JPH0778037B2 - Analgesics and vasodilators containing a capsaicin derivative or its acid ester as an active ingredient - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to capsaicin, which has a high solubility in weakly alkaline aqueous solutions.
An analgesic consisting of a derivative obtained by modifying the chemical structure of
A vasodilator.

[0002]

2. Description of the Related Art Conventionally, the Solanaceae plant Capsicum a
nnuum L. , C. frutescens L. ，
C. minimum L. The fruit is a capsicum agricultural product, and the capsicum is a food product very close to human life as a spice. The cabbage component of capsicum was about 1919 by Nelson in Capsicum
nnuum and its homologous plant fruits were extracted and isolated, and its chemical structure was determined to be 8-methyl-N-vanillyl-6-nonenamide, and the general name was capsaicin (Capsa).
icin). There are many studies on the pharmacology of capsaicin. That is, Skofitsch et al. Reported that the vagus nerve C-fiber effector in the rat airway
It is shown that capsaicin has a selective activating effect on ents, and that it releases a peptide having a physiological activity, which excites central nerves and local reflexes. According to Lundberg et al., Substance P and C present in the trachea when administered to the respiratory tract of animals.
GRP (Carcitonin generalate)
dpeptide) is thought to be depleted as a function of capsaicin. If the cat's nasal mucosa is topically treated with capsaicin, the mucosa's capsaicin sensitivity C
-Fiber affect is stimulated to increase mucosal blood flow. Since capsaicin can promote the permeability of the capillaries of animals (rat, guinea pig, etc.), the protein in the capillaries escapes from the body (extravasa).
It was sometimes done. To after 1955
Studies in the groups of h, Colleride, and Virus have revealed that capsaicin has a significant dilating effect on the coronary arteries, and particularly reduces the degree of stenosis of the coronary arteries. From the results of various animal experiments, capsaicin also has the effects of lowering blood pressure and reducing heart rate.

According to the recent research of capsaicin biochemistry,
Hormone-sensitive lipase (ho) present in adipose tissue
rmon sensitive lipase, HS
L) activity is promoted by capsaicin, while calmodulin-dependent cyclic adenosine 3 ', 5'-phosphate (CAM) in adipose tissue
P) ・ Ca ⁺⁺ and phosphodiesterase (phosph)
It has also been found that capsaicin suppresses the activity of oxidase (PDE). Since the above-mentioned capsaicin has two effects on adipose tissue, capsaicin has an activity of degrading fat in the living body (ie, lipase).
It can also be understood that there is lytic activity). It has also been reported that it has the activity of reducing serum lipids and exhibits a marked inhibitory effect on platelet aggregation.

From the pharmacological study of capsaicin, it is known that capsaicin has remarkable irritation and neurotoxicity to organisms. If the concentration of the capsaicin solution is 1/8000 mg /
It has a strong tingling sensation even when diluted to 1, and besides, it has various side effects and poor solubility, such as protein in capillaries escaped by the action of capsaicin, and tracheal smooth muscle also contracts. Clinically, capsaicin is not widely used.

[0005]

The capsicum has been closely related to human diet as a spice for a long time. As described above, capsaicin has various pharmacological activities as the main pungency of capsicum and has side effects and disadvantages. According to the reports so far, in order to improve the disadvantage of poor solubility of capsaicin, alcohol, dimethylsulfoxide (DMSO),
Although the solubility of capsaicin can be slightly increased by using an organic solvent such as Tween 80 as a cosolvent, the solubility is not sufficiently satisfactory. Increasing the solubility of capsaicin is believed to have a significant effect on the pharmacological action of capsaicin solutions. Therefore, an object of the present invention is to introduce a hydrophilic group into the chemical structural formula of capsaicin to modify the structure of capsaicin to increase the solubility and to be used as an analgesic or vasodilator.

[0006]

[Means for Solving the Problems] Solanaceae plant Capsic
The hot pepper component of the um genus was isolated by Nelson et al. and its chemical structure is 8-methyl-N-vanillyl-6.
-Nonenamide (8-methyl-N-Vanill
yl-6-nonenamide). The structural formula is represented by [Formula III].

[0007]

[Chemical 3]

[Formula III] The compound is named Capsaicin and the molecular formula is C ₁₈ H ₂₇ NO _3.
Is. The physical properties of this product are crystalline, its melting point is 65 ° C, and its solubility is poorly soluble in cold water and easily soluble in hot water. In addition, it is extremely soluble in organic solvents such as alcohol, benzene, ether and chloroform. Characteristic absorption bands in the visible-ultraviolet spectrum are observed at 227 and 281 nm.

The chemical nature of capsaicin has a significant influence on the chemical reaction of capsaicin, as the unsaturated carbon double bond shown in the structural formula, that is, the acrylic group of the side chain. The chemical changes related to the acrylic group can lead to addition reactions such as cleavage of double bonds, electrophilic addition, nucleophilic addition, etc. to form individual complex products, which easily go through the planned reaction process. Have difficulty.

The present invention introduces a hydrophilic group into the chemical structure of capsaicin, and by the main product synthesized after the addition reaction, its pharmacological action retains most of the original pharmacological action of capsaicin. It aims to improve the side effects and the drawbacks of poor solubility. To that end, we first investigated the problem of unstable double bonds in capsaicin. According to Nelson et al., The carbon number of the product is reduced due to a chemical reaction in which an acrylic group in the side chain of capsaicin is cleaved by a double bond. Alternatively, the double bond undergoes an addition reaction to increase the carbon number of the product. When the derivatives are compared with capsaicin, the pungency of the derivatives is reduced, and the degree of the reduction is changed depending on the degree of increase in water solubility of the derivatives. According to Toh et al., A chemical reaction that cleaves the acrylic group leaves only the amine group on the side chain of capsaicin. The side chain of this product was vanillylamide. This compound loses its pungency and its pharmacological activity is significantly reduced or eliminated. According to Jones et al., When a methylation reaction occurs in the phenol group of capsaicin and a methoxy group is generated,
The pungency of the synthesized compound is also reduced.

With respect to the reaction for introducing a modification group into the structure of capsaicin as described above, how to selectively introduce a functional carbon side chain into an appropriate position was examined. Although various methods have been tried, the addition reaction that saturates at the double bond position of the side chain in the first step, when comprehensively judging various conditions such as difficulty of synthesis, ease of operation, yield and complexity of intermediates. The two-step synthetic method of the reaction in which the hydrophilic group is introduced after that is the preferred method.

The present invention also provides nonanoyl vanillyl amide represented by the formula IV.
Using lylamide) as a starting material for the synthesis reaction, the possibility of a one-step synthesis, that is, a reaction of directly introducing a hydrophilic group from nonanoylvanillylamide was examined instead of the above-mentioned two-step synthesis method.

[0013]

[Chemical 4]

Nonanoyl vanillyl amide (nonano
There are various reports by Northan et al. regarding the pharmacological activity between yl vanillylamide) and capsaicin. Main Literature Life Science 35 , 2
93-302, 1561-1568 (1984), Dr.
ug Res. 25 , 1877 (1975), Arc
h. Int pharmacodyn. 280, 165
-176 (1986), it is estimated that the pharmacological activity of nonanoylvanillylamide is similar to that of capsaicin. When a synthetic reaction was chemically conducted, it was observed that the method of directly introducing a hydrophilic group using nonanoylvanillylamide as a reaction raw material was superior to that of using natural capsaicin as a raw material.

The reaction for introducing a hydrophilic group from the nonanoyl vanillyl amide of the present invention is as follows. Addition reaction is carried out in the presence of a suitable catalyst at a temperature of 10 to 100 ° C. After completion of the reaction, the mixture is cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography column to obtain the product. However, the above-mentioned purification process has drawbacks such as a reduced yield and a longer purification time. Another purification method of the present invention, i.e., the reaction of the resulting product A _c OE _t, after stirring by adding an organic solvent such as chloroform, washed with water, the organic solvent layer was collected by filtration, alkalized Are collected. Then again A _c OE _t like partitioned extracted with an organic solvent After oxidation, the organic solvent layer obtained was dehydrated and dried, the residue was distilled off the organic solvent under reduced pressure, the precipitated compound of benzene or benzene and hexane It is carried out by recrystallization from a mixed solvent. Stability is judged by dissolving the product and capsaicin separately in a weak alkaline aqueous solution and observing the characteristic absorption band of the visible light-ultraviolet spectrum. Other physical constants such as IR, melting point, NM
Measure R, MS, etc. and compare with the standard.

Pharmacological studies on the synthesized capsaicin derivatives include analgesic experiments, circulatory system action experiments, and cardiac arrhythmia experiments. Acetylcholine (acetylcho)
line), acetic acid, phenylquinone (phenylqu)
Inone) is administered to the abdominal cavity of mice using a stimulating chemical substance. The reaction state of mice (referred to as "Writing symptom") to this chemical substance is suppressed by the experimental drug. The degree of inhibition is recognized as the analgesic effect of the experimental drug.
Capsaicin and its capsaicin derivatives were used as experimental drugs in the analgesic experiment of capsaicin, and the results show that the analgesic effect and the dose-dependent relationship in the dose range used. Also, the analgesic effects of both are similar.

Cardiovascular effects experiments include vasorelaxation, heart and blood pressure experiments. For vasorelaxation, phenylephrine HCl was used to test whether or not the action of contracting a guinea pig thoracic artery ring (aorta) sample has an inhibitory action in the presence of capsaicin or a capsaicin derivative.

The vasorelaxant activity of the capsaicin derivative is significantly increased depending on the dose concentration, and is generally dose-dependently active. However, the activity of the capsaicin derivative is shown to be stronger than that of capsaicin.

Regarding the measurement experiment of blood pressure and heart rate using the rat anesthetized by Donnerer et al., The experimental result when a 250 nmole dose of capsaicin was administered was a three-phase reaction (Benzold Jarish resp).
onse, or bradycardi
a), respiratory depression, lowering of blood pressure, etc. are included. In the present invention, a similar reaction is performed by using the guinea pig thoracic artery ring preparation with 25 nmol of capsaicin or a capsaicin derivative.
It also appears when e and 250 nmole doses are administered. In the reaction of the present invention, the blood pressure rapidly decreases in phase A, and then increases in phase B, which is higher than the blood pressure at normal times, followed by a continuous hypotensive reaction in phase C.

The above measurement experiment was repeated using capsaicin or a capsaicin derivative. As a result, capsaicin or a capsaicin derivative does not show tachyphylaxis drug resistance to blood pressure and heart rate.

In the present invention, a tablet, a mixture of a capsaicin derivative component or a salt thereof and an pharmaceutically conventional pharmaceutical additive (eg, carrier, excipient, diluent, etc.) are usually mixed.
It can be safely administered to patients in need of treatment in the form of granules, powders, capsules, injections and the like. The dose may vary depending on the patient's symptoms, body weight, age and the like, but is usually preferably in the range of 10 to 500 mg per day for an adult. It is preferable to administer this once or divided into several times a day.

[0022]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto. Example 1 Synthesis Reaction of Capsaicin Derivative 3 mol of capsaicin was dissolved in DMF (N, N-dimethylformamide), and 3 mol of succinic anhydride (Succinic anhydride) was heated under vigorous stirring.
e) was added and reacted for 2 to 3 hours, then the reaction was stopped while examining by TLC, the reaction product was cooled to room temperature, left for a while, the DMF solution was distilled off under reduced pressure, and the residue was dried. The silica gel column is advanced by, and the remaining DMF solution is eluted with 100 ml benzene. Benzene: Ethyl acetate (9:
1) The compound obtained by separating from the solvent is referred to as A. Subsequently, the solvent was changed to benzene: ethyl acetate (8: 2), and the compounds obtained therefrom were B and C. When these compounds A, B, and C were separately confirmed by melting point and NMR spectrum, it was found that A is capsaicin, C is a mixture of succinic anhydride and capsaicin, and B is the produced compound. Then B is purified by chromatography,
Capsaicin succinate
succinate) was obtained.

Recrystallization was carried out with benzene to obtain white needle-like crystals, the melting point was 104 to 106 ° C., Tf developed with benzene: ethyl acetate (1: 1) showed Rf of 0.3, and color reaction Is a methanol solution of 2,6-dicyclorophenol intophenol and used as a coloring reagent, the molecular formula is estimated to be C ₂₁ H ₃₁ NO ₆ by elemental analysis, and the calculated value is C 64.10: H 7.94: N.
3.56, experimental value was C63.79: H 7.90: N
It is 3.57. 1698 cm ^{−1 for} IR spectrum
To have absorption band of the carboxylic acid groups are there in the absorption band and 1700 cm ^-1 of the ketone group, since showed no absorption bands of capsaicin hydroxyl groups 3450 cm ^-1, the IR spectrum shows that different capsaicin. Also ¹ H-N
Δ 0.87, δ 1.25 to 2.2 from MR spectrum
5, δ2.77 to 2.90 is a signal based on 10 methyl groups, δ3.75 is one methoxy group, δ4.
34 is a signal based on one aromatic methyl, δ6.
32 has a signal based on one amine, δ6,76-
6.97 has a signal based on one aromatic ring, δ9.9.
2 shows a signal based on one carboxylic acid and ¹ H-NHR spectrum of capsaicin showed δ2.7.
7-2.90 two methylene-based signals and δ
A signal based on one acid was observed at 9.92. Furthermore, the ¹³ C-NMR spectrum has 21 absorptions, and for example, δ14.1, 22.7, 25.9, 28.
9, 29.1, 29.2, 29.4, 31.9, 36.
1, 43.5, 56.0, 112.4, 120.3, 1
23.1, 137.7, 139.3, 151.5, 17
1.2, 174.5, 177.1, 177.3 and ¹³ C-NMR spectrum of capsaicin
It was observed that the number of carbons increased. The compound synthesized from the above data is capsaicin succinate,
Its structure was presumed to be [formula II].

Example 2 Capsaicin and DMF were heated as in Example 1 above, and succinic anhydride was added under heating to stop the reaction. The reaction product was likewise cooled to room temperature. Then, it was partitioned and extracted with ethyl acetate, the obtained ethyl acetate layer was treated with 0.5N sodium hydroxide, the aqueous layer was oxidized with hydrochloric acid, and further partitioned and extracted with ethyl acetate. The obtained ethyl acetate layer was dehydrated with magnesium sulfate, ethyl acetate was distilled off under reduced pressure, the residue was crystallized from benzene, and recrystallized with a mixed solvent of benzene and n-hexene to obtain white needle crystals. It was

EXAMPLE 3 Analgesic Experiments The method of Koster et al. Was modified to use 0.2% 0.7% acetic acid.
ml was intraperitoneally administered to male mice, and the number of Writing was measured for 10 minutes after 30 minutes. Further, as experimental drugs, 10 ⁻⁷ , 10 ⁻⁶ , 10 ⁻⁵ mole / Kg of capsaicin and capsaicin succinate were separately administered intraperitoneally 30 minutes before administration of acetic acid. The results are shown in FIGS. As shown in the figure, when capsaicin and capsaicin succinate were administered, the writ was dose-dependently.
The number of hings decreased. In particular, the effect of capsaicin succinate was remarkable.

Example 4 Effects on the circulatory system 10 ⁻⁶ M phenylephrine hydrochloride was added to the modified Krebs solution in which the guinea pig thoracic artery ring specimen was immersed, and the vasoconstriction results were recorded. Also, 10 ^-8 , 10 ^-7 , 10
^-6, administered ^{10 -5} M capsaicin or capsaicin succinate to the Krebs solution, the vasorelaxant results were recorded and calculated by the following formula.

[0027]

[Equation 1]

The meaning of this formula is Relaxation% = falling width after administration / PE contraction width × 100, that is, drug phenylephrine (PE) 10
^{At −6} M, vasoconstriction is induced, and the degree of contraction is used as the denominator, and the degree of contraction is decreased by administration of capsaicin or capsaicin succinate, and the measured decrease width is taken as the numerator. Let the percentage of both be the percentage of the relaxation effect. Rel
It is convenient to use axation% to compare the degree of difference from the control value. The result is shown in FIG. As shown in this figure, capsaicin succinate showed significant vasorelaxation results with capsaicin. Therefore, it has a remarkable effect in a dose-dependent manner. In addition, quick tolerance (tachy)
phylax) also occurs, but if it forms sufficiently fast, a contraction phenomenon appears in blood vessels. In addition, the addition of capsaicin or capsaicin succinate showed remarkable vasorelaxation in a dose-dependent manner.

Example 5 Example of Injection Solution (1) Capsaicin succinate 100 mg Tween 80 10 ml ethanol 10 ml physiological saline 80 ml Capsaicin succinate was dissolved in ethanol,
Tween 20 is added to it and mixed well with saline to make an injection.

Example of Injection Solution (2) Capsaicin succinate 100 mg Sodium carbonate (0.1%) 100 ml Capsaicin succinate was added to sodium carbonate (0.
Dissolve well in 1%) to make an injection solution.

[Brief description of drawings]

1 shows the analgesic effect of capsaicin according to Example 3. FIG.

[Explanation of symbols]

FIG. 2 shows the analgesic effect of capsaicin succinate according to Example 3.

[Explanation of symbols]

FIG. 3 shows the blood vessel relaxing effect of Example 4.

Claims (4)

[Claims] 1. An analgesic or vasodilator containing a capsaicin derivative represented by the formula [I] or an acid ester thereof as an active ingredient. [Chemical 1] [Wherein R ₁ is a carboxyl group or an acyl group (R ₁ 'CO-, R ₁ ' is an alkyl group or an alkenyl group), R ₂ is a lower alkyl group or -CO- (C
Shows the H _{2) n} COOH. However, n shows the integer of 1-5. ] 2. In the formula [I], R ₁ is —CO— (CH ₂ ) ₇
The analgesic and vasodilator according to claim 1, which is -CH ₃ . 3. In the formula [I], R ₁ is —CO— (CH ₂ ) ₇
Is -CH _{3, R 2} is _-CO-CH 2 _CH 2 COOH
An analgesic or vasodilator comprising the capsaicin derivative according to claim 1 as an active ingredient. 4. A capsaicin derivative represented by [Formula II]. [Chemical 2]