JP3139690B2 - Anticancer agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a colorectal cancer development inhibitor containing a conjugated .gamma.-hydroxybutenolide compound as an active ingredient.

[0002]

2. Description of the Related Art At present, surgical treatment, radiation therapy, chemotherapy (drug administration) and the like are generally performed as treatments for cancer. Among these, chemotherapy has been widely applied to treatments that administer drugs that kill tumor cells by directly acting on tumor cells. Proposals for antitumor agents used in this type of treatment have been made. Many.

For example, 5-hydroxy-4- [2-phenyl- (E) -ethenyl] -2 (5H) -furanone has cytocidal activity against mouse neuroblastoma N18TG-2 cells. Is known [ Int. J. C
ancer , 33 , 677 (1984)]. However, the activity of this compound on human tumor cells is not known.

[0004]

Further, not only the treatment of cancer but also the process of carcinogenesis have been studied, and the following findings have been obtained. Independent processes called initiation and promotion are involved in the process of chemical carcinogenesis.
Two processes are involved. This is called the two-stage carcinogenesis theory and was raised by BERENBLUM [Cancer Res. , 1.
807-814 (1941)]. Here, the initiation is a DNA change caused by a chemical substance called an initiator, and is a reversible reaction. Subsequent to this, the process by which a cell is finally led to cancer by a chemical substance called a promoter is called promotion.

[0005] Recently, clear that the bile acids and hormones are biological component is also clear that can be a promoter, also such that the salt can be a promoter in cancer, quite familiar has an action as tumor promoter It is being made. More recently, the incidence of colorectal cancer has tended to increase.

[0006] From these viewpoints, there is a strong demand for the development of a compound having an inhibitory action on carcinogenic promotion against colorectal cancer.

[0007]

Means for Solving the Problems The present inventors have found that a conjugated γ-hydroxybutenolide compound represented by the following general formula (I) has an inhibitory effect on carcinogenesis promotion against colorectal cancer, and thereby complete the present invention. Reached.

[0008]

Embedded image (In the formula, n is an integer in the range of 1-3, and R ₁ , R ₂ ,
R ₃ , R ₄ and R ₅ are the same or different,
Represents a hydrogen atom, a methoxy group, a halogen atom or a lower alkyl group. In the above formula (I), the lower alkyl group is preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group,
An isopropyl group, an n-butyl group, an n-pentyl group, an isoamyl group, an n-hexyl group and the like are included, and a halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a chlorine atom. It is.

Conjugated γ-hydroxybutenolide compounds represented by the general formula (I) are described in Chem. Pharm. Bull
l. , 34 (10), 4346 (1986).

This reaction is represented by the following formula.

[0011]

Embedded image That is, a conjugated aldehyde having a substituted or unsubstituted phenyl group at the end and pyruvaldehyde dimethyl acetal in a methanol or tetrahydrofuran solvent, a base such as sodium hydroxide, potassium hydroxide,
An alkali such as barium hydroxide, or pyrrolidine, piperidine, DBU (1,8-diazabicyclo [5.4.
0] in the presence of an organic base such as unde-7-cene )
The reaction is carried out at 65 ° C (methanol reflux temperature) for 1 to 10 hours to synthesize an unsaturated ketone. Purification can be performed by pouring the reaction-terminated solution into water, extracting the solution with ethyl acetate, washing the organic layer with water, and distilling off the solvent. This compound is then reacted with a phosphonate ester by the Emmons-Horner reaction to give the unsaturated ester. At this time, the reaction conditions may be those commonly used for the Emmons-Horner reaction, for example, n-BuL as a base.
Using i, NaH, NaOH, NaEt or the like, and using benzene, toluene, tetrahydrofuran or the like inert to the reaction as a solvent, the reaction is carried out at about room temperature for 1 to 24 hours. Purification can be performed by pouring the reaction-terminated liquid into water, extracting with ethyl acetate, washing the organic layer with water, and distilling off ethyl acetate.

Next, the unsaturated ester thus obtained is treated with a 20 to 50% aqueous sulfuric acid solution at room temperature to 90 ° C. for 1 to 10 hours to obtain the desired conjugated γ-hydroxybutenolide compound. . During this reaction, iodine may be added as a reaction accelerator in an amount of 0.01 to 1.0% by weight based on the reaction solution. Purification can be easily performed by column chromatography or recrystallization.

In the present invention, the colorectal cancer development-inhibiting agent is used by itself or appropriately mixed with excipients, binders, and diluents in the preparation, and is used as a powder, granules, tablets, capsules, syrups, injections. Oral or parenteral administration can be carried out in any dosage form.

The dose may be adjusted according to the age, body weight and symptoms, but it is usually about 10 mg to 10 g orally, more preferably 50 mg to 5 g as a compound of the formula (I) orally. is there. A preferred embodiment according to the present invention is a unit dosage form for taking the above-mentioned daily dose in one or several divided doses. Needless to say, other drugs may be prepared as needed.

[0015]

Next, examples and reference examples of the present invention will be described. Reference Example Synthesis of 5-hydroxy-4- [2-phenyl- (E) -ethenyl] -2 (5H) -furanone (compound (1)) 3 g (75 mmole) of sodium hydroxide was added to 1,200 g of methanol, and dissolved. To this solution, 159 g (1.5 mole) of benzaldehyde and 354 g (3 mole) of pyruvaldehyde dimethyl acetal were charged, and the mixture was stirred at room temperature for 7 hours.

After completion of the reaction, 600 g of water was added, and the mixture was extracted three times with 2 liters of n-hexane. The n-hexane layer was concentrated with an evaporator to obtain 269 g of a residue. As a result of GLC analysis, 236.3 g of E-1,1-dimethoxy-4-phenyl-3-buten-2-one was contained in the residue.

Next, 30 g of sodium hydride (0.75
(mole) was added to 300 g of toluene and cooled with ice.
While maintaining the temperature at １５15 ° C., a solution obtained by diluting 179 g (0.8 mole) of triethylphosphonoacetate with 150 g of toluene was added dropwise over 1 hour. After completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was further stirred for 1 hour. Next, the E obtained earlier
-1,1-dimethoxy-4-phenyl-3-butene-2
-120 g (0.58 mole) of toluene in 150
g diluted solution was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was further stirred for 1 hour and left overnight.

After adding 500 ml of a 10% ammonium chloride solution to the reaction mixture, the mixture was extracted twice with 1 liter of isopropyl ether. The obtained isopropyl ether layer was washed twice with 500 ml of 10% saline, and isopropyl ether was removed by evaporation using an evaporator to obtain 203 g of a residue. As a result of GLC analysis, this residue contained 72.8% of ethyl 3-dimethoxymethyl-5-phenyl-2,4-pentadienylcarboxylate.

50 g of this residue is mixed with 950 ml of dioxane.
Then, 0.05 g of iodine and 700 ml of a 30% aqueous sulfuric acid solution were added to this solution, and the mixture was heated to reflux while stirring for 4 hours. After completion of the reaction, extraction was performed twice with 2 l of isopropyl ether. The obtained isopropyl ether layer was washed with 2 liters of saturated saline, and then isopropyl ether was removed by evaporation using an evaporator. The obtained residue was dissolved in benzene (105 ml) and acetone (14 ml) at room temperature, and n-hexane (35 ml) was added. When left overnight, colorless crystals were precipitated. Then, it is filtered and dried under reduced pressure.
g was obtained.

The ¹ H-NMR spectrum confirmed that this was 5-hydroxy-4- [2-phenyl- (E) -ethenyl] -2 (5H) -furanone.

¹ H-NMR (270 MHz, DMSO-
d ₆ / TMS) δ : 6.20 (1H, s, 10-H), 6.36 (1H,
s, 10'-H), 7.12 (1H, d, J = 16H)
z, 8-H), 7.28 (1H, d, J = 16 Hz, 7
-H), 7.35 to 7.65 (5H, m, ArH),
7.80 (1H, s, OH ). IR (KBr): 3220 ( OH ), 1730 (α, β
-Unsaturated γ-lactone), 1630, 1595 (C =
C) m. p. 159-160 ° C. Example 1 Inhibitory Effect on the Development of Colorectal Cancer by Carcinogenic Promoter 5-Hydroxy-4- [2-phenyl- (E) -ethenyl] -2- (5H) -furanone (Compound
(1)) . Tumor promoter A
The effect on the occurrence of colorectal cancer caused by zomethane (AOM) was determined by calculating the ratio of the number of tumor-bearing animals that occurred in the intestinal tract and the average value of the number of tumors per individual using 6-week-old male rats F344 rats. investigated.
The test period was one year. The results are as shown in Table 1.

The incidence of intestinal tumors was found only in the first and second groups, and the incidence of intestinal tumors in the first group was lower than that in the second group. (P <0.02). This result is considered promising as a chemopreventive agent for colorectal cancer. Note that no significant difference was found in the body weight and liver weight between these experimental groups.

[0023]

[Table 1] Example 2 Acute toxicity An acute toxicity test by oral administration was performed using ICR male mice (5 weeks old). The LD50 value of compound (1) is 20
It was 00 mg / kg or more, and higher safety was confirmed than the effective dose.

[0024]

The conjugated .gamma.-hydroxybutenolide compound of the general formula (I) has a carcinogenesis-suppressing (anti-carcinogenic promoter) effect on colorectal cancer. And to the comprehensive field of treatment of cancer.

Claims (1)

(57) [Claims] [Claim 1] The following general formula: (In the formula, n is an integer in the range of 1-3, and R ₁ , R ₂ ,
R ₃ , R ₄ and R ₅ are the same or different,
Represents a hydrogen atom, a methoxy group, a halogen atom or a lower alkyl group. A carcinogenesis preventive agent comprising the conjugated γ-hydroxybutenolide compound represented by the formula (1) as an active ingredient.