JPH01294657A - Novel amide compound and production thereof - Google Patents

Abstract

NEW MATERIAL:An amide compound expressed by the formula. USE:An anesthetic agent, capable of exhibiting rapid and prolonged paralytic and anesthetic effects and useful for relieving pains, anesthetization in operation, etc. PREPARATION:An optional part, preferably pericarp part of a plant (e.9., Zanthoxylum bungeanum Maxim. or Zanthoxylum periperitum De Candolle) belonging to the genus Zanthoxylum of the family Rutaceae is dried or used in the state and directly extracted. The extraction is carried out by using water or an organic solvent (e.g., chloroform) at <=40 deg.C for 20-40 hr by stirring, shaking, etc. The resultant extract, as necessary, is concentrated at a low temperature under reduced pressure or freeze-dried and subsequently purified by chromatography to afford the aimed substance.

Description

[Detailed Description of the Invention] [Background of the Invention] Development of the present invention...
This article relates to a new amide compound obtained from @mono and its manufacturing method. More specifically, Zanthoxylum bunBeanum M
axim, ) and a method for producing the same.

Zanthoxylum+ bungeanum
Maxim, ) is a shrub or small tree with a height of 3 to 61 fi, distributed in most areas in China.
lum piperitum De Candolle
) and is not produced in China [Compiled by Shanghai Science and Technology Publishing Company, "Dictionary of Chinese Medicine," Volume 1, pp. 279-282 (published by Shogakukan Co., Ltd. (December 10, 1985))]. This Hanashuku and other congeners are divided into phases, leaves, seeds, stems, pericarp,
All parts, including the outer skin, can be medicinal, and various pharmacological actions are known (for example, medicinal effects have been confirmed for indigestion, diarrhea, myalgia, toothache, ascariasis, etc.).

By the way, trace components such as geraniol, limonene, cumin alcohol, sterol or estragol, bergabuten or benzoic acids have been confirmed in the flower [Compiled by Shanghai Science and Technology Publishing House, "Dictionary of Traditional Chinese Medicine, Vol. 1"] 2
Pages 79-282 (published by Shogakukan Co., Ltd. (February 10, 1985))]. Also, the spiciness component is Zanth.
oxylum bungeanum Maxim,), the presence of α-sanshool, hydroxy-α-sanshool, β-sanshhol, hydroxy-β-sanshool, γ-sansimil, and hydroxy-γ-sanshhol has also been confirmed ( J,Chem,Soc,,2
760 (1957), Phytochemistry,
21.1295 (1982)).

[Summary of the Invention] 1-Dan The present invention is based on the discovery that a novel amide compound was found in the extracted fraction, especially the extracted fraction of Hanaga Yuba, as a result of intensive research on the components of plants of the genus Salmonella. It is something.

Therefore, the amide compound according to the present invention is characterized by being represented by the following formula (1).

CH3CH2CH=CHCH2CH=CH-CH2CH
2CH=CHCH=CHCONIi-CH2C(CH3
)2OH Furthermore, the method for producing the amide compound represented by the above formula (1) is as follows:
It is characterized in that it is obtained from the Zanthoxy lum plant.

The present invention relates to Zanthoxylum spp.
The discovery of a new amide compound in plants was unexpected, and since the amide compound of the present invention has an anesthetic effect, it will not only provide an anesthetic, but will also make a meaningful contribution to countering various diseases. be.

[Detailed Description of the Invention] The amide compound according to the present invention is a compound represented by the above formula (1). Since this compound has four double bonds in its molecule, it has one variety of geometric isomers, and the present invention includes all of them. Among these compounds, specific examples are as follows.

Compound ■ Properties: Pale yellow oily substance, irritating (Z) (Z) (E) (E) CH3
CH2CH=CHCH2CH=CH-Cl12CH2C
H=CHCH=CH(CONH-CH2C(CH3)2
OH Compound II Properties: Pale yellow oily substance, irritating (E) (Z) (E) (E) CH3
CH2CH=CHCH2CH=CH-CH2CH2CH
=CHCH=CHCONH-CH2C(CH3)2OH [In the formula, (E) and (Z) indicate stereoisomerism. ] Plants of the genus Zanthox as used in the present invention may be plants belonging to the genus Zanthox of the Rutaceae family, such as flowers [(Zanthoxylum bun8eanumM
axim, ), Zanthoxylum pip
eritum CD), Fuyuyama JZanthoxylum
planispinum 5ieb, et Zucc
, ], Bird Mountain [(Zanthoxylum ailan
thoides 5ieb, etZucc, ), Inuyama 1fi (Zanthoxylum schinifo
lium 5ieb.

et Zucc, ) etc. (published by Seibundo Shinkosha, written by Bonjin Izawa, primary color version Japanese Medicinal Plant Dictionary j, p. 238-243 (19
(Published on April 15, 1981), and the above-mentioned book, Volume - No. 27
(Refer to 9-282) Any one can be used. Among these, a preferred specific example is Hanaku, as shown in Examples below.

Flowering plant is a shrub or small tree (height 3
~6m) plant, flowering period is March to May, fruiting period is July to October
The fruit is red or purplish-red and has fist-shaped dots all over it, and the single seed inside is black. Other names for Kong Kai include Daisho (Oma), Shinsho (Qin Shu), Shokusho (Shusen), and Tensho (Nanbeo).
, Hashiyou (6 paddles, Kansho (Chinese mark), Sensho (
There are many other names such as ``symbol'' or ``dot marker'' (see the above-mentioned Dictionary of Crude Drugs), but in the present invention, the term ``hole-open'' refers to these synonyms collectively.

Obtaining amidation An amide compound can be obtained from a plant of the genus Salmonella by any means commonly used for the extraction and purification of herbal medicines.

First, the target for extraction may be any part of a plant of the genus Salmonella, but the pericarp is particularly preferred.

The collected material can be dried or used as is. Furthermore, it goes without saying that extraction efficiency can be increased by appropriately crushing plant parts that can be used as medicines.Extraction and purification will be specifically explained below.

B) Extraction The extraction step referred to in the present invention can basically be carried out by any means commonly used for extracting botanical herbal medicines. For example, water or water-containing,
Extraction can be carried out using water-free organic solvents.

Extraction can be carried out once or multiple times under heating, room temperature, or low temperature; however, extraction time at room temperature or low temperature is usually long, ranging from several tens of minutes to several days. be. Preferably, the extraction is carried out at 40°C or below for 20 to 40 hours. Furthermore, it goes without saying that operations such as stirring or shaking may be performed in order to increase extraction efficiency. The extractant is water or any organic solvent containing water or water-free, preferably water or a lower alcohol containing water or water-free (usually a monohydric alcohol having 1 to 4 carbon atoms) or a water-distributable organic solvent. Organic solvents can be used.

The term "organic solvent that can be distributed with water" as used herein refers to any organic solvent that is completely or almost immiscible with water, such as chloroform, dichloromethane, ethyl acetate,
Examples include benzene, ether, petroleum ether, hexane, and butanol.

The extracted fraction thus obtained can be concentrated under reduced pressure at low temperature or freeze-dried to obtain the desired fraction, if necessary.

(1) Purification The target fraction can be obtained from the extracted fraction obtained in (a) above by appropriately combining normal phase and reversed phase chromatography. Although the order of combination may be either, it is preferable to perform normal phase chromatography and then reverse phase chromatography at least once, as shown in the experimental examples below.

Here, normal phase chromatography refers to column chromatography using a highly polar resin such as silicic acid or silica gel as a solid phase carrier, and the mobile phase is usually a nonpolar one such as chloroform, dichloromethane, hexane, or ethyl acetate. A solvent having less polarity than the solid phase support can be used, such as a mixture of a solvent and a water-containing or non-water-containing lower alcohol. An example of the above method is silica gel column chromatography [developing solvent: chloroform-methanol (
30:1) or benzene-acetone (17:3)]
It can be purified using

On the other hand, reversed phase chromatography refers to silanes such as the above silica gel chemically bonded with silanes having hydrocarbon residues having 1 to 18 carbon atoms, such as dimethylsilane, octadecylsilane, and octyldecylsilane, or styrene-divinylbenzene. This refers to column chromatography using a resinous solid phase carrier with low polarity, such as a copolymer or a gel filtration agent, and any solvent having a higher polarity than the solid phase carrier can be used as the mobile phase. For example, water-containing or water-free lower alcohols [those having 1 to 3 carbon atoms (usually monohydric alcohols)], or mixtures of water and organic solvents that are miscible with water, such as acetone and acetonitrile, can be used. As a preferred specific example, octadecylsilane can be used as a solid phase carrier and hydrous acetonitrile can be used as a developing solvent, as shown in the experimental examples below.

The amide compound in the present invention has immediate and long-lasting paralyzing and anesthetic effects, as shown in the experimental examples below.

Therefore, this effect extends to comprehensive therapeutic fields such as pain relief and anesthesia during surgery.

Chestnut Rat: The amide compound of the present invention itself or mixed with appropriate formulation excipients, binders, and diluents, and can be used as an ointment,
It can be administered orally or parenterally in the form of cream, liquid, capsule, syrup, injection, etc. Other drugs may be mixed as needed. The dosage may be increased or decreased as appropriate depending on age, body weight, and symptoms.
(Refer to Publication No. 2003)) is usually 0-1 mg to 10 g of amide compound (in oil form) per day for adults.
The amount is about 0.5 mg to about 5 g, more preferably about 0.5 mg to 5 g. In addition, the toxicity of the amide compound in the present invention is generally low because, for example, plants of the genus Salmonella are commonly used in folk medicine or as food.

[Experiment Example 1, amide compound 1 Extract 450 g of pericarp with pores with chloroform at room temperature,
The obtained extract was concentrated under reduced pressure to obtain 87 g of extract. This extract was subjected to column chromatography using silica gel [
Developing solvent: chloroform-methanol (30:1)] to obtain 5 fractions. Fraction 3 (13,48) was further subjected to silica gel column chromatography [developing solvent: benzene-acetone (17:3)] to obtain three fractions. TSK g for both 3-2 (6,43g)
High performance liquid chromatography (developing solvent: 50% acetonitrile) was performed using el 0DS120T [Toyo Soda Kogyo Co., Ltd.], and 7 fractions were obtained. After solvent distillation, fraction 3
A mixture of hydroxy-a-sanshool and hydroxy-β-5anshool (yield: 0.45%) was obtained from fraction 3-2-1, and hydro
xy-y -5anshool (yield: 0.13χ)
, Compound I from fraction 3-2=5 (yield: 0.016%)
, compound II from fraction 3-2-6 (yield: 0.008
%), compound III from fraction 3-2-4 (yield: 0.
013%) (see Figure 1).

Compound ■ and compound! ■ is C18H29N 02 (compound ■, actual value: 291.
219 Theoretical value: 291.220 Compound II + Actual value: 2
91.219 theoretical value: 291.220) are both given. The EI-MS spectra of Compound 1 and Compound II are very similar, showing the following M+ and a series of fragment ions.

m/z 291: (M”) 273: (“-H2O) 258: (M”-H2O-CH3) 244: (M”-)120-(CH3-CH2-))2
33: (M”-H2O-3XCH3) 218: (M”
-H2O-(CI(3-CH2-CH=CH-))21
8: (M”-H2O-(CH3-CH2-CH=CH
-))204: (M”-H2O-(CH3-CH2
-CH=CH-CH2-))203: (M”-(NH
-CH2-C(CH3) 2OH)]178: (M”
-H2O-(CH3-CH2-CH=CH-CH2-C
H=CH-))164: [M”-H2O-(CH
3-CH2-CH=CH-CH2-CI(=CH-CH
2-)] 150: (M”-H2O-(CH3-CH2-C)l
=CH-CH2-CH=CH-CH2-CH2-)] 124: (M"-H2O-(CH3-CH,, -CH
=CH-CH2-CH=CH-CH2-CH2-CH=
CH-)) 109: (CH3-(CH2-CH=CH) 2-CH
2) “93:(M”-H2O-(CH3-(CH2
-CH=CH)2-CH2-CH2-(CH=CH)
2)) In addition, IHNMR of Compound I and Compound 1■ (Table 1
) and 13CNMR (Table 2) spectrum, Compound I and Compound n are CH3-(CHz-CH:CH) 2-CH2-CH2
-(CH”CH) 2CO-NH-CH2-(1:(C
It was presumed to be a geometric isomer represented by the structural formula H3)2OH(A).

The 13C NMR spectra of Compound Ⅰ and Compound II were compared to Compound III and its geometric isomer hydroxy-γ-
5anshoo I” CNMR spectrum, and consideration of the shielding effect of 13C NMR chemical shift in geometric isomers by Haan et al. (Organic Ma
gnetic Re5onance.

(3), 147 (1973)], and assigned the 13C NMR signals of Compound I and Compound I as shown in Table 2.

From the above, compound ■ and compound n are 11 of skeleton (A).
．． It is a geometric isomer based on the double bond at position 12, and compound I is (2E, 4E, 82,112)-2°-1sobu
tyl-2,4,8,11-tetradeatet
raenamlde, compound I! is (2E, 4E, 8Z
, IIE)-2°-1sobutyl-2,4,8,1
It was determined to be 1-tetradecatetraenamide.

The compositional formula of Kita J1 Aisei Compound 111 is CIBH27HO□ (actual value: 289.204) from high-resolution mass spectra.
Theoretical value: 289.204) is given. The EI-MS spectrum gives the M+ and series of fragment ions shown below.

E I -MS of compound m/z 289: (M”) 271: [M”-H20] 258: (M”-H2O-CH3) 231: (M”-H2O-3XCH3) 230:
(M”-H2O-(CH3-CH=CH-))204
: (M”-H2O-(CH3-CH=CH-CH=C
H-))201: (M”-H2O-(NH-CH
“C(CH3)2))164: (M”-H2O-((
:H3-(CH=CH)3-CH2-))150: (
M”-H2O-(CH3-(CH=CH) 3-CH2
-CH2-) )124 : (M”-H2O-(CH
3-(CH=CH) 3-CH2-CH2-CH=CH
-)) 107: (CH3-(CH=CH)3-C12)”6
7: (CI, (CH=CH)2)"Also, compound (F
) IHNMR (Table-1') and (F13CNMR (Table-1')
2) From the spectrum, compound III is hydroxy-
It was presumed to be a geometric isomer of γ-5anshool. Compound III is hydroxy-y-sanshoo
Comparison of the 13CNMRX vector with 1 shows that the signals of one methylene and methine are different. This is hydroxy-α-5anshoo (62) and hydroxy-β-5anshoo 1 (6E) shown in Table 2.
It agrees well with the chemical shift based on the geometric isomer observed in the carbon signals at the C-5 and C-8 positions.

From the above, compound III is hydroxy-7-5an
Geometric isomers based on the double bond at position 8.9 of shoo I (2E, 4E).

8E, IOE, 12E) -2°-hydroxyl
-N-! 5obutyl-2, 4.8.10゜12-t
It was determined to be ettradeeapentaenamide.

6 adult males (25-42 years old) and 6 adult females (22 years old)
Compound 610n+g prepared in the above experimental example was applied directly to the tongues of four subjects (aged 26 to 26 years old) to determine the anesthetic effect.

Both compounds have a paralyzing effect within 30 seconds, and 20
Lasted for ~80 minutes.

[Brief explanation of the drawing]

FIG. 1 shows a separation diagram of an amide compound. Patent applicant: Yukinaga Pharmaceutical Co., Ltd. U) target

Claims (1)

[Claims] 1. An amide compound represented by the following formula CH_3CH_2CH=CHCH_2CH=CH-CH
_2CH_2CH=CHCH=CHCONH-CH_2
A method for producing an amide compound represented by the following formula, characterized in that C(CH_3)_2OH 2 is obtained from a plant of the genus Zanthoxylum CH_3CH_2CH=CHCH_2CH=CH-CH
_2CH_2CH=CHCH=CHCONH-CH_2
C(CH_3)_2OH 3, Plants of the genus Zanthoxylum are called pepper [Zanthoxylum bungeanum M
axim. ] The manufacturing method according to claim 2, which is