DD259405A5 - PROCESS FOR PREPARING COMPOUNDS WITH CYTOTOXIC EFFECT - Google Patents

Abstract

According to the invention, compounds of the formula I RYPO 2 XR 1 I or a physiologically acceptable salt thereof are prepared in which, for example: R is a saturated or unsubstituted hydrocarbon radical having 12 to 24 carbon atoms, which may also be halogen-substituted, X is an oxygen atom, NH or NR 2, Y is an oxygen atom or NH, R1 is a C1-C8 alkyl group, or wherein R1 represents a C2-C8 alkyl group unsupported and / or containing halogen, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, tri-C1 C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl is substituted u. a.

Description

RO-PO (OH) -O-CH ₂ -CH ₂ -OH

getting produced,

wherein R is hexadecyl, tetradecyl, octadecyl or oleyl by reacting phosphorus oxychloride first with hexadecanol, tetradecanol, octadecanol or octadecene (9c) -ol, then reacting the reaction mixture with ethylene glycol, treating the reaction product with water and optionally the compounds obtained in the Salts transferred.

6. Process according to claims 1 to 3, characterized in that compounds of the formula

RO-PO (OH) -NHCH ₂ -CH ₂ -Oh

getting produced,

wherein R is hexadecyl, tetradecyl, octadecyl or oleyl, characterized by reacting phosphorus oxychloride first with hexadecanol, tetradecanol, octadecanol or octadecene (9c) -ol, then reacting the reaction mixture with ethylene glycol and treating the reaction product with potassium carbonate and optionally the resulting Compounds converted into the salts.

Field of application of the invention

The invention relates to a process for the preparation of compounds having cytotoxic activity.

The compounds according to the invention are used as medicaments, for example for the treatment of tumors.

Characteristic of the known state of the art

European application 108565 relates to compounds of the formula

It

wherein R ^{1 is} an aliphatic C ₈ -C ₃₀ hydrocarbon radical and R ² , R ³ and R ^{4 are} hydrogen or lower alkyl radicals or the group

R ²

NR ³

R ⁴

a) cyclic ammonium radical, and η = O or 1. These compounds are said to inhibit the proliferation of tumor cells and prolong the lifetime of warm-blooded animals having tumors; In addition, an antifungal effect is mentioned.

It is known that to date no satisfactory in all respects medicine for the treatment of tumors, especially of malignant tumors, is available. For example, the topical treatment of skin metastases at. Currently, only 5-fluorouracil is available for patients with metastatic tumors, although this type of treatment has not been clinically proven for this type of application, and, from a clinical point of view, such a concept is particularly desirable in the palliative treatment approach as alternative treatment approaches such as surgical intervention, radiation therapy, and In addition, a significant number of patients are potential candidates for treatment for such topical treatment, for example, the proportion of mammary carcinoma patients with skin involvement is approximately 25 to 35%. The prerequisite for topisch treatment on the part of the active substance to be used is compatibility on the skin, cytotoxic activity against tumor cells and adequate depth penetration.

Object of the invention

The aim of the invention is the provision of a medicament which is suitable for the topical treatment of tumors. A further Ziei of the invention is the provision of a generally applicable in other forms of application drug that combines good activity against tumors with low toxicity and therefore is generally used in tumor therapy.

Explanation of the essence of the invention

The invention has for its object to find new compounds and processes for their preparation, which have strong antitumor effect with low toxicity and are suitable for the treatment of tumors. According to the invention, novel compounds of the general formula I or Γ are prepared.

or a physiologically acceptable salt thereof, which is useful as an active ingredient in medicaments for the treatment of tumors

The medicinal product contains common pharmacological additives and diluents. Preferred active substances are: hexadecylphosphochelin, oleylphosphocholine, hexadecylphosphoric acid (N, N) -bis (2-chloroethyl) -amide.

Formulas I and Γ also include the possible enantiomers and diastereomers. If the compounds are racemates, these can be cleaved into the optically active isomers in a manner known per se, for example by means of an optically active acid. However, enantiomeric or optionally diastereomeric starting materials are preferably used from the outset, in which case the end product obtained is a corresponding pure optically active or diastereomeric compound.

In the context of the invention, R is preferably an alkyl group of the specified chain length which is linked to the oxygen of the glycol radical via a terminal C atom or else via a C atom within the alkyl chain (for example via the C atom 2 or C). Atom 3 or another middle C-atom). This alkyl chain can be straight-chain or branched. The Aikylkette R can contain one, two or three carbon double bonds or triple bonds, which can also be present mixed, and / or having halogen substituents. Suitable halogen atoms are: fluorine, chlorine or bromine. In the chain R, one to three such halogen atoms may be present, which may be located at one or at different C atoms of the radical R.

In addition to the saturated straight-chain alkyl radicals, preference is given to those having one or two carbon double bonds in the molecule. Particular preference is given to those substituents R which contain an alkyl radical having 14 to 20, preferably 15 to 20, in particular 16 to 20 C atoms or a corresponding alkenyl radical having 14 to 20, preferably 15 to 20, in particular up to 20 C atoms.

Examples of halogen-substituted radicals R are: chlorohexadecyl, bromohexadecyl, fluorohexadecyUiiJO-dibromoctadecyl, 2,3-dibromoctadecyl, 15,16-dibromohexadecyl, bromotetradecyl.

Examples of unsaturated radicals R are: 9-octadecenyl radical (oleyl alcohol radical, especially in formula I or I'R this 9-octadecenyl radical), 15-hexadecenyl radical, 9,12-octadecadienyl radical (linoleyl radical).

, If there is more than one double or triple bond, these are conjugated. Examples of saturated and unsubstituted radicals R are: tetradecyl radical, hexadecyl radical, octadecyl radical. If R 1 and R ₂ denote an unsubstituted alkyl group, this consists for example of 1-6, preferably 1-4 C atoms. If R 1 or R _{2 is} an unsaturated alkyl group, it consists in particular of 3 to 6 C atoms, wherein between the unsaturated function of such an unsaturated alkyl group and X at least one simple CC bond must be present. In particular, they are Cr-Ce-alkenyl groups. Examples of these are: allyl, butenyl, pentenyl, hexenyl.

If R 1 or R _{2 are} substituted, these are, in particular, straight-chain alkyl or alkenyl radicals, in which case R ₂ preferably consists of 2-6 C atoms, where the substituents indicated are preferably in the ω-position of the alkyl or alkene group R 1 or R ₂ R ₂ are; for example, it is the ethyl or straight propylene radical with one of the specified substituents in the ω-position (that is, 2 in the ethyl position and 3 in the propyl position). If R _{1 is} a 2-tert-butyloxycarbonylaminoethyl radical or a 2-tert-butyloxycarbonylethyl radical, it is preferably the D or L form.

- 4 - 4.OV «* uo

Among the substituents of R ₁ , the trialkylammoniumethyl radicals are preferred when X is an oxygen atom, the trialkyl radicals preferably each consisting of one, two or three carbon atoms, preferably methyl groups. Therefore, the trimethylammonium ethyl radical is particularly preferred.

In this particularly preferred embodiment, the compounds of the formula I are phosphatidylcholine derivatives.

In the case of the Cr-C ₈ -cycloalkyl substituent, this consists in particular of 3-6 C atoms (for example cyclopropyl to cyclohexyl). The 2,3-dihydroxy-propyl (1) group is in particular the sn-1,2-dihydroxy-propylamino (3) structure or the sn-2,3-dihydroxy-propylamino ( 1) -Struktur.Die agents according to claim 8 are new compounds. Of these new compounds, the active ingredients according to the invention are preferably the following:

Oleyl-phospho- (N, N, N-trirnethyl) -propanolamine,

Oleyl-phospho- (N, N, N-trimethyl) -bUtanolarnin,

Oleyl-phospho- (N, N, N-trimethyl) -pentanolarnin,

Oleylphosphoserine, oleylphosphoethanolamine,

Oleyl phosphopropanolamine, oleyl phosphobutanolamine,

Oleyl phosphoglycerol,

Hexadecyl-phospho- (N, N, N-trimethyl) -propanolamine.

Suitable salts are internal salts (for example when R _{1 is a} trimethylammonium-alkyl group) or salts with physiologically compatible cations. The medicaments or compounds according to the invention can be present as internal salts, for example when R ₁ contains an amino group. If there are no internal salts, or the radical R _{1 contains} no basic group, the negative charge of the phosphoric acid group is saturated by a physiologically acceptable cation. Examples of suitable physiologically acceptable cations are: alkali cations (Na, K), alkaline earth cations (Mg, Ca) or the cations of organic amines, such as guanidinium, morpholinium, cyclohexylammonium cation, ethylenediamonium cation, piperazonium cation (in both latter cases or dibasic) or the cation which is derived from an Am in the formula NR _a RbR _c , in which the radicals R _a to R _{0 are} identical or different and denote hydrogen, CT-C ₂ -alkyl groups or oxyethyl groups. In the case of cations derived from an amine of the formula R _a RbRc, it is preferably the ammonium cation or an ammonium cation substituted with one to three C ₁ -C ₂ -alkyl groups or one with one to three 2 -Hydroxyethyl groups substituted ammonium cation.

The preparation of the active compounds according to the general formula I or Γ can be carried out by methods known per se. The backbone can be easily obtained by reacting a compound of the formula ROH or a functional derivative thereof with phosphorus oxychloride and triethylamine, reacting the product with a compound HXR-i and acid cleavage, wherein R, R ₁ and X have the above significance.

The preparation process for the compounds of the formulas I and I 'is illustrated schematically by way of example in the following reaction equations: (The group OCH ₃ in the corresponding formulas is representative of the group OZ.)

Il

1) RO-PO- (CH ₀ )

LiBr

RO-PO- (CH) -CH ₀

OLi Alkylphosphoalky! Ester

(x = 1-7)

II

2) RO-P-O- (CH-) -Br

y

'3

a) LiBr

b) N (CH ₃ )

- ^ RO-PO- (CH-) -Br * Y

OLi

Alkylphosphobronoalkylester

(y = 2 - 12)

0 U

-> RO-PO- (CH ₂ JN (CH ₃ )

Alkylphospho (N, N) dimethylanikanolamine

O RO-PO- (CH ₀ J ₁ -N (Ql ₀ ) H.

a ₃ )

Il

Alk \ 'lphospho-N-methyl-Alkanolarain

- ^ Alkylphosphc-Alkanolairdn

f RO-P ₁ O- (CH ₅ ) * -N (CH ₀ )

O ^y phosphatidylcholine

3) RO-PO- (CH ₂ ) HD-Tr

OCH

a) LiBr

a.) acid hydrolysis;

NaH COA EO-P-O- (CH-) -OH

2'y

Alkylphospho-hydroxyalkyl esters (y = 2 - 20); Tr = trityl

4) RO-PO- (CH ₉ ) -C CCH ₃

(CH

₃ J ₃

a) LiBr

a ..) acid hydrolysis; Na HCO *

RO-P-O- (CH.) - C ONa

^S GH

AlkylphosphoH-carboxyoxyester (Z = 1 - 20)

5) RO-PO-CH ₉ -CHOCH ₃

NH-BOC NH.

a) LiBr

a ..) acid hydrolysis; Na H CO _3. O

If

-> RO-PO-CH ₀ -CH '2

ONa

Alkylphospho-serine (BOC = tert-butoxycarbonyl)

6) RO-P-O-CH - CH - CH - O 2 ²

Oech

CH.

.0

'CH.

a) LiBr

a ..) acid hydrolysis; Na H CO ₃

RO-P-0-CH - CH-CH-

I ² II ²

ONa OH OH alkylphospho-glycerol

7) RO-PO- (CH ₀₎ -NH-BOC

^2y

OCH,

a) LiBr;

a.) Saiore hydrolysis

RO-P-O- (CH-) -NH-ι-yy

Alkvlphospho-etiianolaitiin (y = 2 - 20); BOC = butoxycarbonyl

Il

RO-P-O- (CH-) -N-BCC

OCH.

CH.

a) LiBr;

a.) acid hydrolysis alkylphospho-N-methylethanoiamine (y = 2 - 20) BCC = butoxycarbonyl

9) RO-P-NH- (CH ₀₎ - Br

OCH.

a) LiBr

RD-P-NH- (CH-) _- Br, ZL

OLi

Alkylphosphc-Bronalkylamide

0 (Z = 2 - 12)

aj

-> RO-P-NH- (CH ₂ ) _Z -N (CH ₃ )

Alkylphosphine-N, N-dimethyl-1-aminoalkylanide

a ₂ ) H (CH ₃ ) H ₂ O-RO-P-NH- (CH ₂ J ₂ -N (CH ₃ ) H

Alkylphospho-N-methyl-aminoalkyloinide

a ₃ ) NH ₃

- ^ RO-P-I-JH- (CH-) -NH-.

ÄDcylphospho-öminoalkylainid

b) K (Gi

-> RO-P-NH- (CHJ -N (CHJ ^

Alkylphospho-N, N, N-trimethy1-aminoalkylamide

-9- 253 405

Il

11) KO-P-NH- (CJ ₀ J ₁₇ -OTdLtVl

OCH

RO-P-NH- (CH _n) "-OH

a) LiBr ONa

a ^) acid hydrolysis; Alkylphospho-hydroxyai-ryl-

amide

Il

12) RO-P-NH- (CK), OC _n

a) LiBr

a _n ) acid hydro-

analysis;

NaKCO ^

Il

.0

-> RO-P-NH- (CH) "-C ¹

£. Li

^N 0Na

ONa

Alkylphospho-carlx) xyalk \ 'lamid

Il

13) RO-P-NK-CH _n -CH

^z i

OCH ₃ . O _n CH _n "

- CH _n 2

CH.

a) LiBr

a ..) acid hydrolysis; NaIiCO ₃ "

Il

RO-P-NH-CH-CK-CH _n ι ^ ι ι

ONa OH OH alkylphospho-dihydroxvprcpylamide

Further information on the process according to the invention:

In the starting materials of the formula III, existing hydroxy groups, carboxy groups, amino groups or C ₁ -C ₆ -alkylamino groups which occur in the radical R ¹ or also in the radical R ² (if X is the group NR ² ) can be protected by customary protective groups his. Adjacent hydroxy groups may be protected by ketalization with an aliphatic saturated Cy-C ₆ ketone.

These are radicals which can be easily cleaved off by hydrolysis or hydrogenolysis and are split off during or after the reaction. If such protective groups are not cleaved in the process reaction, then there is a cleavage after the reaction. Frequently, the starting compounds already contain such protective groups because of their preparation.

These protective groups are, for example, easily solvolytically removable acyl groups or hydrogenatable cleavable groups. The solvolytically cleavable protecting groups are, for example, by saponification with dilute acids (for example acetic acid, perchloric acid, hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid) or by basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, NH ₃ ) at temperatures between -50 and 150 ⁰ C, in particular between 0und.100 ° C, split off. Hydridgeable cleavable groups such as arylalkyl (benzyl) or hydroxycarbonyl (Carbobenzoxyrest) are suitably by catalytic hydrogenation in the presence of conventional hydrogenation catalysts (noble metal catalysts), in particular palladium catalysts or platinum catalysts (platinum oxide), Raney nickel, in a solvent or suspending agent, optionally under elevated pressure, (for example 1-50bar) at temperatures between 20-150 ⁰ C, in particular 30-100 ⁰ C, preferably 40-80X split off.

Suitable solvents or suspending agents for the removal of such protective groups are, for example: water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, halogenated hydrocarbons, dimethylformamide and so on, and mixtures of these agents. Examples of protective groups which can be eliminated by hydrogenolysis are: benzyl radical, a-phenylethyl radical, benzyl radicals substituted in the benzene nucleus (p-bromo or p-nitrobenzyl radical), carbobenzoxy radical, carbobenzene thio radical, tert-butyloxycarbonyl radical. Examples of hydrolytic cleavable radicals are: Trifluqracetylrest, phthalyl radical, trityl radical, p-toluenesulfonyl radical, tert-butyloxycarbonyl radical, tert-butyl radical, dimethylmethylene radical and the like, and lower alkanoyl radicals such as acetyl radical, formyl radical, tert-butylcarboxy radical and the like.

In particular, the customary in the peptide synthesis protecting groups and the usual there cleavage methods come into question. Reference may also be made, inter alia, to the book by Jesse P. Greenstein and Milton Winitz "Chemistry of Amino Acids", New York 1961, John Wiley and Sons, Inc. Volume 2, for example page 883 and following, and also the carbalkoxy group (U.S. Example low molecular weight) is suitable.

The cleavage of the group OZ (preferably this OCH ₃ ) is carried out, for example, with alkali bromides or alkali metal iodides, lower alkyl magnesium halides or with primary, secondary or tertiary amines, in particular the corresponding lower alkylamines, such as tertiary C ₁ -C ₆ -alkylamines (trimethylamines As alkali bromides For example, lithium bromide, sodium bromide, lithium iodide, sodium iodide are suitable as lower alkyl magnesium halides: methyl magnesium iodide, methyl magnesium bromide (solvents in this case lower aliphatic ethers, such as diethyl ether).

The cleavage of the group OZ from a compound of formula III is carried out at temperatures between 10 and 150 ⁰ C, preferably 10 and 8O ⁰ C, in particular 50 and 80 ° C, wherein the reaction product thus far obtained after removal of the solvent in an inert medium dissolves. As such inert agents are: saturated aliphatic C ₃ -C ₈ ketones (ethyl methyl ketone, diethyl ketone, acetone), cyclic ethers, noncyclic lower aliphatic ethers (for example, diethyl ether).

In general, 1.5 to 3 mol of the abovementioned elimination agents, preferably 2 mol, are used per 1 mol of compound III employed.

The reaction of products obtained (for example compounds in which R ¹ and / or R ^{2 is} haloalkyl) with ammonia or an amine of the formula NR ³ R ⁴ R ⁶ takes place at temperatures between 10 and 200, preferably 20 and 15O ⁰ C, in particular 40 and 80 ° C with or without solvent. If a solvent or suspending agent is used, this may be:

Aromatic hydrocarbons, such as pentane, hexane, heptane, benzene, mesitylene, toluene, xylene; lower aliphatic ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, trichlorethylene, carbon tetrachloride, chlorobenzene, methylene chloride; cyclic ethers such as tetrahydrofuran and dioxane; lower aliphatic non-cyclic ethers (diethyl ether, diisopropyl ether); lower aliphatic alcohols (1-6 C-atoms), such as, for example, methanol, ethanol, isopropanol, amyl alcohol, butanol, tert-butanol; Amides and N-alkyl-substituted amides of aliphatic C 1 -C 4 -carboxylic acids (dimethylformamide, dimethylacetamide); Ci-Ce-dialkyl sulfones (dimethylsulfone, tetramethylsulfone); Ci-Ce-dialkyl sulfoxides (dimethyl sulfoxide) and other aprotic agents such as N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, acetonitrile. The individual alkyl radicals of the abovementioned solvents contain, for example, 1-6, in particular 1-4, carbon atoms. Mixtures of these agents and mixtures with water come as a reaction medium in question. The reaction is carried out for example at temperatures of 0 to 200 ⁰ C, preferably 20 to 15O ⁰ C or even 50 to 12O ⁰ C. When a solvent or dispersant is used, one often works at the reflux temperature of this agent.

This amination reaction is conveniently carried out in the presence of basic substances. Suitable basic substances are, for example: alkali metal hydroxides, alkali metal carbonates, tertiary amines.

The alkylation of free amino groups in the radicals R ¹ and / or R ² is carried out at temperatures between 0 and 200, preferably between 20 and 150, in particular 20 and 8O ⁰ C. This alkylation erfoJgt example by reaction with compounds of the formula R'Hal, ArSO ₂ OR 'and SO ₂ (OR ^) ₂ , wherein Hal represents a halogen atom (in particular chlorine, bromine or iodine) and Ar denotes an aromatic radical (for example a phenyl or naphthyl radical optionally substituted by one or more lower alkyl radicals and R' Examples are p-toluenesulfonic acid C ₁ -C ₆ -alkyl esters, C ₁ -C ₆ -dialkyl sulfates, C ₁ -C ₆ -alkyl halides The alkylation reaction is optionally carried out with the addition of customary acid-binding agents, such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates , Alkaline earth metal carbonates, alkali metal acetates, tertiary amines (for example trialkylamine such as triethylamine), pyridine or alkali metal hydrides in inert solvents or suspending agents ührt. Suitable solvents or dispersants are, for example: Aromatic

Hydrocarbons ₍ such as benzene, toluene, xylene, aliphatic ketones such as acetone, methyl ethyl ketone, halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride, aliphatic ethers such as butyl ether, cyclic ethers such as tetrahydrofuran, dioxane, sulfoxides tertiary acid amides such as dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, aliphatic alcohols such as methanol, ethanol, isopropanol, amyl alcohol, tert-butanol, cycloaliphatic hydrocarbons such as cyclohexane, etc. Aqueous mixtures of said solvents may also be used The alkylation reaction components are frequently used in excess in the presence of tetraalkylammonium salts (esp the halides) in combination with alkali metal hydroxides at temperatures between 0-100 ⁰ C, preferably 20-80 ⁰ C in an aprotic solvent or in chloroform or methylene chloride are made. Suitable aprotic solvents are, in particular: tertiary amides (dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide), dimethylsulfoxide, acetonitrile, dimethoxyethane, aceto-η, tetrahydrofuran, and the like.

The active compounds of the general formula I or I 'contained in the medicament according to the invention are in part new and to that extent likewise an object of the invention. They have a pronounced cytotoxic activity, which has been demonstrated both in vivo on the chemically induced mammary carcinoma of the rat, as well as in vitro on leukemia cells in cell culture. In addition, in a clinical pilot study in breast cancer patients, skin metastases were brought to complete healing with topical application

 The following compounds and their physiologically acceptable salts are novel: compounds of the general formula

RY-POf-XR ₁ , I '

wherein R is a saturated or unsaturated hydrocarbon radical having 12 to 24C atoms, which may also be halogen-substituted, X is an oxygen atom, NH or NR ₂ and Y is an oxygen atom or NH, the radical Ri

a) a Ci-C ₈ alkyl group, an unsaturated C3-C ₈ alkyl group or an optionally unsaturated C ₃ -C _s alkyl group which may be substituted by halogen, amino, C ^ Ce-alkylamino, di-Ci-Cg-alkylamino Tri-Ci-Ce-alkylamino, hydroxy, carboxy, Qr-Cs-cycloalkyl or phenyl substituted, represents or

b) a C ₂ alkyl group which is substituted by halogen, hydroxy, carboxy, C ₃ -C ₈ cycloalkyl or phenyl, or

c) an unsaturated C ₂ alkyl group which is substituted by di-C ₁ -C ₆ -alkylamino, tri-d-C ₁ -C ₆ -alkylamino, carboxy, C ₃ -C ₈ -cycloalkyl or phenyl, or

d) a C ₂ alkyl group substituted by amino, C ₁ -C 6 alkylamino, di-C ₁ -C 6 alkylamino or tri-C ₁ -C 6 alkylamino, if X is oxygen, NH or NR ₂ and Y is the group NH is or if X is the group NH or NR ₂ and Y is oxygen and R has the meanings indicated, or

e) 2-tert-butyloxycarbonylaminoethyl, 2-tert-butyloxycarbonylethyl, 2,3-isopropylidenedioxy-propyl- (1), 2,3-dibenzyloxypropyl-d), 1,3-dibenzyloxy-propyl- (2) or NC ^ Cg-alkylamino-C ^ Ce-alkyl, when X is an oxygen atom and Y and R have the meanings indicated,

f) may be 2,3-dihydroxypropyl- (1) when X is the NH group and Y and R are as defined,

and R _{2 is} a 2,3-dihydroxypropyl (1) group, a Ci-C ₈ alkyl group or a C ^ Ce alkyl group which is unsaturated and / or halogen, amino, C ^ Ce-alkylamino, di-Ci -C ₆ -alkylamino, tri-C ₁ -C ₆ -alkylamino, hydroxy, carboxy, C 3 -C ₈ -cycloalkyl or phenyl, with the exclusion of those compounds where in the formula Γ X and Y are both oxygen, Ri is a saturated or unsaturated C ₁ -C ₈ -alkyl radical which may also be substituted by hydroxy, amino, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkylamino or tri-C ₁ -C 8 -alkylamino, and R is a saturated or unsaturated C ₁ -C ₈ -alkyl radical unsaturated Ci ₂ -C ₂₄ -Aikylrest represents.

In particular for topical application, but also for preparation as medicaments for other types of administration, it has been found to be particularly advantageous to use the compounds of general formula I or II together with at least one alkylglycerol having 3 to 4 carbon atoms in the alkyl radical Ether group can be bonded to one of the primary or secondary OH groups of glycerol used. Such alkylglycerols increase or improve the effect of the compounds of general formula I or Γ synergistically. Alkylglycerols having 3 to 9 carbon atoms are preferably used here alone or mixed. Particularly favorable effects therefore have a synergistically acting drug which a) at least one compound of the general formula

RY-POf-XR ₁ - I

or a physiologically acceptable salt thereof, wherein in the formula I is pure saturated or unsaturated hydrocarbon radical having 12 to 24C atoms, which may also be halogen-substituted, X is an oxygen atom, NH or NR ₂ and Y is an oxygen atom or NH, Ri is a C ₁ -C ₆ alkyl group, or wherein R _{1 represents} a C ₂ -C ₈ alkyl group which is unsaturated and / or halogen, amino, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, tri-C C 1 -C 6 -alkylamino, hydroxy, carboxy, C 1 -C 6 -cycloalkyl or phenyl, and in which R 1 additionally also denotes 2-tert-butyloxycarbonylaminoethyl, 2-tert-butyloxycarbonylethyl, 2,3-isopropylidenedioxy-propyl- (1) , 2,3-dibenzyloxy-propyl- (1), 1,3-dibenzyloxy-propyl- (2) or N-Ci-C _e -alkylamino-C ₂ -C ₆ -alkyl, when X is an oxygen atom, and wherein R _{1 may} also be 2,3-dihydroxyphenyl- (1) when X is the NH group and R _{2 is a} 2,3-dihydroxypropyl (1) group, a Ci-Ca-alkyl group or a C ^ Ca-alky lgruppe which is unsaturated and / or substituted by halogen, amino, C ₁ -IC ₆ alkylamino, di-C ₁ -C ₆ -alkylamino, tri-C ₁ -C ₆ -alkylamino, hydroxy, carboxy, C ₃ -C ₈ -cycloalkyl or phenyl is, represents, and

b) an alkylglycerol of the general formula II

H ₂ C - O - R ₃

HC - O - R ₄ H ₂ C - OH

in which one of the radicals R ₃ and R _{4 is an} alkyl group having 3 to 12C atoms and the other radical is a Η atom, and optionally further customary pharmacological additives and diluents. Such a mixture is also referred to below as a cascade.

The content of compound of general formula I or Γ in mg / ml cascade is denoted by a suffix index, such that, for example, a cascade mixture containing 5 mg / ml compound of formula I or,, as a cascade ₅ , a mixture with 200 mg of compound of formula I or Γ per ml cascade is referred to as cascade ₂ oo. The preparation of alkylglycerols is known, for example from DE-OS 3343530.8. For example, alkylglycerol-water mixtures containing, for example, nonylglycerol, octylglycerol, hexylglycerol, pentylglycerol, propylglycerol and ethylglycerol are preferred. Preferably, such aqueous mixtures contain 3 of said glycerol ethers namely a lower (ethyl, propyl), a middle (pentyl, hexyl) and a higher (nonyl, octyl), wherein the amount by weight of the lower ether is about as large as the sum of Weight amounts of the other two glycerol ethers. The amount of water is about equal to the amount of the lower glycerol ether, and is, for example, half of the total amount of the present glycerol ethers. Examples of such glycerol ether-water mixtures are given below:

water Glycerol propyl ether Glycerol-hexyl ether Glycerol nonyl ether parts by weight 2: CSI 1 . : 1 parts by weight Water 2: Glycerol ethyl ether 2: Glycerol pentyl ether 1: Glycerol octyl ether 1

Zurtopischen application of the medicaments of the invention are particularly suitable. To treat skin tumors or skin metastases with this drug, the affected skin areas are rubbed in, for example, cascade ₅ to cascade _2o ozwei- to thrice daily. No harmful side effects have been observed, even in patients treated for a period of 3 months. The remission of the skin metastases is accompanied by a normalization of the skin, as clearly demonstrated by tissue sections. Several patients with skin metastases were treated in this way, with complete disappearance of mammary carcinoma skin metastases.

The topical treatment with the preferred agent according to the invention in the formulation cascade ₅ to cascade ₂ oq can be

also for the treatment of internal tumors or metastases by extensive rubbing of the skin. Through absorption through the skin, therapeutically effective blood levels are achieved. An advantage of this type of administration is that the formulations cascade _B to cascade ₂₀ O o are easily tolerated by the skin.

This preferred preparation of the medicament according to the invention in the form of the solutions cascade ₅ to cascade ₂ oo is also well suited for the preparation of suppositories for rectal introduction. Hereby, internal tumors or inner metastases can be treated well.

Another type of application of the medicament according to the invention consists in the installation in preformed body cavities.

This type of application is particularly suitable for pleural carcinomas, malignant ascites, malignant pericardial effusions and bladder carcinomas. In this case, the antitumor agents of the general formula I according to the invention will be used either alone or in combination with conventional carriers and diluents, in particular also with cascade.

For systematic administration, oral or intravenous administration is contemplated.

For oral administration, the compounds of general formula I are expediently used in the form of a drink solution. Suitable carriers are, for example, milk, cocoa, fruit juice or drinking water. The preparation of such a drinking solution can be carried out, for example, by diluting a concentrated alcoholic solution of a compound of formula I or Γ according to claims 1 and / or 2 with water or another of the aforementioned agents.

In rats, daily doses of 20.40 and 60 mg / kg body weight using hexadecylphosphocholine and oleyl phosphocholine resulted in complete remission of chemically induced mammary carcinomas. These compounds proved to be more effective and better tolerated than i-Octadecyl ^ -methyl-rac-glycero-S-phosphochloline. The tumor model used for these experiments is a so-called hard model. This means that the findings made on this model can also be transferred to the humane situation.

For intravenous administration by intravenous infusion therapy, the compounds of formula I or I 'are suitably used in physiological saline. Other infusion solutions can be used here. For example, human dose for such solutions is 1-10mg / kg of body weight.

Finally, several types of application of the medicament according to the invention can be used in combination, the particular topical compatibility resulting in that, on the one hand, a rubbing in of the skin is combined with one of the other forms of application.

Another carrier mixture for the compounds of the formula I or Γ which has proven particularly useful consists of a mixture of about 4 parts by weight of water, 4 parts by weight of propylglycerol and 2 parts by weight of hexylglycerol and nonylglycerol.

Topical application of the drug of the present invention in the most preferred formulation, cascade ₅ to cascade ₂ oo over a period of several months, demonstrated that local toxicity is limited to increased scaling of the skin, similar to the local use of acetylsalicylic acid.

The invention thus provides a new drug for the treatment of tumors and not only provides a further antitumor agent at all, but for the first time brings a proven even in topical application in a clinical trial effective means. This opens up new possibilities for the treatment of cancer patients.

For the preparation of corresponding medicaments, at least one compound of the formula I or II with customary pharmaceutical excipients and / or _; Diluents or other excipients processed into pharmaceutical preparations or brought into a therapeutically applicable form. This is effected, for example, by reacting compounds of the formula I or II in which the individual radicals and symbols have the meanings indicated, or their physiologically tolerable salts together with customary carriers and / or diluents or auxiliaries at temperatures between 20 and 120 ° C., preferably 30-100 ⁰ C mixed or homogenized, the mixture thus obtained for the production of preparations containing in the dosage unit 5 to 2000mg, preferably 10 to 500mg, in particular 30 to 400 mg of active ingredient of the formula I or,, pours in hollow cells of appropriate size or filled into capsules of appropriate size or granulated and then, optionally compressed with the addition of other conventional excipients to tablets. For example, by mixing compounds of the formula I or Γ with one or more of the following substances: starch, cellulose, lactose, formalin, casein, modified starch, magnesium stearate, calcium hydrogen phosphate, highly dispersed silicic acid, talc, phenoxyethanol, the mixture obtained, if appropriate granulated with an aqueous solution containing at least gelatin, starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate, copolymer and / or Polyoxyethylsorbitanmonooleat as a component, optionally homogenized the granules with one or more of the above auxiliaries, and this mixture compressed into tablets or filled into capsules in which such tablets or capsules in the dosage unit contain in each case 5 to 2000 mg of active compound of the formula I or I '; or that compounds of formula I or salts thereof after addition of soybean lecithin and optionally 0.1-0.5 parts by weight of phenoxyethanol (based on one part by weight of compound I or Γ) at temperatures between 33-37 ⁰ C suspended in molten hard fat and homogenized and then the mixture is poured into hollow cells, wherein the dosage unit contains 5 to 2000 mg of active ingredient and optionally 0.1-0.5 parts by weight of phenoxyethanol (based on one part by weight of compound I or Γ); or that compounds of the formula I or Γ or salts thereof at a temperature between 50 to 12O ⁰ C, preferably 50 to 100 ⁰ C, optionally in the presence of one or more emulsifiers and / or 0.1-0.5 parts by weight of phenoxyethanol (related to one part by weight of compound I or Γ) with at least one of the following substances: paraffin, vaseline, aliphatic alcohol having 12 to 25 carbon atoms, aliphatic monocarboxylic acid having 15 to 20 carbon atoms, sorbitan monopalmitate, polyoxyethylene polyol fatty acid ester, and the resulting mixture between 50 and 12O ⁰ C emulsified with water, optionally with the addition of a polyhydric lower aliphatic alcohol and / or phenoxyethanol; or that compounds of the formula I or Γ or salts thereof in water or vegetable oil, optionally in the presence of 0.1-0.5 parts by weight of phenoxyethanol (based on one part by weight of compound I or Γ) and optionally in the presence of an emulsifier, at temperatures between 30-100 ⁰ C dissolves, and optionally the resulting solution with sufficient water or vegetable oil fills that the final solution 0.05 to 10 wt .-%, preferably 0.1 to 5Gew .-% of active compound of the formula I or I 'contains , Suitable emulsifiers are, for example: nonionic emulsifiers and ionic emulsifiers. The nonionic emulsifiers are, for example, triglyceride mixtures of saturated vegetable fatty acids with C ₈ , C ₁₀ and C ₁₂ or emulsifiers based on polyaddition products of ethylene oxide, such as alkyl or acylsubstituieite polyaddition of ethylene oxide, polyethylene glycol fatty acid esters, reaction products of Ethylene oxide with castor oil or hydrogenated castor oil, esters of hydrogenated castor oil fatty acids with oxyethylated glycerol. Furthermore, it may be emulsifiers based on fatty acid amides or fatty acid condensation products with hydrophilic groups. Suitable ionogenic emulsifiers are, for example, emulsifiers based on fatty acid monoesters of glycerol or other polyhydric alcohols (Lunaceraalba).

If, in the preparation of the medicament as indicated above, the active compound of the formula I or II is used in the presence of a glycerol ether of the formula II or a mixture of such glycerol ethers of the formula II, a synergistic increase in the activity of the antitumor effect is observed.

For this purpose, the active compounds of the formula I or Γ with 1 to 30, preferably 2 to 20 parts by weight (based in each case on one part by weight of compound I or Γ) of at least one glycerol ether of the formula I! or a mixture of such glycerol ethers and optionally 0.5-30, preferably 1-20 parts by weight of water (also based on one part by weight of compound I or Γ) used. This mixing with the glycerol ethers can be done initially in the preparation of the corresponding drugs, but optionally also at a later stage of manufacture.

The compounds of the formulas I and I 'according to the invention exhibit, for example, a good action on rat 7,12-dimethylbenzanthracene-induced mammary gland cancer; also on methyl nitrosourea-induced mammary carcinoma of the rat.

For example, in the above-mentioned test method at a dose of 10 mg / kg body weight rat growth arrest of the tumors, at higher doses, a complete disappearance of the tumors is achieved. The lowest, already effective dose in the animal experiment given above is, for example

5 mg / kg orally ^;

5 mg / kg intravenously.

As a general dose range for the effect (animal experiment as above) is for example in question:

5-50mg / kg orally, especially 15-32 mg / kg

5-50mg / kg intravenously, especially 15-32mg / kg.

The direction of action of the compounds according to the invention is comparable with the action of the known drug substance TAMOXIFEN, but in particular the following differences exist: The effect is stronger and has a longer duration than that of TAMOXIFEN.

Indications for which the compounds of the invention may be considered: mammary cancer and other human cancers.

The pharmaceutical preparations generally contain between 5-2000 mg, for example 10-400 mg, of the active components according to the invention.

The administration can take place, for example, in the form of tablets, capsules, pills, dragees, suppositories, ointments, gels, creams, powders, dusting powders, aerosols or in liquid form. Suitable liquid application forms are, for example: oily or alcoholic or aqueous solutions and suspensions and emulsions. Preferred embodiments are tablets containing between 40 and 400 mg or solutions containing between 0.1% to 5% of active substance.

The single dose of the active components according to the invention may be, for example

a) for oral dosage forms between 5-1000mg / kg body weight, preferably 15-50mg / kg body weight,

b) in parenteral dosage forms (for example intravenously, intramuscularly) between 5-100 mg / kg body weight,

c) in dosage forms for topical application to the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, ointments and so on) between 50-2000mg, preferably 80-1 500mg.

- (The cans are each based on the free base) -

For example, 1 tablet with a content of 40-400 mg of active substance or, for example, with intravenous injection 1-5 times daily, an ampoule of 1-5 ml content with 50-250 mg substance can be recommended 3 times a day. For example, when administered orally, the minimum daily dose is 120 mg; the maximum daily dose for oral administration should not exceed 100mg / kg body weight.

The acute toxicity of the compounds according to the invention in the mouse (expressed by the LD50 mg / kg, method according to Miller and Tainter: Proc. Soc., Exper., Biol. A., Med., 57 [1944] 261) is, for example, between 200 and 200 when administered orally 450mg / kg body weight.

The medicaments according to the invention are particularly suitable for the treatment of tumors.

For example, the pharmaceutical compositions of the present invention have an improved activity over the agents known from European application 108585.

They can be used in human medicine, veterinary medicine as well as in agriculture alone or in admixture with other pharmacologically active substances.

embodiment

The invention is illustrated by the following examples.

example 1

Hexadecylphosphoethanolamine (phosphorylation, ring closure and ring opening)

Hexadecanol (1 mole, 243g) and triethylamine (1.8 mole, 180g) are dissolved in 1.51 of THF (tetrahydrofuran) and added dropwise to a well-stirred solution of phosphorus oxychloride (1.2 mole, 184g) in 120 ml of THF so that the temperature in the reaction vessel (three-necked, 5I, with dropping funnel, thermometer and stirrer) does not exceed 10 ^° C. To speed up the process, the reaction vessel is cooled with an ice-salt mixture. Immediately after the dropwise addition, the reaction is complete (detection by TLC in ether: Rf values of 0.8 for the starting product, of 0.0 for the reaction product after hydrolysis with water).

The ice bath is removed and added dropwise to the reaction mixture under vigorous stirring, a solution of ethanolamine (1.5 mol, 92g) and triethylamine (1,8MoI, 180g) in dioxane 11 in such a way that the temperature in the reaction vessel at 65 to 70 ⁰ C. increases. Then the ring formation is complete (detected by DSC in ether: Rf value of 0.2). It is filtered from precipitated triethylamine hydrochloride still warm and the filtrate is added at 40 to 50 ° C with 1.512N formic acid. After 15 minutes, the ring opening is complete (detection by TLC in ether: Rf value 0.0, DSC in chloroform / methanol / acetic acid / water 100: 60: 20: 5 by volume: Rf value 0.8). It is cooled to -2O ⁰ C and filtered from the precipitate, which consists of largely pure Hexadecylphosphoethanolamin. For light impurities, a chromatographic purification is connected (see Example 2)

 Microanalysis (MW 365.50):

(%): C 59.15 H 11.03 N 3.83 P 8.48 F (%): C 59.01 H 10.95 N 3.79 P 8.31

Example 2

Hexadecylphosphocholine * 1H ₂ O (methylation of 1)

The crystals obtained according to Example 1 are taken up without further purification in 1,21 2-propanol and 0.41 dichloromethane. The suspension of the crystals is added with vigorous stirring with potassium carbonate (4 mol, 560 g) in 11 water. The biphasic reaction mixture is treated with dimethyl sulfate (4 mol, 500g) dropwise and with stirring so that the temperature does not exceed 4Q ° C. The reaction is completed 60 minutes after the dropping (detection by DSC in chloroform / methanol / 25% ammonia 50: 50: 5 by volume: Rf value 0.3). After phase separation at 20 ^° C., the upper phase contains the product. The solvent is removed on a rotary evaporator under vacuum and the viscous residue is chromatographed on silica gel (Merck Art. 7733, Kieselgel 60, particle size 0.2 to 0.5 mm).

chromatography

Silica gel, 2 kg, are mixed with chloroform / methanol / 25% ammonia (200/15/1 by volume) and filled in a chromatography column. Dissolve the viscous oil in 800 ml of the above solvent mixture and add the crude product to the column (insoluble portions are filtered off in advance). It is eluted with eluents of increasing polarity until the impurities are washed out. The product is finally eluted with chloroform / methanol / 25% ammonia (50/50/5 by volume). The combined eluates are concentrated by rotary evaporation and the remaining water is removed with toluene. The residue is taken up in 600 ml of dichloromethane and combined with 41% acetone. The deposited at -20 ⁰ C crystals are washed with cold acetone, then with pentane and dried in vacuo. The yield of pure hexadecylphosphocholine is 250 g (about 70% based on hexadecylglycerol).

Microanalysis (MW 407.58):

(%): C 59.27 H 11.37 N 3.29 P 7.28 F (%): C 58.98 H 11.31 N 3.21 P 7.11

Corresponding phosphoethanolamines and phosphocholines were prepared with tetradecanol, octadecanol, eicosanol, oleyl alcohol, cis-11-hexanedine-i-ol and dodecanol.

Example 3

2-Hexadecylphosphoethanolamine (Phosphorylation, Ring Closure, Ring Opening) The reaction is carried out as described in Example 1, but for 0.1 mol. To achieve good yields, the phosphorylation conditions must be slightly modified, ie. H. the temperature in the phosphorylation step is raised to 25 ° C. Otherwise the procedure is as described and worked up.

Microanalysis (MW 365.50):

calc. (%): C59.15 H11.03 N3.83 P8.48 F (%): C, 58.96, H, 10.91, N, 3.69, P, 8.39

Example 4

2-hexadecylphosphocholine * 1H ₂ O (methylation of 3)

It can proceed as described in Rule 2, worked up and cleaned.

Microanalysis (MW 407.58):

(%): C 59.27 H 11.37 N 3.29 P 7.28 F (%): C 59.14 H 11.11 N 3.14 P 7.09

Example 5

Oleyl phosphomethyl ester, sodium salt * 1 H ₂ O '

(Phosphorylation, methanolysis and LiBr cleavage) The phosphorylation step is carried out as in Example 1. For methanolysis, the reaction mixture is diluted with methanol (10 mol; 320g) and triethanolamine (1.8 mol; 180g) at 20 ⁰ C was added. The methanolysis is completed after 30 minutes. It is mixed with 1.51 hexane and 1.51 of water, shaken well and the solvent is removed from the hexane phase. The oily residue is refluxed with LiBr (2 mol, 174 g) in 1.5 l of ethyl methyl ketone. After one hour, the reaction is complete. The solvent is removed, taken up in a mixture of 11 methanol / water / chloroform, shaken well and ^N isolated the lower chloroform phase containing the product. For conversion into the sodium salt, the chloroform phase is treated with 11% saturated NaCl solution. The chloroform phase is isolated and concentrated by rotary evaporation. The product is purified by chromatography on silica gel (see Example 2).

Microanalysis (MW 402.50):

(%): C 56.70 H 10.02 P 7.70% (F): C56.65 H 9.98 P7.45

Accordingly, the allyl ester was prepared. Furthermore, methyl and Allylphosphorsäureester of the following alcohols were prepared by the method described: tetradecanol, hexadecanol, octadecanol and eicosanol.

Example 6

Hexadecylphosphohexyl ester, sodium salt χ 1 H ₂ O (phosphorylation with phosphorus oxychloride, phosphorylation with hexadecylphosphoric acid dichloride, methanolysis, cleavage with LiBr)

The phosphorylation of hexadecanol is carried out as described in Example 1. The reaction mixture is further reacted directly with dropwise addition of hexanol (1.5 mol, 303 g) and triethylamine (1.8 mol, 180 g) in 1.51 THF. The temperature is now increased to 3O ⁰ C. After two hours the reaction is over. Methanolysis is carried out as described in Example 5, as well as LiBr cleavage.

Microanalysis (MW 446.59):

(%): C59.17 H 10.83 P6.94 Fp (%): C59.08 H 10.74 P6.71

The following alkyl esters were prepared by this process: hexadecylphosphobutyl, octyl, decyl and dodecyl esters.

Example 7

Ttexadecylphosphoglykolester, sodium salt χ 1 H ₂ O (phosphorylation, ring closure with glycol, ring opening) The phosphorylation is carried out as described in Example 1. The reaction mixture is further reacted directly with dropwise addition of ethylene glycol (1.5 mol, 93 g) and triethanolamine (1.8 mol, 180 g) in 1.51THF. The temperature is increased to complete the ring formation to 60 ⁰ C after 2 hours at this temperature, the reaction is complete. The precipitated triethylamine hydrochloride is filtered off on a porcelain frit and the filtrate is added with vigorous stirring at 20 ° C with 1.51 of water. After 2 hours, the hydrolysis is complete. The solvent is removed from the upper THF phase by rotary evaporation in vacuo. The residue is mixed with a mixture of chloroform / methanol / semi-saturated NaCl solution, shaken and waited for phase separation. The lower chloroform phase contains the product. The solvent is removed and the product is purified by chromatography (Example 2).

Microanalysis (MG406,48):

(%): C 53.19 H 9.92 P 7.62

% (%): C 53.07 H 9.73 P 7.53

The following glycol esters were prepared analogously: tetradecylphosphoglycol ester, octadecylphosphoglycol ester, oleylphosphoglycol ester.

Example 8

Hexadecylphospho-hydroxymethylamide, sodium salt + 1 H ₂ O (phosphorylation, ring closure with ethanolamine, opening with potassium carbonate in water)

The phosphorylation is carried out as described in Example 1, as is the ring closure. After removal of the triethylamine hydrochloride, the filtrate is mixed with vigorous stirring with 111 M potassium carbonate solution in water. After 1 hour, the ring opening is completed. The solvent is removed in the upper THF phase, taken up in a mixture of 11 chloroform / methanol / half-saturated NaCl solution, shaken well and the chloroform phase is separated off. After removal of the solvent, the product is chromatographed on silica gel and purified.

Microanalysis (MG405,50)

Calc. (%): C 53.32 H 10.19 N 3.46 P 7.64

% (%): C 53.26 H 10.07 N 3.21 P 7.59

The following compounds were prepared analogously: tetradecyl, optadecyl, oleylphospho-hydroxyethylamide.

Example 9

Hexadecylphosphoglycerol, sodium salt + H ₂ O

(Phosphorylation with phosphorus oxychloride, phosphorylation with the resulting phosphoric acid dichloride, methanolysis, LiBr cleavage, hydrolysis in 70% acetic acid)

The phosphorylation corresponds to Example 1. The reaction mixture is further reacted directly with dropwise addition of 1,2-isopropylidene-glycerol (1.5 mol, 198 g) and triethylamine (1.8 mol, 180 g) in 1.51 THF.

The temperature is raised to 30 ° C after dripping. The reaction is over after two hours. Methanolysis is carried out according to Example 5, as is the LiBr cleavage. The reaction product, sodium salt, is taken up in 2170% acetic acid and warmed to 6O ⁰ C. The resulting acetone is removed in a slight vacuum (water jet vacuum). The reaction is complete after 2 hours. It is mixed with 21% water and extracted with 21% chloroform. The chloroform phase is treated with 210.5 M sodium carbonate solution and separated after phase separation. The solvent is removed and chromatographed on silica gel.

Microanalysis (MG436.51):

(%) C 52.28 H 9.70 P 7.10.

% (%) C 52.13 H 9.59 P 6.91

The following glycerol esters were prepared analogously: tetradecyl, octadecyl and oleylphosphoglycerol.

Example 10 '

Hexadecylphosphoric acid-F, N, -bis-dichloroethyl amide, Na-salt + H ₂ O (phosphorylation with phosphorus oxychloride, amide formation with bis (chloroethyl) amine, hydrolysis)

The phosphorylation step corresponds to Example 1. The reaction mixture is further reacted directly with dropwise addition of bis (chloroethyl) -amine in 1.01 THF. Thereafter, triethylamine (0.4 mol, 40g) in 0.51THF is added. After 3 hours at 20 ⁰ C, the reaction is complete. The precipitated triethylamine hydrochloride is separated off over a porcelain frit and the filtrate is added to the filtrate with vigorous stirring with 111 M acetic acid for hydrolysis. After 4 hours, the upper THF phase is separated off, freed from the solvent and taken up in 11 of chloroform / methanol / 0.5M sodium carbonate. The chloroform phase is removed, the solvent removed and the product purified by chromatography on silica gel.

Microanalysis (MG486,452):

Calc. (%): C49.38 H 8.91 Cl 14.58 N 2.88 P6.37

(%): C49.21 H 8.75 Cl 14.11 N 2.76 P6.31

The following compounds were prepared analogously:

Tetradecyl, octadecyl, oleylphosphoric (N, N) -bis (chloroethyl) -amide.

Examples of pharmaceutical preparations

Example of a solution: <

25 g of i-n-propyloxy ^^ -propanediol, 12.5 g of i-n-hexyloxy ^ -proanediol, 12.5 g of i-n-nonyloxy ^ .S-propanediol, 44 g of water and 1 g of phenoxyethanol are mixed and 5 g of hexadecylphosphocholine are dissolved in this mixture. The solution is freed of visible particles by filtration through suitable filters.

1 g of solution contains 50 mg of hexadecylphosphocholine.

Example of an ointment:

5 g of substance hexadecylphosphoglycerin are suspended in 35 g of viscous paraffin, 30 g of emulsifying cetylstear alcohol and 30 g of white vaseline are added and melted. This melt is stirred for cooling.

A homogeneous distribution of active ingredient is achieved by processing the cooled, melt by means of a suitable homogenizer (for example, three-roll mill).

1 g of the hydrophilic salt contains 50 mg of hexadecylphosphoglycerol.

Example of an emulsion:

11.83 g of 1-n-propyloxy-2,3-propanediol, 5.91 g of 1-n-hexyloxy-2,3-propanediol, 5.91 g of 1-n-nonyloxy-2,3-propanediol, 20.35 g Water and 1.0 g of phenoxyethanol are mixed and 5 g of hexadecylphosphocholine are dissolved in this mixture. On a water bath, 30 g white vaseline, 15 g of partisan groups! Melted alcohol and 5 g of sorbitan monopalmitate, heated to 70 ⁰ C and also at 70 ° C heated solution of active substance with the aid of a high-speed disperser in the fat phase emulsified. The cream is then cooled to 30 ^° C. with stirring.

1 g of water-in-oil cream contains 50 mg of hexadecylphosphocholine.

Example of capsules:

1.25 kg of hexadecylphosphoglycerol are dissolved in 5 kg of chloroform and suspended in this solution 1.25 kg of Aerosil.

Subsequently, the solvent is removed in vacuo. The dry mass is passed through a 1 mm sieve and again dried in vacuo at 30 ° C to remove residual solvent residues. This granulate is filled in a known manner on a suitable capsule machine in gelatin hard capsules size 00 to 500mg.

One capsule contains 250mg of hexadecylphosphoglycerol.

Example of a lyophilisate:

In 3 liters of water for injection 500 g of mannitol are dissolved under nitrogen, 50 g of hexadecylphosphoglycerol dispersed using a high-speed homogenizer and made up to 4 liters with water for injections. This milky dispersion is converted into a slightly opalescent colloidal disperse system by sonication or by means of a gap homogenizer.

Under aseptic conditions, a membrane filter of 0.22 μm pore size is now sterile filtered and filled into 40 ml in 100 ml injection bottles under nitrogen fumigation. The bottles are provided with freeze-drying stoppers and lyophilized in a suitable plant. After drying, gassed with sterile, dried nitrogen and the bottles in the system

locked. The plugs are secured with a crimp cap. - -

For intravenous use, the lyophilisate is reconstituted in 100 ml of water for injections.

1 bottle contains 500 mg of hexadecylphosphoglycerol.

Claims (5)

1. A process for the preparation of compounds of the formula RY-POf-XR _{1 t} I in the R is a saturated or unsaturated hydrocarbon radical having 12 to 24 carbon atoms, which may also be halogen-substituted, X is an oxygen atom, NH or NR ₂ and Y is an oxygen atom or NH, R _{1 is} a C ^ -Cs alkyl group or R is _{1 represents} a C ₂ -C ₈ -alkyl group which is unsaturated and / or with halogen, amino, C ₁ -C ₆ -alkylamino, di-C ₁ -C ₆ -alkylamino, T ₁ -C ₆ -alkylamino, hydroxy, carboxy , C 3 -C ₈ -cycloalkyl or phenyl, and in which R _{1 is} also substituted for 2-tert-butyloxycarbonylaminoethyl, 2-tert-butyloxycarbonylethyl, 2,3-isopropylidenedioxy-propyl- (1), 2,3-dibenzyloxy- propyl (1), 1,3-dibenzyloxy-propyl (2) or NC ₁ -C ₆ -alkylamino-C ₂ -C ₆ -alkyl, when X is an oxygen atom, and also wherein R _{1 is} also 2,3 -Dihydroxypropyl- (1) when X is the NH group, and R _{2 is} a 2,3-dihydroxypropyl (1) group, a C ^ Cs alkyl group or a C ₂ -C ₈ alkyl group, the unsaturated and / or with halogen, amino, C 1 -C 4 -alkylamino, Di-CH ^ -alkylamino, Tn-C ₁ -C ₆ -alkylamino, hydroxy, carboxy, C ₃ -C ₈ -cycloalkyl or phenyl, and their physiologically acceptable salts, characterized in that a compound of the formula -RIK) -XR ₁ I (III) OZ wherein R, R _1, Y and X are as defined above, Z is benzyl, Ci-C ₆ alkyl or C ₂ -C ₆ alkenyl, existing hydroxy groups, carboxy groups, amino or C ₁ -C ₆ alkylamino group, a conventional protecting group or 2 adjacent hydroxy groups can also be acetalated by an aliphatic C ₃ -C ₆ -alkyne, treated in an inert medium with alkali bromides, alkali metal iodides, lower alkyl magnesium halides or amines, optionally cleaving off protective groups present in the compounds obtained, optionally obtained reaction products, in which Ri contains a halogen atom, with ammonia or an amine of the formula NR ₅ R ₆ R _{7 is} reacted, wherein the radicals R ₅ , R ₆ and R _{7 are} identical or different and denote hydrogen or C ₁ -C ₆ -Alkyl, and or in products containing an amino group containing this amino group by C ₁ -C ₆ -alkyl, and / or in products containing an amino group containing this amino group alkylated Ci-C ₆ alkyl groups, and optionally the resulting products are converted into the salts. 2. The method according to claim 1, characterized in that the radical R ₁ a) a C ₁ -C ₈ alkyl group, a C ₃ -C ₈ unsaturated alkyl group or an optionally unsaturated C ₃ -C ₈ alkyl group represented by halogen, amino, C ₁ -C 6 -alkylamino, di-C ₁ -C ₆ -alkylamino, tri - ^ - Ce-alkylamino, hydroxy, carboxy, C ₃ -C ₈ -cycloalkyl or phenyl, or represents b) a C ₂ alkyl group which is substituted by halogen, hydroxy, carboxy, C ₃ -C ₈ -CyClOaIkYl or phenyl, represents, or c) an unsaturated C ₂ alkyl group which is substituted by di-C 1 -C 4 alkylamino, tri-C 1 -C 4 alkylamino, carboxy, C ₃ -C ₈ cycloalkyl or phenyl, or d) a C ₂ alkyl group substituted by amino, C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino or TnC ₁ -C ₆ alkylamino, if X is oxygen, NH or NR ₂ and Y is the group NH or if X is the group NH or NR ₂ and Y is oxygen and R has the meanings indicated, or e) 2-tert-butyloxycarbonylaminoethyl, 2-tert-butyloxycarbonylethyl, 2,3-isopropylidenedioxypropyl-d), 2,3-dibenzyloxypropyl- (1), 1,3-dibenzyloxy-propyl- (2) or N-Cr -Ce-alkylamino-C ^ C ₆ alkyl, when X is an oxygen atom and Y and R have the meanings indicated ,. or f) may be 2,3-dihydroxypropyl- (1) when X is the NH group and Y and R have the meanings indicated. 3. A process for the preparation of compounds of formula I according to one or more of the preceding Verfahrensansprüche, characterized in that R is an unsaturated hydrocarbon radical having 12 to 14 carbon atoms, which may also be halogen-substituted, and Y, X, Ri and R ₂ have the meanings given, and in which R can also be a saturated, optionally halogen-substituted, cobalt radical having 12 to 14 C atoms, if X is the group NH or NR ₂ and Y is oxygen or NH. 4. The method according to claims 1 to 3, characterized in that hexadecyl, tetradecyl, octadecyl, eicosyl, dodecyl, oleyl and cis-11-hexadecenyl-phosphoethanolamine and the corresponding choline are prepared by phosphorus oxychloride first with hexadecanol, tetradecanol, octadecanol, eicosanol, dodecanol, octadecene (9c) -ol or cis-11-hexadecanol- (1), the reaction mixture is then reacted with ethanolamine and the reaction product treated with formic acid, and optionally the resulting products to the corresponding cholins methylated. 5. Process according to claims 1 to 3, characterized in that compounds of the formula