JPH0696561B2 - Novel 2- (4-phenyl-1-piperazinylalkyl) aminopyrimidine derivative and acid addition salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (In the formula, R ₁ and R ₃ are a hydrogen atom, a halogen atom, an amino group,
A linear or branched alkoxy group, an aralkyloxy group or a lower alkyl group; R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower acyl group or a linear or branched alkoxycarbonyl group; R ₄
And R ₅ represents a hydrogen atom, a halogen atom, a lower alkyl group or a linear or branched alkoxy group; n is 2 to
The present invention relates to a novel 2- (4-phenyl-1-piperazinylalkyl) aminopyrimidine derivative represented by the formula 6) and an acid addition salt thereof.

The compound of formula I can be easily produced by the production method described below. General formula II (Wherein R ₁ , R ₂ and R ₃ have the above-mentioned meanings, and X represents a halogen atom), a 2-halogenopyrimidine derivative represented by the general formula III It can be produced by reacting a compound represented by the formula (wherein R ₄ , R ₅ and n have the above-mentioned meanings).

Among the compounds of the formula II, those not mentioned in the literature, for example, compounds in which R ₂ represents an acyl group or an alkoxycarbonyl group are described in, for example, Journal of Chemical Society, 196
5-year-old, 5-carboxy-2-chloro-4,6-dimethylpyrimidine produced by the method described on page 6695, is used as a starting material and is produced by the reaction process shown by the following formula.

That is, when a lower alkyl sulfate is allowed to act in an acetone solvent in the presence of anhydrous potassium carbonate, or thionyl chloride is acted to form an acid chloride and then a lower alcohol is allowed to act, a 5-lower alkoxycarbonylpyrimidine derivative is obtained. . On the other hand, by reacting the acid chloride with a Grignard reagent, a 5-lower acylpyrimidine derivative can be produced.

Examples of compounds of formula II include the following: 2-chloropyrimidine, 2,4-dichloropyrimidine, 2-chloro-4-aminopyrimidine, 2-chloro-
4-methoxypyrimidine, 2-chloro-4-benzyloxypyrimidine, 2-chloro-4,6-dimethylpyrimidine, 2-chloro-5-bromo-4,6-dimethylpyrimidine, 2-chloro-5-carboxy-4 , 6-Dimethylpyrimidine, 2-chloro-5-acetyl-4,6-dimethylpyrimidine, 2-chloro-5-ethoxycarbonyl-4,6
-Dimethylpyrimidine, 2-5-methoxycarbonyl-
4,6-dimethylpyrimidine and the like.

As the compound of formula III, for example, the following compounds are used. 2- (4-phenyl-1-piverazinyl) ethylamine, 2- [4- (2-methoxyphenyl) -1-piperamadinyl] ethylamine, 2- [4- (3-methoxyphenyl) -1-piperazinyl] ethylamine, 2 −
[4- (4-methoxyphenyl) -1-piperazinyl]
Ethylamine, 2- [4- (4-methoxyphenyl)-
1-piperazinyl] ethylamine, 2- [4- (2-chlorophenyl) -1-piperazinyl] ethylamine, 2
-[4- (2-Methylphenyl) -1-piperazinyl]
Ethylamine, 2- [4- (2,4-dimethoxyphenyl) -1-piperazinyl] ethylamine, 2- [4-
(3,4-Dioxomethylenephenyl) -1-piperazinyl] ethylamine, 3- [4- (2-methoxyphenyl) -1-piperazinyl] propylamine, 4- [4-
(2-Methoxyphenyl) -1-piperazinyl] butylamine, 5- [4- (2-methoxyphenyl) -1-piperazinyl] pentylamine, 6- [4- (2-methoxyphenyl) -1-piperazinyl] hexylamine Such.

In a preferred embodiment of the method of the present invention, the following operation is performed, for example. An amount of 1 to 10 moles, in particular 1 to 3 moles, of a compound of formula III is used in an inert solvent or in the absence of solvent, per mole of a compound of formula II. As the solvent, for example, water, lower alcohol, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, benzene, xylene, or a solvent mixture of two or more of these is used. In that case, as the dehydrohalogenating agent, 1 to 10 mol of an inorganic base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., per 1 mol of the compound of the formula II Alternatively, organic bases such as pyridine, dimethylaniline or triethylamine are preferably added to the reaction mixture. The reaction proceeds smoothly at a temperature between room temperature and 150 ° C. The reaction time varies depending on the reaction temperature, the type of solvent, the properties of the raw materials, etc., but is usually 10 minutes to 100 minutes.
Finish in time. The reaction mixture is usually worked up by conventional procedures to allow the compound of formula I to be isolated in a yield of 30 to 98% of theory relative to the compound of formula II.

Furthermore, if desired, an acid is added to the compound of formula I to neutralize and recrystallize to give an acid addition salt of the compound of formula I. Examples of the acid used include pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as acetic acid and propionic acid.
Examples include oxalic acid, malonic acid, succinic acid, tartaric acid, malic acid, and benzoic acid.

The thus-obtained novel compound of the formula I has a sustained antihypertensive action and a blood flow increasing action, and also suppresses the agglutination reaction of platelets. Therefore, the compound of the present invention is useful as a therapeutic agent for hypertension and also as a cerebral circulation improving agent such as a blood flow improving agent for central blood flow disorder, ischemic cerebral blood flow disorder, and cerebral thrombosis.

The effective dose of the compound of the present invention is 0.01 to 160 mg / kg · day. The administration method includes oral administration, enteral administration, injection and the like. For oral administration, tablets or capsules may be used.

When the toxicity of the compound of the present invention was examined, any acute toxicity,
No subacute toxicity was observed, and it was found that it can be safely administered to the human body.

Example 1 a) Preparation of 2-chloro-5-ethoxycarbonyl-4,6-dimethylpyrimidine 18.66 g of 5-carboxy-2-chloro-4,6-dimethylpyrimidine and 23.6 g of anhydrous potassium carbonate are suspended in 280 ml of acetone. The mixture was turbid, 30.8 g of diethylsulfate was slowly added thereto with stirring at room temperature, then the temperature was raised and the mixture was boiled under reflux for 2 hours. After cooling to room temperature, the insoluble material is removed and the liquid is concentrated under reduced pressure. The residual oily substance is distilled under reduced pressure, and distillates having a boiling point of 99 ° C / 3 mmHg or less are collected to obtain 16.73 g (yield 78.4%) of a colorless oil. Distill under reduced pressure again, boiling point 114.5-117 ℃ / 3mm
From the Hg distillate fraction, 14.66 g (yield 68.7%) of 2-chloro-5-ethoxycarbonyl-4,6-dimethylpyrimidine can be obtained.

b) 2- [2- (2-methoxyphenyl) -1-piperazinyl] ethyl] amino-5-ethoxycarbonyl-4,
Preparation of 6-dimethylpyrimidine hydrochloride; Preparation of salt; 2-chloro-5-ethoxycarbonyl-obtained in a)
To a solution of 430 mg of 4,6-dimethylpyrimidine in 6 ml of ethanol, 404 mg of triethylamine and 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylamine 51
Add 8 mg and stir at 80 ° C. for 14 hours. The reaction solution is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution is added to the residue to make it alkaline, and the mixture is extracted with chloroform. After washing the extract with water and drying with sodium sulfate, the solvent was distilled off under reduced pressure.
The residue obtained is purified by silica gel chromatography. Fractions flowing out with chloroform containing 5% ethanol were collected and recrystallized from normal hexane to give a melting point of 154
2- [2- [4- (2-methoxyphenyl)-at ~ 6 ° C
1-Piperazinyl] ethyl] amino-5-ethoxycarbonyl-4,6-dimethylpyrimidine trihydrochloride 717 mg (yield
55.1%) is obtained.

Mass spectrum; m / e 413 (M ), 368,351,218,205 NMR spectrum; δ (ppm, free form in CDCl₃Measured in 1.38 (3H, triple line), 2.44 (6H, single line) 2.5 to 3.8 (12H, multiple line), 3.86 (3H, single line) 4.45 (2H, quad line), 5.74 (1H, bvs ) 6.93 (4H, single line), elemental analysis value C_{twenty two}H₃₀N_FiveO₃CH3 theoretical value (%) 50.77 6.30 13.34 Actual value (%) 50.53 6.55 13.39 Example 2a) 5-acetyl-2-chloro-4,6-dimethylpyrimy
Preparation of gin; 2-chloro-5-carboxy-4,6-dimethylpyrimidi
Thionyl chloride 5ml was added to 1.87g and heated at 80 ℃ for 2 hours.
After that, concentrate under reduced pressure and add 10 ml of anhydrous benzene to reduce the volume.
Repeat the concentration several times under pressure. The obtained acid chloride is sealed
save. Ribbon-shaped magnesium metal 730mg, methyl iodide
Grignard by a conventional method using 4.40 g and anhydrous ether.
Prepare the reagent. This is ice-cooled, and in an atmosphere of zero argon
A solution of the above acid chloride in 20 ml of anhydrous diethyl ether was added.
The mixture is added dropwise with stirring, and after completion of the addition, the mixture is boiled under reflux for 30 minutes. Decompression
After concentrating under ice-cold water, add ice chips and 1N hydrochloric acid solution (20 ml).
Acidified, extracted with chloroform, washed extract with water
Dry with Glauber's salt. The solvent was distilled off, and the residue was silica gel.
Purify by column chromatography. Chloroform flow
The collected fractions were recrystallized from normal hexane,
5-acetyl-2-chloro-4,6-dime, melting point 88-89 ° C
930 mg (50.3%) of tylpyrimidine are obtained.

b) 2- [2- [4- (2-methoxyphenyl) -1-
Piperazinyl] ethyl] amino-5-acetyl-4,6-
Preparation of dimethylpyrimidine; to a solution of 184 mg of 5-acetyl-2-chloro-4,6-dimethylpyrimidine obtained in a) in 4 ml of absolute ethanol,
250 mg of 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethylamine is added, and the mixture is stirred under reflux boiling for 24 hours. The reaction mixture is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with chloroform. The extract is washed with water and dried with Glauber's salt. The solvent is distilled off and the residue is purified by silica gel column chromatography. After running through with chloroform containing 5% ethyl acetate, the fractions flowing out with chloroform containing 5% ethanol were collected and recrystallized from normal hexane / diethyl ether to give 2- [2- [4- (2 -Methoxyphenyl) -1-piperazinyl] ethyl] amino-
163 mg of 5-acetyl-4,6-dimethylpyrimidine (yield 4
2.6%) is obtained.

Mass spectrum; m / e 383 (M ), 368,234,218,205 NMR spectrum; δ (ppm, CDCl₃2.33 (6H, single line), 2.74 (3H, single line) 2.4 to 3.8 (12H, multiple line), 3.86 (3H, single line) 5.72 (1H, single line), 6.94 (4H, single line) ) Elemental analysis value C_{twenty one}H₂₉N_FiveO₂CHN theoretical value (%) 65.77 7.62 18.26 Measured value (%) 65.88 7.34 18.21 Example 3 a) 2- [2- [4- (2-methoxyphenyl) -1-
Piperazinyl] ethyl] amino-4-benzyloxypi
Preparation of limidine; 2-chloro-4-benzyloxypyrimidine 441 mg, tri
Ethylamine 404 mg, 2- [4- (2-methoxyphenyl)
) -1-Piperazinyl] ethylamine 476 mg and eta
Put 5 ml of Nol in a sealed tube, seal and heat at 120 ° C for 5 hours.
It The solvent was distilled off under reduced pressure and saturated sodium hydrogen carbonate was added to the residue.
Add an aqueous solution of lithium and extract with chloroform. Extract
Is washed with water and then dried with Glauber's salt. Distill off the solvent and leave
The distillate is purified by silica gel column chromatography.
It After flowing 200 ml of chloroform, 5% ethanol
Of the effluent containing chloroform was collected and collected with methanol.
When recrystallized from 2- [2- [4
-(2-Methoxyphenyl) -1-piperazinyl] eth
L] Amino-4-benzyloxypyrimidine 702 mg (yield
A rate of 83.4%) is obtained.

Mass spectrum; m / e 419 (M ), 404,328,257,205 Elemental analysis value C_{twenty four}H₂₉N_FiveO₂CHN theoretical value (%) 68.71 6.97 16.69 Measured value (%) 68.51 7.07 16.43 b) 2- [2- [4- (2-methoxyphenyl) -1-
Piperazinyl] ethyl] amino-4-hydroxypyrimy
Preparation of Zin Oxalate; 2- [2- [4- (2-methoxyphenyl) obtained in a)
) -1-Piperazinyl] ethyl] amino-4-benzi
Dissolve 120 mg of luoxypyrimidine in 4 ml of acetic acid and add 10% para
Add 30 mg of carbon catalyst and introduce 14 ml of hydrogen at atmospheric pressure.
It After removing the catalyst and washing with acetone, combine the solution with the washing solution.
And concentrate under reduced pressure. Saturated sodium bicarbonate is added to the residue.
Add chloroform and extract with chloroform. Wash the extract with water
Then, it is dried with Glauber's salt. After distilling off the solvent, the silica gel column
Purify by chromatography. Black containing 5% ethanol
After flushing with Loform, 2% ammonia saturated ethanol
/ 5% ethanol / 93% chloroform mixed solvent
Collected fractions and dissolved the resulting oil in 2 ml of acetone.
You A solution of 63 mg of oxalic acid in 4 ml of acetone was added to the above
When added slowly to the ton solution, an instantaneous precipitate is formed. room temperature
If it is left for a while, it will have a melting point of 182-183.5 ℃.
[2- [4- (2-methoxyphenyl) -1-piperazi
Nyl] ethyl] amino-4-hydroxypyrimidine oxalic acid
115 mg (93.8%) of salt / hemihydrate is obtained.

Mass spectrum; m / e 329 (free M ), 314,205 Elemental analysis value C₁₇H_{twenty three}N_FiveO₂・ (CO₂H)₂・ 1/2 (H₂O) as CHN theoretical value (%) 53.26 6.12 16.35 measured value (%) 53.06 5.90 16.05 Examples 4 to 19 In the same manner as in Example 1b, 2-chloro-4,6-dimethyl-
5-ethoxycarbonylpyrimidine has the formula III shown in Table 1.
When each of the compounds is reacted, the yield is 50-98%.
The target product shown in 1 is obtained. Also, as in Example 3a
2- [4- (2-methoxyphenyl) -1-piperazi
Nyl] ethylamine for each compound of formula II shown in Table 2
The target compounds shown in Table 2 are obtained with a yield of 30 to 80% when acted upon.
To be

Experimental Example 1 Measurement of changes in systemic blood pressure and changes in common carotid blood flow; Changes in systemic blood pressure and changes in common carotid blood flow were simultaneously measured and recorded. That is, a male rabbit weighing about 2.5 kg was anesthetized with pentobarbital, a catheter was inserted into a carotid artery that was incised according to a conventional method, and changes in systemic blood pressure were recorded via a pressure transducer. An electromagnetic blood flow probe was attached to the carotid artery on the remaining side of the rabbit, and changes in the blood flow in the common carotid artery were recorded. Table 3 and FIG. 1 show the decrease in blood pressure and the change in common carotid blood flow when 100 μg / kg of the compound of the present invention was dissolved in 50% ethanol and intravenously administered. In addition, Table 3 and FIG.
The numbers of the compounds therein indicate the numbers of the above examples.

Experimental Example 2 Inhibitory action on platelet aggregation: Blood is collected through a catheter inserted into the carotid artery of a rabbit weighing about 3 kg, 10% volume of 3.8% sodium citrate aqueous solution is added as an anticoagulant, and centrifugation is performed at 90 G for 15 minutes.
The platelet-rich plasma obtained from Kamito was measured according to the method of Born et al. That is, a dimethylsulfoxide solution of the compound of the present invention was added to the platelet aggregation-inhibiting reaction caused by adding sodium arachidonic acid [125 μmol] or ADP (adenosine diphosphate) [30 μmol] to the platelet-rich plasma as an aggregation inducer. The inhibition rate in the case of pretreatment was determined, and the results are shown in Table 4. The compound numbers in Table 4 mean the above-mentioned example numbers.

[Brief description of drawings]

1 and 2 show changes in systemic blood pressure and changes in common carotid blood flow (male rabbit, body weight 2.2 kg) upon administration of the compound 2b of the present invention in Experimental Example 1, respectively.

Claims (7)

[Claims] 1. A general formula I (In the formula, R ₁ and R ₃ are a hydrogen atom, a halogen atom, an amino group,
A linear or branched alkoxy group, an aralkyloxy group or a lower alkyl group; R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower acyl group or a linear or branched alkoxycarbonyl group; R ₄
And R ₅ represents a hydrogen atom, a halogen atom, a lower alkyl group or a linear or branched alkoxy group; and n is 2 to
2- (4-phenyl-1) represented by
-Piperazinylalkyl) aminopyrimidine derivatives and acid addition salts thereof. 2. 2- (4-Phenyl-1-piperazinylalkyl) amino according to claim _1, wherein R ₁ and R ₃ are hydrogen atom, halogen atom, amino group or lower alkyl group. Pyrimidine derivatives and acid addition salts thereof. 3. A 2- (4-phenyl-1-piperazinylalkyl) aminopyrimidine derivative or an acid addition salt thereof according to claim 2, wherein R ₁ and R ₃ are lower alkyl groups. 4. A general formula (Wherein R ₁ , R ₂ and R ₃ have the meanings described below, and X represents a halogen atom), the pyrimidine derivative represented by the general formula A 4-phenyl-1-piperazinylalkylamine derivative represented by the formula (wherein R ₄ , R ₅ and n have the meanings given below) in an inert solvent or in the absence of a solvent, or in the presence or absence of a base. Of the general formula I, characterized in that the product is converted into an acid addition salt if desired. (In the formula, R ₁ and R ₃ are a hydrogen atom, a halogen atom, an amino group,
A linear or branched alkoxy group, an aralkyloxy group or a lower alkyl group; R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower acyl group or a linear or branched alkoxycarbonyl group; R ₄
And R ₅ represents a hydrogen atom, a halogen atom, a lower alkyl group or a linear or branched alkoxy group; and n is 2 to
The method for producing the compound represented by the formula (6). 5. The general formula I (In the formula, R ₁ and R ₃ are a hydrogen atom, a halogen atom, an amino group,
A linear or branched alkoxy group, an aralkyloxy group or a lower alkyl group; R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower acyl group or a linear or branched alkoxycarbonyl group; R ₄
And R ₅ represents a hydrogen atom, a halogen atom, a lower alkyl group or a linear or branched alkoxy group; and n is 2 to
2- (4-phenyl-1) represented by
An antihypertensive agent containing a piperazinylalkyl) aminopyrimidine derivative or an acid addition salt thereof as an active ingredient. 6. The general formula I (In the formula, R ₁ and R ₃ are a hydrogen atom, a halogen atom, an amino group,
A linear or branched alkoxy group, an aralkyloxy group or a lower alkyl group; R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower acyl group or a linear or branched alkoxycarbonyl group; R ₄
And R ₅ represents a hydrogen atom, a halogen atom, a lower alkyl group or a linear or branched alkoxy group; and n is 2 to
2- (4-phenyl-1) represented by
-Piperazinylalkyl) aminopyrimidine derivative or an acid addition salt thereof as an active ingredient. 7. The general formula I (In the formula, R ₁ and R ₃ are a hydrogen atom, a halogen atom, an amino group,
A linear or branched alkoxy group, an aralkyloxy group or a lower alkyl group; R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower acyl group or a linear or branched alkoxycarbonyl group; R ₄
And R ₅ represents a hydrogen atom, a halogen atom, a lower alkyl group or a linear or branched alkoxy group; and n is 2 to
2- (4-phenyl-1) represented by
-Piperazinylalkyl) aminopyrimidine derivative or an acid addition salt thereof as an active ingredient, a platelet aggregation inhibitor.