JPH01254671A - Novel ligustilides - Google Patents

Abstract

NEW MATERIAL:Ligustilides expressed by formula I. USE:Useful as a medicine having sedative action on central nervous systems and orally or parenterally administrable in a dosage form, such as tablet or suppository. PREPARATION:A crude drug Japanese angelica root (root of umbelliferous, Lugistricum acutilobum or relative plants thereof) or Cnidium (rhizome of umbelliferous Cnidium officinale) is extracted with a solvent, such as water, alcohols or hexane, and the resultant extract solution is partitioned and extracted with a mixed solvent of water, methanol and chloroform to remove a fat-soluble fraction passed into the organic solvent. The obtained extract solution is then subjected to column chromatography with one of the water, methanol, etc., as an elution solvent using silica gel, etc., as a support and subsequently fractionated by thin-layer chromatography to afford the aimed compounds expressed by formula I. Furthermore, other compounds expressed by formulas II-IV are also novel substances.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention has a sedative effect on the central nervous system of 'F7L.
, concerning new ligmethylides for use as medicines.

[Prior art and problems] Toki is a plant that belongs to the Umbelliferae family (Umbclircrac).
^ngelica acuLiloba KITAGA
W^) or other related plant roots, and is a medicinal ingredient added to Chinese herbal medicine for the purpose of analgesia, fever reduction, etc.

In addition, Yoxun is also called Cnidium (Cnidium crow), which is a member of the Umbelliferae family.
ricinalc MAKINO), #A
It is a filter medicine that is added to Chinese herbal medicine for the purpose of spasm, antithrombotic treatment, etc.

Compounds with a structure similar to ligustilide, which is one of the components contained in these tokitokawa t°j, include butylidenephthalide, cnidylide, neocnidylide, etc.
(T
It is a substance with known pharmacological effects.

[Means to Solve the Problem] The Ministry of the Invention and others have conducted intensive research on this ligustilide and found that it has a sedative effect on the central nervous system.
They discovered 4' ligmethylides and completed the present invention.

4"), and the present invention is as shown below.

A new compound represented by

(2) Formula■ A new compound represented by

A new compound represented by

(4) Formula 1 ■ A new compound represented by

(5) Formula A new compound represented by

(6) Formula■] A new compound is represented by .

Hereinafter, (1) to (6) will be combined with the compound of the present invention.
Ru.

The compounds of the present invention have a sedative effect on the central nervous system and are of therapeutic use as pharmaceuticals.

For example, the following methods can be used to prepare the compound of the present invention.

The compound of the present invention is obtained by extracting the herbal medicine Toki or Kawasaki with at least one solvent selected from water, alcohols, hexane, ether, and chloroform, and then extracting the extracted liquid with water, methanol, and chloroform. 11. Extract by partition with a mixed solvent of ) After removing l1ff soluble components that migrate to the solvent, water, methanol, ethanol, acetic acid,
Chloro[7polm, benzene, acetone, ethyl acetate, n
- Using at least one selected from hexane and petroleum ether as an elution solvent, porous polymers such as Diamond Ion L20 and MCI Gel CII P 20 P, Sephadex f [・20, etc.], reversed phase silica gel, It can be obtained by subjecting it to column chromatography once or several times using silica gel, polyamide, cellulose, etc. as a 11-molecule, and fractionating it while confirming the target component using thin layer chromatography. Further, the product may be purified by recrystallization using a suitable solvent such as methanol, ethanol, or water.

The compound of the present invention can be administered to animals and humans as it is or with a commonly used pharmaceutical carrier.The dosage form is not particularly limited and can be appropriately selected and used as required, such as tablets, capsules, etc. Examples include oral preparations such as laxatives, fine granules, powders, etc., injections, and suppositories with a diameter of 1".

``One drug is, for example, starch, lactose, white sugar, mannilla!
・Carboxymethyl cell [1-su, cornstarch,
It is manufactured using conventional methods using inorganic salts, etc.

In addition to the excipients listed above, this type of preparation uses binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, etc. can be done. Specific examples of each are shown in 1. below.

[Binder] Starch, dextrin, gum arabic, gelatin,
Hydroxypropyl starch, methylcellulose, carpoquin methylcellulose sodium 1%, hydroxypropyl cellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cell [J-su, low substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate , polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate 12°.The compound of the present invention can also be used in suspensions, emulsions, liquids, elixirs, etc. These various dosage forms may also contain flavoring agents and coloring agents.

Valve diameter 1'' is manufactured according to conventional methods, and diluents generally include distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame 7111, peanut oil, soybean oil, corn oil, propylene glycol, Polyethylene glycol or the like can be used.

If necessary, add fungicides, preservatives, and stabilizers. In addition, from the viewpoint of stability, this drug with a valve diameter of 1" is frozen after being filled into a vial, water is removed using normal freeze-drying technology, and the liquid drug is re-extracted from the freeze-dried product immediately after use.
It can be manufactured by Il. Furthermore, as necessary,
It is best to add tonicity agents, stabilizers, preservatives, soothing agents, etc.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, and suppositories for intrarectal administration, which are manufactured according to conventional methods.

Examples of manufacturing the compounds of the present invention are shown below.

Manufacturing example! Add 9 to 4.5 to n-hexane-diethyl ether (2
:I) and then further extracted with chloroform-methanol (III). 450v of the obtained extract was distributed with a mixed solvent of chloroform-methanol-water (8:4:3) to obtain 96g of chloroform 11 extract. I got it.

This extract and the above 11-hexane-diethyl ether extract 582 were mixed and distributed with a mixed solvent of n-hexane-methanol-water (20:IO:2), and the resulting lower layer was subjected to solvent distillation. The residue was removed to obtain 37.1 g of residue.

This residue was flash-colored using silica gel for 12 days [
The mixture was subjected to muddography and eluted using ethyl acetate-n-hexano as an eluent at varying ratios. The fractions eluted with ethyl acetate-n-hexano (2:8) were subjected to Fratunyl column chromatography, and the fractions eluted with ethyl acetate-n-hexano (1:49) and diethyl ether chloride (1:49) and ethyl acetate-n-hexano (1:49) 9) to obtain fractions a, b and C. The solvent of this fraction a was distilled off to obtain an oily substance. The physicochemical properties of this oily substance are as follows, and based on these data, it was determined to be a compound represented by Formula I.

Specific optical rotation [α], +26° (c = 0.70, CI
I CQs) Mass spec] m/z (%): 288, 231, 205, l 89 Infrared absorption spectrum ν2u J +'''on-': 1770
．． 1715 Bu [J ton nuclear magnetic resonance spectrum (δppm in CI) eta): 0.98 (31
1, t, J=7.311z).

1.91 (3II, q, J = 1.5 [1z
).

2.00 (311, dQ, J = 7.3.1.511z
).

5.15 (I II, d, J = 8.011z).

5.77 (I Il, ddd, J = 8.1.7.0.6.2
117. ).

G, OG (I tl, dL, J = 9.9.4.
011z).

6.09 (I Il, qql = 7.3, I , 5
11z).

0.29 (I tl, dL, J = 9.8, 1.8 L
lz) Production Example 2 The fraction obtained in the second flash column chromatography in Production Example I was then evaporated to remove the oil. The physicochemical properties of this oily substance are as follows, and based on these data, it was determined to be a compound represented by formula (2).

Specific optical rotation [α], 0° (c = 0.6, CHCl2
a) Mass spectrum 1/z (%): 380.191,190,161,148 Infrared absorption spectrum +m: #'''α-1゜1760.170
0 Proton nuclear magnetic resonance spectrum (δppm in CDCl5): 0.80 (31
1, t, J=7.311z).

0.94 (311,t, J=7.311z).

2.39 (I II, ddd, J = l 8.3.6.2.
3.5 ■iz).

2.56 (I If, ddd, J = I 8.3.9.3.5
, G tlz).

2.90 (l II , ddd, , J = 9.8, G
, 8.4. 4 1 [z).

3.2 3 (I If, d, J = 9.3
11z).

4.6 6(l II, dd, J =8.3,7.
311z).

5.2 1 (I II, t, J = 7.811z).

8.0 0 (I II , d , J = 9.8
11z).

0.1 1 (l Il, br dt, J = 9
．． 8.4. 0112) Production Example 3 The solvent was distilled off from the fraction C obtained by flash column chromatography in Production Example (2) [1] to obtain an oily substance. The physicochemical properties of this oily substance are as follows, and based on these data, it was determined to be a compound represented by formula 111.

Specific optical rotation [α] o Oo (c = 0, 6, Ct
l C(!s>Mass spectrum m/z (%): 380.191°190,161 Infrared absorption spectrum ν2;4al, -1°1775.
1755.1695 Bu [1 ton nuclear magnetism] (Sound spectrum (δppm+ in CDCl2): 0.82 (31
1, t, J = 7.31 (z).

0.88 (3H, t, J=7.311z).

l, G O (l I-1, m).

2.07 (I If, dL, J = 18.1, I
O, 3tlz).

2.26-2.30 (2H, m).

2.49 (IH, t, J=9.5Hz).

3, IO (I II, m).

4.02 (I II, dd, J = 8.8, 6.811
z).

5.92 (I II, (IL, J = 9.5.4.
011z).

6.1 7(I II, d, J = 6.61
1z).

7.53 (I II, d, J = G, G H
z) Production example 4 River 7! J3, I kg was extracted with n-hexane-diethyl ether and then with methanol. The obtained methanol extract was distributed with a mixed solvent of chloroform-methanol-water (8:1:3) to obtain 110 g of chloroform extract.

Mix 215 g of black Cl form extract tto9 and 215 g of ROHEKI->N-diethyl ether extract,
-hexane-methanol-water (20:IO:2)
The mixture was partitioned twice, and the solvent in the lower layer was distilled off to obtain a residue 95y. Of the residue, 541 was subjected to flash column chromatography using silica gel, and eluted with ethyl acetate-n-hexane and methanol (IC1 form) as elution solvents by changing the ratio sequentially. Ethyl acetate-n-hexane (13:87,1512), ethyl acetate-〇-hexane (3N, 5Q), methanol-chloroporno, (
G: 94, G 12) and methanol-chloroform (3 near, 5 Q) were sequentially eluted by IQ to obtain a fraction eluted with 31N.

The fractions collected from eluate 812 to 1512 were subjected to column chromatography, eluted with 780 d of ethyl acetate-n-hexane (4:6), and subfraction A was obtained.
(0~450II11) and subfraction +3 (45
0I! ! fl~780d).

Subfraction B was subjected to chromatography and eluted with 7501 dl of methanol-chloroporm (1:99), and the resulting eluate (375I11 to 750I11) was subjected to column chromatography and eluted with diethyl ether Cl roporum (1:9). ), the solvent was distilled off, and crystallization was performed to obtain an oily substance 22.3JI9.

The physical and chemical properties of this oily substance are as follows (and based on these data, it was determined to be a compound represented by 2).

Specific optical rotation [α] o 6° (c = 1.27, C
I-I C123) Mass spectrum +m/z (%): 208.190,133,105 Infrared absorption spectrum νwax'CM-': 34
00.17G0,1730.1610 Proton nuclear magnetic resonance spectrum (δppm in CDCl5): 0.91 (31
[,t,J=7.0tlz).

4.70 (Ai II, t, J = 7.511z)
.

5.24 (I tl, dd, J = 7.5.3.5
11z).

6.04 (I II, dL, J = 10.0.4.
511z).

8.3 0 (I 11 ,,brd,J = I
0, O11z) Production Example 5 The subfraction 8 obtained in Production Example 4 was drained [17
Methanol-chloropol l, (1
:99), then diethyl etheruk [10 hol/,
(1:19), and also Methanol Roof CI Cl Pol 1
Elution with - (1:19), evaporation of the solvent, and crystallization gave 13.219 of an oily substance.

The physicochemical properties of this oily substance are as follows, and based on these data, it was determined to be a compound represented by formula (2).

Specific optical rotation [α] no °C (c = 0.72, CI
I Cd3) Mass spectrum a+/z (%): 278.235, 207, 190, 180° 175, I
(i5.IGI, 71 Infrared absorption spectrum ν:::”can-’:3400
．． 1760.1700,1G75° proton nuclear magnetic resonance spectrum (δppm in CDCl5): 0.95 (311,t, J =7.311z).

! , 5 0 (211,5ext, J = 7
．． 3 +1z).

2.36 (2tl, dL, J = 7.8.7.31
-1z).

5.26 (IN, t, J=7.8Hz)'? J Preparation Example 6 10 The subfraction 8 obtained in Preparation Example 4 was subjected to a second column chromatography, and the resulting eluate was further subjected to column chromatography, and ethyl acetate-
Elute with 〇-hegizan (4:6), evaporate the solvent, crystallize,
67 oily substances were obtained.

The physical and chemical properties of this Ab-like substance are as follows, and from these data it was determined to be a compound represented by formula V.

Specific optical rotation [α] on ° (c = 1.24, CII
C (!3) mass spectrum s+/z (%): 242 and 244 (M'), 213,207°200
．． 198.169 Infrared absorption spectrum ν+++ *: ' 611-
"', 3400, l 745.1640bu [J
ton nuclear magnetism (Sound spectrum (δPP0I in CDCl5) +0.9 G (
3II, L, J = 7.3112).

1.51 (2II, 5axt, J = 7.311
z).

2.38 (2+1.(lL, J = 7.8.7.3
11z).

5.30 (III, L, , I = 7.811z) Patent applicant YLT Mura Juntendo Co., Ltd.

Claims (6)

[Claims] (1) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I A new compound represented by (2) Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II A new compound represented by (3) Formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼III A new compound represented by (4) Formula IV ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV A new compound represented by (5) Formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼V A new compound represented by (6) Formula VI ▲Contains mathematical formulas, chemical formulas, tables, etc.▼VI A new compound represented by