JPH02111777A - Bisbenzylisoquinoline derivative - Google Patents

Abstract

NEW MATERIAL:Bisbenzylisoquinoline derivative expressed by formula I (R1 and R2 are methoxy or the both are joined to form methylenedioxy; one of R3 and R4 is H and the other is 2-10C alkoxy or cyclohexylmethyldioxy) or acid-added salt of said derivative. EXAMPLE:12'-O-ethylcepharanoline. USE:Useful as anticancer compound having excellent inhibitory action against cancer cell multiplication. Capable of performing oral administration. PREPARATION:A compound expressed by formula II (one of X and Y is H and the other is hydroxyl group) is reacted with a compound expressed by the formula R-Z (R is 2-10C alkyl or cyclohexylmethyl; Z is halogen) in a solvent such as dimethylformamide, in the presence of reaction agent such as sodium hydride and preferably in an inert gas such as argon gas to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel bisbenzylisoquinoline derivative and an anticancer agent containing the same as an active ingredient.

It is known that bisbenzylisoquinoline alkaloids, such as tetrandrine and cephalanthine, contained in plants of the family Tiliaceae and other plants, have anticancer effects (Chem, Pharm).

Bull, Vol. 24, pp. 2413-2420, 1976). The present inventors synthesized various derivatives by introducing an alkyl group into the hydroxyl group of bisbenzylisoquinoline alkaloids having a hydroxyl group on the benzene ring, such as cephalanoline, berbamine, and oxyacanthene, and examined the pharmacological effects of these compounds. did. As a result, we found that certain bisbenzylisoquinoline derivatives exhibit excellent cell proliferation inhibiting activity.

The present invention is based on this knowledge, and is based on the general formula (wherein R1 and R2 are methoxy groups or both together are methylenedioxy groups, R3 and Cucumber are one hydrogen atom, and the other is C2-
C1°-alkoxy group or cyclohexylmethyloxy group) or an acid addition salt thereof.

The compound of formula I is a novel compound that has not been described in any literature, and includes, for example, the following compounds. 12'-0-ethylcephalanoline (compound 1), 12'-0-n-propylcephalanoline (compound 2), 12'-0-n-butylcephalanoline (compound 6), 1τ-0-n-pentyl Cephalanoline (Compound 4), 12'-〇-n-hexylcephalanoline (Compound 5), 12'-0-
n-octylcephalanoline (compound 6), 12'-
0-n-decanylcephalanoline (compound 7), 1τ-
0-cyclohexylmethylcephalanoline (compound 8)
, 12-O-n-7' lovilperbamine (compound 9
), 12-0-cyclohexylmethylberbamine (Compound 10), 12'-0-n-hexyloxyacanthine (Compound 11), 12'-0-n-decanylacanthine (Compound 12), and the like.

The compound of formula I is a compound represented by the general formula (in which one of X and Y represents a hydrogen atom and the other represents a hydroxyl group, and R and R2 have the above-mentioned meanings). ) (wherein R represents a C8-C8°-alkyl group or a cyclohexylmethyl group, and 2 represents a halogen atom).

As a compound of formula (■), cephalanoline (R.

and R,= -OCH, 0-1Y=-OH), oxyacanthin (R,= R,= -0CH8, y=-OH),
Berbamine (R,=R,=-OCH,,X=-OH
) etc.

The compound of formula (1) has four stereoisomers: SS form, SR form, R8 form and RR form, and these isomers may also be used.

Examples of the halogen atom for the substituent Z in the compound of formula m include a chlorine atom, an iodine atom, and a bromine atom.

Examples of the 02-C1° alkyl group for the substituent R include an ethyl group, a propyl group, a butyl group, a hentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decal group. Straight chain alkyl groups are preferred.

The reaction of the compounds of formulas (1) and (2) is preferably carried out in a solvent in the presence of a reactant. As the solvent, for example, dimethylformamide, tetrahydrofuran, diethyl ether, etc. are used. Further, as a reactant, for example, sodium hydride is used.

This reaction is preferably carried out in an inert gas such as argon gas or nitrogen gas.

Compounds of formula I can be converted into acid addition salts by conventional methods. Preferred acids include physiologically harmless acids, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, acetic acid, fumaric acid, malic acid, citric acid, and sulfuric acid.

The compounds of formula I exhibit excellent cytostatic activity. Accordingly, the present invention further provides an anticancer agent containing a compound of formula I as an active ingredient.

Although the compound of formula I may be used as it is as an anticancer agent, excipients, binders, lubricants, solvents, stabilizers, etc. are usually added to form tablets, powders, granules, capsules, etc. It is used in formulations such as injections. Excipients include starch, lactose, methylcellulose, crystalline cellulose, synthetic aluminum silicate, etc. Binders include hydroxypropyl cellulose, polyvinylpyrrolidone, etc. Lubricants include talc, magnesium stearate, calcium stearate, etc. can give.

In the case of oral administration, the dosage of the drug of the present invention is 10 to 1000 m9 as the active ingredient per day, preferably 60 to 60 m9.
It is 0m9.

Production Example 1 To a solution of cephalanoline 592rn9 (1 mmol) dissolved in 5 ml of anhydrous dimethylformamide, 44 ml (1.1 mmol) of sodium hydride (60%) was added.
Ethyl bromide 120711 & (1
, 1 mmol) in anhydrous dimethylformamide
Drop ml. After standing at room temperature overnight, the reaction was poured into ice water and extracted with ether. After washing the ether layer with water and drying, the solvent was distilled off. Recrystallization of the residue from ether-hexane gives compound 1 as an amorphous powder with a melting point of 75-85°C.

Compounds 2 to 8 were obtained in the same manner.

Compound 2: Melting point 70-78°C, amorphous powder Compound 6:
70-75°C, Compound 4: 76-78
°C, Compound 5: 75-80 °C, Compound 6: 60-70 °C, Compound 7:
〃 55-60°C1 // Compound 8: 〃 65-75
°C1〃 Production Example 2 To a solution of 200 m9 (0.33 mmol) of berbamine dissolved in 5 ml of anhydrous dimethylformamide, 14 m9 (-0.35 mmol) of sodium hydride (60%) was added, and to this was added n-propyl Bromide 58m9 (0
, 65 mi! J mol) and stirred at room temperature for 6 hours. 2
After adding 1Qml of N hydrochloric acid and extracting with ether, the hydrochloric acid layer was adjusted to pH 10 with 2N caustic soda and extracted with dichloromethane. After washing with water and drying, the solvent is distilled off and the residue is recrystallized from hexane to obtain Compound 9 as an amorphous powder with a melting point of 62 to 64°C.

Compound 10 was obtained in the same manner.

Compound 10: melting point 161-132°C1 Amorphous powder production example 6 To a solution of 200 m9 (0.33 mmol) of oxyacanthine dissolved in 5 ml of anhydrous dimethylformamide was added 14 μm (0. 35 mmol)
Add 70 m of n-hexylmethyl to this and 55 m of n-hexylmethyl
9 (0.33 mmol) and stirred at room temperature for 3 hours. When processed in the same manner as in Production Example 2, the melting point was 190-192.
Compound 11 is obtained as an amorphous powder at .

Compound 12 was obtained in the same manner.

Compound 12: melting point 50-52°C, amorphous powder Experimental Example Using the human colon cancer-derived cultured cell line RPMI4788 cells, dye-up take method of Yamazaki et al. (Jpn, J
, Med.

SC1, B101. Vol. 69, pp. 105-118, 1986
The degree of inhibition of canal cell proliferation by the test substance was determined by

The concentration of the test substance that inhibits the proliferation of cancer cells by 50% (IC
so) are shown in the table below.

Formulation Example 1 Compound 10500■, lactose 3.0g, corn starch 1.28g, hydroxypropyl cellulose 200Fn
9 and magnesium stearate 2Q m9 are thoroughly mixed, granulated, and then compressed into tablets with a weight of 100 rn9 per tablet.

Formulation Example 2 Compound 2 500~, lactose 2.5g, potato starch 1
．． 75,9. 240 m9 of crystalline cellulose and 10 m9 of calcium stearate are thoroughly mixed and this mixture is filled into capsules to obtain capsules containing 10rn9 of the active ingredient per capsule.

Formulation Example 6 Compound 3 hydrochloride 500rn9 and D-mannitol 1
．． Dissolve 0g in distilled water for injection to make a total volume of 10Qml. This solution is filtered through a 0.2 μm membrane filter, dispensed into 2 ml ampoules, sealed and heat sterilized to obtain an injection.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 and R_2 are methoxy groups or both together are methylenedioxy groups, and R_3 and R_4 are one of them A bisbenzylisoquinoline derivative or an acid addition salt thereof, represented by a hydrogen atom and the other representing a C_2-C_1_0-alkoxy group or a cyclohexylmethyloxy group. 2. An anticancer agent containing the bisbenzylisoquinoline derivative or its acid addition salt according to claim 1 as an active ingredient.