JPS59515B2 - N-(1-adamantylmethyl)-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 expected as an intermediate thereof.

As a result of intensive research from the above viewpoint, the present inventors found that
As mentioned below, we have succeeded in developing a new substance that is highly effective as a cerebral vasodilator with few side effects and is highly safe.In the course of this research, we have investigated the production method of several types of adamantane derivatives that are useful as precursors for this new substance. This led to the completion of the present invention.

That is, the present invention combines piperazine with the formula (Here, X represents a halogen atom.

) is a method for producing N-(1-adamantylmethyl)-piperazine, which is characterized by reacting N-(1-adamantylmethyl)-piperazine with 1-adamantylmethyl halide represented by:

The method of the present invention is shown in the following reaction formula. here? 1) is piperazine, (2) is 1-adamantylmethyl halide, (3) is N-(1-adamantylmethyl)
-Piperazine.

The 1-adamantyl methyl halide used in the present invention is derived by a known method using adamantane as a raw material. For example, 1-adamantanoic acid is synthesized by using adamantane as a raw material and reacting it with formic acid and sulfuric acid. and then by reducing this carboxyl group, 1
- There is a method of obtaining adamantyl methyl alcohol and halogenating it to synthesize 1-adamantyl methyl halide.

In the method of the present invention, the reaction proceeds even if the ratio of 1-adamantylmethyl halide and piperazine is equimolar, but in order to suppress by-products such as N-merized 1-(1-adamantylmethyl)-piperazine, It is advantageous to use piperazine in excess (for example on the order of 6 times the molar amount).

Further, the method of the present invention can be carried out in a solvent or without a solvent.

In the absence of a solvent, the reaction temperature is preferably 150 to 300°C and the reaction time is preferably about 20 hours. Suitable solvents are dimethylformamide and hexamethylphosphoramide, and the reaction temperature is 150 to 250°C.
The reaction time is preferably about 20 hours. moreover,
In the method of the present invention, a dehydrohalogenating agent is not necessarily required.

However, when a tertiary amine such as triethylamine is used as a dehydrohalogenating agent, it has the effect of accelerating the progress of the reaction and facilitating post-processing such as separation of the reaction product. After the reaction, the target product N-(1-adamantylmethyl)-piperazine can be separated, for example, in the absence of a solvent and when a dehydrohalogenating agent is not used, after an alkali treatment, chloroform extraction and silica It can be carried out by column chromatography.

In addition, when the reaction is carried out without a solvent in the presence of a dehydrohalogenating agent, the reaction product is dissolved in chloroform, then washed with water, dried, concentrated, and purified by silica column chromatography. . Furthermore, when the reaction is carried out in a solvent, separation can be carried out by the above method after distilling off the solvent. Novel adamantane derivative N-(1-adamantylmethyl) obtained by the method of the present invention
- Reacting piperazine with (1) cinnamyl chloride.

(2) A new substance N-(1-adamantylmethyl)- It is possible to synthesize N5-cinnamylpiperazine. Experiments have revealed that this new substance has fewer side effects such as excessive hypotensive effects, is less toxic, and has excellent performance as a cerebral vasodilator. Therefore, the method of the present invention is useful for providing intermediates for producing the above-mentioned novel substances with high pharmacological effects.

Next, the present invention will be explained in detail with reference to Examples.

First, before giving Examples, a method for producing 1-adamantylmethyl halide used in the present invention will be shown as a reference example. Reference Example 1 Method for producing 1-adamantylmethylfuromide (1) Synthesis of 1-adamantanic acid 101 23507 (24 mol) of 9
8% concentrated sulfuric acid and 500me of carbon tetrachloride and 687(0
．． Add 5 moles of adamantane, stir well, and add 1 mole of adamantane to the
Add 5me of 98% formic acid to this while cooling to 7-19℃.
added.

Next, a solution of t-butyl alcohol 148y (190ml, 112 moles) in 98-100% formic acid, 2757 (6 moles) was added dropwise. The dropping time was 2 hours, and the temperature was maintained at 17-25°C. Furthermore, after stirring for 30 minutes,
35,007 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 add 550ml of 15N ammonia water.
The ammonium salt of 1-adamantanate was filtered off using a Buchner funnel.

The obtained solid was washed with 100ml of chilled acetone,
Suspend in 250m water and add 125mj of 12N hydrochloric acid to this.
was added and extracted with 500 mj of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to yield approximately 80% of crude 1-adamantanoic acid.
Obtained. This was reconsolidated from a methanol/water (3:1) solution to obtain 1-adamantanoic acid 687. The melting point of the obtained 1-adamantanic acid was measured and was 175-177°C.
The yield was 75%.

(2) Synthesis of 1-adamantylmethyl alcohol 50
15y of lithium aluminum hydride was placed in 0 ml of dry ether and stirred, and 54.07 (0.3
mol) in 500 ml of dry ether was added dropwise at a rate sufficient to maintain mild reflux (approximately 2.5 hours).

After the addition, the mixture was further refluxed for 2 hours. It was then cooled to room temperature and to this was carefully added 75 ml of distilled water, followed by 3 ml of distilled water.
00me of 5N monosulfuric acid and 500me of ether were added. Next, this ether layer was separated and the aqueous layer was further separated by 3
After extraction once with 00 ml of ether, the combined ether layer was washed sequentially with water, saturated aqueous sodium bicarbonate, water, and dried over anhydrous magnesium sulfate.
This ether layer was evaporated, and the resulting solid was reconsolidated with methanol water to obtain 477 1-adamantylmethyl alcohol. The melting point of the obtained 1-adamantyl methyl alcohol was 114-116°C, and the yield was 94%.
It was hot. (3) Synthesis of 1-adamantylmethylbromide 397 (0.17 mol) of zinc bromide and 29% of hydrobromic acid
．． After adding 11.5 V (0.069 mol) of 1-adamantyl methyl alcohol obtained by the method (2) above to the solution containing 8 ml (about 47%, 0.17 mol),
It was refluxed for 11 hours.

After cooling to room temperature, add 200ml of water and
Extracted twice with 0 ml of ether. After washing with 100 me of 5% aqueous sodium bicarbonate solution and 100 me of water, drying over anhydrous magnesium sulfate and filtering, the ether was distilled off under reduced pressure.

The obtained solid was reconsolidated or sublimated with methanol (1 m77
! Purification using Hgl (75°C) yielded 137 1-adamantylmethylbromide.

The melting point of the product was 37-39°C, and the yield was 84%. Reference Example 2 Production method of 1-adamantylmethyl chloride 1 obtained by the same method as Reference Example 1 (1) and (2)
Reference example 1 (3) using adamantyl methyl alcohol
) The chlorination reaction was carried out under the same conditions as the bromination reaction, except that zinc chloride was used instead of zinc bromide and hydrochloric acid was used instead of hydrobromic acid.

However, purification was performed by methanol recondensation. Obtained 1
-The melting point of adamantyl methyl chloride was 32-34°C, and the yield was 91%. Example 1 1- obtained in Reference Example 1 in a 10 m1 autoclave
Adamantylmethylbromide 0.5f7 (0.0022
mol) and anhydrous piperazine 1.137 (0.013 mol)
and replaced with argon, heated in an oil bath at 200°C.
The mixture was heated for 20 hours.

After cooling this to room temperature, it was dissolved in 100ml of chloroform, washed with 20ml of water, dried over anhydrous magnesium sulfate, filtered through a sieve, and chloroform was distilled off under reduced pressure. The obtained sample was purified by silica column chromatography (developing solution was chloroform-methanol). The obtained N-(1adamantylmethyl)-piperazine was reconsolidated with acetone. The melting point of the product is 107~
The temperature was 109°C, and the yield was 58%. Example 2 The same procedure as in Example 1 was repeated except that 1-adamantylmethyl chloride obtained in Reference Example 2 was used instead of 1-adamantylmethyl bromide in Example 1.

The obtained N-(1-adamantylmethyl)-piperazine was reconsolidated with acetone. The melting point of the product is 107-1
At 09°C, the yield was 48%. The analysis results of the new substance N-(1adamantalmethyl)-piperazine obtained in Examples 1 and 2 are shown below.

Note that FIG. 1 shows the mass vector of the compound, FIG. 2 shows the infrared absorption spectrum, and FIG. 3 shows the nuclear magnetic resonance spectrum. Analysis results of N-(1-adamantylmethyl)-piperazine (1) Elemental analysis value (2) Mass spectrometry cumulative calculation value 234 MassN0. M+ 234 (3) Absorption range by infrared absorption spectrum (KBr tablet method) 145011360, 1130, 1010? -1
(Adamantane) (4) Nuclear magnetic resonance (solvent: deuterated chloroform CDCl3)
absorption range 8.50τ (S.6H, β-CII2), 8.32τ (
S. 6Hlδ-CIl[2), 8.08τ(S.5H,
γ−Cdan+CIlI2−N), 7.84τ(S.lHl
-NIi), 7.56τ (T.4H.b-Cdan,),
7.12τ(T.4H.aCU2) (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 application example 107-109°C 15ml of 0.137 (0.00055 mol) of N-(1-adamantylmethyl)-piperazine obtained by the method of the example and 0.057f (0.00055 mol) of triethylamine was dissolved in isopropanol, and 3 ml of a solution of 0.08 f (0.00055 mol) of cinnamyl chloride in isopropanol was added dropwise at 0°C.

After the dropwise addition, the mixture was reacted under reflux for 5 hours, and then the isopropanol was distilled off under reduced pressure, and the residue was dissolved in chloroform 20me. Next, after washing with water and drying, 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)-N-cinnamylpiperazine was reconstituted with ethanol, the melting point was 85-87°C.
The yield was 58%. New substance N obtained in application example
The analysis results and medicinal efficacy of -(1-adamantylmethyl)-N5-cinnamylpiperazine are shown below.

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)-N'-cinnamylpiperazine (1) Elemental analysis value (2) Mass spectrometry cumulative calculation value 350 MassN0. M+ 350 (3) Absorption range by infrared absorption spectrum (KBr tablet method) 160011580, 150011450, 108
0, 1010 (71L-1 (phenyl), 970'1
(Trans-text) C-c (arm), 7501700C! T
L-1 (monosubstituted phenyl), 1450, 13501
1150cm-1 (Adamantane) (4) Absorption range by nuclear magnetic resonance (solvent: deuterated chloroform CDCl3) 8,52τ (S.6Hlβ-Cdan,), 8.36τ (S.6Hlδ-C] {2), 8 ,08τ(
S. 5H,. r-Cdan+Ma-CU2), 7.52τ(
S. 8H,. a-CII2+b-Cdan,), 6.90τ
(D.J-4.0Hz, 2HMc-CH2). 3.70
τ (M.2H1 vinyl), 2.70τ (M.5H1 phenyl) (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°C The medicinal efficacy of N-(1-adamantylmethyl)-N-cinnamylpiperazine was investigated in comparison with Cinnarizine, which is commercially available as a cerebral vasodilator.

The comparative pharmacology results are as follows. (1) The LD5O values of acutely toxic mice determined by the Up&Down method are as follows.

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

The results are as follows. As a result of the experiment, the smooth muscle relaxing effect of N-(1-adamantylmethyl)-N-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, cerebral cortical blood flow was clearly increased by N-(1-adamantylmethyl)-N-cinnamylpiperazine 1η/Kg, which was superior to the effect of cinnarizine 1T119/Kg. On the other hand, N-(1-adamantylmethyl)-N5-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. It was hot. (4) Blood pressure lowering effect Cinnarizine already showed a clear decrease in blood pressure at 0.57r9/Kg, but N-(1-adamantylmethyl)-N-cinnamylpiperazine was effective for the first time at 5η/K9 or higher. It showed a depressing effect.

Therefore, since this substance has a clearly weaker blood pressure lowering effect than cinnarizine, it is presumed to be highly safe.

[Brief explanation of the drawing]

FIG. 1 shows the mass spectrum of N-(1-agmanthylmethyl)-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 N- characterized by reacting piperazine with 1-adamantylmethyl halide represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (where X represents a halogen atom). A method for producing (1-adamantylmethyl)-piperazine.