JPS6251672A - Novel 2-(4-phenyl-1-piperazinyl alkyl)-aminopyrimidine derivative and acid addition salt thereof - Google Patents

Abstract

NEW MATERIAL:2-(4-Phenyl-1-piperazinylalkyl) aminopyrimidine derivative expressed by formula I (R1 and R3 represent H, halogen atom, amino, OH, alkoxyl, aralkyloxy or alkyl; R2 represents H, halogen atom, alkyl, carboxyl, acyl or alkoxycarbonyl; R4 and R5 represent H, halogen, alkyl or alkoxyl, n is 2-6) and its acid addition salt. EXAMPLE:2-[ 2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl ]-amino-5-ethoxycarbo nyl-4,6-dimethylpyrimidine. USE:A hypotensor, blood stream-ameliorating agent or platelet agglutination inhibitor. PREPARATION:A 2-halogenopyrimidine derivative expressed by formula II (X is halogen atom) is reacted with a compound expressed by formula III to obtain the compound expressed by formula I.

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, R and R3 are hydrogen atoms and halogen atoms.

Amino atom, hydroxyl group, linear or branched alkyloxy group, aralkyloxy group, or lower alkyl group; R2 is 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 and R5 mean a hydrogen atom, a halogen atom, a lower alkyl group, or a linear or branched alkoxy group; n is an integer of 2 to 6) The present invention relates to novel 2-(4-phenyl-1-piperazinylalkyl)aminopyrimidine derivatives and acid addition salts thereof.

The compound of formula (1) can be easily produced by the production method described below. A 2-halogenopyrimidine derivative represented by the general formula ■ (wherein R, R, and R3 have the above-mentioned meanings, and X means a halogen atom) is added to a 2-halogenopyrimidine derivative represented by the general formula It can be produced by reacting a compound represented by

Compounds of the formula (2) that are not described in the literature, for example, compounds in which R2 represents an acyl group or an alkoxycarbonyl group, are:
For example, Journal of Chemical Society,
It is produced by the reaction steps shown in the following formula using 5-carboxy-2-chloro-4,6-dimethylpyrimidine produced by the method described in 1965, p. 0695 as a starting material.

That is, by reacting with a lower alkyl sulfate in the presence of anhydrous potassium carbonate in an acetone solvent, or by reacting with thionyl chloride to form an acid chloride, and then reacting with a lower alcohol, a 5-lower alkoxycarbonyl is produced. A pyrimidine derivative is obtained.

On the other hand, the acid chloride was treated with Grignard reagent c5
't! Then, a 5-lower acylpyrimidine derivative can be produced.

Examples of the compound of formula (1) include the following. 2-Chlorpyrimidine, 2.4-'dichlorpyrimidine, 2-chloro-4-hydroxypyrimidine, 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-
Chlor-5-carboxy-4,6-dimethylpyrimidine, 2-chloro-5-acetyl-4,6-dimedylpyrimidine, 2-chloro-5-ethoxycarbonyl-6-simethylpyrimidine, 2-5 -methoxycarbonyl-4.6
-Simethylpyrimidine, etc.

As the compound of formula (1), for example, the following can be used. 2-(4-phenyl-1-piperazinyl)ethylamine, 2-[4-(2-methoxyphenyl)-1-piperazinyl-11thylamine, 2-[4-(3-methoxyphenyl)-1-piperazinyl]ethylamine, 2
- [4- (4-methoxyphenyl)-1-piperazinyl]ethylamine, 2- [4- (2-chlorophenyl)-1-piperazinyl]ethylamine, 2-[4-
(2-methylphenyl)-1-piperazinyl 1-ethylamine, 2- [4- (2. 4-dime[.xyphenyl)-1-piperazinyl] ethylamine, 2- [4
- (3. 4=dioxomethylenephenyl)-1-piperazinyl]ethylamine, 3- [4- (2-methoxyphenyl)-1-piperazinyl 1-propylamine,
4-[4-(2-methoxyphenyl)-1-piperazinyl-1 butylamine, 5-[4-(2-methoxyphenyl)-1-piperazinyl
-diphenyl)-1-piperazinyl]pentylamine,
6-[4-(2-methoxyphenyl)-1-piperazinyl 11-thylamine, etc.

In a preferred embodiment of the method of the present invention, the operation is performed as follows, for example. 1 to 10 per mol of compound of formula (■)
A compound having a molar ratio of ω of 1 to 3 is allowed to react in an inert solvent or in the absence of a solvent. Examples of the solvent include water, lower alcohol, tetrahydrofuran, dimedylformamide, chloroform, dichloromethane, and benzene.

Xylene or a mixture of two or more of these solvents is used. At that time, as a dehydrohalogenating acid agent, the formula ■
1 to 10 El of inorganic bases, such as sodium hydroxide, per mole of compound.

Potassium hydroxide, sodium carbonate, potassium carbonate.

Preferably, sodium bicarbonate or the like or organic salts such as pyridine, dimedylaniline or triethylamine are added to the reaction mixture. The reaction proceeds smoothly at temperatures between room temperature and 150°C. Although the reaction time varies depending on the reaction temperature, type of solvent, properties of raw materials, etc., the reaction time is usually completed within 10 minutes to 100 hours. When the reaction mixture is worked up by conventional operations, the formula ■
30 to 98% of the theoretical amount of the compound of formula (■)
can be isolated with a yield of .

Furthermore, if desired, the acid addition salt of the compound of formula I can be obtained by neutralizing the compound of formula I with an acid and recrystallizing it. The acids used include pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc. a acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, tartaric acid, malic acid,
Examples include benzoin M.

The novel compound of formula I thus obtained has a sustained casting pressure effect, an effect of increasing blood flow m, and also suppresses the aggregation reaction of platelets. Therefore, the compound of the present invention is useful as a therapeutic agent for hypertension, and is also used as a cerebral circulation improving agent such as a blood flow improving agent for peripheral blood flow disorders, ischemic cerebral blood flow disorders, and cerebral thrombosis.

The effective dose m of the compound of the present invention is 0.01 to 10011 g.
/Kct day. Further, examples of the administration method include oral administration, enteral administration, and injection. For oral administration, it may take the form of tablets or capsules.

When the toxicity of the compound of the present invention was investigated, there was no acute toxicity,
°No subacute toxicity was observed, and it was found that it can be safely administered to humans.

Example 1 a) 2-chloro-5-ethoxycarbonyl-4,6
-Preparation of dimethylpyrimidine 18.66 g of 5-carboxy-2-chloro-4,6-dimethylpyrimidine and 23.6 g of anhydrous potassium carbonate were suspended in 280 d of acetone, and while stirring at room temperature, 30.8 g of diethyl WISQ was added. Slowly add the ingredients, then warm and boil under reflux for 2 hours. After cooling to room temperature, insoluble materials are removed and the P solution is concentrated under reduced pressure.

The remaining oil was distilled under reduced pressure to a boiling point of 99℃/31111
Collecting less than 111 g of distillate yields 16.739 (78.4% yield) of colorless oil. Distillation under reduced pressure was performed again to obtain 2-chloro-5-ethoxycarbonyl-4,6-
Dimethylpyrimidine 14.66 g (yield 68.1%)
(can be seen)

b) 2-[2-[4-(2-methoxyphenyl)
-Production of 1-piperazinylconitylamine-5-ethoxycarbonyl-4,6-dimethylpyrimidine hydrochloride; 2-chloro-5-ethoxycarbonyl- obtained in a)
4,6-dimethylpyrimidine 430η ethanol 6d
Triethylamine 404 Ilg and 2-
[4-(2-methoxyphenyl)-1-piperazinylconitylamine 518I! g and stirred at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure, the residue was made alkaline by adding saturated aqueous sodium bicarbonate solution, and extracted with chloroborm. After washing the extract with water and drying with Glauber's salt, the solvent was distilled off under reduced fl. The resulting residue was purified by silica gel chromatography. The effluent fractions were collected in chloroform containing 5% ethanol and re-ligated from n-hexane to give 2-[2
-[4-(2-methoxyphenyl)-1-piperazinylconitylamine-5-ethoxycarbonyl-4,6-
Dimedylpyrimidine trihydrochloride 711η (yield 551%)
147 will be added.

Mass spec 1 hell; m/e 413 (H ■), 3
68.351.218°NMR spectrum: δ(Fll
) Lffi@type measured in CDCl3) 1.38 (3 + 1. three central lines), 2.44 (61
1, single line) 2.5 to 3.8 (12+1. multiple line), 3
．． 86 (311, single line) 4.45 (2+1.Fil)
, 5.74 (11!, bvs) (3,93 (4
11, single line).

Elemental analysis 1ifl C22nd 3ON5 C3,3(II
CJ! ) L/TCHN Theoretical value (%) 50,77 6.30 13.34
Actual value (%) 50.5] 6.55 13.39
Example 2 a) Production of 5-acetyl-2-chloro-4,6-dimethylpyrimidine; Thionyl chloride 5- was added to 1.87 g of 2-chloro-5-carboxy-4,6-dimethylpyrimidine, and 2 time 80
Heat immersion at ℃, concentrate under reduced pressure, and add anhydrous benzene 10-
is added and concentrated under reduced pressure several times. The obtained acid chloride is stored tightly closed. Ribbon metal magnesium 730
IIt! j. Grignard reagent is prepared by a conventional method using 440 U of methyl iodide and anhydrous needles. This is cooled with water, and in an argon atmosphere, a solution of the acid chloride in anhydrous diethyl ether 20 is added dropwise with stirring, and after the dropwise addition is completed, the solution is boiled under reflux for 30 minutes. After concentrating under reduced pressure, the mixture was made acidic by adding wood chips and 20 ml of 1N aqueous hydrochloric acid solution, extracted with chloroform, and the extract was washed with water and dried over Glauber's salt.

The solvent is distilled off, and the residue is purified by silica gel column chromatography. The chloroform effluent fractions are collected and recrystallized from n-hexane to yield 1q of 5-acetyl-2-di0-4,6-dimethylpyrimidine (50.3%) having a melting point of 88-89°C.

b) 2-[2-[4-(2-methoxyphenyl)-
1-Verazinyl]ethyl]amino-5-acetyl-4
, 6-dimethylpyrimidine; 5-obtained in a)
Acetyl-2-chloro-4,6-dimethylpyrimidine 1
844 in absolute ethanol 4d.
Add 250 IyJ of (2-methoxyphenyl)-1-piperazinyl 1-ethylamine, and stir for 24 hours while boiling under reflux. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with chloroform. After washing the extract with water, dry it with Glauber's salt. Distill the solvent,
The residue is purified by silica gel column chromatography. After flushing with chloroform containing 5% ethyl acetate, 5
Collect the effluent fractions in chloroform containing % ethanol;
Recrystallization from n-hexane/diethyl ether gives 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]amino-5 with a melting point of 104-5°C.
-acenal-4,6-dimethylpyrimidine 163 II
rg (yield 42.6%) is obtained.

Mass spectrum; 11/a 383 (H■), 36
8,234,218°NMR spectrum; δ(DDI,
Measured in COCl 3) 2.33 (611, single line)
, 2.74 (311, single line) 2.4-3.8 (
1211, multi-712 wire), 3.86 (311, single wire), 5.72 (IH, single wire), 6.94 (4H
, single line) HN as elemental analysis value C21H29N502 Theoretical value (%) 65.77 7.62 18.26
Actual value (%) 65,88 7.34 18.21
Example 3 a) 2-[2-[4-(2-methoxyphenyl)
= Production of 1-piperazinyl]ethyl]amino-4-benzyloxypyrimicin; 2-chloro-4-benzyloxypyrimicin 441■,
Triethylamine 404■, 2-[4-(2-methoxyphenyl)-1-piperazinyl 1-ethylamine 476
■Put 5 m of ethanol into a sealed tube, seal, and heat to 120°C.
Heat for 5 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. Wash the extract with water and dry with Glauber's salt. The solvent is distilled off, and the residue is purified by silica gel column chromatography. After flowing 200 d of chloroform, the flowing fractions were collected with chloroform containing 5% ethanol and recrystallized from methanol, resulting in a melting point of 151-15.
2-[2-[4-(2-Me-1-xyphenyl)-1-piperazinylconityl 1-amino-4-benzyloxypyrimidine 702 IIPg (yield 834%) at 1.5°C
is obtained.

Mass spectrum; m/e 419 (H■), 40
4.328.257゜Elemental analysis It1C24H29N5
CI-I N Theoretical value (%) as 0□ 68.71 G, 97 16.6
9 Actual value (%) 68.51 7.07 16.4
3b) Production of 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]amino-4-hydroxypyrimidine oxalate; 2-[2-[4-(2 -methoxyphenyl)-1-piperazinyl]ethyl]amino-4-benzyloxyvirimicin 120 II! J was dissolved in 4-acetic acid, 30 μl of 10% palladium on carbon catalyst was added, and 14 IRIl of hydrogen was introduced at normal pressure. After removing the catalyst and washing with aretone, the P solution and washing solution are combined and concentrated under reduced pressure. Add saturated sodium hydrogen carbonate to the residue and extract with chloroform. After washing the extract with water, dry it with Glauber's salt. After distilling off the solvent, the product is purified by silica gel column chromatography.

After flushing with 5% ethanol-containing chloroform, the effluent fractions are collected with a mixed solvent of 2% ammonia-saturated ethanol, 15% ethanol/93% chloroform, and the resulting oil is dissolved in acetone 2d. 63 parts of kojic acid to 4 parts of acetone
When the solution dissolved in Id is slowly added to the ahitone solution, a precipitate is instantly formed and covered. When left at room temperature for a while, 2-[2-[4-(
2-methoxyphenyl)-1-piperazinyl]ethyl]
115 IIg (93.8%) of amino-4-hydroxypyrimidine oxalate hemihydrate are obtained.

Mass spectrum: n+/e 329 (free p),
314゜Elemental analysis value C11H23N502 ・<Go2I112 ・1/2
C11N as (1120) Theoretical value (%) 53.26 6.12 16.35
Actual value (%) 53.06 5.90 16.05
Examples 4 to 19 In the same manner as in Example 1b, when 2-chloro-4,6-dimethyl-5-ethoxycarbonylpyrimidine is treated with the compound of formula (1) shown in Table 1, yields of 50 to 98% are obtained. The target products shown in Table 1 are obtained. In addition, 2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethylamine is reacted with each of the compounds of the formula (2) not shown in Table 2 to obtain the desired products shown in Table 2 in a yield of 30 to 80%.

(See 1 in the margin) Experimental Example 1 Measurement of changes in systemic blood pressure and segmental arterial blood flow; Changes in systemic blood pressure and segmental arterial blood flow were simultaneously measured and recorded. Specifically, a male rabbit weighing approximately 2.5 kg was anesthetized with pendoparbital, a catheter was inserted into the carotid artery incised according to a conventional method, and changes in systemic blood pressure were recorded via a pressure transducer. In addition, an electromagnetic blood flow meter probe was attached to the lateral carotid artery of the same eel, and changes in segmental arterial blood flow were recorded. Table 3 and FIG. 1 show the decrease in blood pressure and changes in arterial blood flow when 100 μg/KH of the compound of the present invention dissolved in 50% ethanol was administered intravenously. Note that the compound numbers in Table 3 and FIG. 1 indicate the numbers of the examples.

Experimental Example 2 Platelet aggregation inhibitory effect: Blood was collected through a catheter inserted into the carotid artery of a rabbit weighing 3 kg, 10% volume of 3.8% sodium citrate aqueous solution was added as an anticoagulant, and centrifuged at 90G for 15 minutes. . Platelet-rich plasma obtained from the supernatant was used for measurement according to the method of Horn et al.

That is, sodium arachidonate [125 μmol] or ADP (
The inhibition rate of the platelet aggregation inhibition reaction caused by the addition of 30 μmol of adenosine diphosphate) when pretreated with a dimedyl sulfate small oxide solution of the compound of the present invention was determined, and the results are shown in Table 4. The compound numbers in Table 4 refer to the above Example numbers.

(hereafter "margin") Table 3 Systemic blood pressure lowering effect (n=3) Table 4 Platelet aggregation inhibitory effect (r1=3)

[Brief explanation of the drawing]

FIG. 183 and FIG. 2 respectively show changes in systemic blood pressure and changes in segmental arterial blood flow (male rabbit, weight 2.2?) upon administration of the compound 2b of the present invention in Experimental Example 1. IB applicant 1 koku Irie Taira attorney for patent attorney Yoshio Kuchi Figure 1 Kiriboshi f! Polar hour (m)/Tatono

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_3 are hydrogen atoms, halogen atoms, amino groups, hydroxyl groups, linear or branched alkoxy groups, aralkyloxy groups, or lower alkyl Group; R_2 is 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 are a hydrogen atom, a halogen atom, a lower alkyl group, or a linear or A 2-(4-phenyl-1-piperazinylalkyl)aminopyrimidine derivative represented by a branched alkoxy group; n is an integer of 2 to 6, and an acid addition salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2 and R_3 have the meanings below,
4-phenyl-1 represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R_4, R_5 and n have the meanings given below) - the general formula ▲ mathematical formula, characterized in that the piperazinyl alkylamine derivative is reacted in an inert solvent or in the absence of a solvent, in the presence or absence of a base, optionally converting the product into an acid addition salt; There are chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_3 are hydrogen atoms, halogen atoms, amino groups, hydroxyl groups, linear or branched alkoxy groups, aralkyloxy groups, or lower alkyl groups; R_2 is hydrogen atoms, halogen atom, lower alkyl group, carboxyl group, lower acyl group, or linear or branched alkoxycarbonyl group; R_4 and R_5 mean a hydrogen atom, a halogen atom, a lower alkyl group, or a linear or branched alkoxy group. ; n represents an integer of 2 to 6). (3) An antihypertensive agent, a blood flow improving agent, and a platelet aggregation inhibitor containing the compound according to claim 1 as an active ingredient.