JPH08301831A - Stilbene derivative and carcinostatic agent containing the same - Google Patents

Abstract

PURPOSE: To obtain a readily synthesized combretastatin derivative useful as a carcinostatic agent having low toxicity and high therapeutic effects. CONSTITUTION: This stilbene derivative of formula I (X is H or nitrile; Y is an L-α-amino acid acyl), e.g. (Z)-1-(3-amino-4-methoxyphenyl)-2(3,4,5- trimethoxyphenyl)-ethene-glycinamide. The derivative of formula I is obtained by reacting (Z)-1-(3-amino-4-methoxyphenyl)2-(3,4,5-trimethoxyphenyl)-ethene of formula II with an N-α-9-fluorenylmethoxycarbonylamino acid derivative of formula III (Fmoc is N-α-9-fluorenylmethoxycarbonyl; AA is an amino acid acyl) in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in dimethylformamide at ambient temperature for 6-12hr, purifying the resultant compound and then deprotecting the purified compound with aqueous sodium hydroxide. The compound of formula I as a carcinostatic agent is usually used in a dose of 1-3000mg for an adult and daily 1-9000mg divided into several portions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cis-stilbene derivative and a carcinostatic agent containing these compounds as active ingredients.

[0002]

2. Description of the Related Art Combretastatins having cis-stilbene as a basic skeleton are known to have strong mitotic inhibitory activity and strong cytotoxicity, but such compounds are difficult to dissolve in water. For some reason, it has not been put into practical use as a medicine. Therefore, various developments of its derivative have been studied (CHII M LIN et al, Molecular Phar.
macology 34, 200-206, 1988. Mark Cushman et al, J.
Med. Chem., 1991, 34, 2579-2588, International Patent Publication WO 92/16486, Mark Cushman et al, J. Med. C.
hem., 1992, 35, 2293-2306, International Patent Publication WO
93/23357, Mark Cushman et al, J. Med. Che
m., 1993, 36, 2817-2821, Ryuichi Shiraiet al, Bioo
Med. Chem. Let., Vol. 4, No. 5, pp699-704, 199
4), no effective compound has been found yet.

[0003]

DISCLOSURE OF THE INVENTION It is an object of the present invention to find a combretastatin derivative which is easy to synthesize, has low toxicity and high therapeutic effect, and provides it as an anticancer agent.

[0004]

Means for Solving the Problems The present inventors have diligently searched for compounds having an antitumor activity by binding an amino acid acyl group to various stilbene derivatives, and as a result, compounds represented by the following general formula (1) In animal tests, they found that they have a remarkable anti-cancer effect and have low toxicity, and completed the present invention. These compounds have never been synthesized and are completely novel cis-stilbene derivatives.

[0005]

Embedded image (In the formula, X represents a hydrogen atom or a nitrile group, and Y represents an amino acid acyl group.)

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), the amino acid acyl group is an acyl group derived from an amino acid.
-Amino acids are included. Preferred amino acids are glycine, alanine, leucine, serine, lysine, glutamic acid, aspartic acid, threonine, valine, isoleucine, ornithine, glutamine, asparagine, tyrosine, phenylalanine, cysteine, methionine, arginine, β-alanine, tryptophan, proline,
Histidine and the like can be mentioned, and threonine or serine is particularly preferable from the viewpoint of efficacy and safety. These amino acids are L
Either the body or the D body may be used, but the L body is preferred.

Examples of preferable compounds include the following compounds. (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Glycinamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-alaninamide, (Z) -1-
(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -ethene-β-alanine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl)
-Ethene-L-leucinamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-serinamide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
L-threonine amide, (Z) -1- (3-amino-4)
-Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-valinamide, (Z) -1
-(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -ethene-L-isoleucinamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L -Prolinamide, (Z) -1- (3
-Amino-4-methoxyphenyl) -2- (3,4,5)
-Trimethoxyphenyl) -ethene-L-methioninamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-glutamineamide , (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-glutamylamide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
L-aspartylamide, (Z) -1- (3-amino-
4-Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-asparaginamide.

(Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-lysineamide, (Z) -1- (3-
Amino-4-methoxyphenyl) -2- (3,4,5-
Trimethoxyphenyl) -ethene-L-histidine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-argininamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-cysteine amide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
L-tryptophanamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-tyrocyanianamide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
L-phenylalanine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-L-ornithine amide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
D-alanine amide, (Z) -1- (3-amino-4-
Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-leucinamide, (Z) -1
-(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -ethene-D-serinamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl)-
Ethene-D-threonine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-valine amide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
D-isoleucine amide, (Z) -1- (3-amino-
4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-prolinamide, (Z)
-1- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -ethene-D-
Methioninamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-glutamineamide, (Z) -1
-(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -ethene-D-glutamylamide.

(Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-aspartylamide, (Z) -1-
(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -ethene-D-asparaginamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D -Lysine amide, (Z) -1- (3-
Amino-4-methoxyphenyl) -2- (3,4,5-
Trimethoxyphenyl) -ethene-D-histidine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-argininamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-cysteine amide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
D-tryptophanamide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-tyrosineamide,
(Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
D-phenylalanine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -ethene-D-ornithine amide,
(E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-glycinamide, (E) -3- (3
-Amino-4-methoxyphenyl) -2- (3,4,5)
-Trimethoxyphenyl) -prop-2-enenitrile-L-alanine amide, (E) -3- (3-amino-4)
-Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-β-alanine amide, (E) -3- (3-amino-4-methoxyphenyl) -2- ( 3,4,5-trimethoxyphenyl)
-Prop-2-enenitrile-L-leucinamide,
(E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-L-isoleucine amide, (E)-
3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-L-serinamide, (E) -3- (3-
Amino-4-methoxyphenyl) -2- (3,4,5-
Trimethoxyphenyl) -prop-2-enenitrile-
L-threonine amide, (E) -3- (3-amino-4)
-Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-L-phenylalanine amide.

(E) -3- (3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-L-tyrosineamide, (E) -3 -(3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-L-prolinamide, (E)
-3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-L-lysine amide, (E) -3- (3-
Amino-4-methoxyphenyl) -2- (3,4,5-
Trimethoxyphenyl) -prop-2-enenitrile-
L-histidine amide, (E) -3- (3-amino-4)
-Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-L-argininamide, (E) -3- (3-amino-4-methoxyphenyl) -2- ( 3,4,5-Trimethoxyphenyl) -prop-2-enenitrile-L-cysteine amide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxy Phenyl) -prop-2-enenitrile-L-methioninamide,
(E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-L-tryptophanamide, (E)
-3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-L-α-aspartylamide, (E)-
3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-L-β-aspartylamide, (E)-
3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-L-asparaginamide, (E) -3-
(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -prop-2-enenitrile-L-α-glutamylamide, (E) -3- (3
-Amino-4-methoxyphenyl) -2- (3,4,5)
-Trimethoxyphenyl) -prop-2-enenitrile-L-γ-glutamylamide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl)- Prop-2-enenitrile-L-
Glutamine amide, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-L-ornithine amide.

(E) -3- (3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D-alaninamide, (E) -3 -(3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D-leucinamide, (E)
-3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-D-isoleucine amide, (E) -3-
(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -prop-2-enenitrile-D-serinamide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl)- Prop-2-enenitrile-D-threonine amide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D- Phenylalanine amide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D-tyrosineamide, (E) -3 -(3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D-prolinamide, (E)
-3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-D-lysine amide, (E) -3- (3-
Amino-4-methoxyphenyl) -2- (3,4,5-
Trimethoxyphenyl) -prop-2-enenitrile-
D-histidine amide, (E) -3- (3-amino-4)
-Methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D-argininamide, (E) -3- (3-amino-4-methoxyphenyl) -2- ( 3,4,5-Trimethoxyphenyl) -prop-2-enenitrile-D-cysteine amide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxy Phenyl) -prop-2-enenitrile-D-methioninamide,
(E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-D-tryptophanamide.

(E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D-α-aspartylamide, (E ) -3- (3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl)
-Prop-2-enenitrile-D-β-aspartylamide, (E) -3- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2- Ennitrile-D-asparaginamide,
(E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-D-α-glutamylamide, (E)
-3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile-D-γ-glutamylamide, (E) -3
-(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -prop-2-enenitrile-D-glutamine amide. (Z) -1- (3-Amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) -prop-2-enenitrile-D
-Ornithine amide.

The compound of the present invention represented by the general formula (1) can be synthesized, for example, according to the following production route.

[0014]

Embedded image (In the formula, Fmoc represents an N-α-9-fluorenylmethoxycarbonyl group, and AA represents an amino acid acyl group.)

[0015]

[Chemical 4] (In the formula, Fmoc and AA have the same meanings as described above.
Represents a t-butoxycarbonyl group. )

The compound represented by the formula (5) which belongs to the compound of the present invention is, for example, (Z) -1-represented by the formula (2).
(3-amino-4-methoxyphenyl) -2- (3,
4,5-Trimethoxyphenyl) -ethene and the N-α-9-fluorenylmethoxycarbonylamino acid derivative represented by the formula (3) were mixed with dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzomide in dimethylformamide at room temperature. 6-1 in the presence of triazole (HOBt)
After reacting for 2 hours, it is purified by using chromatography or the like to obtain the intermediate (4), which can be obtained by deprotecting the intermediate with aqueous sodium hydroxide.

Further, the compound represented by the formula (10), which belongs to the compound of the present invention, is represented by the formula (6) (E), for example.
-3- (3-amino-4-methoxyphenyl) -2-
(3,4,5-Trimethoxyphenyl) -prop-2-
Ennitrile and an N-α-t-butoxycarbonylamino acid derivative represented by the formula (7) were added to 1-ethyl-3- (3-dimethylaminopropyl) in dimethylformamide.
It can be obtained by reacting in the presence of carbodiimide (WSCI) at 50 ° C. for 4 hours to synthesize (9) and then deprotecting with hydrochloric acid-dioxane. Alternatively, the compound represented by the formula (6) and the amino acid derivative represented by the formula (3) are mixed with benzotriazol-1-yl-oxy- in acetonitrile.
What is obtained by reacting in the presence of tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) and triethylamine at 60 ° C. for 24 hours to synthesize (8) and then deprotecting with aqueous sodium hydroxide or piperidine You can

The stilbene derivative of the present invention produced by the above method can be easily separated and purified from the reaction mixture by a conventional isolation and purification means, for example, extraction with a solvent, chromatography, crystallization and the like. .

In the present invention, when the stilbene derivative is used as a carcinostatic agent, it is administered orally or parenterally (intramuscularly, subcutaneously, intravenously, suppository, etc.). Although the dose varies depending on the symptoms, it is generally 1 to 9000 mg per day in a dose range of 1 to 3000 mg per adult, generally divided into several doses.

Further, when preparing the oral preparation of the stilbene derivative of the present invention, after adding an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. , Tablets, coated tablets, granules, capsules and the like are prepared by a conventional method. As the excipient, for example, lactose, corn starch, sucrose, butter sugar, sorbit, crystalline cellulose and the like, and as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, acacia, tragacanth, gelatin, shellac, hydroxypropyl. Examples include cellulose, hydroxypropyl starch, polyvinylpyrrolidone, and the like.

Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextran, pectin and the like, and examples of the lubricant include magnesium stearate, talc and polyethylene glycol. , Silica, hydrogenated vegetable oil, etc., which are allowed to be added to pharmaceuticals as a coloring agent, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder etc. are used as flavoring agents. To be Granules of these tablets may be coated with sugar, gelatin, or any other suitable coating, if necessary.

When preparing an injection, the pH may be adjusted as necessary.
A regulator, a buffering agent, a stabilizer, a preservative and the like are added, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method. The stilbene derivative of the present invention is pharmaceutically acceptable with inorganic salts such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic salts such as oxalic acid, fumaric acid, maleic acid, malic acid, citric acid, tartaric acid and glutamic acid, if necessary. Acid addition salt.

[0023]

The present invention will be described in detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of glycinamide

Step 1 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of Fmoc-glycinamide (Z) -1- (3-amino-4-methoxyphenyl)-
2.0 g (6.3 mmol) of 2- (3,4,5-trimethoxyphenyl) -ethene, Fmoc-Gly2.3
g, BOP reagent 11 g (25 mmol) were dissolved in dimethylformamide 40 ml and heated at 60 ° C. for 2 hours.
After cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted 3 times with dichloromethane. Dried over anhydrous sodium sulfate,
The residue was dried under reduced pressure. Purification by silica gel column chromatography (ethyl acetate: hexane / 1: 2) gave 1.63 g of the desired product. (Yield 43.5%)

1H-NMR (CDCl3) δ; 8.29 (1H, s), 8.11 (1H
, s), 7.76 (2H, d, J = 7.5), 7.60 (2H, d, J = 7.5), 7.39
(2H, t, J = 7.2), 7.30 (2H, m), 7.00 (1H, dd, J = 1.8, 8.
7), 6.70 (1H, d, J = 8.7), 6.51 (1H, d, J = 12,3), 6.44
(1H, d, J = 12.3), 4.44 (2H, d, J = 6.6), 4.25 (1H, m),
4.04 (2H, 2H, br), 3.84 (3H, s), 3.79 (3H, s), 3.68 (6
H, s); Mass spectrum m / z: 594 (M ⁺ )

Step 2 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of glycinamide (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
1.08 g of Fmoc-glycinamide (1.82 mmo
1) was dissolved in 20 ml of methanol, 1.0 ml (2.0 mmol) of 2N aqueous sodium hydroxide was added, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate was added, the mixture was extracted 3 times with dichloromethane, dried over anhydrous sodium sulfate, and dried under reduced pressure. Purification with silica gel plate (5% methanol / dichloromethane) gave 479 mg of the desired product. (Yield 70.7%)

1H-NMR (CDCl3) δ; 9.61 (1H, brs), 8.36 (1
H, d, J = 1.8), 7.00 (1H, dd, J = 1.8,8.4), 6.72 (1H, d,
J = 8.4), 6.51 (2H, s), 6.53 (1H, d, J = 12.0), 6.42 (1
H, d, J = 12.0), 3.87 (3H, s), 3.83 (3H, s), 3.68 (6H,
s); Mass spectrum m / z: 373 (MH ⁺ ); High resolution mass spectrum Calculated value 373.1763, Measured value 373.1751

Example 2 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-alanine amide

Step 1 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of Fmoc-L-alanine amide (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene 2.2 g (6.9 mmol), Fmoc-L-Ala.
2.7 g (8.3 mmol), BOP reagent 12.1 g
22 ml of dimethylformamide (27.6 mmol)
And heated at 60 ° C. for 4 hours. After cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted 3 times with dichloromethane. It was dried over anhydrous sodium sulfate and dried under reduced pressure. Purification by silica gel column chromatography (ethyl acetate: hexane / 1: 2) gave 1.79 g of the desired product.
(Yield 41.4%)

1H-NMR (CDCl3) δ; 8.32 (1H, d, J = 1.8),
8.19 (1H, brs), 7.76 (2H, d, J = 7.2), 7.59 (2H, d, J = 7.
2), 7.39 (2H, t, J = 6.9), 7.32 (2H, m), 7.01 (1H, dd, J
= 1.8,8.7), 6.69 (1H, d, J = 8.4), 6.52 (2H, s), 6.51 (1
H, d, J = 12.0), 6.44 (1H, d, J = 12.0), 5.35 (1H, brs),
4.42 (3H, br), 4.24 (1H, m), 3.84 (3H, s), 3.79 (3H,
s), 3.69 (6H, s), 1.48 (3H, d, J = 6.9); mass spectrum m / z: 608 (M ⁺ ).

Step 2 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-alanine amide (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
1.0 g of Fmoc-L-alanine amide (1.6 mmo
l) was dissolved in 10 ml of methanol, 0.9 ml (1.76 mmol) of 2N aqueous sodium hydroxide was added, and the mixture was stirred for 3 hours. Saturated saline was added, the mixture was extracted 3 times with dichloromethane, dried over anhydrous sodium sulfate, and dried under reduced pressure. Purification with silica gel plate (5% methanol / dichloromethane) gave 543 mg of the desired product. (Yield 87.9%)

1H-NMR (CDCl3) δ; 9.72 (1H, brs), 8.39 (1
H, d, J = 2.1), 6.99 (1H, dd, J = 2.1,8.4), 6.71 (1H, d,
J = 8.4), 6.52 (1H, d, J = 12.3), 6.52 (2H, s), 6.42 (1
H, d, J = 12.3), 3.86 (3H, s), 3.83 (3H, s), 3.68 (6H,
s), 3.64 (1H, m), 1.43 (3H, d, J = 7.2); mass spectrum
m / z: 387 (MH ⁺ ); High-resolution mass spectrum calculated 38
7.1920, measured 387.1922.

Example 3 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-leucinamide

Step 1 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of Fmoc-L-leucinamide (Z) -1- (3-amino-4-methoxyphenyl)-
1.92 g (6.1 mmol) of 2- (3,4,5-trimethoxyphenyl) -ethene, Fmoc-L-Leu
2.58 g (7.3 mmol), DCC 1.5 g (7.
3 mmol), HOBt · H ₂ O 1.1 g (7.3 mm)
was dissolved in 40 ml of dimethylformamide and reacted at room temperature for 12 hours. The mixture was diluted with ethyl acetate and then filtered and concentrated. Purify by silica gel column chromatography (ethyl acetate: hexane / 1: 2) to obtain the desired product 3.05.
g was obtained. (Yield 76.9%)

1H-NMR (CDCl3) δ; 8.32 (1H, d, J = 2.1),
8.19 (1H, s), 7.75 (2H, d, J = 7.5), 7.58 (2H, d, J = 7.
5), 7.39 (2H, t, J = 6.9), 7.29 (2H, m), 7.00 (1H, dd, J
= 2.1, 8.4), 6.69 (1H, d, J = 8.4), 6.51 (2H, s), 6.50
(1H, d, J = 12.3), 6.43 (1H, d, J = 12.3), 5.29 (1H, br
s), 4.43 (2H, d, J = 6.9), 4.23 (1H, t, J = 6.9), 3.83 (3
H, s), 3.79 (3H, s), 3.68 (6H, s), 1.75 (2H, br), 11.
55 (1H, br), 0.95 (6H, br); Mass spectrum m / z: 650 (
M ⁺ )

Step 2 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-leucinamide (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
1.0 g of Fmoc-L-leucinamide (1.54 mm
10 ml of methanol and 10 ml of dichloromethane.
Dissolved in 2N sodium hydroxide water 0.9ml (1.7m
(mol) was added and stirred for 3 hours. Saturated saline was added, the mixture was extracted 3 times with dichloromethane, dried over anhydrous sodium sulfate, and dried under reduced pressure. Purification with a silica gel column (10% methanol / dichloromethane) gave 560 mg of the desired product. (Yield 84.9%)

1H-NMR (CDCl3) δ; 9.78 (1H, brs), 8.41 (1
H, d, J = 1.8), 6.99 (1H, dd, J = 1.81,8.4), 6.70 (1H,
d, J = 8.4), 6.52 (1H, d, J = 12.3), 6.52 (2H, s), 6.42
(1H, d, J = 8.4), 3.87 (3H, s), 3.83 (3H, s), 3.68 (6H,
s), 3.51 (1H, m), 1.80 (2H, m), 1.42 (1H, m), 0.98 (6
H, t, J = 6.6) Mass spectrum m / z: 429 (MH ⁺ ); High resolution mass spectrum Calculated 429.2389, Measured 429.2
391

Example 4 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-serinamide

Step 1 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of Fmoc-L-serinamide (Z) -1- (3-amino-4-methoxyphenyl)-
1.5 g (4.76 mmol) of 2- (3,4,5-trimethoxyphenyl) -ethene, Fmoc-L-Ser
(Ac) 2.1 g (5.7 mmol), DCC 1.2 g
(5.7 mmol), HOBt · H ₂ O 0.87 g
(5.7 mmol) was dissolved in 30 ml of dimethylformamide and reacted at room temperature for 5 hours. The mixture was diluted with ethyl acetate and then filtered and concentrated. Purification by silica gel column chromatography (ethyl acetate: hexane / 1: 2) gave 1.96 g of the desired product. (Yield 61.8%)

1H-NMR (CDCl ₃ ) δ; 8.38 (1H, br), 8.30 (1H,
d, J = 1.8), 7.76 (2H, d, J = 7.8), 7.59 (2H, d, J = 7.
8), 7.40 (2H, t, J = 7.2), 7.32 (2H, m), 7.03 (1H, dd, J
= 1.8, 8.7), 6.71 (1H, d, J = 8.7), 6.51 (2H, s), 6.51
(1H, d, J = 12.3), 6.45 (1H, d, J = 12.3), 5.53 (1H, br
s), 4.62 (1H, br), 4.45 (2H, d, J = 6.9), 4.25 (1H, m),
3.83 (3H, s), 3.80 (3H, s), 3.69 (6H, s), 2.65 (2H,
d, J = 9.3), 2.1 (3H, s) ； Mass spectrum m / z: 666 (M
⁺ )

Step 2 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-serinamide (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
1.04 g of Fmoc-L-serinamide (1.56 mm
10 ml of methanol and 10 ml of dichloromethane.
Dissolved in 2N aqueous sodium hydroxide 1.7 ml (3.4 m
(mol) was added and the mixture was stirred at room temperature for 24 hours. Saturated saline was added, the mixture was extracted 3 times with dichloromethane, dried over anhydrous sodium sulfate, and dried under reduced pressure. Silica gel plate (5
% Methanol / dichloromethane) to give the desired product 31
5 mg was obtained. (Yield 50.2%)

1H-NMR (CDCl3) δ; 9.77 (1H, brs), 8.34 (1
H, d, J = 2.1), 7.01 (1H, dd, J = 2.1,8.7), 6.73 (1H, d,
J = 8.7), 6.52 (2H, s), 6.51 (1H, d, J = 12.3), 6.43 (1
H, d, J = 12.3), 3.98 (1H, dd, J = 4.8, 11.1), 3.87 (3H,
s), 3.84 (3H, s), 3.79 (1H, dd, J = 5.4, 11.1), 3.69 (6
H, s), 3.59 (1H, dd, J = 5.1, 5.4); mass spectrum m /
z: 403 (MH +); High-resolution mass spectrum calculated 403.18
69, measured 403.1862

Example 5 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-threonine amide

Step 1 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of Fmoc-L-threonine (Ac) amide (Z) -1- (3-amino-4-methoxyphenyl)-
1.5 g (4.76 mmol) of 2- (3,4,5-trimethoxyphenyl) -ethene, Fmoc-L-Thr
(Ac) 2.2 g (5.7 mmol), DCC 1.2 g
(5.7 mmol), HOBt · H ₂ O 0.87 g
(5.7 mmol) was dissolved in 30 ml of dimethylformamide and reacted at room temperature for 6 hours. 50 ml of ethyl acetate
It was diluted with and filtered and concentrated. Purification by silica gel column chromatography (ethyl acetate: hexane / 1: 2) gave 2.97 g of the desired product. (Yield 91%)

1H-NMR (CDCl3) δ; 8.36 (1H, brs), 8.29 (1
H, d, J = 2.4), 7.77 (2H, m), 7.61 (2H, m), 7.28-7.44
(4H, m), 7.02 (1H, dd, J = 2.1, 8.7), 6.72 (1H, d, J =
8.7), 6.51 (2H, s), 6.51 (1H, d, J = 12.0), 6.45 (1H,
d, J = 12.0), 5.72 (1H, m), 5.40 (1H, m), 4.48 (2H, m),
4.25 (1H, m), 3.83 (3H, s), 3.82 (3H, s), 3.69 (6H,
s), 2.08 (3H, s), 1.24 (3H, m); mass spectrum m / z: 6
80 (M ⁺ )

Step 2 (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
Synthesis of L-threonine amide (Z) -1- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -ethene-
1.0 g of Fmoc-L-threonine (Ac) amide
Dissolve (1.47 mmol) in 20 ml of dioxane 2
N sodium hydroxide water 1.76 ml (3.5 mmol)
Was added and stirred for 24 hours. Saturated saline solution was added, extracted three times with dichloromethane, dried over anhydrous sodium sulfate,
The residue was dried under reduced pressure. Silica gel plate (7.5% methano-
(Chloroform / dichloromethane) to obtain the desired product (448 mg). (Yield 73.4%)

1H-NMR (CDCl3) δ; 9.86 (1H, brs), 8.37 (1
H, d, J = 2.1), 7.01 (1H, dd, J = 2.1,8.7), 6.72 (1H, d,
J = 8.7), 6.52 (2H, s), 6.52 (1H, d, J = 12.0), 6.43 (1
H, d, J = 12.0), 4.42 (1H, m), 3.87 (3H, s), 3.84 (3H,
s), 3.69 (6H, s), 3.38 (1H, m), 1.25 (3H, d, J = 6.3);
Mass spectrum m / z: 417 (MH ⁺ ); High resolution mass spectrum Calculated value 417.2026, Measured value 417.2050

Example 6 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-glycinamide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-glycinamide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
700 mg of 2-enenitrile hydrochloride (1.86 mmo
l), WSCI478mg, HOBt · H 2 O375m
g, Boc-Gly 486 mg were dissolved in dimethylformamide 100 ml, triethylamine 0.35 ml was added, and the mixture was reacted at 50 ° C. for 3.5 hours. After adding 700 ml of water and extracting with ethyl acetate, the ethyl acetate layer was washed 3 times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with silica gel column (developing solvent ether),
It was dissolved in a small amount of dichloromethane and ether was added for crystallization to obtain 851 mg of the desired product (1.71 mmol,
92%).

1H-NMR (CDCl3) δ; 1.481 (s, 9H), 3.759 (s,
6H), 3.855 (s, 3H), 3.883 (s, 3H), 3.901 (d, J = 5.7Hz),
5.1 (br, 1H), 6.603 (s, 2H), 6.696 (d, J = 8.5Hz, 1H), 6.89
2 (dd, J = 1.8Hz, 8.5Hz, 1H), 7.245 (s, 1H), 8.295 (br.s, 1
H), 8.333 (d, J = 1.8Hz, 1H); Mass spectrum: 497 (M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-glycinamide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-Ennitrile-Boc-glycinamide 800 mg
Was dissolved in 3 ml of dichloromethane, 3 ml of 4M hydrochloric acid-dioxane solution was added, and the mixture was reacted at room temperature for 2 hours. 30 ml of ether was added and filtered, and the obtained powder was chloroform-
Wash with hot with isopropanol-toluene (6: 8: 20), 483 mg (1.11 mmol, 65%) of the desired product.
I got

1H-NMR (CD3OD) δ; 3.735 (s, 6H), 3.807 (b
r, 2H), 3.812 (s, 3H), 3.888 (s, 3H), 6.662 (s, 2H), 6.97
8 (d, J = 8.6Hz, 1H), 7.102 (dd, J = 2.1Hz, 8.6Hz, 1H), 7.3
46 (s, 1H), 8.018 (d, J = 2.1Hz, 1H); High-resolution mass spectrum calculated 398.1716, measured 398.1723

Example 7 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-ornithinamide dihydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-L-ornithinamide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
700 mg of 2-enenitrile hydrochloride (1.86 mmo
l), WSCI463mg, HOBt · H 2 O463m
g, Boc 2 -L-Orn 767 mg were dissolved in dimethylformamide 70 ml, and triethylamine 0.35 m
1 was added and reacted at 50 ° C. for 41 hours. 400 ml of water
Was added thereto, the mixture was extracted with ether, the ether layer was washed with water three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
After purification with a silica gel column (developing solvent ether), the product was dissolved in a small amount of dichloromethane and ether was added for crystallization to obtain 737 mg (1.13 mmol, 61%) of the desired product.

1H-NMR (CDCl3) δ; 1.432 (s, 9H), 1.451 (s,
9H), 1.5 (m, 2H), 1.65 (m, 1H), 1.9 (m, 1H), 3.2 (m, 2H),
3.764 (s, 6H), 3.857 (s, 3H), 3.875 (s, 3H), 4.2 (br, 1H),
4.8 (br, 1H), 5.1 (br, 1H), 6.600 (s, 2H), 6.704 (d, J = 8.6
Hz, 1H), 6.901 (dd, J = 2.1Hz, 8.6Hz, 1H), 7.236 (s, 1H),
8.266 (d, J = 2.1Hz, 1H), 8.329 (br.s, 1H); Mass spectrum: 654 (M ⁺ ).

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-ennitrile-L-ornithinamide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Boc-L-ornithinamide 73
0 mg (1.11 mmol) was dissolved in 5 ml of dichloromethane, 5 ml of 4M hydrochloric acid-dioxane solution was added, and the mixture was reacted at room temperature for 1 hour. Add 100 ml of ether and filter,
The obtained powder was recrystallized from methanol-ethyl acetate (1: 1) to obtain the desired product (286 mg, 0.542 mmol, 4).
8%).

1H-NMR (CDCl3) δ; 1.7 (m, 2H), 1.9 (m, 2H),
2.973 (d, J = 6.3Hz, 1H), 3.003 (d, J = 6.3Hz, 1H), 3.768
(s, 6H), 3.820 (s, 3H), 3.898 (s, 3H), 4.176 (t, J = 6.3Hz,
1H), 6.675 (s, 2H), 7.014 (d, J = 8.5Hz, 1H), 7.173 (dd,
J = 2.0Hz, 8.5Hz, 1H), 7.368 (s, 1H), 7.801 (d, J = 2.0Hz, 1
H); High resolution mass spectrum; Calculated value 455.2288, Measured value 455.2300

Example 8 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-phenylalanine amide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-L-phenylalanine amide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile hydrochloride 998 mg (2.65 mmo
1), BOP reagent 1290 mg, Boc-L-Phe7
77 mg was dissolved in 50 ml of acetonitrile, 0.8 ml of triethylamine was added, and the mixture was reacted at room temperature for 18 hours and at 50 ° C. for 20 hours. 100 ml of water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with a silica gel column (developing solvent dichloromethane), the product was dissolved in a small amount of dichloromethane and ether and hexane were added for crystallization to give 1082 mg (1.
84 mmol, 69%) was obtained.

1H-NMR (CDCl3) δ; 1.426 (s, 9H), 3.12 (br.
t, 2H), 3.744 (s, 3H), 3.766 (s, 6H), 3.888 (s, 3H), 4.4
(br, 1H), 5.1 (br, 1H), 6.613 (s, 2H), 6.639 (d, J = 8.8Hz,
1H), 6.875 (dd, J = 2.1Hz, 8.8Hz, 1H), 7.18-7.36 (m, 5H),
8.030 (br.s, 1H), 8.345 (d, J = 2.1Hz, 1H); FAB mass spectrum: 587 (M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-phenylalanine amide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Boc-L-phenylalanine amide (1082 mg, 1.11 mmol) was dissolved in dichloromethane (10 ml), and 4 M hydrochloric acid-dioxane solution was added (5 ml).
The reaction was continued for 1 hour at room temperature. 100 ml of ether was added and filtered, and the obtained powder was chloroform-methanol-
Recrystallize from ethyl acetate (4: 1: 4) to give the desired product 450
Obtained mg (0.859 mmol, 77%).

1H-NMR (CD3OD) δ; 3.106 (d, J = 7.3Hz, 1H),
3.119 (d, J = 7.3Hz, 1H), 4.312 (t, J = 7.3Hz, 1H), 3.751 (s,
6H), 3.792 (s, 3H), 3.819 (s, 3H), 6.672 (s, 2H), 6.936
(d, J = 8.7Hz, 1H), 7.173 (dd, J = 2.2Hz, 8.7Hz, 1H), 7.2
(m, 2H), 7.3 (m, 3H), 7.339 (s, 1H), 7.878 (d, J = 2.2Hz, 1
H); High-resolution mass spectrum calculated 488.2186, measured 488.2162

Example 9 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-prolinamide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-L-prolinamide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile hydrochloride 998 mg (2.65 mmo
l), BOP reagent 1300 mg, Boc-L-Pro6
05 mg was dissolved in 50 ml of acetonitrile, 0.8 ml of triethylamine was added, and the mixture was reacted for 18 hours at room temperature and 20 hours at 50 ° C. 100 ml of water and a small amount of sodium hydrogen carbonate were added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with a silica gel column (developing solvent dichloromethane), the product was concentrated to give the desired product 1
310 mg (2.44 mmol, 92%) were obtained.

1H-NMR (CDCl3) δ; 1.4-1.5 (br, 9H), 1.9 (b
r, 2H), 2.1-2.3 (br, 1H), 2.3-2.5 (br, 1H), 3.3-3.5 (br,
2H), 3.753 (s, 6H), 3.838 (s, 3H), 3.876 (s, 3H), 4.2-4.
5 (br, 1H), 6.609 (s, 2H), 6.677 (d, J = 8.4Hz, 1H), 6.871
(m, 1H), 7.238 (s, 1H), 8.39 (br.s, 1H), 9.2 (br, 1H); FA
B mass spectrum: 537 (M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-prolinamide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Boc-L-prolinamide 125
0 mg (2.33 mmol) of dichloromethane 10 ml
Was dissolved in 5 ml of 4M hydrochloric acid-dioxane solution, and the mixture was reacted at room temperature for 1 hour. 100 ml of ether was added and filtered, and the obtained powder was subjected to medium pressure liquid chromatography (OD
S, water-acetonitrile 70:30) and recrystallized three times with chloroform-ethyl acetate 1:10 to obtain 465 mg (0.980 mmol, 42%) of the desired product.

1H-NMR (CDCl3) δ; 2.0 (m, 3H), 2.4 (m, 1H),
3.4 (m, 2H), 3.745 (s, 6H), 3.805 (s, 3H), 3.895 (s, 3H),
4.45 (m, 1H), 6.660 (s, 2H), 6.997 (d, J = 8.6Hz, 1H), 7.
143 (dd, J = 2.1Hz, 8.6Hz, 1H), 7.349 (s, 1H), 7.839 (d, J
= 2.1Hz, 1H); High-resolution mass spectrum calculated 438.202
9, measured value 438.2033

Example 10 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-alanine amide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-L-alanine amide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile hydrochloride 1053 mg (2.65 mmo
l), BOP reagent 1300 mg, Boc-L-Ala5
54 mg was melt | dissolved in 50 ml of acetonitrile, 0.8 ml of triethylamines were added, and it was made to react at 60 degreeC for 17 hours. Add 100 ml of water and a little sodium bicarbonate,
The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with a silica gel column (developing solvent dichloromethane-ethyl acetate 20:
1), concentrated, 1085 mg (2.12 mmo) of the desired product
1, 80%).

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-alanine amide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Boc-L-alanine amide 100
0 mg (1.95 mmol) of dichloromethane 10 ml
Was dissolved in 5 ml of 4M hydrochloric acid-dioxane solution, and the mixture was reacted at room temperature for 1 hour. 100 ml of ether was added and filtered, the obtained powder was recrystallized twice with chloroform-methanol-ethyl acetate 20: 2: 30, and the obtained powder was subjected to medium pressure liquid chromatography (ODS, water-acetonitrile 75:25). The product was purified by filtration, the ether was added to a small amount of methanol, and the resulting precipitate was collected by filtration to obtain 280 mg of the desired product.
(0.625 mmol, 32%) was obtained.

1H-NMR (CD3OD) δ; 1.503 (d, J = 7.0Hz, 3H),
3.736 (s, 6H), 3.808 (s, 3H), 3.888 (s, 3H), 4.129 (q, J =
7.0Hz, 1H), 6.662 (s, 2H), 6.985 (d, J = 8.6Hz, 1H), 7.12
2 (dd, J = 2.3Hz, 8.6Hz, 1H), 7.345 (s, 1H), 7.900 (d, J =
2.3Hz, 1H); High-resolution mass spectrum calculated value 412.187
3, measured value 412.1873

Example 11 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-threonine amide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-L-threonine amide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile hydrochloride 1000 mg (2.65 mmo
l), BOP reagent 1300 mg, Boc-L-Thr
Dissolve 880 mg of (OtBu) in 50 ml of acetonitrile, add 0.8 ml of triethylamine, and add 2 ml at 60 ° C.
The reaction was performed for 1 hour. 100 ml of water and a small amount of sodium hydrogen carbonate were added, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
After purification with a silica gel column (developing solvent: ethyl acetate-hexane 5: 1), the mixture was concentrated to give 870 mg of the desired product (1.46).
mmol, 55%).

1H-NMR (CD3OD) δ; 1.044 (d, J = 6.0Hz, 3H),
1.315 (s, 9H), 1.463 (s, 9H), 3.760 (s, 6H), 3.844 (s, 3
H), 3.887 (s, 3H), 4.15 (br.m, 1H), 4.22 (br, 1H), 5.64
(br.d, 1H), 6.617 (s, 2H), 6.857 (d, J = 8.5Hz, 1H), 6.897
(dd, J = 2.2Hz, 8.5Hz, 1H), 7.228 (s, 1H), 8.404 (d, J = 2.
2Hz, 1H), 9.3 (br.s, 1H); FAB mass spectrum: 597
(M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-threonine amide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Boc-L-threonine amide 81
0 mg (1.95 mmol) of dichloromethane 10 ml
, And add 5 ml of 4M hydrochloric acid-dioxane solution to 60
The reaction was carried out at 0 ° C for 3 hours. 100 ml of ether was added and filtered, and the obtained powder was subjected to medium pressure liquid chromatography (OD
S, water-acetonitrile 75:25), and the precipitate was filtered out by dissolving acetonitrile-ethyl acetate in a small amount of methanol and collecting 290 mg (0.60) of the desired product.
7 mmol, 31%) was obtained.

1H-NMR (CD3OD) δ; 1.240 (d, J = 6.3Hz, 3H),
3.9 (1H), 3.739 (s, 6H), 3.810 (s, 3H), 3.892 (s, 3H), 4.0
12 (m, 1H), 6.658 (s, 2H), 6.996 (d, J = 8.5Hz, 1H), 7.133
(dd, J = 2.2Hz, 8.5Hz, 1H), 7.350 (s, 1H), 7.923 (d, J = 2.
2Hz, 1H); High-resolution mass spectrum calculated 442.1978,
Measured value 442.1973

Example 12 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-lysine amide dihydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Boc-L-lysine amide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile hydrochloride 1000 mg (2.65 mmo
1), Boc 2 -L-LysOSu 1462 mg were dissolved in acetonitrile 50 ml, and triethylamine 0.8 was added.
Add ml and react at 60 ° C for 20 hours.
Add 0 mg and 1300 mg of BOP reagent and add 60 ° C.
And reacted for 21 hours. Water (100 ml) and a small amount of sodium hydrogen carbonate were added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with a silica gel column (developing solvent dichloromethane), the mixture was concentrated to give 1170 mg of the desired product (1.74 mmo
1, 66%).

1H-NMR (CDCl3) δ; 1.438 (s, 9H), 1.450 (s,
9H), 1.4-1.5 (br, 4H), 1.7 (br, 1H), 1.9 (br, 1H), 3.1 (b
r, 2H), 3.756 (s, 6H), 3.852 (s, 3H), 3.874 (s, 3H), 4.2
(br, 1H), 4.7 (br, 1H), 5.2 (br, 1H), 6.604 (s, 2H), 6.68
5 (d, J = 8.7Hz, 1H), 6.884 (dd, J = 2.2Hz, 8.7Hz, 1H), 7.23
1 (s, 1H), 8.348 (br, 1H); FAB mass spectrum: 668 (
M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-lysine amide dihydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Boc-L-lysine amide 1100
mg (1.64 mmol) was dissolved in 10 ml of dichloromethane, 5 ml of 4M hydrochloric acid-dioxane solution was added, and the temperature was 60 ° C.
And reacted for 3 hours. 100 ml of ether was added and filtered, and the obtained powder was subjected to medium pressure liquid chromatography (OD
S, water-acetonitrile 95: 5 → 85: 15), dissolved in a small amount of methanol and added with acetonitrile-ethyl acetate, and the precipitate was collected by filtration to obtain 300 mg of the desired product.
(0.554 mmol, 34%) was obtained.

1H-NMR (CD3OD) δ; 1.4 (m, 2H), 1.7 (m, 2H),
1.9 (m, 2H), 2.95 (m, 2H), 3.756 (s, 6H), 3.811 (s, 3H),
3.896 (s, 3H), 4.131 (t, J = 6.3), 6.667 (s, 2H), 7.010 (d,
J = 8.9Hz, 1H), 7.164 (dd, J = 2.3Hz, 8.9Hz, 1H), 7.361 (s,
1H), 7.834 (d, J = 2.3Hz, 1H) ； High resolution mass spectrum Calculated value 469.2451, Measured value 469.2454

Example 13 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-serinamide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Fmoc-L-serinamide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile hydrochloride 1007 mg (2.65 mmo
l), Fmoc-L-Ser (OtBu) OH1105
mg, BOP reagent 1370 mg, HOBt · H ₂ O6
Dissolve 18 mg in 50 ml of acetonitrile, add 0.8 ml of triethylamine, react at 60 ° C. for 42 hours, add 100 ml of water and a small amount of sodium hydrogen carbonate,
The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with a silica gel column (developing solvent: ethyl acetate-hexane 2: 3),
Concentrate the desired product 1486 mg (2.14 mmol, 81
%) Was obtained.

1H-NMR (CDCl3) δ; 1.241 (s, 9H), 3.243 (t,
J = 8.5Hz, 1H), 3.760 (s, 6H), 3.832 (s, 3H), 3.874 (s, 3
H), 4.247 (m, 1H), 4.33 (br, 1H), 4.42 (m, 2H), 5.8 (br, 1
H), 6.617 (s, 2H), 6.704 (d, J = 8.8Hz, 1H), 6.904 (dd, J =
2.2Hz, 8.8Hz, 1H), 7.252 (s, 1H), 7.32 (m, 2H), 7.407 (t, J
= 7.5Hz, 2H), 7.612 (d, J = 7.5Hz, 2H), 7.772 (d, J = 7.2Hz, 2
H), 8.406 (d, J = 2.2Hz), 9.0 (br.s, 1H) FAB ； Mass spectrum: 705 (M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-serinamide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-enenitrile-Fmoc-L-serinamide 143
0 mg (2.07 mmol) was dissolved in 5 ml of chloroform and 2 ml of piperidine, reacted for 1 hour, and then purified on a silica gel column (developing solvent ethyl acetate-dichloromethane 1: 1). After concentrating to dryness under reduced pressure, the residue was dissolved in 10 ml of a 4M hydrochloric acid-dioxane solution, reacted at 70 ° C. for 1 hour, 100 ml of ether was added, and the precipitate was filtered out. The obtained powder was purified by medium pressure liquid chromatography (ODS, water-acetonitrile 75:25), dissolved in chloroform-methanol 5: 1 while hot, ethyl acetate was added, and the deposited precipitate was collected by filtration. 460 mg (0.992 mm)
ol, 48%).

1H-NMR (CD3OD) δ; 3.737 (s, 6H), 3.813 (s,
3H), 3.892 (s, 3H), 3.9 (m, 2H), 4.123 (dd, J = 5.1Hz, 6.3
Hz, 1H), 6.662 (s, 2H), 6.981 (d, J = 8.5Hz, 1H), 7.109 (d-
d, J = 2.2Hz, 8.5Hz, 1H), 7.344 (s, 1H), 7.998 (d, J = 2.2H
z, 1H); High-resolution mass spectrum calculated 428.1822, measured 428.1806

Example 14 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-aspartylamide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-Fmoc-L-aspartylamide (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
900 mg (2.65 mmol) of 2-enenitrile, F
1400 mg of moc-L-Asp (OBn), 1300 mg of BOP reagent, and 660 mg of HOBt · H ₂ O were dissolved in 50 ml of acetonitrile, and 0.5 m of triethylamine was dissolved.
1 was added, and the mixture was reacted at room temperature for 86 hours, 100 ml of water and a small amount of sodium hydrogen carbonate were added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification with a silica gel column (developing solvent,
Ethyl acetate-dichloromethane 1:10) and concentrated to obtain 1319 mg (1.80 mmol, 68%) of the desired product.

1H-NMR (CDCl3) δ; 2.76 (br.dd, 1H), 3.15
(br.d, 1H), 3.747 (s, 9H), 3.869 (s, 3H), 4.231 (t, J = 7.0
Hz, 1H), 4.457 (m, 2H), 4.72 (br, 1H), 5.133 (d, J = 12.3H
z, 1H), 5.206 (d, J = 12.3Hz, 1H), 6.607 (s, 2H), 6.662 (d, J
= 9.0Hz, 1H), 6.896 (dd, J = 2.1Hz, 9.0Hz, 1H), 7.20-7.45
(m, 4H), 7.342 (s, 1H), 7.58 (br.d, 2H), 7.762 (dd, J = 2.
5Hz, 7.3Hz, 2H), 8.327 (d, J = 2.1Hz), 8.7 (br.s, 1H); FAB
Mass spectrum: 767 (M ⁺ )

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-aspartylamide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-Enonitrile-Fmoc-L-aspartylamide 1210 mg (1.65 mmol) in dioxane 30
After dissolving in 2 ml of 2 M aqueous sodium hydroxide solution and reacting at room temperature for 1 hour, 100 ml of ether was added and the deposited precipitate was collected by filtration. 30 ml of dioxane again
Dissolved in water, 0.5 ml of 2M sodium hydroxide solution and 1.5 ml of water were added, and the mixture was reacted at room temperature for 1 hour, then ether 10 was added.
0 ml was added, and the deposited precipitate was collected by filtration. The residue was purified little by little by medium pressure liquid chromatography (ODS, water-methanol-hydrochloric acid (12N) 75: 25: 0.3), and the fraction with a purity of 90% or higher was concentrated. : 1 After dissolving in 200 ml, NaOHaq (2M)
Was added to neutralize, and the mixture was allowed to stand for 40 minutes, and the deposited precipitate was collected by filtration. The obtained filter cake was treated with 4M hydrochloric acid-dioxane solution 0.3.
It was dissolved in a small amount of methanol containing ml, ethyl acetate was added, and the deposited precipitate was collected by filtration to obtain 292 mg (0.5
94 mmol, 36%) was obtained.

1H-NMR (CD3OD) δ; 3.08 (m, 2H), 3.752 (s,
6H), 3.812 (s, 3H), 3.868 (s, 3H), 4.256 (t, J = 5.4Hz,
1H), 6.646 (s, 2H), 6.948 (d, J = 8.6Hz, 1H), 7.086 (d
-d, J = 2.0Hz, 8.6Hz, 1H), 7.330 (s, 1H), 7.821 (d, J =
2.0Hz, 1H) ； High-resolution mass spectrum Calculated value 456.17
71, measured 456.1775

Example 15 (E) -3- (3-Amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-glutamylamide hydrochloride

Step 1 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-ennitrile-Fmoc-L-glutamyl (OB
n) Synthesis of amide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
900 mg (2.65 mmol) of 2-enenitrile, F
1500 mg of moc-L-Glu (OBn), 1300 mg of BOP reagent, 643 mg of HOBt.H ₂ O were dissolved in 50 ml of acetonitrile, and 0.5 m of triethylamine was dissolved.
1, and reacted at room temperature for 64 hours, 100 ml of water and a small amount of sodium bicarbonate were added, and the mixture was extracted with dichloromethane,
After washing with saturated saline, drying over anhydrous sodium sulfate,
It was concentrated under reduced pressure. After purification with a silica gel column (developing solvent dichloromethane), the product was concentrated and 1950 mg (2.
55 mmol, 97%) was obtained.

1H-NMR (CDCl3) δ; 1.9-2.1 (br.m, 1H), 2.
1-2.3 (br.m, 1H), 2.4-2.7 (br.m, 2H), 3.745 (s, 6H),
3.788 (s, 3H), 3.868 (s, 3H), 3.85-3.95 (m, 1H), 4.20
7 (t, J = 6.9Hz, 1H), 4.408 (d, J = 6.9Hz, 2H), 5.137 (s,
2H), 5.6-5.7 (br.s, 1H), 6.603 (s, 2H), 6.675 (d, J =
8.7Hz, 1H), 6.899 (dd, J = 2.0Hz, 8.7Hz, 1H), 7.2-7.
4 (m, 10H), 7.577 (d, J = 7.5Hz, 2H), 7.754 (d, J = 7.5H
z, 2H), 8.320 (m, 2H); FAB mass spectrum: 781 (M ⁺ ).

Step 2 (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
Synthesis of 2-enenitrile-L-glutamylamide hydrochloride (E) -3- (3-amino-4-methoxyphenyl)-
2- (3,4,5-trimethoxyphenyl) -prop-
2-ennitrile-Fmoc-L-glutamyl (OB
n) 1940 mg (2.55 mmol) of amide was dissolved in 50 ml of dioxane, and 2M aqueous sodium hydroxide 3.7 was added.
After adding 1 ml and reacting at room temperature for 1 hour, 100 ml of ether
Was added and the deposited precipitate was collected by filtration. This was dissolved again in 30 ml of dioxane and 0.5 ml of 2M sodium hydroxide.
After adding 1.5 ml of water and 1 hour of reaction at room temperature, 20 ml of methanol was added to the reaction solution and poured into 250 ml of ether, and the deposited precipitate was collected by filtration. The residue was purified little by little by medium pressure liquid chromatography (ODS, water-acetonitrile-hydrochloric acid (12N) 75: 25: 0.3), and concentrated so as not to dry. When the solution reached about 50 ml, ethyl acetate-ether (1: 1) was added for precipitation, the supernatant was discarded, and 110 ml of acetonitrile and 350 ml of ether were sequentially added, and the precipitate was filtered and filtered. Wash with tel and dry under reduced pressure, 436mg
(0.838 mmol, 33%) was obtained.

1H-NMR (CD3OD) δ; 2.120 (q, J = 7.0Hz, 2
H), 2.468 (m, 2H), 3.735 (s, 6H), 3.808 (s, 3H), 3.88
8 (s, 3H), 4.131 (t, J = 6.3Hz, 1H), 6.658 (s, 2H), 6.9
95 (d, J = 8.6Hz, 1H), 7.143 (dd, J = 2.2Hz, 8.6Hz, 1
H), 7.349 (s, 1H), 7.861 (d, J = 2.2Hz, 1H); High-resolution mass spectrum calculated 470.1927, measured 470.1914

Example 16 Evaluation of Cytotoxicity Mouse P388 leukemia cells were used as cancer cells, and RPMI-1640 medium containing 5 μM 2-mercaptoethanol and 10% fetal calf serum was used for culture. 1 × 10 4 cells / 50 μl / well were seeded on a 96-well microplate, and the test compound solution aqueous solution (4 μg / ml) was added to 25
Each μl was added and cultured at 37 ° C. for 2 days, and then the number of viable cells was measured by the MTT method to prepare a dose-response curve. From this, 50% growth inhibitory concentration (IC5
0) was calculated. The IC50 value of each compound is shown in the table.
In addition, the doses in which acute death occurs immediately after drug administration are shown in Tables 1 to 4 as the toxicity doses.

Example 17 Drug Efficacy Test in Mouse Colon 26, which has been passaged subcutaneously in mice, was crushed with scissors and transplanted subcutaneously in mice using a trocar. One week later, the tumors were caliper-measured to calculate the tumor volume and divided into groups (n = 3 for each group). The test compound was dissolved in dimethylsulfoxide, diluted with a solution of 5% Tween 80-physiological saline, and 0.2 ml of the diluted solution was administered by intravenous injection.
Drugs are administered 1 day on the 7th, 11th and 15th days after transplantation.
I went there. The tumor volume was measured 21 days after the transplantation, and the tumor volume and the tumor growth inhibition rate (IR) were calculated by the equations 1 and 2, respectively.

[0100]

[Equation 1]

[0101]

[Equation 2]

[0102]

[Table 1]

[0103]

[Table 2]

[0104]

[Table 3]

[0105]

[Table 4]

[0106]

INDUSTRIAL APPLICABILITY The stilbene derivative of the present invention has an excellent antitumor activity and is extremely useful in the pharmaceutical industry.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 255/44 C07C 255/44 C07D 207/16 C07D 207/16 (72) Inventor Yukio Nihei Kanagawa 1-1 Ajinomoto Co., Inc. Central Research Laboratory, Kawasaki-ku, Kawasaki-ku (72) Inventor Ryusuke Nakagawa 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Co., Inc. Central Research Laboratory (72) Inventor Kazuo Oishi 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Co., Inc. Central Research Laboratory

Claims (6)

[Claims] 1. A stilbene derivative represented by the following general formula (1). Embedded image (In the formula, X represents a hydrogen atom or a nitrile group, and Y represents an amino acid acyl group.) 2. The stilbene derivative according to claim 1, wherein X in the general formula (1) is a hydrogen atom. 3. The stilbene derivative according to claim 1, wherein X in the general formula (1) is a nitrile group. 4. Y in the general formula (1) is L-α-.
The stilbene derivative according to claim 1 or 2, which is an amino acid acyl group. 5. The stilbene derivative according to claim 4, wherein Y in the general formula (1) is an amino acid acyl group derived from threonine or serine. 6. A carcinostatic agent comprising the cis-stilbene derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.