DE1768836A1 - Process for the production of bis (beta-chloraethylamino) methyl rutins with cancerostatic effect - Google Patents

Description

Methods for the production of carcinostatically active bis (ß-chloroethylamino) methyl rutins The present invention is concerned with the production of new [bis (ß-chloroethylamino)] methyl rutins which are carcinostatic and their use as remedies of the following Constitution should take place: I a of this formula, R can be a bis (ß-chloroethylamino)) methyl group or ### hydrogen, R1 is a bis (ß-chloroethylamino) methyl group El = - C1 -C1L-iT <'' - L - C1 2 - Cl or a further bis (ß-chloroethylamino) methyl rutin group, so that a dimer rutin of the following constitution is present: III It has been found that # these new bodies are accessible through conversion of rutin with formalin and bis- (ß-chloroethylamine) @ Dinem solvents or diluents. Depending on the use of the molar ratios of mornaldehyde, bis (β-chloroethylamine) and rutin, various suo-substituted rutin derivatives can be obtained. With a L-ratio of rutin: bis- (ß-chloroethylamine) = 1: 1: 1, 8- [bis- (ß-chloroethylamino)] - methyl @ (= I) is formed, with a molar ratio of rutin = X, is-c. lor-, ethylamine) '= 2 and formalin = 2, 6,8-di- [bis- (ß-chloroethylamino) methyl] rutin (= II) is obtained.

With a molar ratio of rutin = 3, bis- (ß-chloroethylamine) = 2 and formaldehyde = 3 becomes a dimer, namely [@ -Di- (o, @ - bis-ß-chloroethylamino-methyl-rutin] -methane (= III) Debated.

The substances 1 - III obtained are soluble in water and also with keep durable.

It is already known that bis (ß-chloroethylamine) derivatives of the most varied Kind of cancerostatically effective. However, it is also known that the largest Number of these derivatives is somewhat stable and, moreover, an unfavorable therapeutic one In the; so that all of these derivatives are unusable for theraneutical use are. So only i) in methyl-1-mustard is the therapeutic index equal to 1, i.e. the The toxic dose is equal to that of the curative.

It has now been found that the present inventive bodies have a very favorable therapeutic index of 4 - 5, like the following Table ergiot. I) The compounds obtained were chemotherapeutic on Yoshida sarcoma the rat checked.

L50 in mg / kg intraperitoneally DC50 curative dose that occurs at 50% of the Animals is effective.

Substance DL50 intraperitoneally DL50 in Therapeutic on rats in mg / kg mg / kg index DL50 DC50 I according to example 1 125 30 4, 16 II according to example 2 100 25 4 111 according to Example 3 140 30 4, 66 The new bodies according to the invention should are used as remedies in human and veterinary medicine.

A few examples show an advantageous production of the same described.

Example 1 8- [bis (ß-chloroethylaminomethyl)] rutin, 22.1 g of rutin (with 3 mol of water) are suspended in about 60 ml of methanol. In this suspension 4.5 g of bis (ß-chloroethyl) amine are stirred in, then 3 ml of 37% aqueous formalin solution admitted. The mixture is stirred for 10 minutes, with slight warming occurring. Then is heated on the water bath for 15-20 minutes to 60-65 ° C. There is dissolution a.

The color Jej solution is reddish-yellow and strikingly bright.

After everything has been solved, the reaction mixture will take another 10 - 12 hours, expediently overnight, left to stand. The clear solution is then poured into 100 ml.] Sopropanol is stirred in in portions.

Yellowish, matted, clearly recognizable needles fall out. After standing for 3 hours, isopropanol is decanted and the deposited crystal layer Made into a paste with 30-50 ml of ether, left to stand again for 1 hour, then suctioned off, and so good that the crystals no longer smell of ether. The Crystals dried at 50 - 600 ° C.

Yield: 25 g, tp. 185 - 1870 C. Sintering to a brownish mass, which flares up at 188 - 1900 C.

The crystals can be dissolved in a little acetone and precipitated with ether or isopropanol.

Example 2 6,8- [di- (bis-ß-chloroethyl-aminomethyl] rutin, 22.1 g of rutin (with 3 mol. Water) are suspended in 50 ml of methanol. There are 9 g of bis (ß-chloroethyl) amine entered and then 6 ml of 37% formalin solution. There is a distinct one Temperature increase by 100 ° C. The mixture is stirred for 10 minutes and heated on the water bath to 500 C, the temperature suddenly rising to 700 C with dissolution of the rutin. It is allowed to cool and the reaction mixture is left to stand for 12-15 hours.

The clear reddish solution is then poured into approx. 100 ml of isopropanol. A bright yellow oil precipitates. After standing for 2 hours, it becomes almost colorless supernatant isopropanol solution decanted from the yellow oil. The yellow oil is 50 ml of isopropanol dough through, slowly becoming a crunchy crystalline texture accepts. After a few hours the oil becomes crystalline, it is suctioned off and dried immediately in a vacuum at 40 - 500 C.

Substance of yellow nature is obtained.

Fp .: sintered at 85 - 950 C, flares up at 1000 e.

Yield: about 25 g of Example 3 8- [di (6,6'bis-ß-chloroethyl-aminomethyl-rutin] methane 22.1 g of rutin (with 3 mol of water) are suspended in 50 ml of methanol. One carries first 9 g of bis (ß-chloroethyl) amine, then 20 ml of 77% formalin. It occurs; one Temperature increase by 100 C eiri. Now there is another 5 - - 10 minutes on the water bath heated until complete dissolution and the reaction material overnight itself left.

The reddish brown solution is poured into 100 ml of isopropanol, whereby a yellow fluffy precipitate precipitates out, which becomes oily on standing.

After standing for 4 hours, isopropanol is decanted and the oil with acetone stirred, whereby it becomes crystalline. Repeat the process 2 more times put the crystals on a suction filter and dry; quickly in a vacuum because the crystals are strong Attract moisture. Yield approx. 24 g.

Fp .: sintered at 1000 C, from 1560 C with effervescence black-brown.

Claims (1)

Claim for a process for the production of cancerostatisci effective [bis- (ß-chloroäthylamino)] methyl rutins and their use as remedies of the constitution below in which R is hydrogen or a bis (ß-chloroethylamino) methyl group, R1 represents an is- (ß-chloroethylamino) methyl group or a doubling of the rutin connected by a methylene bridge and substituted by a bis (ß-chloroethylamino) methyl group, characterized in that 1) rutin with formaldehyde and bis - (ß-chloroethyl) -amine is reacted in changing molar ratios in a solvent or diluent.