JPS59516B2 - N- (1-adamantylmethyl) -N'- cinnamylpiperazine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel adamantane derivatives, namely N-(1
-adamantylmethyl)-N'-cinnamylpiperazine.

Adamantane and its derivatives have long been known to be naturally contained in petroleum, and due to their unique chemical structure, they are highly fat-soluble and have low toxicity to living organisms, making them useful pharmaceuticals. The development of its use as an intermediate or the like has been awaited. From this point of view, the present inventors have developed novel adamantane derivatives, particularly:
As a result of intensive research to produce substances useful as pharmaceuticals, a new substance obtained by reacting a specific adamantylmethyl halide with N-cinnamylpiperazine, namely N-(1-adamantylmethyl)-N
It was discovered that cinnamylpiperazine exhibits high pharmacological effects, and based on this finding, the present invention was completed.

That is, according to the present invention, the general formula (In the formula, X represents a halogen atom.

) and 1-adamantylmethyl halide and N-
Provided is a method for producing N-(1-adamantylmethyl)-N-cinnamylpiperazine, which comprises reacting N-(1-adamantylmethyl)-N-cinnamylpiperazine with cinnamylpiperazine.

The method of the present invention is shown in the following chemical reaction formula.
In the above chemical reaction formula, (1) is 1-adamantylmethyl halide, (branch) is N-cinnamylpiperazine, (
3) is the target product of the present invention, N-(1-adamantylmethyl)-N'-cinnamylpiperazine.

Both 1-adamantylmethyl halide and N-cinnamylpiperazine used in the method of the invention are known substances.

Although the method for producing these substances is arbitrary, one example is as follows. 1-Adamantyl methyl halide is produced by, for example, using adamantane as a raw material and reacting it with formic acid and sulfuric acid to produce 1-adamantanic acid, then reducing this carboxylic acid to obtain 1-adamantyl methyl alcohol, and further producing this compound. can be obtained by halogenating.

The chemical formula for this reaction is as follows.

In addition, in order to obtain N-cinnamylpiperazine, which is one of the reactants, for example, cinnamyl chloride and piperazine are reacted [reaction formula (Q]), and cinnamoyl chloride and piperazine are reacted to obtain N-cinnamylpiperazine. Method for obtaining piperazine and reducing it [Reaction formula ◎]
and so on. The above reaction (0) is carried out in a solvent, and alcohols such as isopropyl alcohol are suitable as the solvent. Room temperature is sufficient for the reaction temperature, but 7
It is preferable to heat it to around 0°C. In addition, although this reaction proceeds with a raw material ratio of approximately K equivalent (mole ratio), by using a large excess of piperazine to cinnamyl chloride, it is possible to produce byproducts such as N-N7-di-cinnamylpiperazine. products can be suppressed. In the above reaction η, the first reaction to obtain N-cinnamoylpiperazine is preferably carried out in a solvent such as chloroform or dichloromethane, and the reaction temperature is preferably room temperature or lower.

When performing the latter stage of reaction D), by-products such as N-N-di-cinnamoylpiperazine can be suppressed by using an excess of piperazine in a molar amount of 6 to 10 times that of cinnamoyl chloride. can. Further, the subsequent step of reducing N-cinnamoylpiperazine is also preferably carried out in a solvent such as tetrahydrofuran or dioxane. The reaction usually starts at low temperature,
It is preferable to complete the reaction by bringing the temperature to around 0° C. and then bringing it to reflux. The type of reducing agent used is not particularly limited, but lithium aluminum hydride is preferred. The method of the present invention can be carried out using 1, both of which are known substances.
- It is carried out by reacting adamantyl methyl halide and N-cinnamyl piperazine in a solvent or without a solvent.

When carried out without solvent, the reaction temperature is 150 to 300°C,
Preferably it is around 200°C.

If necessary, a dehydrohalogenating agent such as sodium carbonate or tertiary amine can be used. Furthermore, since 1-adamantylmethyl halide has sublimation properties, it is generally preferable to carry out the reaction in a sealed tube or in a sealed system. N-(1-adamantylmethyl)-mercinnamylpiperazine obtained by the method of the invention is a new substance.

The present inventors investigated the pharmacological effects, toxicity, and chemical properties of this new substance, and found that it has an effect of increasing cerebral blood flow and relaxing smooth muscle, has low toxicity, and is resistant to heat, alkali, and
We obtained findings such as high stability against acids. or X
N-(1-adamantylmenothyl)-N having the property of
'-Cinnamylpiperazine is useful as a pharmaceutical, especially as a cerebral vasodilator.

It has also been found to be highly safe for the human body, with lower toxicity than conventional cerebral vasodilators and no side effects such as an excessive drop in blood pressure. Moreover, it not only had a remarkable effect of increasing cerebral cortical blood flow, but also had a similar effect on muscle blood flow, particularly gastrocnemius muscle blood flow and deep head muscle blood flow. Furthermore, the new substance according to the present invention has great stability against heat, alkali, acid, etc., and therefore can be said to be fully suitable as a pharmaceutical product.

N-(1-adamantylmethyl)-N'- according to the present invention
Since cinnamylpiperazine has the above-mentioned medicinal efficacy and properties, it can be widely and effectively used for treating stroke or improving subjective or objective symptoms such as cerebrovascular disorders and aftereffects of head trauma.

Next, the present invention will be explained in more detail with reference to Examples. In addition, the preparation method of the raw material used in the Example is shown as a reference example. Reference example 1 (1) Production of 1-adamantanic acid 10f! 9 of 23507 (24 mol) in 30 flasks of
8% concentrated sulfuric acid, 500ml of carbon tetrachloride and 68? (0
, 5 mol) of adamantane, stir well, and while cooling with ice to 17-19℃, add 5 d of 98% formic acid.
added.

Next, a solution of t-butyl alcohol 1487 (12 moles of 190Tn) 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. After further stirring for 30 minutes, 3500 y 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. The carbon tetrachloride layer was collected and washed with 15N aqueous ammonia 5507Z/, and 1-adamantanic acid ammonium salt was passed through the mouth through a Buchner funnel. Cool the obtained solid with acetone 100
Wash with 1250ml of water, suspend in 1250ml of water, and add 12N to this.
Hydrochloric acid 1257TLe was added and extracted with 500 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain about 807 g of crude 1-adamantanoic acid. This was reconsolidated from methanol/water (321) solution, and 1-adamantanoic acid 687
I got it. The melting point of the obtained 1-adamantanic acid was measured to be 175-177°C, and the yield was 75%. (2) Production of 1-adamantyl methyl alcohol 5
157 lithium aluminum hydride was placed in 00 ml of dry ether and stirred, and 54.07 (0.
A solution of 3 mol) dissolved in 500 ml of dry ether was added dropwise at a rate sufficient to maintain mild reflux (about 2.5 hours).

After dropping, reflux for another 2 hours, cool to room temperature, and add 75T! Lj distilled water was carefully added. followed by 30
0ml of 5N sulfuric acid and 500ml of ether were added. Next, this ether layer was separated and the aqueous layer was further
After extraction once with ml of ether, the combined ether layers were washed sequentially with water, saturated aqueous sodium bicarbonate, water, and dried over anhydrous magnesium sulfate. The ether layer was evaporated, and the resulting solid was reconsolidated with methanol and water to obtain 471 1-adamantylmethyl alcohol. The melting point of the obtained 1-adamantylmethyl alcohol was 114-116°C, and the yield was 94%.
It was hot. (3) Production of 1-adamantylmethylbromide Hydrobromic acid 29 to zinc bromide 39y (0.17 mol)
．． After adding 11.5y (0.069 mol) of 1-adamantyl methyl alcohol obtained by the method described above (subsection) to a solution containing 8d (approximately 47% 0.17 mol),
Refluxed for an hour.

After cooling to room temperature, add 200ml of water and
Extracted twice with 0 ml of ether. The ether layer was dissolved in 100 ml of 5% aqueous sodium bicarbonate solution and 100 m2 of water.
The mixture was washed with water, dried with anhydrous magnesium sulfate, and passed through the mouth. Then, the ether was distilled off under reduced pressure. The obtained solid was purified by recrystallization with methanol.
13y of 1-adamantylmethylbromide was obtained. The melting point of the product was 37-39°C, and the yield was 84%. Reference Example 2 Production of 1-adamantylmethyl chloride Using 1-adamantyl methyl alcohol obtained in the same manner as Reference Example 1 (1 limb 2), Reference Example 1 (3) was produced.
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.

Note that purification was performed by methanol recondensation. Obtained 1-
The melting point of adamantyl methyl chloride was 32-34°C, and the yield was 91%. Reference Example 3 Production of N-Cinnamyl Piperazine Anhydrous piperazine 2177 (2.5 mol) was dissolved in 11 isopropanol and allowed to stand at room temperature, and then cinnamyl chloride 72.6y (0.5 mol) was gently added dropwise.

After dropping, the mixture was heated at 70° C. for 3 hours while stirring. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was dissolved in 500 ml of chloroform and washed with an aqueous sodium hydroxide solution and water, respectively. Next, the mixture was dried over potassium carbonate, passed through the mouth, and chloroform was distilled off under reduced pressure. After sublimating the resulting mixture to remove piperazine,
The residue was further distilled to obtain N-cinnamylbiperazine. This material was crystallized and recrystallized from n-hexane. The boiling point of the product was 162-165°C (4m77!Hg), the melting point was 31-33°C, and the yield was 56%. 1-Adamantylmethylbromide 1 obtained in Example Reference Example 1
7 (0.004 mol), 1.6f (0.008 mol) of N-cinnamylbiperazine obtained in Reference Example 3, and 0.43y (0.004 mol) of anhydrous sodium carbonate in 10 m
The autoclave of Step 1 was replaced with argon and heated at 200℃ for 16 hours.
A time reaction was performed.

After the reaction, the temperature was returned to room temperature, 30 ml of chloroform was added, and the mixture was filtered through the mouth, washed with water, and blown dry.The chloroform was then distilled off under reduced pressure.
The residue was subjected to silica column chromatography (developing solution: chloroform-methanol). The reaction product, N-(1-adamantylmethyl)-N/-cinnamylpiperazine, was reconsolidated with ethanol. The melting point of the product is 85
~88°C, yield was 31%. The analytical results and pharmacological effects of N-(1-adamantylmethyl)-N'-cinnamylpiperazine 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.
1. Analysis results (1) Elemental analysis values Analysis values Carbon 82.36%, Hydrogen 10.45%, Nitrogen 7.98% Calculated values Carbon 82.23%, Hydrogen 9
．． 78%, nitrogen 7.99% (2) Mass spectrometry cumulative calculation value 350 MassN0. M+ 350 (3) Absorption range by infrared absorption spectrum (KBr tablet method) 1600115801150011450, 108
0, 1010cTn-1 (phenyl) 970C71L?
1 (trans H] C-C (stone), 7501700cm-
1 (monosubstituted phenyl), 1450,. 11350, 1
150CTIL-1 (adamantane) (4) Absorption range by nuclear magnetic resonance (solvent: deuterated chloroform CDCl3) 8,52τ (S.6Hlβ-ClI2), 836τ (S
．． 6Hlδ-CH2), 808τ(S.5Hlγ-CU+Ma-CH2), 7.
52τ (S.8H.a-CU2+b-Cdan,), 6.9
0τ (D.J-4.0Hz, 2H.Mc-Cdan,), 3
．． 70τ (M.2H, vinyl), 2・70τ (M.5H
, phenyl) (5) Structural formula The above experimental results show that the structural formula of the compound is as follows.

(6) Melting point: 85-87°C (7) Solubility (testing suitability as an injection solution) In order to examine the solubility in tartaric acid aqueous solution,
, 4, 6, and 8 times the molar amount of tartaric acid were added to each aqueous solution, and the compound was added to each aqueous solution at a concentration of 0.
The aqueous solution was heated to 80° C., allowed to cool to room temperature (about 20° C.), and then the state of dissolution was examined.

As a result, it was found that all of the compounds were soluble in each of the above tartaric acid aqueous solutions. Further, the pH of a 0.25% by weight aqueous solution of the compound using twice the molar amount of tartaric acid relative to the compound is 3.10, and the pH when an alkali is added to the aqueous solution and crystals begin to precipitate is 3.10. It was 80. (g) Stability of N-(1-adamantylmethyl)-mercinamylpiperazine using twice the molar amount of tartaric acid.
．． After heating a 25% by weight aqueous solution to about 80°C, let it cool to room temperature (about 20°C), adjust the pH to 8 to 9 with 0.1N aqueous sodium hydroxide solution, and then extract with chloroform. After one week of cooling, we performed thin layer chromatography on the samples extracted with chloroform using the same procedure and compared them, and as a result, it was found that the compound in question had not changed at all. .

Further, nuclear magnetic resonance spectra and infrared absorption spectra were also measured, but no changes were observed. Than this,
It was found that the compound existed stably in this aqueous solution. 2. Pharmacological effects Cinnarizine (Cj
The pharmacological effects were investigated in comparison with nnarjzine).

(1) The LD5O values of acutely toxic mice by the immediate &DOWN method are as follows.

(2) Effect on contraction of isolated smooth muscle The extent to which the contraction effect of contractile substances such as adrenaline on isolated smooth muscle is suppressed by the administration of N-(1-adamantylmethyl)-mercinnamylpiperazine and cinnarizine was investigated.

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

(Support) Effect on blood flow The effect on cerebral blood flow and muscle blood flow was investigated using cats weighing approximately 31<9.

As a result, cerebral cortical blood flow was clearly increased with N-(1-adamantylmethyl)-mercinnamylpiperazine 1W/K9, and cinnarizine 1T! This effect was superior to that of 1f7Ag. On the other hand, N-(1-adamantylmethyl)-N'-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 reduction in blood pressure at 0.5W9/I<9, but N-(1-adamantylmethyl)-N/-cinnamylpiverazine It showed a descending effect for the first time at W/K9 and above.

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-adamantylmethyl)-N'-nonnamylbiperazine, FIG. 2i shows the infrared absorption spectrum of the compound, and FIG. 3 shows the nuclear magnetic resonance spectrum of the compound.

Claims (1)

[Claims] 1 1-adamantylmethyl halide and N- represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (wherein, X represents a halogen atom)
A method for producing N-(1-adamantylmethyl)-N'-cinnamylpiperazine, which comprises reacting N-(1-adamantylmethyl)-N'-cinnamylpiperazine.