DD252541A5 - METHOD FOR PRODUCING PHOSPHOVER BINDINGS CONTAINING PHOSPHOVER BINDINGS FOR TUMOR TREATMENT - Google Patents

Abstract

The inventive method is particularly suitable for the production of medicaments for the topical treatment of apical tumors. A compound of the formula II is reacted with a compound of the formula III HX-R1 in an inert solvent, the resulting reaction mixture is heated to 60 to 80C, treated with water, an organic acid or with an alkaline agent in an inert medium or the reaction mixture with benzyl alcohol, a C1-C6 alcohol or an unsaturated C2-C6-alcohol, the reaction product treated with alkali bromides, alkali metal iodides, lower alkyl magnesium halides or amines and the resulting products are converted into the salts. Formula II

Description

252 5 4 ί

Process for the preparation of pharmaceutical compounds containing phospho compounds ·! for the treatment of tumors

Field of application of the invention

The invention relates to a process for the preparation of phosphorus compounds for the treatment of tumors, in particular compounds of the formula I.

CH ₂ -OH GH-O-PoI-XR ₁

(CH ₂ ) _n

GH ₃

in which R is a saturated or unsaturated hydrocarbon radical having 12 to 24 C atoms, which may also be halogen-substituted, X is an oxygen atom, I ^{4 is} H or JjR ₂ , η is an integer from 0 to 10, R is a Go - Cg alkyl group or wherein R-, a C ₂ -Cg alkyl group which is unsaturated and / or halogen, amino, Cj-Cg-alkylamino, di-Cj-Cg-alkylamino, tri-C.-Cg-alkylamino Is also substituted by hydroxy, carboxy, C 1 -C 6 -cycloalkyl or phenyl, and in which R- is also 2-tert-butyl-oxycarbonyl-aminoethyl, 2-tert-butyloxycarbonylethyl, 2,3-isopropylidenedioxy-propyl (1), May be 2,3-dibenzyloxy-propyl- (i), 1-3-dibenzyloxy-propyl- (2) or UG ^ -Gg-alkylamino-Gg-Cg-alkyl when X is an oxygen atom, and wherein R- also may also be 2,3-dihydroxypropyl- (1) when X is the HH group and R _{2 is} a 2,3-dihydroxypropyl (1) group, a C ₁ -Cg alkyl group or a C ₂ ! -C -Alky _Q group which unsaturated and / or substituted with halogen, amino, C ^ - Cg-alkylamino,

^ 33602

25254

Di-Cj-C / r-alkylamino, tri-Cv-Cg-alkylamino, hydroxy, carboxy, Co-Cg-cycloalkyl or phenyl substituted, and their physiologically acceptable salts.

The process according to the invention is particularly suitable for the preparation of medicaments for the topical treatment of malignant tumors.

Characteristic of the known technical solutions

It is known that to date no satisfactory in all respects medicine for the treatment of tumors, especially of malignant tumors, is available. Thus, for example, only 5-fluorouracil currently available for the topical treatment of skin metastases in patients with metastatic tumors. Further developments of other cytostatic drugs have not been pursued to clinical maturity for this type of administration. On the other hand, from a clinical point of view, such a concept is particularly desirable in the palliative therapeutic approach, since alternative treatment concepts such as surgical measures, radiotherapy and systemic chemotherapy, preferably represent aggressive therapy modalities. In addition, a considerable number of patients are potential candidates for such a topical treatment. The proportion of mammary carcinoma patients having skin involvement, about 25 to 35 %,

The prerequisite for topical treatment on the part of the active substance to be used is on-skin tolerance, cytotoxic activity against tumor cells and sufficient depth penetration.

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Aim of the invention

The object of the invention is to provide a suitable process for the preparation of phospho-compounds. fertilizers used for the treatment of tumors, in increasing the effectiveness of these agents against tumors while reducing toxicity and in improving their applicability in tumor therapy *

Presentation; the essence of the invention

The invention has for its object to provide a process for the preparation of phospho compounds contained drugs for the treatment of tumors, which has a good tolerability on the skin, cytotoxic activity against tumor cells and a sufficient depth penetration on the part of its an adding V /.

According to the invention, this object is achieved by reacting a compound of the formula II

GH ₀ -OR I ²

CH - OPOCl ₂

CH

wherein R and η have the meanings indicated, with a compound of formula II

HX - R .., in which X and R ^ have the meanings indicated, existing

25254

- 2 B -

Hydroxy groups, carboxy groups, amino groups or Cj-Cg-Alky! Amino groups may also contain a conventional protecting group, or 2 adjacent hydroxy groups may also be acetalated by an aliphatic CU-Cg ketone, reacted in an inert solvent, wherein for the lall that R _{1 contains} a free hydroxy group or a free amino group on the carbon atom which is adjacent to the carbon atom which is linked to the group X, the resulting reaction mixture or the resulting reaction product for complete ring closure optionally heated to 60 to 80 ⁰ C. and subsequently optionally treated in an inert medium with water, an inorganic or organic acid or with alkaline agents, in the remaining cases the resulting reaction mixture or the reaction product obtained with benzyl alcohol, a C ₁ -Cg-AIkOhOl or an unsaturated Cg-Cg-alcohol reacted and then the reaction thus obtained product with alkali bromides, alkali metal iodides, lower Alkylmagnesiumhalogeniden or amides treated, optionally splits off in the compounds obtained protecting groups, optionally obtained reaction products in which R ₁ contains a halogen atom, with ammonia or an amine of the formula IHoR ^ R ₅ , wherein the radicals R ^ jR / and R _{5 are the} same or different and are hydrogen or C.-C / -alkyl, and / or in resulting products having an amino group, this amino group is alkylated by Cj-Cg-alkyl groups, and optionally the products obtained in the salts transferred ·

In a preferred embodiment of the invention, R is an alkyl or alkylene radical having 14 to 20 C atoms, Σ β 0 and R ₁ = Trialkylammoniumethyl having 1 to 3 carbon atoms per Alky! Group used. The task will continue by doing so

25254 I

- 2c -

dissolved as 1-hexadecyl-propanediol- (1,2) -piiosphpcholin or 1-Qleyl-propanediol- (1,3-phosphocholine or 1-hexadecyl-propanediol-d, 2) -ph. li,] Sf, -ii-Arimethyl> -propanolaniin or 1-oleyl-propanediol- (1,2) -phospho- (iif, ir, H-Arimetiiyl) -propanolamine or 1-hexadecyl-propanediol- (1, 2) -phospho- (H, jtf, Ii-Ar: ethyl) -butanolanine or 1-O-lyl-propanediol- (1,2) -IT, F, ii-arimethyl) -butanolamine or 1-hexadecyl-propanediol-d, 2J- Phospho (1T, a, II-ethyl) -pentanolamine or 1-oleyl-propanediol- (1,2) -phoshosho- (L \ T, li, H-iimimeth-yl) - pentanolamine is used.

In a further preferred embodiment of the invention, at least one compound of general formula I as active ingredient is at least one alkylglycerol of general formula II together with customary pharmaceutical additives and diluents and, in addition to the compound of formula I.

H ₂ COR ₆

HC-OR ₇ ι '

H ₂ C - OH,

in which one of the radicals Rg and R _{7 is} an alkyl group having 3 to 12 C atoms and the other radical is a Η atom used.

embodiments

The invention will be explained in more detail below with reference to 10 examples. Before presenting the individual examples, the method according to the invention is described by its basic sequence.

25 4

The formula I also includes 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 diastereomers are preferred from the outset - Starting materials used, in which case the end product is a corresponding pure optically active or diastereomeric compound is obtained ·

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 carbon atom or else via a carbon atom within the alkyl chain (for example via the carbon atom 2 or carbon atom 3 or another middle carbon atom). This alkyl chain can be straight-chain or branched. The alkyl chain R can contain two or three carbon double bonds or triple bonds, which can also be mixed, and / or have halogen substituents. Suitable halogen atoms are: fluorine, chlorine or bromine in the chain R may be one to three such halogen atoms, which may be located on one or 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. Particularly preferred are those substituents R which contain an alkyl radical having 14 to 20, preferably 15 to 20, in particular 16 to C atoms or a corresponding Alkenylrest.mit 14 to 20, preferably 15 to 20, in particular 16 to C atoms.

, Examples of halogen-substituted radicals R are: chlorohexadecyl, bromohexadecyl, fluorohexadecyl, 9,1O-dibromoctadecyl, 2,3-dibromo-octadecyl, 15,16-dibromohexadecyl, bromotetradecyl.

Examples of unsaturated radicals R are: 9-octadecenyl radical (oleyl alcohol 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.

252 5 4

If R ₁ or R ₃ signify 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 and X must be at least one simple CC bond. In particular, it is a C ₃ -C _g -alkenyl group. Examples of these are: allyl, butenyl, pentenyl, hexenyl.

Γ * \ If R ₁ or R _{2 are} substituted, is

in particular, straight-chain alkyl or alkenyl radicals, in this case R ₁ preferably consists of 2-6 C atoms, the stated substituents preferably being in the u) position of the alkyl or alkenyl group R ₁ or R ₃ ; for example, it is the'Ethyl- or straight propyl radical having one of the specified substituents in O-position (that is in the 2-position in ethyl and 3-position in propyl). , If R _{1 is} a 2-tert-butyloxycarbonylaminoethyl radical or a 2-tert-butyloxycarbonylethyl radical, it is preferably the D or L form.

Among the substituents of R ₁ , the trialialkylammoniumethyl 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.

5 4

In the case of the C 1 -C 6 -cycloalkyl substituent, this consists in particular of 3 to 6 C atoms (for example cyclopropyl to cyclohexyl). The 2, 3-dihydroxy-propyl (1) group is especially the sn-1,2-dihydroxypropylamino (3) structure or the sn-2,3-dihydroxypropylamino (1) -Structure.

Suitable salts are internal salts, (for example when R- denotes a trimethylammonium-alkyl group) or salts with physiologically tolerated cations. The medicaments or compounds prepared by the process according to the invention can be present as internal salts, for example when R If no internal salts are present or the radical Ru does not contain a basic group, the negative charge of the phosphoric acid group is saturated by a physiologically compatible cation ), Alkaline earth cations (Mg, Ca) or the cations of organic amines, such as guanidinium, morpholinium, cyclohexylammonium cation, ethylenediammonium cation, piperazonium cation (in both latter cases mono- or dibasic), or the cation which is derived from an amine of Formula iJR R ₁ R derives,

a D c

wherein the radicals R to R _{Q are} identical or different and denote hydrogen, C.-Cg-alkyl groups or oxyethyl groups.

In the case of cations derived from an amine of the formula R ₃ R ₃ R ₀ , it is preferably the ammonium cation or an ammonium cation substituted with one to three C 1 -C 3 -alkyl groups or one to one tri-2-hydroxyethyl substituted ammonium cation.

The compounds according to general formula 1 can be prepared by methods known per se. The skeleton can be easily achieved by implementing the following compound

H ₀ C - OR

Ί CH - OH

Γη! ' "

or a functional derivative thereof with phosphorus oxychloride and triethylamine, reaction of the product with a compound HXR and acid cleavage, where R, R. and X have the meanings already given.

The process is schematically illustrated in the following reaction equations, where A is the radical

Hf _ ITD

^CH -

< ^CH 2> n CH ₃

oe means.

^1} ?

⁰ CH ₃ > RO-PO- (CH ₂ J ₃

LiBr OLi

Alkylphosphoalkylester

(X a I - 7)

O i

2) AO-PO ^ (CH ₇ ) -Br ² Y

OCH,

a) LiBr

0 Il

Br

OLi

Alkyl phosphobrande alkyl ester (y = 2 - 12)

a_) N (CH 1) H ₅

"I +

-> AO-PO- (CH ₂ ) -N (CH ₃ ) ₂ H

Alkylphospho- (N, N) -dinethylalkanolamine

AO-P ₁ O- (CH-) -N (CH-) H-

Alkylphospho-N-Kethyl alkanolamine

> Acylphospho-alkanolamine

Il

-> AD-P-O- (CH-) -N (CH-)

o ^ y ^{J 3}

phosphatidylcholine

Il

AO-P-O- (CH-). .-0-Tr

I ^Λ J

OCH

a) LiBr

a.) acid hydrolysis; ¹ NaH CO ₃

Il

AO-PO- (Oi ₂ J-OH

ONa

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

Il

OCH ₃

0-C (CH ₃ ) ₃ -, 0

a) IiBr

a.) Acid hydrolysis, · ¹ Na H CO ₃ ν AQ-PO- (CHJ ₇ -C

ONa ^{2 ZN} 0H alkylphospho-carboxy-alkyl ester (Z = 1 - 20)

Il

5) AO-PO-CH ₉ -CH *

OCH ₃

• NH-BOC C * °

a) LiBr

a,) acid hydrolysis;

NaH CO.

Il

L ·

NH-

AO-PO-CH ₀ -CH ²

ONa

Alkylphospho-serine (BOC = tert-butoxycarbonyl)

Il

A0-PO-CH - CH ²

1 O

CH

a) LiBr

a.) acid hydrolysis;

NaH CO

Il

AO-PO-CH ₀ -CH-CH-

1 1 ^l

ONa OH OH alkylphospho-glycerol

Il

7) AO-PO- (CH ₂ ) _y -NH-BOC OCH,

a) LiBr;

a) acid hydrolysis AO-P-O- (CH-) -NH,

O"

Alkylphosphoethanolamine (y = 2 - 20); BOC = butoxycarbonyl

2525 4 y

Il

AO-P-O- (CH.) -N-BOC ι ^ Yi

OCH.

CH.

a) LiBr;

aj acid hydrolysis alkylphospho-N-methylethanolamine (y = 2 - 20) BOC = butoxycarbonyl

9) AO-P-NH- (CH -), - Br

I ti

OCH ₃

a) LiBr

b) N (CH ₃ ).

It

A AO-P-NH- (CH-). -Br

, £ ti

OLi

UJcylphospho-Bronalkylaniide

0 (Z = 2 - 12) "©

AO-P-NH- (CH,) ₇ -N (CHJ -H ( ^2Z

N (CH ₃ J ₂ H

a ₂ ) Alkylphospho-N, N-dimethyl-1-aminoalkylamide

AO-P-NH- (CH ₂ ) _Z -N (CH ₃ )

Alkylphospho-N-ethyl-aminoalkylsinide

Il

a ₃ ) NH ₃ ^ AO-P-NH-I

1£, ti J

Alkylphospho-amiiioalkylainid

Il

AO-P-NH- (CH ₂ ) _Z -N (CH ₃ ).

Alkylphospho-N, N, N-triethylanancalkylamide

Η) AO-P-NH- (CH _n) "-OTrityl

ι ^2Ζ

OCH

Il

^ AO-P-NH- (CHJ ₇ -OH

a) LiBr

a.) acid hydrolysis; ¹ NaHCO ₃

ONa

Alkylphospho-hydroxyalkylamide

, 1-2) AO-P-NH- (CH ₀ ) _-C *

• ^{g Zv} 0-C (CH.OCH ₃

a) LiBr

a.) acid hydrolysis;

NaHCO,

AO-P-NH- (CH ₀ ) "- C 2 Z _N.

^k 0Na ONa

Alkylphospho-carbojiyalkylandd

Il

i-3) AO-P-NH-CH-j-CH - CH ₀

1 ι

0

OCH,

CH

a) LiBr

a ..) acid hydrolysis;

NaHCO

Il

AO-P-NH-CH ₀ -CH-CH-, ι * ι « ^ί

ONa OH OH alkylphosphodihydroxypropylamide

i 3 4 J t!

- 1JL-

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 Cj-Cg-Alky! Amino groups, in the radical R or in

2 2

the radical R (if X is the group NR) may be protected by customary protective groups. Adjacent hydroxy groups may be protected by ketalization with an aliphatic saturated C_-Cg 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 ° C, in particular between 0 and 10.0 ° C, split off. Hydrogenatable 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 1-50 bar) at temperatures

2525 4

split off between 20-15 ° C., in particular 30-100 ° C., preferably 40-80 ° C.

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. Suitable protecting groups which can be eliminated by hydrogenolysis are, for example: benzyl radical, (X.sup.4 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 removable radicals are:

Trifluoroacetyl, phthalyl, trityl, p-toluenesulfonyl, tert-butyloxycarbonyl, tert-butyl. rest, dimethylmethylene radical and the like as well as 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. Inter alia, reference is also made 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 et seq. The carbalkoxy group (for example low molecular weight) is also suitable.

The reaction of compounds of formula II with a compound of formula III is carried out at temperatures between 0 and 200, preferably 20 and 150 ° C, or between 50 and 100 ° C in a solvent or suspending agent. As such means

suitable solvents include aromatic hydrocarbons, for example penican, hexane, heptane, benzene, mesitylene, toluene, xylene; lower aliphatic ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons, such as. Example chloroform, trichlorethylene, carbon tetrachloride, chlorobenzene, methylene chloride; cyclic ethers such as tetrahydrofuran and dioxane; lower aliphatic noncyclic 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); Cj-Cg dialkyl sulfones (dimethylsulfone, tetramethylsulfone); Cj-Cg 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.

When a solvent or dispersant is used, one often works at the reflux temperature of this agent.

This process is conveniently carried out in the presence of basic substances. Such basic substances are, for example: tertiary amines (such as triethylamine), piperidine, pyridine, alkali metal carbonates (potash, soda), alkali metal acetates, alkali metal or alkaline earth metal hydroxides.

If a compound of formula III is implemented, at

1 2 2

the R (or R, if X is NR) is a hydroxy group

2525

or an amino group on the C atom which is adjacent to the C atom which is linked to the group X, these groups react with the second chlorine atom of the compound I also with ring formation. To complete the ring closure is optionally on Heated to 60 to 80 ° C.

The splitting of this ring is carried out by treatment with an inorganic or organic acid, with alkaline agents or optionally also only by addition of water at temperatures between 10 and 100, preferably 15 and 80 ° C, in particular 30-60 ° C. As acids come for this purpose for example in: Question: formic acid, acetic acid, trifluoroacetic acid, perchloric acid, mineral acids {hydrochloric acid, sulfuric acid, phosphoric acid).

For this ring opening the resulting reaction mixture is suitably used. The acid used is suitably used in dilute form, for example, aqueous acids are used in concentrations between 0.1 and 2N. Suitable alkaline agents are, for example: 0.1 to 1 molar aqueous solutions of sodium carbonate, potassium carbonate or ammonia. If rings are formed during the ring formation, which contain two phosphorus-oxygen bonds, the ring splitting takes place only with water; If the ring contains a phosphorus-nitrogen bond and a phosphorus-oxygen bond, the phosphorus-nitrogen bond is preferably split upon treatment with acids, while the alkaline treatment splits the phosphorus-oxygen bond.

In the cases where, in the reaction of a compound of formula II with a compound of formula III, two chlorine atoms of the compound II each react with 2 moles of the formula III (that is, where no ring closure of functional groups of R or R with the second chlorine atom of Phosphorsäuredichlorid-

To W * - * / -r

group entry), is a subsequent treatment with benzyl alcohol or a C.-Cg-alkanol or a preferably monounsaturated aliphatic C - C, -alcohol (in particular C_-C, - alcohol, where the double bond in ß-position to the hydroxy group is required, such as allyl alcohol). Preferably, methanol is used.

This treatment is carried out at temperatures between 10 and 100 ⁰ C, preferably 15 and 80 ° C, which also generally the resulting reaction mixture is used. The amount of alcohol can be, for example, between 1 and 50 mol, based on 1 mol of the compound II. This reaction is also expediently carried out in the presence of basic substances, such as, for example, C.C.

X5 alkylamines, in particular tertiary C ..- Cg-alkylamines (triethylamine, tripropylamine, pyridine) performed. In this reaction with alcohols, compounds of the formula I are formed in which the free hydroxy group of the phosphoric acid moiety is replaced by the corresponding alkoxy group, benzyloxy group or alkenoxy group. The subsequent cleavage of these alcohol groups is carried out, for example, with alkali bromides, alkali metal iodides / lower Alkylmagnesiumhalogeniden or with primary, secondary or tertiary amines, in particular the corresponding lower alkylamines ι such as tertiary Cj-Cg-alkylamines (trimethylamine). Suitable alkali metal bromides or alkali metal iodides are for example: lithium bromide, sodium bromide, lithium iodide, sodium iodide. Suitable lower alkyl magnesium halides are, for example: methyl magnesium iodide, methyl magnesium bromide (solvents in this case lower aliphatic ethers, such as diethyl ether).

This treatment is carried out at temperatures between 20 and 200, preferably 50 and 150 ° C, in particular 50 and

25254?

-η-

The alkylation of free amino groups in the radicals R and / or R takes place at temperatures between 0 and 200, preferably between 20 and 150 ° C., in particular 20 and 80 ° C. This alkylation is carried out, for example, by reaction with compounds of the formula R ¹ Hal , ArSO ₂ OR ¹ and SO ₂ (OR ' ₃ ) ₂ , where Hal is a halogen atom (especially chlorine, bromine or iodine) and Ar is an aromatic radical (for example a phenyl or naphthyl radical optionally substituted by one or more lower alkyl radicals and R ¹ is a Cj-Cg alkyl group examples. are p-toluenesulfonic acid-Cj-Cg-alkyl, Cj-Cg-dialkyl sulfates, Cj-Cg-alkyl halides. The alkylation reaction is optionally with addition of conventional acid-binding agents, such as alkali metal hydroxides, alkali carbonates, alkali hydrogen carbonates , 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 dur chgeführt. 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 such as dimethylsulfoxide; 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 and the like. It is also possible to use aqueous mixtures of the solvents mentioned

252 5 4

- 18 -

become. Often one works at the return flow temperature of the solvents or dispersants used. Often, the alkylation reaction components are used in excess. The alkylation can also in the presence of tetraalkylammonium salts (in particular the halides) combined with alkali hydroxides at temperatures between 0 - 100 ⁰ C, preferably 20 - 80 ⁰ G be carried out in an aprotic solvent or also in chloroform or methylene chloride. Suitable aprotic solvents are, in particular: tertiary amides (dimethylformamide, II-methyl-pyrrolidone, hexamethylphosphoric triamide), dimethyl sulfoxide, acetonitrile, dimethoxyethane, acetone, tetrahydrofuran.

The drugs produced by the process according to the invention, which contain as active ingredients a compound of general formula I, have a pronounced cytotoxic activity, which was detected both in vivo on the chemically induced mammary carcinoma of the rat, as well as in vitro on leukemia cells in the cell culture. In addition, in a clinical pilot study in breast cancer patients, skin metastases for complete healing in topischa? Application brought.

In particular, for topical application, but also for the preparation as medicaments for other types of administration, it has been found to be particularly favorable, the compounds of general formula I together with at least one alkylglycerol having 3 to 12 carbon atoms in the alkyl radical, in the form of an ether group to a the primary or secondary OH groups of the glycerol

252S4

- 19 -

may be present. Such alkylglycerols can improve the effect of the compounds of the general formula I synergistically and by increased penetration of the tissue. Alkylglycerols having 3 to 9 carbon atoms are preferably used here alone or mixed. Very particular preference is given to a mixture which comprises honylglycerol, hexylglycerol and propyl glycerol, which are expediently present in approximately equal amounts by weight, the mixture advantageously still containing water in approximately the same amount as each of the individual constituents, Such a mixture of lionylglycerol, hexylglycerol , Propylglycerin and water in the weight ratio 1: 1 to 1 j 1 is hereinafter referred to as "cascade". The content of compound of general formula I in mg / ml cascade is indicated by a suffix index such that a cascade mixture containing 5 mg / ml of formula I as cascade, a mixture containing 200 mg of compound I per ml of cascade Cascade ₂ QQ is designated · The preparation of the alkylglycerols is known, for example from DE-OS 33 43 530.8.

For topical application, the medicaments prepared by the process according to the invention are particularly suitable. In order to treat skin tumors or skin metastases with this drug, the affected skin areas are rubbed with cascade to cascade ₂₀₀ two to three times daily. Harmful side effects have not hitherto been possible 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

25254

- 20 -

could be clearly demonstrated. Several patients with skin metastases were treated for this disease, with complete disappearance of mammary carcinoma skin metastases.

The topical treatment with the preferred composition according to the invention in the formulation cascade, - to KaskadeggQ can also be used for the treatment of internal tumors or metastases by large-scale rubbing of the skin, via the absorption through the skin therapeutically effective blood levels are achieved. An advantage of this type of application is that the preparations cascade, - be tolerated by the skin without problems KaskadegQQ ·

This preferred preparation of the medicament according to the invention in the form of the solutions cascade, - to Kaskade2 ₀₀ 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 drug produced by the method according to the invention consists in the instillation into 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 systemic administration, oral or intravenous administration is contemplated. . ·

2525 4

- 21 -

For oral administration, the compounds of the general formula I are expediently used in the form of a drinkable solution. Suitable carriers are, for example, milk, cocoa, fruit juice or drinking water. In rats, daily doses of 20, 40 and 60 mg / kg body weight using hexadecylphosphocholine and oleylphosphocholine resulted in complete remission of chemically induced mammary carcinomas. These compounds proved to be more effective and better tolerated than 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine. The tumor model used for these experiments is a so-called hard model. This means that the findings made on this model are in most cases also transferable to the humane situation.

For intravenous administration by intravenous infusion therapy, the compounds of formula I prepared by the method of the invention are conveniently applied in physiological saline. Other infusion solutions can also be used here.

Finally, several types of application of the drug prepared by the process according to the invention can be used in combination, wherein the particular topical compatibility leads to the fact that on the one hand a rubbing in of the skin combined with one of the other forms of application is used.

A further excipient mixture for the compounds of the formula I 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 each of hexy! Glycerol and nonyl

25254 j

- 22 -

glycerol.

Showed the topical application of the drug produced by the process of this invention in the "particularly preferred preparation form cascade ^ to cascade ₂₀ Q over a period of several months, that local toxicity to an increased desquamation of the skin, similar to the local application of acetylsalicylic acid , limited ·

For example, the compounds prepared by the process of the present invention show a good effect on 7,12-dimethylbenzanthracene-induced mammary gland cancer of the rat; also on the Hethyl-nitrosourea-induced mammary carcinoma of the

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 and a complete disappearance of the tumors is achieved.

The lowest, already effective dose in the above-mentioned animal experiment is, for example

5 mg / kg orally

5 mg / kg intravenously.

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

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

The direction of exposure of the method according to the invention

2525 4 f

- 23 -

ren produced compounds is comparable to the effect of the known drug substance SMO] QIi ¹ EH, but in particular the following differences exist? The effect is stronger and longer lasting than that of TAMOXIi ¹ EIi. , ". '.'

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

The pharmaceutical preparations generally contain between 5 and 2000 mg, for example 10 to 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, jellies, creams, powders, dusting powders, aerosols or in liquid form. Examples of liquid application forms are embossing: oily or alcoholic or aqueous solutions and suspensions and emulsions. Preferred application forms are tablets which contain between 400 and 400 mg or solutions containing between 0.1 % and 5% of active substance.

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

a) in the case of oral dosage forms, between 5 and 100 mg / kg body weight, preferably 15-50 mg / kg body weight,

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

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

- 24 -

(c) 'in the case of medicinal forms for topical application to the skin and mucous membranes (for example in the form of solutions, lotions, e-emulsions, ointments, etc.) between 50 - 2000 mg, preferably 80 - 1500 mg

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

The acute toxicity of the murine compounds produced by the method of the invention (expressed as the LD 50 mg / kg, Miller and Tainter method: Proc. Soc. Exper. Biol. A. Med. J> 2 (1944) 261) for example when administered orally between 200 and 450 mg / kg body weight ·

The medicaments can be used in human medicine, veterinary medicine and in agriculture alone or mixed with other pharmacologically active substances.

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

The invention thus provides a process for the preparation of novel compounds drugs for the treatment of tumors and not only provides this at all a further antitumor agent, but brings first

- 25 -

maize, also proven effective in topical application in clinical trials. This opens up new possibilities for the treatment of cancer patients.

The invention is illustrated by the following examples.

Example 1 .

1-hexadecyl-propanediol- (1,2) -phosphoethanolamine (phosphorylation with phosphorus oxychloride, ring closure of the phosphoric acid dichloride with ethanolamine and ring opening)

1-Hexadecyl-propandiol- (1,2) (1 mol) and triethylamine (1.8 mol) are dissolved in 1.5 1 of tetrahydrofuran (THP) and added dropwise with stirring to a solution of phosphorus oxychloride (1.2 mol) in 120 ml of THP added so that the temperature does not exceed 25 ⁰ (ice bath cooling) · the reaction is off C for 30 minutes after the dropping and maintaining a temperature of 25 ⁰ C

(Evidence of DSC in ether: Rf values of 0.9 for the starting material and of 0.0 for the reaction product after hydrolysis with water.) The ice bath is removed and a solution of ethanolamine is added dropwise to the reaction mixture with vigorous stirring (1). 5 mol) and triethylamine (1.8 mol) so that the temperature in the reaction vessel to 65 to 7O ⁰ C rises Then, the cyclization is complete (detected by TLC in ether:.. Rf value of 0.2) was filtered from the precipitated triethylamine hydrochloride and the filtrate is treated with 1.5 l of 2N formic acid at 40 to 50 ^° C. After 15 minutes, the ring opening is complete (detection via DSC in ether: Rf value 0.0, Rf value in chloroform / methanol / acetic acid / water 100: 60: 20: 5, by volume, 0.8) is cooled to -2O ⁰ C and filtered off the product, which is usually obtained purely the yield of l-hexadecyl-propanediol (1... , 2) -phosphoethanolamine is 90% based on the starting alcohol.

Analytical data:

1-hexadecyl-propanediol- (1,2) -phosphoethanolamine (MW 423,6)

ber./ gef. (%): C, 59.55 / 59.43

H, 10.95 / 10.86

N, 3.31 / 3.26

P, 7,31 / 7,21

1-oleyl-propanediol- (1,2) -phosphoethanolamine (MW 449.6) ber./gef. (%): C, 61.44 / 61.29

H, 10.76 / 10.62

N, 3,12 / 3,03

P, 6.89 / 6.59

252 5 4 f - vt - -

In addition, the following compounds were prepared analogously?

l-tetradecyl-propanediol-tl, 2) -phosphocholine 1-octadecyl-propanediol (1,2) -phosphocholine. 1-Eicosyl-1,2-propanediol-phosphocholine, 1-cis-11-hexadecenyl-propanediol (1,2) -phosphocholine

Example 2

l-hexadecyl-propanediol-d-r-phosphocholine, + IH ₂ O (methylation of 1)

The crystals from Example 1 (1 mol) are taken up in 1.2 2-propanol and 0.4 1 dichloromethane. The resulting suspension is added with vigorous stirring with potassium carbonate (4 mol) in 1 1 of water. The biphasic reaction mixture is treated with dimethyl sulfate (4 mol) dropwise and with stirring so that the temperature does not exceed 4O ⁰ C. The reaction is completed 60 minutes after the dropping (detection by DSC in chloroform / methanol / 25% ammonia 50: 50: 5, by Vol.i Rf value 0.3). After phase separation at 2O ⁰ C, the upper phase contains the product. The solvent is removed in vacuo and the viscous residue is chromatographed on silica gel (Merck Art. 7733, silica gel 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 into a chromatography column. Dissolve the viscous oil in 800 ml of the above solvent mixture and give the

Crude product on the column (insoluble fractions 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 admixed with 4% acetone. The deposited at -2O ⁰ C crystals are washed with cold acetone, then with pentane and dried in vacuo.

Analytical data:

1-hexadecyl-propanediol- (1,2) -phosphocholine (MW 483.7) calc. (%): C, 59.60 / 59.47

H, 11.25 / 11.18

N, 2.90 / 2.73

P, 6,40 / 6,31

1-oleyl-propanediol- (1,2) -phosphocholine, + IUO (MW 509.7)

ber./gef. {%): C, 61.27 / 61.18 H, 11.07 / 11.03

(Λ N, 2.75 / 2.65

P, 6.08 / 6.05

Corresponding compounds were obtained as tetradecyl, octadecyl and eicosyl derivatives.

Example 3

1-hexadecy1-propanediol- (1,2) -phospho- (N-methyl) -ethanolamine (phosphorylation with phosphorus oxychloride, 2. phosphorylation with the phosphoric acid dichloride formed, methanolysis, LiBr cleavage, amination)

The first phosphorylation is carried out as described in Example 1. The reaction mixture, about 1 mole of 1-hexadecyl-propanediol-U ^ -phosphoric acid dichloride, becomes

directly with dropwise addition of bromoethanol, (1.5 mol) and triethylamine (1.8 mol) in 1.5 1 THF further reacted. The temperature is raised to 3O ⁰ C under constant stirring. After two hours at 3O ⁰ C, the reaction is complete. For methanolysis, the reaction mixture is treated with methanol (10 mol) and worked up after 30 minutes. It is mixed with ^ 1.5 1 hexane and 1.5 1 of water, shaken well and separated after phase separation of the upper hexane phase. The solvent is removed in vacuo and the oily residue is combined with a solution of 2 mol of LiBr in 1.5 l of ethyl methyl ketone. It is refluxed for 30 minutes, then the demethylation is complete.

The solvent is removed and the residue is treated with a mixture of 1 l of methanol / water / chloroform, shaken well and using the lower chloroform phase containing the product. The solvent is removed, mixed with 500 ml of chloroform and then with 500 ml of ethanol containing 1 mol of methylamine. The mixture is heated to 50 ^° C., sealed with a ground stopper and the reaction mixture is worked up after 24 hours. First, the solvent is removed in vacuo and the residue is shaken well with a mixture of 1 1 chloroform / methanol / water. After phase separation, the lower chloroform phase is removed and freed from the solvent in vacuo. The product is purified by chromatography (see Example 2).

Analytical data:

l-hexadecyl-propanediol (1,2) - (N-methyl) ethanolamine

(MW 437.6)

ber./gef. (%): C, 60.39 / 60.34

H, 11.06 / 10.93

N _f 3,20 / 3,14

P, 7.08 / 7, OQ

The tetradecyl, octadecyl, oleyl and eicosyl derivatives were also prepared by this method

Example 4

l-Hexadecyl-propandiol- (1,2) -phospho- (Ν, Ν-dimethyl) -ethanolamine (phosphorylation with phosphorus oxychloride, 2. phosphorylation with the phosphoric acid dichloride formed, methanolysis, LiBr cleavage, amination).

The reaction sequence, workup and purification is as described for Example 3. However, the amination is carried out in the presence of 2 moles of diethylamine. Analytical data:

f "Y. l-Hexadecyl-propanediol- (1,2) - (Ν, Ν-dimethyl) -ethanolamine (M.W. 451.6) b./gef. (%): C, 61.17 / 61.09

H, 11,16 / 11,04

N, 3,10 / 3,02

P, 6.86 / 6.75

The tetradecyl, octadecyl, oleyl and eicosyl derivatives were also prepared by this method.

Example 5

1-Hexadecyl-propanediol- (1,2) -phospho- (N, N, N-trimethyl) alkanolamine + 1 H ₉ O

The reaction sequence, workup and purification is as described for Example 3. However, instead of bromoethanol, the corresponding bromoalkanols are used in the second phosphorylation chromatography in order to obtain the desired structures with altered phosphorus-nitrogen spacing in the amination step In the amination step, in the synthesis of the trimethylammonium compounds, the reaction in To prepare the alkanolamines, a mixture of 500 ml each of chloroform / ethanol and a solution of 25% ammonia (150 ml) are added, and the mixture is worked up and purified as described in Example 3.

Analysis data;

1-Hexadecyl-propanediol- (1,2) -phospho- (N, N, N-trimethyl) -butanolamine + IH ₂ O (MW 511.7)

ber./gef. (%): C, 61.03 / 60.87

H, 11,42 / 11,29

N, 2.74 / 2.69

P, 6.05 / 5.94

1-Hexadecyl-propanediol- (1,2) -phospho- (N, N, N-trimethyl) -hexanolamine + 1 H ₂ O (MW 539.8) calc. (%): C, 62.31 / 62.24

H, 11.58 / 11.49

N, 2.58 / 2.42

P, 5.74 / 5.59;

252 5

1-hexadecyl-prbpändiol-U, 2) -phospho- (Ν, Ν, Ν-trimethyl) octanolamine + 1H-O

ber./gef. (%): C, 61.17 / 61.05.

H, 11,16 / 11,09

N, 3,10 / 3,03

P, 6.86 / 6.79

1-oleyl-propanediol- (1,2) -phosphobutanolaine (MW 477,7) calc. (%): C, 62.86 / 62.79

H, 10.97 / 10.84

N, 2.93 / 2.89 "

P, 6,48 / 6,29

l-O-ethyl-propanediol (1,2) -phosphohexanolamine (M.W. 505,7) ber./gef. (%): C, 64.13 / 64.05

H, 11,16 / 11,03

N, 2,77 / 2,7,1

P, 6,12 / 6,02

1-oleyl-propanediol- (1,2) -phosphooctanolamine (M.W. 533.8) ber./gef. (%): C, 65.26 / 65.19

H, 11,33 / 11,21

N, 2.62 / 2.59

P, 5.80 / 5.73

1-Oleyl-propanediol- (1,2) -phospho- (N, N, N-trimethyl) -butanolamine + IH ₂ O (MW 537.8) b./gef. {%): C, 62.54 / 62.42

H, 11.25 / 11.21

N, 2.61 / 2.53

P, 5.76 / 5.69

2525

- 33 -

1-Oleyl-propanediol- (1,2) -phospho- (N, N, N-trimethyl) -hexanolamine + IH 2 O (MW 565.8) b./gef. (%): C, 63.68 / 63.52

H, 11,40 / 11,37

N, 2.48 / 2.35

P, 5,47 / 5,33

1-Oleyl-propanediol- (1,2) -phospho- (N, N, N-trimethyl) -octanolamine + IH-O

ber./gef. (%): C, 64.72 / 64.63

H, 11.54 / 11.49

N, 2.36 / 2.29 - '

P, 5,22 / 5,14

After this process, the tetradecyl, octadecyl and eicosyl derivatives were also shown.

example

1-Oleyl-propanediol- (1,2) -phosphoglycerol, sodium salt + IH ₂ O.

(Phosphorylation with .Phosphoroxychlorid, phosphorylation, with the formed phosphoric acid dichloride, methanolysis, LiBr cleavage, hydrolysis in 70% acetic acid)

The reaction sequence is as described in Example 3 up to and including the demethylation step. The residue from the demethylation is taken up in 2 1 70% acetic acid and heated to 6O ⁰ C. The resulting acetone is removed under a slight vacuum. The reaction is complete after 2 hours.

ί. % J «- W -τ

- ZH -

It is mixed with 2 1 of water and 2 X chloroform and shaken well. The chloroform phase is treated with -2.5 M sodium carbonate solution and separated after phase separation. The solvent is removed and chromatographed on silica gel. Analytical data:

1-oleyl-propanediol- (1,2) -phosphoglycerol, sodium salt '. + IH ₂ O (MW 520.6) ber./gef. (%): C, 55,37 / 55,22

H, 9.68 / 9.57

P, 5.95 / 5.89-

Similarly, the tetradecyl, hexadecyl, pctadecyl, and eicosyl derivatives were also shown.

Example 7

L-01eyl-propanediol (l, 2) -phosphoglycol ester, sodium salt + IH ₂ O (phosphorylation, ring closure, ring opening)

The phosphorylation is carried out as described in Example 1. The reaction mixture, about 1 mole of 1-oleyl-propanediol (1 _f 2) -phosphoric acid dichloride, is further reacted directly with dropwise addition of ethylene glycol (1.5 moles) and triethylamine (1.8 moles) in 1.5 1 of THF , The temperature is raised to 6O ⁰ C to complete the ring formation. After two hours at this temperature, the reaction is complete. One fil 'trated the precipitated triethylamine hydrochloride over a porcelain frit, and the filtrate is mixed with vigorous stirring at 2O ⁰ C and 1.5 1 water. After two hours, the hydrolysis is complete. You remove that

Solvent from the upper THF phase by rotary evaporation in vacuo. The residue is mixed with a mixture of in each case 1 l of chloroform / methanol / semisaturated NaCl solution, shaken well and phase separation is awaited. The lower chloroform phase contains the product, is freed from the solvent under reduced pressure and the residue is purified by chromatography on silica gel

 Analytical data:

1-O-propyl-1-propanediol (1, 2) -phosphoglycol, sodium salt + IH ₂ O (MW 490.6). (%): C, 56.31 / 56.26

H, 9.86 / 9.79

P, 6,28 / 6,23

Accordingly, the tetradecyl, hexadecyl, octadecyl and eicosyl derivatives were prepared.

Example 8

1-Oleyl-propanediol- (1,2) -phosphomethyl, sodium salt + IH ₂ O (phosphorylation, methaholysis and LiBr cleavage)

The phosphorylation step is carried out as described in Example 1. For methanolysis, the reaction mixture, about 1 mole, with methanol (10 mol) and triethylamine (1.8 mol) at 20 ⁰ C added. The methanolysis is completed after 30 minutes. It is mixed with 1.5 1 of hexane and 1.5 1 of water, shakes well and frees the upper hexane from the solvent. The oily residue is refluxed with LiBr (2 mol) in 1.5 l of ethyl methyl ketone. The demethylation is after one hour

OC O 4 j

Completed. The solvent is removed, taken up in a mixture of in each case 1 l of chloroform / methanol / water, shaken well and treated the lower chloroform phase with 1 1 of saturated NaCl solution for conversion to the sodium salt. The lower chloroform phase is concentrated by rotary evaporation and the product is purified by chromatography on silica gel

 Analytical data:

l-O-ethyl-propanediol (1,2) -phosphomethyl, sodium salt + IH ₂ O (MW 460,6). (%): C, 57.38 / 57 / 2S

H, 10.07 / 9.94

P, 6,69 / 6,43

Accordingly, the tetradecyl, hexadecyl, octadecyl and eicosyl derivatives were prepared.

Example 9

1-oleyl-propanediol- (1,2) -phosphopentyl, sodium salt + IH, O (phosphorylation, 2nd phosphorylation with the formed phosphoric acid dichloride, methanolysis, LiBr-cleavage)

The procedure is as described in Example 3. However, the second phosphorylation is with pentyl alcohol instead of bromoethanol. The product of the demethylation with LiBr is taken up to exchange Li for Na ⁺ in a mixture of in each case 1 l of chloroform / methanol / half-saturated NaCl solution, shaken vigorously and the lower chloroform phase is evaporated. The residue is chromatographed on silica gel.

5 4 - U -

Analytical data:

1-O-propyl-1-propanediol (1, 2) -phosphopentyl, sodium salt + IH ₂ O (MW 516.7). (%): C, 60.44 / 60.13

H, 10.53 / 10.39

P, 5.99 / 5.87

Analogous compounds have been synthesized as tetradecyl, hexadecyl, octadecyl and eicosyl derivatives.

Example 10

1-ol-propanediol (1,2) -phosphoserine, sodium salt (phosphorylation, 2. phosphorylation with the phosphoric acid dichloride formed, methanolysis, LiBr cleavage, acid hydrolysis)

The first four reaction steps are carried out as described under Example 3. However, N-tert-butyloxycarbonylserine tert-butyl ester is used instead of bromoethanol in the second phosphorylation step. The acidic hydrolysis of the Serinschutzgruppen takes place in a mixture of 2 1 of methylene chloride, 1 1 trifluoroacetic acid and 500 ml of 70% perchloric acid in an ice bath at temperatures below 1O ⁰ C. After 30 minutes, mixed with 4 1 of water, 2 1 of chloroform and 4 1 Methanol.'Man shakes well and separates the lower chloroform phase. For neutralization, the chloroform phase is extracted by shaking with 2 l of 0.5 M Na ₂ CO ₃ solution. The chloroform phase is concentrated by rotary evaporation and the product is chromatographed on silica gel. Analytical data:

1-Oleyl-propanediol- (1,2) -phosphoserine, sodium salt (MW 515,6)

ber./gef. (%): C, 55.91 / 55.73

H, 9,19 / 9,08

N, 6.01 / 5.92

P, 2.72 / 2.51

Analogous compounds were obtained as tetradecyl, hexadecyl, octadecyl and eicosyl derivatives. *

Claims (6)

claims 1 · Process for the preparation of phoapholic compounds containing medicaments for the treatment of tumors, in particular compounds of the formula (I) CH ₂ -OR GH - 0 - PO ^ - X - GH ₃ 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, HH or UR ₂ ^is η is an integer from 0 to 10, R is a Gj-Cg-alkyl group or R _{1 is} a Cg-Cg-alkyl group which is unsaturated and / or halogen, amino , C 1 -C 6 -alkylamino, C 1 -C 9 -alkylamino, tri-C 1 -C 6 -alkylamino, hydroxy, carboxy, C 1 -C 4 -cycloalkyl or phenyl, and in which R ₁ also also contains 2-tert Butyloxycarbonylaminoeth.yl, 2-tert -butyloxycarbonylethyl, 2,3-isopropyl-idendioxy-propyl- (1), 2,3-dibenzyloxy-propyl- (1), 1,3-Mbenzyloxy-propyl- (2) or HC 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, when X is an oxygen atom and in which R _{1 can} also be 2,3-dihydroxypropyl- (1) when X is the MH group, and R _{2 is} a 2,3-dihydroxypropyl (1) group, a C ₁ -C 6 -alkyl group or a G ₂ -CG-alkyl group which is unsaturated and / or with halogen, amino, C ₁ -C 6 -alkylamino, Di-C ₁ -Ggalkylamino, TrI-C ₁ -Cg -alkylamino, hydroxy, carboxy, Co-Cg-cycloalkyl or phenyl substituted, and their physiologically acceptable salts, characterized -ho- in that a compound of the formula II CH ₀ - 0 - R ^
CH - OPOCl ₂ j ^GH 2> n
CH ₃ wherein R and η have the meanings indicated, with a compound of formula III HX * - R ₁ . wherein X and R _{1 have} the meanings given, hydroxy groups present, carboxy groups, amino groups or C.sub.1 -C.sub.2 alkyl groups can also contain a customary protective group, or 2 adjacent hydroxyl groups can also be acetalated by an aliphatic C.sub.1 -C.sub.G ketone, in an inert solvent, wherein in the event that 'R _{1 contains} a free hydroxy group or a free amino group on the carbon atom adjacent to the carbon atom which is linked to the group X, the resulting reaction mixture or the optionally obtained reaction product for complete ring closure heated to 60 to 80 ⁰ C and then optionally treated in an inert medium with water, an inorganic or organic acid or with alkaline agents, in the remaining cases, the resulting reaction mixture or the resulting reaction product with benzyl alcohol, a C C 1 -C 4 alkanol or an unsaturated Cg Cg Alcohol and then reacting the resulting reaction product with alkali bromides, alkali-odids, lower alky! -w- halides or amides treated, optionally cleaved in the resulting compounds protecting groups, optionally obtained reaction products in which R-. contains a halogen atom, with »ammonia or an amine of the formula KR ^ RR ^ reacted, wherein the radicals R-3, R and Rc are identical or different and denote hydrogen or C.-Cg-AIkS ^ l, and / or in alkyl group-containing products having an amino group, this amino group is alkylated by C 1 -C 6 -alkyl groups and, if appropriate, the resulting products are converted into the salts. 2. The method according to claim 1, characterized in that R is an alkyl or alkylene radical having 14 to 20 carbon atoms, X = O and R ₁ = 2rialkylammoniummethyl having 1 to 3 carbon atoms per alkyl group · 3β The method according to claim 1, characterized in that is used as the phospho compound in the drug 1-hexadecyl-propanediol- (1,2) -phosphocholine or 1-oleyl-propanediol- (1,2) -phosphocholine · 4. The method according to claim 1, characterized in that as phospho compound in the drug 1-hexadecyl-propanediol- (1,2) -phospho- (IT, Ιί, ΪΙ-trimethyl) propanolamine or 1-0leyl-propanediol- (1, 2) -phospho- (N, l, f, trimethyl) -propanolamine is used. 5. The method according to claim 1, characterized in that the phospho compound in the drug 1-hexadecyl-propanediol- (i, 2) -phospho- (Ιϊ, ϊϊ, ΙΪ-trimethyl-butanolamine or 1-0leyl-propanediol- (1,2 ) -phospho- (I \ f, lii _s ii-trimethyl) -butanolamin is used. 25254 -Hl- 6. The method according to claim 1, characterized in that as phospho compound in the drug 1-Hexadecylpropandiol- (1,2) -phospho-Cli ^ jli-trimethyl-pentanolamine or 1-0leyl-propanediol- (1,2) -phospho- ( I \ f, I \ T, Ii-trimethyl-pentanolamine is used 7. The method according to claim 1, characterized in that / at least one compound of general formula (I) is used as an active ingredient together with conventional pharmaceutical additives and diluents in the drug. 8. The method according to claim 1 and 7, characterized in that in the pharmaceutical except the compound of formula (I) at least one alkyl glycerol of the general formula (II) HpG-OR ₆
HC-O-IL ₇
H ₂ C - OH, in which one of the radicals Rg and Rj is an 'alkyl group having 3 to 12 carbon atoms and the other radical is an H atom is used.