JPS591271B2 - N-(1-adamantane carbonyl)-piperazine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel compounds from piperazine and adamantane compounds.

Adamantane and its derivatives have long been known to be naturally contained in petroleum, and their unique structure makes them highly fat-soluble and low in toxicity to living organisms, making them useful pharmaceuticals. Or, its future potential was anticipated as an intermediate.

As a result of intensive research from the above perspective, the present inventors succeeded in developing a new substance that is highly effective as a cerebral vasodilator with few side effects and high safety, as described below. The present invention was completed by studying methods for producing several kinds of adamantane derivatives useful as precursors of substances.

The present invention is a method for producing N-(1-adamantanecarbonyl)-piperazine, which is characterized by reacting piperazine and 1-adamantanoic acid chloride. The method of the present invention is shown in the following reaction formula.

Here, 1 is piperazine, 2 is 1-adamantanyl chloride, and 3 is N-(1-adamantanecarbonyl)-piperazine.

1-Adamantanoic acid chloride used in the method of the present invention is derived from adamantane by a known method as a raw material. For example, adamantane is converted to 1-adamantanoic acid with formic acid and sulfuric acid, and then chloride is converted into 1-adamantanoic acid using thionyl chloride. can be obtained by converting it into

In the method of the present invention, piperazine and 1-adamantanoic acid chloride can be reacted in a solvent or in the absence of a solvent. If the reaction is carried out in a solvent, the type of solvent is not limited, but for example, chloroform, etc. use.

Further, although a dehydrohalogenating agent is not necessarily required in the method of the present invention, the progress of the reaction can be promoted by using a tertiary amine such as triethylamine as a dehydrohalogenating agent.

Although the reaction proceeds even if the ratio of piperazine and 1-adamantanoic acid chloride is equimolar, piperazine is added to suppress by-products such as N,N'-di-(1-adamantanecarbonyl)-piverazine. Large excess (e.g. 1
It is effective to use the amount (approximately 0 times the molar amount).

After the reaction, the target product N-(1-adamantanecarbonyl)-piperazine can be separated, for example, when the reaction is carried out in a solvent, the reaction mixture solution is washed with an alkali, then washed with water, dried, and then the solvent is removed. After evaporation, the residue can be extracted with chloroform and subjected to silica column chromatography.

Novel adamantane derivative N- obtained by the present invention
(1-adamantanecarbonyl)-piperazine is reduced to obtain N-(1-adamantylmethyl)-piperazine, which is then reacted with (1) cinnamyl chloride (2) reacted with cinnamoyl chloride to produce N-(1-adamantylmethyl)-piperazine. -(1-adamantylmethyl)-N'-cinnamoylpiperazine is obtained, and by further reducing it, a new substance N-(1-adamantylmethyl)-N
It is possible to synthesize L-cinnamylpiperazine.
Experiments have revealed that this new substance has fewer side effects such as excessive blood pressure lowering effects, is less toxic, and has excellent performance as a cerebral vasodilator. Therefore, the method of the present invention is extremely useful in providing intermediates for producing the above-mentioned novel substances with excellent pharmacological effects.

Next, the present invention will be explained in detail using examples.

First, before giving Examples, a method for producing 1-adamantanyl chloride used in the present invention will be described as a reference example. ? Example 1) Synthesis of 1-adamantanoic acid 98 of 23509 (24 mol) was placed in a 10 ton 30 flask.
% concentrated sulfuric acid and 500 ml of carbon tetrachloride and 689 (0.
Add 5 moles of adamantane, stir well, and cool with ice.
While cooling to ~19°C, add 5ml of 98% formic acid to this.
added.

Next, a solution of t-butyl alcohol 1489 (2 moles of 190TIII) in 98-100% formic acid 2759 (6 moles) was added dropwise. The dropping time was 2 hours, and the temperature was maintained at 17-25°C. After stirring for an additional 30 minutes, 35,009 g of crushed ice was added, the organic layer was separated, and the resulting aqueous layer was extracted three times with 500 ml of carbon tetrachloride. Collect the carbon tetrachloride layer and wash with 550ml of 15N ammonia water1.
- The ammonium adamantanate salt was filtered through a Buchner funnel. The solid obtained was washed with 100 ml of chilled acetone, suspended in 1250 ml of water, and added with 12 N hydrochloric acid (1 ml).
25ml was added and extracted with 500ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain about 809 grams of crude 1-adamantanoic acid. Add this to methanol and water (3:1)
The solution was recrystallized to obtain 1-adamantanoic acid 689. When the melting point of the obtained 1-adamantanic acid was measured, it was found that 1
The temperature was 75-177°C, and the yield was 75%. 2)
Synthesis of 1-adamantanoic acid chloride 50 ml of thionyl chloride was added to 1-adamantanoic acid 189 obtained by the method (1) above while cooling, and the mixture was heated under reflux for 30 minutes, and then excess thionyl chloride was removed under reduced pressure. Removed below.

Next, 30 ml of dry benzene was added twice to remove traces of thionyl chloride, and then 30 ml of anhydrous ether was added and distilled off.

This gave 1-adamantanoic acid chloride 1929 as a brownish white solid. The melting point of the product is 46-47℃
The yield was about 92%. Example Anhydrous piperazine 21.679 was dissolved in 30 ml of chloroform and while stirring at room temperature, 1-
Chloroform solution of adamantanyl chloride 5.59 2
0ml was added dropwise.

After stirring for an additional 2 hours, the precipitate was separated and the bottom liquid was mixed with 50ml of 5% aqueous sodium hydroxide solution, followed by 200Tn of water.
After washing with water, the chloroform layer was dried, and chloroform was distilled off under reduced pressure. The residue was subjected to silica column chromatography (developing solution: chloroform-methanol). The melting point of the obtained N-(1-adamantanecarbonyl)-piperazine was 134 to 136°C, and the yield was 60%. New substance, N-(1-adamantanecarbonyl)
- The analysis results for piperazine are as follows.

Note that FIG. 1 shows the mass spectrum of the compound, FIG. 2 shows the infrared absorption spectrum, and FIG. 3 shows the nuclear magnetic resonance spectrum. N-(1-adamantanecarbonyl)
- Piperazine analysis result C (1) Elemental analysis value calculation value (Cl5H24N2O) Carbon 73.80% Hydrogen 9
．． 29% Nitrogen 10.76% Actual value: Carbon 72.54%
Hydrogen 9.74% Nitrogen 11.28% (2) Mass spectrometry cumulative calculation value 248 MassN0. M+ 248 (3) Absorption range by infrared absorption spectrum (KBr tablet method) 33000ffL'''l (-NH), 1610cT
rL-1 (amide), 1415, 135
011150 (7L-1 (adamantane) (4) Absorption region by nuclear magnetic resonance (solvent: deuterated chloroform Cn.)
5) Structural formula The above experimental results show that the structural formula of the compound is as follows.

(6) Melting point: 134-136C Application example (1) Synthesis of N-(1-adamantylmethyl)-piperazine 1.39 of N-(1-adamantanecarlbonyl)-piperazine obtained in the example was added to 40 ml of tetrahydrofuran. 0.24% of lithium aluminum hydride powder was gradually added at 0° C., and the reaction was carried out under reflux for 3 hours.

Next, water was carefully added to separate the tetrahydrofuran layer, which was dried and then evaporated under reduced pressure. After extracting the residue with chloroform, 5%. It was washed with an aqueous sodium hydroxide solution and then with water and dried. This was filtered and chloroform was distilled off under reduced pressure, and the residue was subjected to silica column chromatography (developing solution: chloroform-methanol). When the obtained N-(1-adamantylmethyl)-piperazine was reconsolidated with acetone, the melting point was 109°C.
The yield was 7%. The analysis results of the obtained N-(1-adamantylmethyl)piperazine are as follows.

Note that FIG. 4 shows the mass spectrum of the compound, FIG. 5 shows the infrared absorption spectrum, and FIG. 6 shows the nuclear magnetic resonance spectrum. Analysis results of N-(1-adamantylmethyl) piperazine (1) Elemental analysis value (2) Mass spectrometry result (3) Absorption range 145011360, 1130, 1010 CTr by infrared absorption spectrum (KBr tablet method)
L-1 (adamantane) (4) Nuclear magnetic resonance (absorption range due to solvent: heavy chloroform CDCl3) (5) Structural formula From the above experimental results, it can be seen that the structural formula of the compound is as follows.

(6) Melting point (2) N-(1-adamantylmethino(c)-N/-
Synthesis of cinnamylpiperazine 0.1 N-(1-adamantylmethyl)-piperazine obtained by the method (1) above
39 (0,00055) mol) and triethylamine 0.
0579 (0.00055 mol) was dissolved in 15TI11 isopropanol at 0°C and cinnamyl chloride 0.0.
3 ml of an isopropanol solution of 089 (0.00055 mono(c)) was added dropwise.

After the dropwise addition, the mixture was reacted under reflux for 5 hours. Then, the isopropanol was distilled off under reduced pressure, and the residue was dissolved in 20 ml of chloroform.
It was dissolved in Next, after washing with water and drying, chloroform was distilled off under reduced pressure, and the residue was subjected to silica column chromatography (
The developing solution was chloroform-methanol). When the obtained N-(1-adamantylmethyl)-N/-cinnamylpiperazine was reconstituted with ethanol, the melting point was 85~
The yield was 58% at 87°C. The analysis results and medicinal efficacy of the new substance N-(1-adamantylmethyl)-N'-cinnamylpiperazine obtained in the application example are shown below.

Note that FIG. 7 shows the mass spectrum of the compound, FIG. 8 shows the infrared absorption spectrum, and FIG. 9 shows the nuclear magnetic resonance spectrum.

Analysis results of N-(1-adamantylmethino(c)-N' cinnamyl piperazine) (1) Elemental analysis calculated value (C24H34N2) Carbon 82.23% Hydrogen 9
．． 78% Nitrogen 7.99% Carbon 82.36% Hydrogen 10
．． 45% Nitrogen 7.98% (2) Mass spectrometry cumulative calculation value 350 MassN0. M+ 350 (3) Absorption range by infrared absorption spectrum (KBr tablet method) 160011580, 1500, 1450, 108
0, 1010 phenyl) 970cTn-1 (trans 1 (mono-substituted phenyl) 145011350, 115
0cTn'1 (Atatantan) (4) Absorption area by nuclear magnetic resonance (solvent: deuterated chloroform CDCl3) (5) Structural formula From the above experimental results, it can be seen that the structural formula of the compound is as follows. .

(6) Melting point 85-87 The medicinal efficacy of N-(1-adamantylmethyl)-N'-cinnamylpiperazine was investigated in comparison with cinnarizine (Cinnarizine), which is commercially available as a cerebral vasodilator.

The comparative pharmacology results are as follows.

1) The LD5O values of acutely toxic mice according to the Up&Down method are as follows.

(2) Effect on contraction of isolated smooth muscle To what extent is the contraction effect of contractile substances such as adrenaline on isolated smooth muscle suppressed by the administration of N-(1-adamantylmethyl)-N-cinnamylpiperazine and cinnarizine? I looked into it.

The results are as follows. As a result of the experiment, the smooth muscle relaxing effect of N-(1-adamantylmethyl-NL cinnamylpiperazine) was observed.

(3) Effect on blood flow The effect on cerebral blood flow and muscle blood flow was investigated using a cat weighing approximately 3k9.

As a result, N-(1-adamantylmethyl)-N! -Cinnamylpiperazine 1η/K9 clearly increased cerebral cortical blood flow, which was superior to the effect of cinnarizine 1W/K9. On the other hand, N-(1-adamantylmethyl)-NL cinnamylpiperazine also showed a clear increasing effect on muscle blood flow (gastrocnemius muscle blood flow and deep head muscle blood flow), which was more pronounced than that of cinnarizine. Ta. (4
) Blood pressure lowering effect Cinnarizine already showed a clear decrease in blood pressure at 0.5~/Kg, but N-(1-adamantylmethyl)-N/-cinnamylpiperazine showed a significant decrease in blood pressure for the first time at 5η/Kg or more. It showed a depressing effect.

Therefore, it is assumed that this substance has a significantly weaker blood pressure lowering effect than cinnarizine and is therefore safer.

[Brief explanation of drawings]

FIG. 1 shows the mass spectrum of N-(1-adamantanecarbonyl)-piperazine, FIG. 2 shows the infrared absorption spectrum of the compound, and FIG. 3 shows the nuclear magnetic resonance spectrum of the compound.

Claims (1)

[Claims] 1. A method for producing N-(1-adamantanecarbonyl)-piperazine, which comprises reacting piperazine and 1-adamantanoic acid chloride.