IE44927B1

IE44927B1 - Tumor antidote

Info

Publication number: IE44927B1
Application number: IE888/77A
Authority: IE
Original assignee: Max Planck Gesellschaft
Priority date: 1976-05-04
Filing date: 1977-05-03
Publication date: 1982-05-19
Also published as: LU77248A1; IL51988A; CA1094455A; SE7705071L; ZA772649B; JPS52134027A; DE2619686A1; NZ183981A; IL51988A0; DE2619686C2; IE44927L; JPS6146455B2; IT1071329B; NL7704723A; FR2364656A1; NL189672B; NL189672C; AU517586B2; FR2364656B1; AU2481977A

Abstract

HOE 76/S 005 TUMOR ANTIDOTE of the disclosure: The present invention provides tumor antidotes consisting of or containing a short chain synthetic lysolecithin analog.

Description

The present invention relates to a tumour antidote.

German Offenlegungsschrift No. 2,009,342 (British Patent No. 1,334,137) and U.S. Patent No. 3,752,886 describe the use of synthetic lysolecithin compounds for increasing resistance to diseases and tumours and for use as immunological auxiliaries.

It is also known that lysolecithin analogues, which may alternatively be called lysophosphatides, increase phagocytosis of peritoneal macrophages.

Moreover, after an injeotion of lysophosphatides, activated cells are formed which are able to increase the resistance of the body against damaging influences.

It has now been found surprisingly that certain lysolecithin analogues have a special effect on the growth of tumours.

The present invention provides a pharmaceutical preparation which comprises, in admixture or conjunction with a pharmaceutically suitable carrier, a compound of the general formula I HC-R I R2-C—R3 (I) h2c-o-r4 wherein R^ represents an alkylcarbonyl or alkoxy group having from 8 to 20 carbon atoms, preferably 16 to 18 carbon atoms? 8.% represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, a hydroxyl group, an alkyl-carbonyl or alkoxy group having a chain length of from 1 to 8, preferably 1 to 3,carbon atoms, or a benzyl group; R^ and R^ may be interchanged; R, represents the group if P-O-CH^-CH.j-Nv-l {Rc)Q (phosphorylcholine derivatives) OV in which R_ represents a hydrogen atom or a lower alkyl 5 group having 1 to 3 carbon atoms, preferably a methyl group, or R^ represents the group ti -P-G-CB^ ^2 -KH2 ^11° sphoryl -ethanol -amine) HO with the exception of those compounds in which Ro represents a hydrogen atom and Ro represents a hydrogen atom or a hydroxyl group, and those in which K2 represents a methyl group and R^ represents a hydroxyl group.

Those compounds in which R is a long chain group are analogous of α-lysolecithin, whereas those in which is the long chain group are β-lysoieci'chin analogues.

The compound cited as example and hereinafter called ET-18-OCH^ in a thoroughly abbreviated manner has the following formula IX 02c-o-(ch2)17-ch3 HC -0CH3 (II) O II The compounds of the formula I may be prepared according to any of the methods described in the literature, for example according to Arnold D„, Weltzien, H. U. and 0. Westphal; Uber die Synthese von Lysolecithinen und ihren Atheranaloga; Liebigs Ann. Chem. 709, 234-239 (1967) Weltzien, H. U. and 0. Westphal; 0-methylierte und 0-acetylierte Ly.solecithine; Liebigs Ann. Chem. 709, 240-243 (1967) .

Eibl. H. and 0. Westphal; Palmitoyl-propandiol(1,3)-phosphorylcholin (2-Dssoxy-lysolecithin) und Cb,oo-Alkandiol-Anal.6ga Liebigs Ann. Chem. 709 244-247 (1967).

The activity of compounds Of the formula I against the growth Of tumours is advantageously demonstrated on tumours cfe te'st animals. For this purpose, various experiments tumours are used, for example, Ehrlich ascites 'tumohr, a methylcholanthrene-indueed f tumour and a mydloma tumour in mice, furthermore a chemically-induced rat tumour. f }ϊο «j γ The anti-tumour substances may be administered parenterally to ths tumour-carrying test animals or to a patient preferably by intravenous, intra- or subcutaneous injection. Oral administration also is possible when the tumour antidote is used in a physiologically tolerable formulation, for example, soft and hard capsules and tablets.

The pharmaceutical preparations of the invention are, therefore, for example, in a form suitable for parenteral, especially intravenous, intraautaneous or subcutaneous administration, or for oral administration. There may be used any pharmaceutical carrier suitable for tha chosen galenic form.

The preparations may be in unit dosage form.

An advantageous dosage for parenteral administration is from 0.05 to 5 mg/kg of a compound of formula 2 body weight, and for oral administration from 0.01 to 10 mg/kg body v/eight, The preparations may contain from 0.05 to 5 mg and from 0.01 to 10 mg of the compound per ml, respectively. When the preparation is for oral administration, it advantageously comprises a solution or suspension of the compound of formula I in a soft gelatin capsule.

Especially efficient are the compounds of the formula II. At low concentration, they cause a reduction of the growth rate of tumours and at mean concentration, a regression of the tumours is often observed. After regression of the tumours, the test animals display a specific resistance to attempts to implant again a tumour of the same kind: the tumour does not grow any more. In order to enable the compound of formula I to remain in the circulatory system for a prolonged period, it is often useful to administer pharmaceutical preparation of the invention daily or in intervals of 2 or 3 days.

The invention further provides a method of treating an animal having a tumour, which comprises administering to the' animal a compound of the general formula I. The amount of the compound administered is preferably from 0.05 to 5 mg parenterally and from 0.01 to 10 mg orally. The animal is especially a human being.

The following Examples illustrate the activity of the tumour medicaments of the invention.

TEST EXAMPLE 1: Mice carrying Ehrlich ascites carcinoma cells (see Table 1) were treated the 7th day after the tumour inoculation with the anti-tumour compound ET-IB-OCH^ by means of intravenous injection.

The survival rate was evaluated of the mice which had been inoculated intraperitoneally with a varying number of tumour cells. Table 1 shows the test results and the dependence of the efficiency of the tumour antidote ET-IS-OCH^ on the daily doSe intravenously administered, expressed as ratio of surviving animals to total number of mice.

TABLE 1 Number of tumour ceils applied per Daily doses of mouse for tumour inoculation ET-18-0CH 5 3 per 20 9 mouse 1 x IO3 lx 104 5 x 10 zJ. ζ - 1 x 10 5 x 10' 1 i-t-ci 0/5*1 3/5 3/5 3/5 1/5 10 (ig 0/5 1/5 1/5 1/5 1/5 100 ug 0/5 3/5 2/5 3/5 1/5 Control (without 10 ΞΤ-18-OCH ) 0/5 0/5 0/5 0/5 0/5 Surviving/total number of test < animals TEXT EXAMPLE 2: x IO4 myeloma tumour cells (Potter x 5563) were subcutaneously inoculated in C3H mice. The mice were then treated with ths tumour antidote ET-18-OCHg by administering 10 'ig/20 g mouse intracutaneously for 14 days at a place remote from the tumour. The following Table 2 shows the survival rate of the test animals, depending on the start of treatment with the tumour antidote.

TABLE 2 Start of treatment/day + 1 + 7 + 11 + 15 Control (without ET-18-OCHg) Surviving/total number of test animals 4/5 3/5 3/5 1/5 0/5

Claims

1. CLAIMS : 1. A pharmaceutical preparation which comprises, in admixture or conjunction with a pharmaceutically suitable carrier, a compound of the general formula I (I) wherein R^ represents an alkylcarbonyl or alkoxy group having a chain length of 8 to 20 carbon atoms; R^ represents a hydrogen atom or a methyl group; R^ represents a hydrogen atom, a hydroxyl group, or an alkylcarbonyl or alkoxy group having a chain length of 1 to 8 carbon atoms, or represents a benzyl group; R^ and R^ being interchangeable; R^ represents the group II —P-O-CH 2 -CH 2 -N' in which R^ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, or R^ represents the group p-o-ch 2 -ch 2 -nh 2 HO II with the exception of those compounds in which Rj represents a hydrogen atom and Rg represents a hydrogen atom or a hydroxyl group, and those in which / represents a methyl group and Rg represents a hydroxyl group.

2. , A pharmaceutical preparation as claimed in Claim 1, wherein R^ represents an alkylcarbonyl or alkoxy group having a chain length of from 16 to 18 carbon atoms and R, represents an alkylcarbonyl or alkoxy group having a chain length of from 1 to 3 carbon atoms, R., and R, being interchangeable; and R = represents a methyl group.

3. A pharmaceutical preparation as claimed in Claim 1, wherein R^ represents an alkoxy group having a chain length of 18 carbon atoms, Eg represents a hydrogen atom, Rg represents a methoxy group, and R^ represents the group 0 l! ΛΤ, - Ρ-CHg -CHg -N j ( CHg ) g i©

4. A pharmaceutical preparation as claimed in 20 any one of Claims 1 to 3, in a form suitable for parenteral administration.

5. A pharmaceutical preparation as claimed in Claim 4, in a form suitable for intravenous, intracutaneous or subcutaneous administration. 25 S.A pharmaceutical preparation as claimed in Claim 4 or Claim 5, which comprises from 0.05 to 5 mg of the compound of formula I per ml.

6. 7. A pharmaceutical preparation as claimed in any one of Claims 1 to 4, in a form suitable for oral admini stration.

7. 8. A pharmaceutical preparation as claimed in 5 Claim 7, whioh comprises from 0.01 to 10 mg of the compound of formula I per ml.

8. 9. A pharmaceutical preparation as claimed in Claim 7 or Claim 8, in the form of a soft gelatin capsule.

9. 10 10. A method of treating a non-human animal having a tumour; which comprises administering to the animal a compound as defined in any one of Claims 1 to 3.

10. 11. A method as claimed in Claim 10, wherein 15 the compound is administered intravenously, intracutaneously or subcutaneously.

11. 12. A method as claimed in Claim 10, wherein the compound is administered orally.

12.

13. A method as claimed in Claim 12, wherein 20 from 0.01 to 10 mg of the compound is administered per kg body weight. F. R. KELLY + CO. AGENTS FOR THE APPLICANTS.