JPH03200736A - Novel polyacetylene-base compounds and antitumor agent containing thereof as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I and formula II. USE:Used as an antitumor drug. PREPARATION:A Ginseng Radix or Panax ginseng as a raw plant of said Ginseng Radix, etc., is extracted with hexane, diethyl ether, petroleum ether, ethyl acetate or methanol, etc., and the solvent is removed from the extracted solution, then resultant residue is subjected to a column chromatography or a high-performance liquid chromatography in one to several times by using a porous polymer such as Diaion(R) HP-20, or sephadex, silica gel or polyamide, etc., as a carrier, thus purified by a thin-layer chromatography or a high- performance liquid chromatography to afford the aimed material.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is directed to anti-II! This invention relates to polyacetylene compounds that are useful as medicines such as cancer drugs.

[Conventional technology and issues] Stroke has replaced stroke as the leading cause of death in Japan.
There is still a high level of social interest in cancer, and comprehensive research is being conducted on all aspects of cancer prevention and treatment. Although these research results are steadily contributing to the eradication of cancer, there has been a desire to develop antitumor agents with even higher antitumor activity and fewer side effects.

[Means for Solving the Problems] As a result of extensive research to develop an antitumor agent with higher antitumor activity and fewer side effects, the present inventors discovered the crude drug ginseng, which is widely used clinically. (Ginseng Ra
dix), its original plant Pana ninnon (Pana
The inventors discovered that some polyacetylene compounds contained in X. ginseng C, A, Meyer) and other plants of the same genus have excellent anti-Lit IIK activity, and thus completed the present invention.

The present invention (as shown below).

(1) An antitumor agent containing a polyacetylene compound represented by the following formula 1 as an active ingredient.

(4) The following formula■ A new polyacetylene compound represented by

(2) An antitumor agent containing a polyacetylene compound represented by the following formula II as an active ingredient.

(5) A novel polyacetylene compound represented by the following formula (hereinafter referred to as formula I)
4; The compounds represented by L and II are collectively referred to as the compounds of the present invention. ).

(However, R1 represents an ethyl group or an ethylene group, and R
6 and R3 are the same or different and represent a hydrogen atom or a hydroxyl group, or R2 and R3 together represent an oxygen atom.

In addition, when R8 is an ethyl group, R is a hydroxyl group, and R3 is a hydrogen atom, and R1 is an ethyl group, R2 is a hydrogen atom, R
Except when 3 is a hydroxyl group. ) is an antitumor agent whose active ingredient is a polyacetylene compound.

(6) The following formula (where R6 represents a chlorine atom, a bromine atom, an iodine atom, or a hydroxyl group, R5 and R6 are the same or different and represent a hydrogen atom or a hydroxyl group, or R and R6 together represent Indicates an oxygen atom.

In addition, when R4 and n are a hydroxyl group and R6 is a hydrogen atom, when R4 and R6 are a hydroxyl group and R6 is a hydrogen atom, when R4 is a chlorine atom, R5 is a hydroxyl group, and R6 is a hydrogen atom, and cases where R4 is a chlorine atom, R6 is a hydrogen atom, and R6 is a hydroxyl group are excluded. ) An antitumor agent whose active ingredient is a polyacetylene compound represented by

(7) The active ingredient is a polyacetylene compound represented by the following formula (where R7 and R8 are the same or different and represent a hydrogen atom or a hydroxyl group, or R7 and R8 together represent an oxygen atom) Antitumor agent.

Hereinafter, the compounds represented by formula (1), (2) or V are collectively referred to as compounds of the formula.

For example, the following methods can be used to obtain the compound of the present invention and the compound of the formula.

The compound of the present invention and the compound of the formula can be obtained by combining herbal ginseng, its original plant Panax ginseng, or other congenerous plants with hexane, diethyl ether, petroleum ether, ethyl acetate,
Extraction is performed with at least one solvent selected from chloroform, acetone, methanol, and ethanol, and the solvent is removed from the resulting extract, and the resulting residue is extracted with hexane, diethyl ether, petroleum ether, edyl acetate, chloroform, acetone, methanol, Using at least one solvent selected from ethanol and water as an elution solvent, Diaion HP
Column chromatography or high performance liquid chromatography using Sephadex such as -20, MCI gel CI-I P 20 P, etc. as a carrier, Sephadex L) (Sephadex such as -20, reversed-phase silica gel, silica gel, polyamide, cellulose, etc.) It can be obtained by subjecting it to chromatography once or several times and purifying it by thin layer chromatography or high performance liquid chromatography.

In some cases, the raw material component may be activated manganese oxide (r
V), obtained by oxidizing using a general oxidizing agent such as chromium oxide (Vl), brominating using hydrobromic acid, etc., or iodizing using hydroiodic acid, etc. I can do it.

A specific example of the production of a compound of the formula is shown below.

Specific Example I Pulverized carrots 15 and 9 were extracted with 200 g of hexane, and the solvent was removed from the resulting extract to obtain 40 g of hexane extracted extract. This hexane extract was subjected to column chromatography using silica gel, eluted first with hexane and successively increasing amounts of ethyl acetate, and the fraction eluted with hexane-ethyl acetate (7:3) (hereinafter referred to as fraction 8). ) 24.9 g and the fraction eluted with hexane-ethyl acetate (1:1) (hereinafter referred to as fraction B)5. ．． I got 09. This fraction A was subjected to medium pressure preparative chromatography using silica gel and diluted with hexane-ethyl acetate (7:2).
Fraction 1 eluted from 9812 to 1.2812
4.229 was obtained, which was then subjected to medium pressure preparative chromatography using silica gel, and hexaneacetone (5
:I) The fraction eluted from 1.0412 to 1.25Q (hereinafter referred to as Fracun Yon C) 5.65
Fracunion eluted from 9 and 1.2612 to 1.41 (hereinafter referred to as fraction D) 0.419
I got it. Furthermore, fraction D was added to YMC-8-343 (
The product was subjected to high performance liquid chromatography using Yamamura Kagaku Kenkyushin Co., Ltd. and eluted with acetonitrile-water (4:I) to obtain 0.18y of a colorless oily substance. This colorless oily substance has the physical and chemical properties shown below, so it has a rating of 910. -epoxy-1,16-hebutadecanoen-4,6-diyn-3-ol.

Specific optical rotation: [α] 2-121.9° (c = 0.99.chloroform) Mass spectrum E I-MS m/z: 2 5 B(M'), 1
2 1.9 1FD-MS m/z:2 59(M
"+1-1) Infrared absorption spectrum ν';:+parable"
CM-I: 3436.2932, 2256° 1228.986 Ultraviolet absorption spectrum λ: Buttocks' 711W (log
ε) = 201 (3,82), 215 (sh 2.69)
.

230 (2,80), 243 (2,76) 256 (2,
54) Proton nuclear magnetic resonance spectrum (δ ppm in CDC1,): 1.38-1.42 (4T-1, m>).

1.51-1.55 (4H, m).

2.06 (28, brqt, J=7. eyes, 5Hz
).

2.38 (IH, ddd, J=18.7.IHz).

2.71 (11-1, ddd, J=18.5.IHz)
.

2.98 (I H, br td, J = 6.41-
1z).

3.10(I　)I,br　s).

3.15 (I H, ddd, J=7.5.4l-1z)
.

4. 8 9 (I H,br d
, J = 5 Hz).

4.94 (I H, ddL, J=IO, 2, 1, 5Hz
).

5.01 (I H, ddt, J = I 7.2,1
．． 5 l-1z).

5.23 (I H, ddd, J= I O, 1, 5, 1
1-1z).

5.45 (I H, ddd, J= I 7.1.5, 1
Hz).

5.81 (l H, ddd, J = I 7 , I
O, 7Hz).

5.93 (IH, ddd, J=17, 10.5Hz) 1
3C-Nuclear Magnetic Resonance Spectrum (δ ppm in CDCl5): 19.4(t), 26.3(t), 27.4(t).

28.8(t), 28.9(t), 33.6(t).

54.4 (cl), 5 7.0 (d), 63.3 (c
l).

6 G, 5(s), 7 0.6(s), 7 5.4(s
).

7 6.5 (s), 1 1 4.4 (t), l I
6.9(t).

1 3 6.3 (cl), 1 3 8.9 (d) Specific Example 2 Fraction C obtained in Specific Example 1 was subjected to medium pressure preparative chromatography using silica gel, and hexane-acetone (5:1 ) to obtain a fraction 0.169 eluting from 0.7i to 0.9/[, which was then subjected to medium pressure preparative chromatography using silica gel and eluted with hexane-acetone (18:l). A colorless oil of 0.19% was obtained. This colorless oily substance was determined to be 9°IO-evoquinol-1-heptadecen-4,6-diyn-3-one since it had the following physical and chemical properties.

Specific optical rotation, [α]! -82.9° (c=0.8.chloroform) Mass spectrum F D-MS m/z: 259 (M”+)l)E
I-MS m/z: 258 (M″″) HR-E I
-MS m/z: Calculated value 258.1620 CI? H□O7 actual value
258.11323 Infrared absorption spectrum ν Gg"c711-':2
932.2236, 1644.1202 UV absorption spectrum λ = 221" nm (Iogε); 208 (4
, 16), 261(3,70).

275(3,87), 291(3,82) proton nuclear magnetic resonance spectrum (δ pp+* in CDCl5): 0.88 (3H
, br t, J=71-1z).

1.10-I, 42 (10H, m).

1.42-1.58 (2H, m).

2.51 (I H, dd, J = I 8.6 Hz
).

2.77 (I H, dd, 1 = 18.51-f
z).

3.00 (l H,brdt, J = 6.4 Hz
).

3.19 (I H, ddd, J = 6.5.4 H
z).

6. 2 3 (l summer (, dd, J = I
O, 1.5Hz).

6.4 1 (I H, dd, J = I 7 ,
IOHz).

6.58 (II-1, dd, J=17.1.5Hz)1
3C-nuclear magnetic resonance spectrum (δ ppm in CDCl5): 14.0 (q), 19.8 (t), 22.6 (t).

26.4(t), 27.5(t), 29.1(t).

29.4(t), 31.7(t153,8(d).

56.9(d), 65.6(s), 71.0(s).

76.4(s), 84.5(s), 134.2(t).

137.7(d), 177.5(s) Specific Example 3 Fraction B obtained in Specific Example I was divided into several times and subjected to medium pressure preparative chromatography using silica gel, and hexane-ethyl acetate (7 :3) from 1.11 to 1.3072
A fraction of 0.699 was obtained. Both fractions were subjected to medium-pressure preparative chromatography using silica gel, and 0.0% was added with chloroform-methanol (100:I).
Fraction 0.2 eluted from 21 to 0.3112
I got 89. Regarding this fraction MMC-S-3
43 (manufactured by Yamamura Kagaku Kenkyushin), a peak with a retention time of about 40 minutes was fractionated with methanol-water (4:l), and a colorless oily substance (10-chloro~■- Hebutadecene-4,6-diyne-3,9-diol) was obtained.

This colorless oily substance 1819 was dissolved in dichloromethane,
0.12 g of activated manganese (IV) oxide was added, and the mixture was stirred for 30 minutes at 0°C to room temperature, and after the reaction was completed, it was filtered. After concentrating the filtrate under reduced pressure, it was subjected to medium pressure preparative chromatography using silica gel, and a slightly yellow oily substance 1219 was obtained from the fraction eluted from 187 to 24- with hexane-acetone (5:l). This pale yellow oily substance was determined to be 10-chloro-9-hydroquine-lheptadecen-4,6-diyn-3-one, based on the physical and chemical properties shown below.

Specific optical rotation: [α]. +12.8° (c=1.1.chloroform) Mass spectrum CI-MS m/z:295.297HR-CI
-M S t*/z: CI? Summer (t 4o z”CI(M ”+H
) Calculated value 295.14363 Actual value 295.14456 Infrared absorption spectrum ν CHI; 13α subtraction: 292
8.2236.1644 Ultraviolet absorption spectrum λ = buy” nm (log ε) ~
212 (4, 22), 263 (3, 74).

277(3,93), 293(3,89).

Proton nuclear magnetic resonance spectrum (δ ppIIlin CDCl5): 0.89 (3H
,br t, J=7Hz).

1.24-1.37 (8F (, m).

1.41-1.47 (I I(, m).

1.52-1.59 (l I-1, m).

1.8 mouths ~ 1. 8 6 (21-[, m)
.

2.21 (IH, d, J = 8Hz).

2.75 (2H, d, J = 6.5 Hz).

3.9 2(l I-1, dtd, J = 3.6.
5.8 Hz).

4.1 Mouth (IH, m).

6.22 (IH, dd, J=0.7.10Hz).

6.4 1(l H,dd,, I= I O,1
7Hz).

6.56 (11-1, dd, j=0.7.17Hz)1
20-Nuclear magnetic resonance spectrum (δ ppm in CDC13): 14.1(q), 22.6(t), 26.1(t).

2e, 5(t), 29.0(t), 29.1(t).

31.7(t), 34.8(t), 66.0(s).

66.8(d), 71.0(s), 71.9(d).

76.4 (s), 85.0 (s), 134.5 (t).

137.7(d), 177.7(s) Specific Example 4 Fraction C obtained in Specific Example 1 was subjected to medium pressure preparative chromatography using silica gel, and 1. By eluting from Off to 1,26e and distilling off the solvent, 5.09 of a colorless oily substance (9,10-epoxy-1-hebutadecen-4,6-diyn-3-ol) was obtained. This colorless oily substance 40Q was dissolved in 1% hydrobromic acid-acetone (20) 5- and stirred at room temperature for 4 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. After concentrating the ethyl acetate layer under reduced pressure, it was subjected to medium-pressure preparative chromatography using silica gel to obtain a colorless Ab-like substance 43, which was eluted from 0.26f2 to 0.31Q with chloroform-methanol (+00:l). I got a 9.

Based on the physical and chemical properties shown below, this mubara-like substance was determined to be 10-bromo-hebutadecene-4°6-noine-3.9-diol.

Specific optical rotation [/r1. , 38.6' (c=0.43.chloro[l-form) mass spectrum CI-MS m/z: 343.34 +.

325.323 II El -CI -MS tn/z:CIV+1
too t"I'3 r(M 11+ II) Calculated value 341.11158 Real-1 value 341.10878 Infrared absorption spectrum ν εhalf"em-'3384.
2928.2256 Ultraviolet absorption spectrum λ m S voice' nm (I
Ogε) 201 (3,98), 2 + 9 (3,10
).

230 (2,97), 243 (2,89) 257 (2,
65) Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5) 0.89 (3H, br t, J=71-1z).

1.23-I, 37 (8H, m).

1.40-I, 47 (l H, m).

1.51～! , 59 (114, m).

1.85-2.00 (2) (, m).

2, I 6 (I I-1, br).

2.23 (l H,br d,J = 81-1z
).

2.67 (2H, dd, J = 0.9.6.51 (
z).

3.71 (IH, m).

4.28 (I H, ddd, J = 3.5.9 H
z).

4.92 (I H, br t, J = 5 Hz)
.

5.26(l　H,ddd.

J=0.9.1.5.1 0Hz) 5. 4 7 (IN, ddd.

J = 0.9.1. 5.1 7 Llz).

5.94 (lH, ddd, J=5.IO, 17Hz)1
3cm nuclear magnetic resonance spectrum (δ ppm in CDCl5) 1·1.1(q), 22.6(t), 27.0(t).

27.8(L), 28.9(t), 29.1(t).

3 + , 7(t), 35.7(t), 62.7(d)
.

63.5(d), 66.8(s), 70.8(s).

72.0(d), 75.1(S), 77.0(S).

117.2(t)l 36.0(r+) Specific Example 5 Compound 22■ obtained in Specific Example 4 was dissolved in nochloromethane, 0.16 g of activated manganese (IV) oxide was added, and the mixture was heated at 0°C.
Stirred at ~room temperature for 30 minutes. After the reaction was completed, it was filtered, and the filtration filter was subjected to medium pressure preparative chromatography using silica gel after condensation under reduced pressure. d
) to 5672 (h) #1, nine slightly yellow oily substances were obtained. This pale yellow oily substance has the following physical and chemical properties, so it is known that 10-bromo-
9-Hydroxy-lheptadecene-4,6-diyne-3
- determined to be on.

Specific optical rotation = [α]D 9.8° (c = 0.97.chloroform) Mass spectrum CI-MS m/z: 34 1.399HR-CI
-MS m/z: CI? ! (th Ot" B r(M'+
H) Calculated value 341.09398 Actual value 341.09238 Infrared absorption spectrum ν=F□"an-': 301
6.2236.1644 Ultraviolet absorption spectrum λ 2 m2” 71ffi (l
ogε): 212 (4, 21), 263 (3, 72) 2
77(3,91), 294(3,87) proton nuclear magnetic resonance spectrum (δ ppm in CDCIa): 0. 8 9 (3H, br t , J =
7 Hz).

! , 23-1. 3 7 (8H, m).

1. 4 0-1. 4 9 (I H, m).

1. 52-I, 6 2 (IH, m).

1.86-2.0 1 (2H, m).

2.1 9 (IN, d, J = 8Hz).

2.7 6 (21-1, d, J = 6.5 H
z).

3.7 6 (I I-1m).

4.2 5 (I N , ddd, J = 3.5.
911z).

6.2 2(1)1. dd,,l ~0.6.1 01
1z).

6.4 1 (l [1, dd, J −1
0, I 7 1-1z).

6.56 (+11.dd, J=0.6,1711z)1
3c-nuclear magnetic resonance spectrum (δ ppn+ in CDC13): 14.1 (Q)
, 22.6(t), 25.5(t).

27.8(t), 28.9(t), 29.1(t).

31.7(t), 35.7(t), 62.6(d).

66.1(s), 71.1(s), 71.8(d).

76.4(s), 84.9(s), 134.4(t).

+37°7(d), 177.6(s) Specific Example 6 9,1O-epoxy-1-heptadecen-4,6-diyn-3-ol 40'R9 obtained in Specific Example 4 was dissolved in 1% hydrogen iodide. It was dissolved in acid-acetone (2:I) 51111 and stirred at room temperature for 4 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. After condensing the ethyl acetate layer under reduced pressure, it was subjected to medium pressure preparative chromatography using silica gel, and the concentration was reduced from 0.31C to 0.42C with chloroform-methanol (+00:I).
From the fractions eluted up to 12, a colorless oily substance 25
11 g was obtained. This colorless curved material was determined to be 10-iodo-1-hebutadecene-4,6-diyne-3°9-diol based on the physical and chemical properties shown below.

Specific optical rotation: [α], -35.4° (c = 2.57.Chloroform) Mass spectrum CI-MS m/z: 389.371 Infrared absorption spectrum ν Cow C13, -1.

3408.2928.2256 Ultraviolet absorption spectrum λ Wag”ryl (log
ε): 201 (4, 15), 232 (2, 93).

244(2,99), 257(2,96) Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 0.89(31(,br t, J=7Hz).

1.23-I, 36 (8H, m).

1.38-1.46 (IH, m).

1.51-I, 59 (I) [, m).

1.77-I, 85 (I I-1, m).

1.97-2.06 (IH, m).

2.05-2.09 (21-1, br).

2.61 (l H, ddd, J ~0.9.7.17
Hz).

2.6 5(l I(,ddd,,1 ~0.
9,6,17l-1z).

3.09 (l tl, m).

4.38 (I H, ddd, J = 3.5.9 t
lz).

4.92 (I H, br t, J = 611z)
.

5.26 (IH, dt, J=1.5, 1OHz).

5.47 (IH, ddd.

J~0.9, 1.5.17Hz).

5.9 5(I H, ddd, J = 5.1 0
, I7)[z)'3C-nuclear magnetic resonance vector (δ ppm in CDC13): 14.1(q), 22.6(t), 28.8(t).

29.2 (t), 29.1 (t), 29.8 (t).

31.8(t), 37.6(t), 47.1(d).

63.5(d), 66.9(s), 70.8(s).

72.4(d), 75.1(s), 76.9(s).

117.2(t), 136.0(d) Specific Example 7 Compound 24R2 obtained in Specific Example 6 was dissolved in dichloromethane, 0.12 g of activated manganese oxide (ff) was added, and the mixture was heated at 0°C.
Stirred at ~room temperature for 30 minutes. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure, subjected to medium pressure preparative chromatography using silica gel, and diluted with hexane-acetone (5:I) at 427 °C.
A slightly yellow oily substance 1319 was obtained from the fraction eluted from to 56-.

This slightly yellow oily substance was determined to be 9-hydroxy-10-iodo I-heptadecen-4,6-diyn-3-one, based on the physical and chemical properties shown below.

Specific rotation = [α] D-22,4° (c = 0.76, chloroform) Mass spectrum CI-MS m/z: 387,2591-1 re-
CE-MS m/z:Cl71-1 tho t
E (M'+ 1() calculation (lli 387
, 08230 Actual value 387.08330 Infrared absorption spectrum ν Cod: "C711-'
:3448.2926,2236.1644 Ultraviolet absorption spectrum λ Z"a'*" nm (logε);
212(4,14), 263C3,88).

27 B(3,85), 294(3,80) proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 0.89 (3H, br t , J = 7 + 1z)
.

1.23-1.35 (81-1, m).

1.40-1.47 (l H, m).

1.52-1.59 (IH, m).

1. 7 8-I, 8 6 (IH, m).

1.9 8 to 2.0 7 (IH, m).

2.07 (IH, d, J=8Hz).

2.70 (I H, dd, J = 7.1 7 Hz
).

2.7 5 (I H, dd, J = 6.1 7 Hz).

3.1 7 (I H, m).

4.3 5 (I H, ddd, J = 3.5.9
Hz).

6.22 (IH, dd, J=0.6.1 0Hz).

6.4 1 (I H, dd, J = 1 0.
17 Hz).

6.56 (IH, dd, J=0.6,171-1z)1
3c-Nuclear magnetic resonance spectrum (δ ppm in CDC13): 14.1 (Q), 22.6 (t), 28.7 (t).

29.1(t), 29.5(t), 29.8(t).

s t, 7(t), a 7,5(t), 46.8(d)
.

66.2(s), 71.2(s), 72.2(d).

76.4(s), 84.7(s), 134.4(t).

137.7(d), 177.6(s) Specific Example 8 The hexane extracted extract 1409 obtained in the specific fPJ1 was subjected to column chromatography using silica gel, and eluted with hexane at first and successively increasing amounts of ethyl acetate. Fraction IO eluted with hexane:ethyl acetate (8:2)
, 3g was obtained.

This fraction was divided into several times and subjected to medium pressure preparative chromatography using silica gel, and the fractions eluted from 0.95Q to 1.19Q with hexane and acetone (6:l) were collected as a colorless curved substance with 4.59 I got it. This colorless curved material has the physical and chemical properties shown below.S, (9Z) River,
It was determined to be 9-hebutadecadien-4°6-diyn-3-ol.

Specific optical rotation; [α]″7.-34.7° (c = 4.7, chloroform) Mass spectrum FI) -M S m/z: 2 4 4 (M')
, 2 2 7HR-CI-MS m/z: C
+711tsO(M”+H) Calculated value 245.190
56 Actual value 245.19246 Infrared absorption spectrum ν C kidney 13, -1.

3.100,2929.2256 Ultraviolet absorption spectrum λ222” rull (log
ε): 204 (4,08), 218 (sh 2.93)
.

23 + (2,94), 243 (2,90) 256 (2
, 64) Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 0.88 (
3H, br t, J=7Hz).

1.24-1.31 (8H, m).

1.36 (2H, br qui, J = 7 Hz)
.

2.02 (2H, br q , J = 7) 1z)
.

2.16 (IH,brs).

3゜03　(2H, ddq.

J = 6.9.1.6.0.8)1z).

4.91 (IH, br).

5.23 (IH, ddd.

J=　I　O, 1, 5, 0, 9Hz).

5.37 (l H, dtt.

J=10.6,9,1.6 Summer 1z).

5.46 (IH, ddd.

J = 17.1.5, 0.9Hz).

5.51 (1 summer (, dtt.

J~0.7.3, 1.6Hz).

5.93 (I H, ddd, J = 17.10.5
H2) 13c-nuclear magnetic resonance spectrum (δ ppm in CDCl*): 14.1(q), I 7.7(t), 22.7(t).

27.2(t), 29.1(t), 29.2(t).

29.3(t), 31.9(t), 63.5(d).

64.1(S), 71.3(S), 74.3(S).

80.3(s), 117.0(t), 122.0(d)
.

133.1(d), 136.2(d) Specific Example 9 0.079% of the compound obtained in Specific Example 8 was dissolved in dichloromethane, and 0.07% of the compound obtained in Specific Example 8 was dissolved in activated manganese (IV) oxide. Ig9 was added and stirred at room temperature for 2 hours and 30 minutes. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure and subjected to medium pressure preparative chromatography using silica gel.
．． From the fraction eluted at 0.1'L from 109, 0.049 of a slightly yellow oily substance was obtained. This pale yellow oily substance was determined to be (9Z)-1,9-hebutadecadien-4°6-diyn-3-one from the physicochemical properties shown below.

Mass spectrum FD-MS s/z: 243 (M'+H) Hlt-C
I-MS ta/z: CI? H130(M”+
H) Calculated value 243.17488 Actual value 243.17488 Infrared absorption spectrum ν gas13(?lF-':
2928.2232.1644 Ultraviolet absorption spectrum λ 222”m (logε):
203(4,16), 264(3,62).

27g(3,81), 294(3,77) proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 0.88(
3H, br t, J=7Hz).

1.25-1.32 (8H, m).

1.37 (2H, br qui, J = 7) (z
).

2.04 (2H, brq, J = 7 Hz).

3.13 (2H, dat.

J=6.9, 1.6.0.8Hz).

5.3 9 (l H, dtt.

J=10.6.9, 1.6Hz).

5.5 7 (l H, dtt.

J=IO, 7, 4, 1, 6 Hz).

6.1 9(I H, dd,, 1 =
1 0.0.6H2).

6, 4 0 (l H, dd, J= 1
7,10Hz).

6.54 (IH, dd, J=17, 0.6Hz) 13C
- Nuclear magnetic resonance spectrum (δ ppm in CDCl5): 14.1 (q), 18.0 (t), 22.6 (t).

27.3(t), 29.1(x2.t), 29.2(t
).

31.8(t), 63.5(s), 70.7(s).

77.3(s), 88.1(s), 120.7(d).

134.0((1), 134.1('t).

137.8(d), 177.8(s) Specific Example IO Hexane extract obtained in Specific Example 1 140? was subjected to column chromatography using silica gel and eluted first with hexane and successively with increasing amounts of ethyl acetate to obtain a fragment (hereinafter referred to as fraction E) 4.89 eluted with 100% ethyl acetate. This fraction was divided into several portions and subjected to medium pressure preparative chromatography using silica gel.
It eluted from i2 to 2.3012. Furthermore, this fraction was added to chromatin (18:1)
) From the fraction eluted from 0.20Q to 0.22Q, a white substance, 1-hebutadecene-4,6-diyne-
3,9°IO-triol 205ff9 was obtained. 20q of this white substance was dissolved in dichloromethane, 160i+y of activated manganese (IV) oxide was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure and subjected to medium pressure chromatography using silica gel.
7 sets: / (3:1) t'0.26ff to 0.31
Ten slightly yellow substances were obtained from the fraction eluted with &. From the physical and chemical point of view shown below, this pale yellow substance is 9.1
It was determined to be 0-dihydroxy-rhoheptadecen-4°6-diyn-3-one.

Specific optical rotation = [α] 7.9° on the field side (c = 0.65.Chloroform) Mass spectrum CI-M S m/z: 277 (M'+H)
HR-CI-MS m/z: C+t
HtsOs(M”+H) calculated value 277.1802
6 Actual value 277.17906 Infrared absorption spectrum ν K, 2r, -1°330
0.2924,2232.1646 Ultraviolet absorption spectrum λ 'mad' 77I11 (logε): 2 +
3 (4,15), 267 (3°67).

279(3,87), 295(3,85) proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 0.89 (3H, br t, J=7Hz).

l, 24-1.34 (8[-10m).

1. 3 4 ~ I , 4 0 (I
I-1, m).

1.43-1, 49 (IH, m).

1.52 (21-1, br q, J=7Hz) 1.92
．． 2.43 (l H, br s ).

2.6[3(IH, dd J=6.5 17.5Hz).

2.7 0 (I H, dd, J = 5.8.1
7.5 Hz).

3.6 0(l H, br q,, I=6.
0Hz).

3.7 0 (I Hlbr q , J = 6.
0 Hz).

6.2 2 (I H, dd.

J=10.0.7Hz).

6.4 1 (I I-1, dd.

J = 1 0.1 7.5I-1z).

6.5 6 (I H, dd.

J=17.6,0.7Hz) 13G-Nuclear Magnetic Resonance Spectrum (δ pI) min CDC13): 14.1(q)
,22.6(t),25.3(t)25.6(t),2
9.2(t), 29.5(t).

31.8 (t), 33.7 (t), 65.7 (s) 70
．． 8. (s), 72.0(d), 73.1(d).

76.8(s), 86.2(s), I34.4(t).

137.8(d), 177.8(s) Next, the fact that the compound of the present invention and the compound of the formula have an antitumor effect and are useful as an antitumor agent will be explained by giving experimental examples.

Experimental Example 1 10% L1210 mouse leukemia cells, Ehrlich cancer cells, and HeLa (II e La) cervical cancer cells
RP%+11640 (L1210° Ehrlich) or Jagle medium (II) containing tallow calf serum.
After dissolving the compound obtained in the specific example or example (hereinafter referred to as test drug) in dimethyl sulfoxide (DMSO) , diluted in physiological saline and added to various concentrations (DMSO: 0.
5%). This was placed in a carbon dioxide incubator at 37°C.
, After 48 hours of culture, cell proliferation was measured using the MTT method (j, 1 mm
unol.

Method 65, 55.1983).

The absorbance at each concentration after 48-hour incubation is A, the absorbance of the control after 48-hour incubation is 81, and the absorbance before adding the test drug is C, and the proliferation reaction rate at each 'a degree is determined from the following formula. , the test drug concentration at which the proliferation response rate is 50% of the control (IC
s. value) was calculated.

-C The results are shown in Table 1.

From the above results in Table 1, the inhibitory effect of the test drug on mouse and human cancer cell proliferation was confirmed. In addition, some compounds, such as the compounds obtained in Specific Example 5 and Specific Example IO, were found to have a stronger inhibitory effect on human cancer cell growth than naturally occurring polyacetylene compounds.

Experimental Example 2 Two million Ehrlich cancer cells were intraperitoneally transplanted into IcR female mice, and from the next day, 9 was added to 110 OR/1 of the test drug.
Suspended in physiological saline containing 0% DMSO, 3 times daily.
The drug was administered intraperitoneally, and the average survival days and survival rate (%) were determined. In addition, for the control group, only physiological saline containing 10% DMSO was administered intraperitoneally.

The results are shown in Table 2.

From the above results, the life prolonging effect of the compound obtained in Example 6 was confirmed.

Dosage forms and formulations of the compounds of the present invention and formulas will now be described.

The compounds of this invention and formulas can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and can be selected and used as necessary, and examples include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and incarcerated medicines. .

In order to exert the desired effect as an oral agent, it is usually necessary for an adult to administer 5 to 500 doses of the compound of the present invention or the compound of the formula for several days, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take the drug in divided doses.

Oral agents include, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[t01 Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, 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.

The compounds of the invention can also be administered as suspensions, emulsions, syrups, elixirs,
These various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, the compound of the present invention or the compound of the formula must be administered in an amount of 0.00 mg per day for an adult, although this will vary depending on the patient's age, weight, and severity of the disease.
Intravenous injection, intravenous drip infusion, subcutaneous injection, and intramuscular injection up to 5 to 1 OO19 are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the lyophilized product before use. Furthermore, an isotonizing agent, a stabilizer, a preservative, an anti-notification agent, etc. may be added as appropriate.

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

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to this in any way.

Example 1 Fraction A obtained in Example I was divided into several portions and subjected to medium pressure chromatography using silica gel, and hexane:
The fractions eluted from 0.98ff to 1.28Q with ethyl acetate (7:2) were eluted with hexane:acetone (5:I
) was eluted from 0.8812 to 1.01&, and a fraction of 0.59 g was obtained. This fraction was converted into MMC-S
-343 (manufactured by Yamamura Kagaku Kenkyushin) and frankin eluted with methanol:water (4:I) was subjected to medium pressure preparative chromatography using silica gel. Setoni/(10:I)
0.0149 of a colorless oily substance was obtained from the fraction eluted with 0.16812 from TEO,I 62 (2).This colorless oily substance has the following physicochemical properties, so it is 9,IO-epoxy-4. ,6-heptadecadiine-
It was decided to be 3-all.

Specific optical rotation: [α], -90.7° (c = 3.0, chloroform) Mass spectrum CI-MS m/z: 2 6 3
(M" + f-1) HR-CI-M S l
/Z:Cl? Hyso t(M”+ l-1) Calculated value +
263.20113 Actual value: 263.20153 Infrared absorption spectrum ν g':"113c11-
': 3400.2256.1462 Ultraviolet absorption spectrum λ Z'a2" 7+Il! (
IOgε); 200 (3,68), 230 (2,76)
241 (2,75), 255 (2,62) proton nuclear magnetic resonance spectrum (δ ppm in CDCl, ); 0.89 (3H, br t, J=71-1z).

1.01 (3H, t, J = 7 Hz).

1.25-1.40 (8H, m).

1.43-1.56 (4H, m).

1.68-1.80 (2H, m).

2.17 (IH, br).

2.3 8 (I H, ddd, J = I 7
,5. IHz).

2.70 (l H, ddd, J = 17.5.1 H
z).

2. 9 7 (I r-1, br td, J
= 6. 4 Summer (2).

3.15 (I H, ddd,, I=7.5.4l-1z
).

4.36 (I H, br L, J = 6 Hz)
13c-nuclear magnetic resonance spectrum (δ pp+n in CDC11): 9.3(q),
14.1(Q), 19.4(t).

22.6(t), 26.5(t), 27.5(t).

29.2(t), 29.4(t), 30.7(t).

31.8(t), 54.4(d), 57.0(d).

64.0(d), 66.5(s), 69.5(s).

7 6.0 (s), 7 7.5 (s) Example 2 Fraction E obtained in Specific Example 10 was divided into several portions and subjected to medium pressure chromatography using silica gel, and hexane:acetone (3: 1) from 2.3012 to 3.0012
The fraction eluted from 0.05Q to 000912 was eluted with chloroform:methanol (25:l), and this fraction was further eluted with hexane:acetone (6:1).
A white substance 17iy was obtained from the fraction eluted from 0.28C to 0.3812 in 1). This white substance was determined to be 1,16-hebutadecadien-4,6-diyne-3,9,10-)liol because it had the following physical and chemical properties.

Specific optical rotation = [α]D -t6.5° (c = 1.5, chloroform) Mass spectrum CI-MS m/z: 277 (M'+1-1-1)H
R-CI-l/Z:C1? Hts03 (M'+H) Calculated value: 277.18027 Actual value: 277.17987 Infrared absorption spectrum ν Cod s C71K -"34
00,2256.1422 Ultraviolet absorption spectrum λ Hto”nmcIogε)
=201(4,51), 217(2,83).

231 (2,88), 243 (2,84).

257 (2,61) Proton nuclear magnetic resonance spectrum (δ pPn+ in CDCl5): 1.30 (6
H, m).

1.45-1.53 (211, m).

2.06 (2H, br Qt, J = 7, I, 5
Hz).

2.56 (l H, ddd, J = 17, 6.5.I
Hz).

2.6 0(I H, ddd, 1 - 1
7.5.7. IHz).

3.59 (I tl, br ddd, J = 6.5
．． 4 Hz).

3.64 (I H, ddd, 1 = 6.5.4
Hz).

4. 9 2 (I H, br d, J
= 5 Hz).

5.00 (l H, ddt, J = 17.2, 1.5
Hz).

5.25 (l H, ddd, J= I O, 1, 5, 1
Hz).

5.47 (I H, ddd, J = 17.1.5.I
Hz).

5.8 I (I H, dat, J
= 1 7. 1 0. 7 Hz).

5.94 (IH, ddd, J = I7, 10.5 Hz) C-nuclear magnetic resonance vector (δ ppm in CDC13): 25.0 (t), 25.4 (t), 28.8 (t ).

29.0(t), 33.5(t), 33.7(t).

63.5(d), 66.5(s), 70.9(s).

72.2(d), 73.1(d), 74.8(s).

78.1 (s), 114.4 (t), I I 7.2 (
t).

136.1 (d), 139.0 (d) Example 3 ■Corn starch 449 ■Crystalline cellulose 409 ■Carboxymethylcellulose calcium 5g ■Light silicic anhydride 0.59■Magnesium stearate 0.59■Specific examples! Compound obtained with
10g total 1009 According to the above recipe, ① to ② were mixed uniformly and compressed using a tablet machine to obtain tablets of 200 my in size.

These tablets contain compound 20119, and adults take 5 to 25 tablets a day in several doses.

Example 4 ■ Crystalline cellulose 84.59 ■ Magnesium stearate 0.59 ■ Calcium carboxymethyl cellulose 5 g ■ Compound obtained in specific example 2 109 Total 1009 Parts of ■, ■, and ■ were uniformly mixed according to the above recipe, After compression molding, the mixture was pulverized, the remaining amounts of (1) and (2) were added and mixed, and the mixture was compressed and molded using a tablet machine to obtain 20011 g of tablets.

This tablet-tablet contains compound 2 (Mg,
For adults, take 5 to 25 tablets a day in several divided doses.

Example 5 ■Crystalline cellulose 49.59■■0% hydroxypropyl cellulose ethanol solution 359 ■Carboxymethylcellulose calcium 59 ■Magnesium stearate 0.5g■Specific example! Compound 109 (Total: 100g) According to the above recipe, mix ■, ■, and ■ uniformly, neutralize by conventional method, granulate with extrusion granulator, dry and crush, and then mix ■ and ■. The mixture was compressed and molded using a tablet machine to obtain 200 tablets.

These tablets contain the compound 2ON9 obtained in Specific Example (1), and are taken by adults in 5 to 20 tablets a day in several doses.

Example 6 ■Corn starch 84g ■Magnenium stearate 0, '59■Carboxymethyl cellulose calcium 59 ■Light silicic anhydride 0.59■Compound obtained in Example 2 10g Total 100g Mix ■~■ uniformly according to the above recipe. After compression molding using a compression molding machine, the mixture was crushed using a crusher and sieved to obtain granules.

To 1 g of this granule, add C, the compound obtained in Example 2 + 00M
9, and adults should take 1 to 10 g per day in several doses.

Example 7 ■ Crystalline cellulose 559 ■ 35 g of 10% hydroxypropylcellulose in ethanol ■ Compound obtained in Example 3 109 Total 100 g According to the above recipe, ■ to ■ were mixed uniformly and made into a paste. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

1 g of this granule contains 100 R of the compound obtained in Specific Example 3.
9, and adults should take 1 to 4 g per day in several doses.

Example 8 ■Corn starch 8959 ■Light silicic anhydride 0.5 g ■Compound obtained in specific example 4 tog Total 100 g Mix ■~■ uniformly according to the above recipe, and mix 200 R
9 was filled into a No. 2 capsule.

One capsule of this preparation contains Compound 20 Ash 9 obtained in Example 4, and adults should take 5 to 20 capsules a day in several doses.

Example 9 ■ Distilled water for injection 89.5g ■ Soumoura
59 ■Soybean phospholipid 2.5g ■Glycerin
29 ■ Compound obtained in Specific Example 5 19 Total amount +009 Dissolve ■ in ■ and ■ according to the above recipe, and add ■ to this.
and (2) were added to emulsify the mixture to obtain an injection.

Claims (7)

[Claims] (1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I A new polyacetylene compound represented by (2) Formula II below ▲There are mathematical formulas, chemical formulas, tables, etc.▼II A new polyacetylene compound represented by (3) The following formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ An antitumor agent whose active ingredient is a polyacetylene compound represented by I. (4) An antitumor agent whose active ingredient is a polyacetylene compound represented by the following formula II ▲Mathematical formulas, chemical formulas, tables, etc.▼II. (5) Formula III below ▲Mathematical formulas, chemical formulas, tables, etc.▼III (However, R_1 represents an ethyl group or an ethylene group,
R_2 and R_3 are the same or different hydrogen atoms,
It represents a hydroxyl group, or R_2 and R_3 together represent an oxygen atom. Note that cases in which R_1 is an ethyl group, R_2 is a hydroxyl group, and R_3 is a hydrogen atom and cases in which R_1 is an ethyl group, R_2 is a hydrogen atom, and R_3 is a hydroxyl group are excluded. ) is an antitumor agent whose active ingredient is a polyacetylene compound. (6) Formula IV below ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV (However, R_4 represents a chlorine atom, bromine atom, iodine atom, or hydroxyl group, and R_5 and R_6 are the same or different and represent a hydrogen atom, a hydroxyl group, or R_5 and R_
6 together represent an oxygen atom. In addition, when R_4 and R_5 are a hydroxyl group and R_6 is a hydrogen atom, when R_4 and R_6 are a hydroxyl group and R_5 is a hydrogen atom, when R_4 is a chlorine atom, R_5 is a hydroxyl group, and R_6 is a hydrogen atom, and when R_4 is a hydroxyl group and R_6 is a hydrogen atom, Excludes cases where chlorine atom, R_5 is a hydrogen atom, and R_6 is a hydroxyl group. ) An antitumor agent whose active ingredient is a polyacetylene compound represented by (7) Formula V below ▲There are mathematical formulas, chemical formulas, tables, etc.▼V (However, R_7 and R_8 are the same or different and represent a hydrogen atom or hydroxyl group, or R_7 and R_8 together represent an oxygen atom.) An anti-tumor agent containing the above polyacetylene compound as an active ingredient.