DE2619686A1 - ANTI-TUMOR AGENTS - Google Patents

Description

MAX ^ PLANCK SOCIETY FOR THE PROMOTION OF SCIENCE E.V.

File number: Hoe 76 / S oo5 = Ma 267

Date: 3o. April 1976

Dr.St/Gr

ANTI-TUMOR AGENTS

The invention relates to an anti-tumor agent containing compounds of the lysolecithin type in a pharmaceutically common one Preparation.

In the German patent applications P 2oo9 342 and P 2 oo9 343 the use of synthetic lysolecithin compounds is to increase resistance and as immunological adjuvants.

It is also known that lysophosphatides, like the lyso-leeithin analogs can also be called that increase the phagocytosis of peritoneal macrophages. Also comes it after injection of lysophosphatides to the formation of activated cells that increase the body's resistance to harmful ones Ability to increase influences.

It has now surprisingly been found that lysolecithin analogs of the general formula I are particularly effective exercise on the growth of tumors.

'109047/0082

The invention accordingly relates to anti-tumor agents, consisting of / or containing compounds of the general Formula I, in a conventional pharmaceutical preparation.

Formula I:

H ₉ C - R ₁

* 2 - ^C - ^R 3

H ₂ CO

in it is:

R ₁ = alkylcarbonyl (ester) or alkoxyl (ether) with chain lengths Cg - C ₂₀ , preferably C ₁₆ - C ₈

R ₂ = H or CH ₃

R_ = H, OH, alkylcarbonyl or alkoxyl with chain lengths C. - Cg, preferably C-. - C ₃ or benzyl

R-. and R ₃ are in principle interchangeable: R., long-chain substituted = ot-lysolecithin analogue R ₃ long-chain substituted = ß-lysolecithin analogue

R ₄ = O

Il

-PO- CH ₂ - CH ₂ - N ^ ⁺ ^ R ₅ K (phosphorylcholine-I derivatives, where R ₅ = H

O (-) or a low one

Alkyl with C1-C3, preferably CH ₃ )

or O

-PO- CH ₂ - CH ₂ - NH ₂ (phosphorylethanolamine) O (-)

709041/0002

The compound, abbreviated several times below with ET-18-OCH ₃ as an example, has the following structural formula:

Formula II:

- 0 - (CH ₂ ) ₁₇ - CH ₃

HC - OCH

0 - P - CH ₂ - CH ₂ - KT ^; (CH ₃ )

The compounds of the formula I can be prepared in one of the ways described in the literature, for example after:

Arnold, D., Weltzien, H.U. and 0. Westphal: "on the synthesis of lysolecithins and theirs Ether analogs ". Liebigs Ann. Chem. 709, 234-239 (1967)

Weltzien, HU and 0. Westphal: "O-methylated and O-acetylated lysolecithins" Liebigs Ann. Chem. 709 / 240-2 43 (1967)

Eibl / H. and 0. Westphal:

"Palmitoyl-propanediol- (1,3) -phosphorylcholine (2-deoxy-lysolecithin) and tacj-alkanediol analogues " Liebigs Ann. Chem. 709 / 244-247 (1967)

709847/0082

The effectiveness of compounds of the general formula I on the growth of tumors is expedient proven on tumors in laboratory animals. Come for this various experimental tumors for use, for example the Ehrlich Ascites Tumor, a MethyIchölan ~ thren-induced tumor and a myeloma tumor in mice, also a chemically induced rat tumor. The antitumor substances are parenterally into the tumor-bearing Administered to experimental animals. Preference is given to intra-venous and intra- or subcutaneous application. Oral administration is also possible with a correspondingly higher dosage of the anti-tumor agent and with a Physiologically compatible preparation, e.g. in capsules, cannot be excluded.

In the case of parenteral administration, the dosage has proven to be expedient, about 0.05 to 5 mg / kg of body weight to use.

Especially effective in this case the compounds prove to be corresponding to the formula Π and those that instead of the methoxy! Group of the formula \ OH or H wear. In low concentrations, they lead to a reduction in the rate of growth of the tumors. In medium concentrations, the tumors often come to regression. After regression of the tumors, the test animals show a specific resistance to the attempt to re-implant a tumor of the same type. The tumor no longer grows. In order to allow the anti-tumor agents to persist in the circulation for a longer period of time, it is often advisable to apply the agents daily or at 2 to 3-day intervals.

709847/0082

The following test examples show the effectiveness of the tumor agents according to the invention:

Test example 1 :

Mice with Ehrlich Ascites Carcinoma cells (cf. Tab. 1) were treated intravenously with the anti-tumor compound ET-18-OCH ₃ on the 7th day after tumor inoculation.

The survival rate of the mice was determined were originally inoculated intraperitoneally with different numbers of tumor cells. The table 1 shows the test result and the dependence of the effectiveness of the anti-tumor agent ET-18-0CH- on the daily intravenous dose as a ratio of survivors Animals to the total number.

Table 1:

Daily doses of ET-18-0CH-,

Number of tumor cells applied to inoculate the tumor

per 20 g mouse 1 χ 10 per mouse 5 χ 10 ⁴ 1 χ 10 ⁵ 5 χ 10 ⁵ 0/5 ^{+) 3} 1 χ 10 ⁴ 3/5 3/5 1/5 1 pg 0/5 3/5 1/5 1/5 1/5 10 ] ig 0/5 1/5 2/5 3/5 1/5 100 pg 0/5 3/5 0/5 0/5 0/5 control
(without
ET-18-OCH ₃ ) 0/5

Survivors / total number of animals

7Ö9847 / OÖ62

Experimental example 2;

The growth of methylcholanthrene-induced tumor cells in (Balb / c χ C57bl / 6) _F mice can be controlled by intravenous injection of ET-18-OH (see formula II, in which OCH _{3 is replaced by OH).} The following table shows the possibility of varying the start of treatment over several days after tumor inoculation. With an appropriate dose of the anti-tumor agent, the ratio of the surviving number of test animals to the total number is always more favorable than in the case of the untreated control animals, none of which survived.

Table 2 shows the survival rate of the animals at staggered Start of treatment. The intravenous application of the anti-tumor agent took place daily for 14 days.

Table 2:

Start of dose ET-18-OH / 2O g mouse

Treatment on day _{1 µg 1Q yg 1QQ µg}

+ 1

+ 3

+ 5

+ 7

+ 9

2/5 ⁺⁾ 3/5 4/5 3/5 3/5 2/5 3/5 4/5 3/5 2/5 1/5 3/5 3/5 2/5 4/5

Control 0/5

survivors / total number of test animals

709847/0082

A comparable test result is obtained if the anti-tumor agent is used instead of intravenous administration was injected intracutaneously.

Experimental example 3 ;

5 × 10 ⁴ myeloma tumor cells (PotterX556 3) were inoculated subcutaneously in C3H mice. The mice were then treated with the anti-tumor agent ET-18-OCH ₃ by applying 10 pg / 20 g mouse intracutaneously at a location remote from the tumor for 14 days. Table 3 below shows the survival rate of the test animals as a function of the start of treatment with the anti-tumor agent.

Table 3:

Start of survivors / total number

Treatment on the day of the test animals

+ 1 4/5 + 7 3/5 + 11 3/5 + 15 1/5 Control (without ET-18-OCH ₃ ) 0/5

709847/0082

ORIGINAL INSPECTED

Claims (3)

PATENT CLAIMS 1. Anti-tumor agents consisting of or containing a compound of the general formula I in one customary pharmaceutical preparation. formula I: H ₀ C -
I. ^R 1 R. 1
HC- ^R 3
0 - in this is: R ₁ = AUcylcarbonyl (ester) or alkoxyl (ether) with chain lengths Cg - C ₀₀ / preferably Cg - C. _ß R ₀ = H or CH ₃ R ₃ = H, OH, alkylcarbonyl or alkoxyl with chain lengths C. - Cg, preferably C. - C_ or benzyl R- and R ₃ are basically interchangeable: R. long-chain substituted = α - lysolecithin analogue R ₃ long-chain substituted = 0 - lysolecithin analogue R ₄ = 0 -PO- CH ₀ - CH ₀ - N ^{i +)} (RcK (Phosphorylcholine-I derivatives, where R ₅ = H 0 (-) or a lower one Is alkyl with C ₁ -C ₃ , preferably CH-) or 0 ■ I -PO- CH ₀ - CH ₀ - NH ₀ (phosphorylethanolamine) 0 (-) 709847/0082 ORIGINAL INSPECTED 2. Anti-tumor agent according to claim 1, characterized in that that it is in a preparation suitable for parenteral administration of about 0.05 5 mg / ml of a physiologically acceptable solution contains a compound of the general formula I. 3. Anti-tumor agent according to claim 1, characterized in that it is in one for oral administration suitable physiologically acceptable preparation 5-10 mg / ml of a compound of the general Formula I contains. 709847/008