JP2860385B2 - Bisbenzyl isoquinoline derivative - Google Patents

Description

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

Bisbenzylisoquinoline-based alkaloids contained in other plants such as serrata, such as tetrandrine,
It is known that cepharanthin and the like have an anticancer effect (see Chem. Pharm. Bull. Vol. 24, 2413-2420, 1976). The present inventors synthesized various derivatives by introducing an acyl group into a hydroxyl group of a bisbenzylisoquinoline-based alkaloid having a hydroxyl group on a benzene ring, for example, isoliensinine and nepheline, and examined the pharmacological action of these compounds. As a result, they have found that certain bisbenzylisoquinoline derivatives exhibit an excellent cancer cell growth inhibitory action.

The present invention is based on this finding, and has the general formula (Wherein R ₁ is a C ₃ -C ₁₀ -acyl group or a methoxy group, R ² is a C ₃
To a C ₁₀ -acyl group) or an acid addition salt thereof.

The compound of the formula I is a novel compound which has not been described in the literature, and examples thereof include the following. 7,12-O, O-dipropionyl isoliencinine (compound 1), 7,12-O, O-di-n
-Caproyl isoliencinin (compound 2), 12-O-
n-valeryl nepheline (compound 3), 12-On-caprynephrine (compound 4) and the like.

Compounds of formula I have the general formula (Wherein X represents a hydroxyl group or a methoxy group) by converting a compound represented by the general formula RY (III) (wherein R represents a C ₃ -C ₁₀ -acyl group, and Y represents a halogen atom or a hydroxyl group) Or a compound represented by the general formula R-O-R (IV) (wherein R has the above-mentioned meaning).

That is, when a compound of the formula II in which X is a hydroxyl group is used,
R ₁ and R ₂ are identical C ₃ -C ₁₀ - compound of formula I is an acyl group can be obtained. In this case, the R of the compound of formulas III and IV
And R ₁ and R ₂ of the compound of formula I are identical. Also the use of a compound of formula II X is a methoxy group, R ₁ is methoxy, R ² is C ₃ -C ₁₀ - compound of formula I is an acyl group can be obtained.

Compounds of formula II include isoliencinin (X = -O
H), Nefuerin (X = -OCH _3), and the like. There are four types of stereoisomers of the compound of formula II: SS, SR, RS and RR, and these isomers may be used.

Halogen atoms for substituent Y in compounds of formula III include, for example, chlorine, iodine and bromine. Examples of the C ₃ -C ₁₀ -acyl group for the substituent R in the formulas III and IV include a propionyl group, a butyryl group, a valeryl group, a caproyl group, and a capryl group. Linear acyl groups are preferred.

The reaction of the compound of formula II with the compound of formula III or the compound of formula IV wherein Y is a halogen atom is preferably carried out in a basic solvent. As the basic solvent, pyridine, triethylamine or the like is used, but a solvent such as ether, benzene or dichloromethane may be mixed.

The reaction of the compound of the formula II with the compound of the formula III wherein Y is a hydroxyl group is preferably carried out in the presence of a condensing agent in a solvent. As the condensing agent, for example, dicyclohexylcarbodiimide is used. As the solvent, for example, dichloromethane, tetrahydrofuran, dioxane and the like are used.

Compounds of formula I can be derivatized to acid addition salts by conventional methods. Physiologically harmless acids such as hydrochloric acid, sulfuric acid,
Preferred are inorganic acids such as nitric acid and phosphoric acid, and organic acids such as acetic acid, fumaric acid, malic acid and citric acid.

The compounds of the formula I show an excellent inhibitory action on cancer cells.
Therefore, the present invention is further an anticancer agent comprising a compound of the formula I as an active ingredient.

The compound of the formula I may be used as it is as an anticancer agent, but usually, excipients, binders, lubricants, solvents, stabilizers and the like are added, and tablets, powders, granules, capsules and injections are added. It is used after being formulated into an agent. Excipients include, for example, starch, lactose, methylcellulose, synthetic aluminum silicate, etc., binders, for example, hydroxypropylcellulose, polyvinylpyrrolidone, etc., and lubricants, for example, talc, magnesium stearate, calcium stearate and the like.

The dose of the drug of the present invention is 10 to 1000 mg, preferably 30 to 300 mg, per day as an active ingredient in the case of oral administration.

Production Example 1 100 mg of isoliencinine was dissolved in 2 ml of a mixed solvent of pyridine and dichloromethane (1: 1), and 100 mg of propionyl chloride was added under ice cooling. After reacting at room temperature for 2 hours, 20 ml of water is added and extracted with ether. The extract was separated and subjected to column chromatography [silica gel; chloroform-methanol (5:
Purification in 1)] gives compound 1 as an amorphous powder having a melting point of 55-58 ° C.

 Compounds 2 and 3 are obtained in a similar manner.

Compound 2: Amorphous powder having a melting point of 37 to 40 ° C. Amorphous compound 3: {47 to 52 ° C.} Preparation Example 2 100 mg of nepheline and 25 mg of caprylic acid in dichloromethane
34 mg of N, N'-dicyclohexylcarbodiimide is added to the solution dissolved in ml under ice-cooling. After reacting at room temperature for 1 hour, the insoluble matter is removed. After the solution was concentrated under reduced pressure, the residue was subjected to column chromatography [silica gel; chloroform-methanol (5:
Purification in 1)] gives compound 4 as an amorphous powder with a melting point of 40-43 ° C.

Experimental Example Using the human colon cancer-derived cultured cell line RPMI4788 cells, the dye-uptake method of Yamazaki et al. (Jpn. J. Med. Sci. Biol. Vol. 39, 105
, P. 118, 1986), the degree of suppression of cancer cell growth of the test substance was measured.

Test substance concentration that inhibits cancer cell growth by 50% (I
_C50 ) is shown in the table below.

Formulation Example 1 500 mg of compound 1, lactose 3.0 g, corn starch 1.28
g, 200 mg of hydroxypropylcellulose and 20 mg of magnesium stearate are mixed well, granulated, and tableted to give a tablet of 100 mg per tablet.

Formulation Example 2 500 mg of compound 2, lactose 2.5 g, potato starch 1.75 g,
240mg crystalline cellulose and 10mg calcium stearate
Are mixed well, and the mixture is filled into capsules to give capsules containing 10 mg of the active ingredient in one capsule.

Formulation Example 3 500 mg of the hydrochloride of Compound 3 and 1.0 g of D-mannitol are dissolved in distilled water for injection to make a total volume of 100 ml. This solution
The mixture is passed through a 0.2 μm membrane filter, dispensed into 2 ml ampules, sealed, and then heat-sterilized to prepare an injection.

Claims (2)

(57) [Claims] (1) General formula (Wherein R ₁ is a C ₃ -C ₁₀ -acyl group or a methoxy group, R ² is a C ₃
~ C ₁₀ -acyl group) or a bisbenzylisoquinoline derivative or an acid addition salt thereof. 2. An anticancer agent comprising the bisbenzylisoquinoline derivative according to claim 1 or an acid addition salt thereof as an active ingredient.