgene 2.33
20 ml of acetic acid in which 1.32 g of the benzamide derivative obtained previously was dissolved was added dropwise to 10 ml of toluene in which 1.3 g of benzamide derivative had been dissolved while stirring at room temperature. After the dropwise addition, the mixture was boiled under reflux for 1 hour, cooled to room temperature, and the precipitated crystals were dried.
The obtained crystals were suspended in a mixed solvent of 10 ml of methanol and 10 ml of water, hydrogen chloride gas was introduced for about 5 minutes, and the solvent was distilled off under reduced pressure to obtain a crystalline residue. This was recrystallized from water-methanol-ether with a melting point of 266-268℃.
(decomposition), colorless needles of 7-chloro-6-sulfamoyl-3-[2-[4-(2-methoxyphenyl)]
-1-piperazinyl]ethyl]-2,4-(1H,
3H) Obtain 200 mg of quinazolinedione hydrochloride.

Elemental analysis value C ₂₁ H ₂₄ N ₅ O ₅ S・HCl・1/2H ₂ O C H N Calculated value (%) 46.76 4.86 12.98 Actual value (%) 46.47 4.86 12.22

Claims (1)

[Claims] 1. General formula (In the formula, R1 means a linear or branched saturated or unsaturated alkyl group having 1 to 8 carbon atoms, which may be substituted at any position with a hydroxyl group, carboxyl group, lower alkoxycarbonyl group, or oxo group) A phenylpiperazine derivative represented by