IE59664B1 - Phosphorus-containing organic compounds, process for the preparation thereof and medicaments containing them - Google Patents

Abstract

Cytostatically-active compounds of formula (I) in which R is a saturated or unsaturated carbon residue with 12 to 24 C atoms, which can also be halogen-substituted, X is an oxygen atom, NH or NR2, n is a whole number from 0 to 10, R1 is a C1-C8-alkyl group or wherein R1 is a C2-C8-alkyl group which is unsaturated and/or is substituted with halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl and wherein R1, in addition, may also be 2-tert-butyloxycarbonylaminoethyl, 2-tert-butyloxycarbonylethyl, 2,3-isopropylidene-dioxy-propyl-(1), 2,3-dibenzyloxy-propyl-(1), 1,3-dibenzyloxy-propyl-(2) or N-C1-C6-alkylamino-C2-C6-alkyl, if X is an oxygen atom, and wherein R1, may, in addition, also be 2,3-dihydroxypropyl-(1), if X is the NH group and R2 is a 2,3 dihydroxy-propyl-(1)-group, a C1-C8-alkyl group or a C2-C8-alkyl group, which is unsaturated and/or substituted with halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl and their physiologically compatible salts, and processes for their manufacture.

Description

The invention concerns new phospho compounds and medicaments containing these» which are especially suitable for the treatment of tumours.

Description It is known that hitherto no medicament for the treatment of tumours, especially of malignant tumours, was available which was satisfactory in all respects. Thus, for example, for the topical treatment of skin metastases in patients with metastasing tumours, at present only 5-fluorouracil is available. Further developments of other cytostatics have hitherto not progressed to clinical maturity for this manner of administration. On the other hand, from a clinical point of view, such a concept of palliative therapeutic use is especially desirable since alternative concepts of treatment, such as surgical measures, radiation therapy and systemic chemotherapy, constitute comparatively aggressive therapy modalities. Furthermore, a considerable number of patients are available as potential treatment candidates for such a topical treatment. Thus, e.g. the proportion of mammary carcinoma patients who display a skin attack amount to about 25 to 35%.

The prerequisite for topical treatment on the part of the active material to be used are compatibility to the skin, cytotoxic effectiveness against tumour cells and sufficiently deep penetration.

From EP-A1 0061872 are known ethyleneglycol derivatives in which an OH group is etherified with an aliphatic hydrocarbon group and a phosphocholine radical is on another 0-atom. Since the phosphocholine radical is here bound to a primary 0-atom, these substances are cleaved by 0-alkyl-cleaving enzymes and do not display sufficient therapeutic effectiveness. -3Therefore, the object of the invention is, in the first places to provide new compounds and medicaments which are suitable for the topical treatment of tumours. A further object of the invention is, furthermore , in general to provide compounds and medicaments also usable in other forms of administration which combine a good effectiveness against tumours with low toxicity and are, therefore® generally usable in tumour therapy.

According to the invention® these tasks are 10 solved by compounds of the general formula I CH, CH - 0 - PO θ - X R, <™2>n CHO in which R signifies a saturated or unsaturated hydrocarbon radical with 12 to 24 Caroms which can also be halogen-substituted, X is an oxygen atom® NH or NR2® n signifies a whole number of 0 to 10® R-, is a C-^-Cgalkyl group or wherein Rj represents a C9-Cg-alkyl group which is unsaturated and/or substituted with halogen® amino® C^-Cg-alkylamino, di-C^-Cg-alkylamino, tri-C^-Cg-alkylamino® hydroxyl® carboxyl® Cg-Cg-cycloalkyl or phenyl and wherein Rj furthermore can also signify 2-tert.-butyloxycarbonylaminoethyl, 2-tert.. butyloxycarbonylethyl® 2®3»isopropylidenedioxypropyl-(1) 2.3- dibenzyloxypropyl-(1), 1®3-dibenzyloxypropyl-(2) or N-C1-Cg-alkylamino-C2-C,-alkyl when X is an oxygen atom or wherein Rj can, furthermore® signify 2®3-dihydroxypropyl-(l) when X is the NH group® and R2 represents a 2.3- dihydroxypropy1-(1) group® a C^-Cg-alkyl group or a C2~Cg-alkyl group which is unsaturated and/or substituted with halogen® amino® C^-C,-alkylamino„ di-Cj-Cg-alkylamino, tri-C.,-Cg-alkylamino , hydroxy® carboxyl® Cg-Cg-cycloalkyl or phenyl® and their physiologically acceptable salts. 4The formula I also includes the possible enantiomers and diastereomers. If the compounds are racemates» these can be resolved in per se known way, e,g. by means of an optically-active acid,, into the y optically-active isomers. Preferably5 however, enantiomeric or possibly diastereomeric starting materials are used ab initio», whereby, as end products, a corresponding pure,, optically-active or diastereomeric compound is then obtained.

In the scope of the invention, R is preferably an alkyl group of the given chain length which is attached with the oxygen atom of the glycol residue via a terminal C-atom or also via a C-atom within the alkyl chain (e.g. via the C-atom 2 or C-atom 3 or another middle C-atom). This alkyl chain can be straight-chained or branched. The alkyl chain R can contain one, two or three carbon double bonds or triple bonds» which can also be present mixed, and/or have halogen substituents. As halogen atoms„ there come into questions fluorine, chlorine or bromine. In the chain Rs, one to three of such halogen atoms can be present,» whereby these can be present on one or on different C-atoms of the radical R.

Besides the saturated straight-chained alkyl radicals, those with one or two carbon double bonds in the molecule are preferred. Those substituents R are especially preferred which contain an alkyl radical with 14 co 20., preferably 15 to 20, especially 16 to 20 C-atoms or a corresponding alkenyl radical with 14 to 20s preferably 15 to 20s especially 16 to 20 C-atoms.

A Examples for halogen-substituted radicals R are: chlorohexadecyla bromohexadecyl, fluorohexadecyl, 9,101 dibromooctadecyl, 2,3-dibromooctadecyl» 15,16-dibromohexadecyls bromotetradecyl» -5Examples for unsaturated radicals R are: 9octadecenyl radical (oleyl alcohol radical)9 15-hexadecenyl radical, 9,12-ocCadecdienyl radical (linoleyl radical).

If more than one double or triple bond is presents, these are conjugated.

Examples for saturated and unsubstituted radicals R are: tetradecyl radical, hexadecyl radicals octadecyl radical.

If R^ or R2 signifies an unsubstituted alkyl group, this consists, for example, of 1 - 6, preferably 1 - 4 C-atoms. If Rj or R2 signifies an unsaturated alkyl group, this consists especially of 3 to 6 C-atoms,,, whereby between the unsaturated function and X there must stand at least one single C-C bond. In particular, it is a question of a C^-C^-alkanyl group. Examples herefor ares allyl, butenyl, pentenyl, hexenyl.

If Rj or R2 are substituted, it is especially a question of straight-chained alkyl or alkenyl radicals, in this case R-^ preferably consisting of 2 - δ C-atoms, whereby the given substituents preferably stand in the «-position of the alkyl or alkenyl group R1 or R2; for example, if it is a question of the ethyl or straight propyl radical with one of the given substituents in «-position (that is in the 2-position in the case of ethyl and the 3-position in the case of propyl). If Rj is a 2-tert.-butyloxycarbonylaminoethyl radical or a 2-tert.-butyloxycarbonylethyl radical, it is preferably a question of the D- or L-form.

Amongst the substituents of R^, the trialkylammonium ethyl radicals are preferred when X is an oxygen atom, whereby the trialkyl radicals preferably each consist of one, two or three C-acoms, it preferably being a question of methyl groups. Therefore, the trimethylammonium ethyl radical is especially -6preferred. In this especially preferred embodiments! forms, in the case of the compounds of formula I „ it is preferably a question of phosphatidylcholine derivatives. < In the case of the C^-Cg-cycloalkyl substituents, these consist especially of 3 - 6 C-atoms (e.g. cyclopropyl to cyclohexyl). In the case of the 2S,3dihydroxypropyl-(1) group, it is especially a question of the sn-1»2-dihydroxypropylamino-(3) structure or of the sn-2,3-dihydroxypropylamino-(1) structure.

Especially preferred compounds are 1-hexadecylpropanediol- ( 1,2)-phosphocholine, l-oleylpropanediol(1»2)-phosphocholine, 1-hexadecylpropanediol-(1»2) phospho- (N j, N j, N-trimethyl )~propanolamine s l-oleylpropanediol- (1 ,2)-phospho-(Ν,Ν,Ν-trimethyl) propanolamine» l-oleylpropanediol-(1.2)-phospho-(Ν5,Ν»Νtrimethyl)-butanolamine, 1-hexadecylpropanediol-(1,2)phospho-(N/N/N-trimethyl)-butanolamine, 1-oleylpropanediol-(1»2)—phospho—(N,N,N-trimethyl)-pentanolamine and 1-hexadecylpropanediol- (1 » 2)-phospho- (N ,N .„N-tr imet’nyl) pentanolamine.

As salts, there come into question internal salts (e.g. when Rj signifies a triethylammonioalkyl group) or salts with physiologically acceptable cations. The medicaments or compounds according to the invention can be present as internal salts» e.g. when Rn contains an amino group. If no internal salts are present or the radical R^ does not contain a basic group» the negative charge of the phosphoric acid group is satisfied by a physiologically compatible cation. As such physiologically compatible cations there come into question» e.g.: alkali metal cations (Na. K)» alkaline I earth metal cations (Mgs Ca) or the cations of organic amines» such as e.g. guanidinium» morpholinium» cyclohexyl ammonium cation» ethylenediammonium cation» -7piperazonium cation (in both latter cases mono- or dibasic) or the cation which is derived from an amine of the formula NR R, R ., wherein the radicals R to R a b c' a c are the same or different and signify hydrogen, alkyl groups or oxyethyl groups. If it is a question of cations which are derived from an amine of the formula RaR^Rc? it is preferably a question of the ammonium cation or of an ammonium cation substituted with one to three C^-C2~alkyl groups or of an ammonium cation substituted with one to three 2-hydroxyethyl groups .

A further subject of the invention is a process for the preparation of compounds of the formula I CH„ - 0 ~ R ' Θ CH - 0 - P0~u - X - R« I I <™2>n ch3 in which R^ signifies a saturated or unsaturated hydrocarbon radical with 12 to 24 C-atoms, which can also be halogen-substituted, X is an oxygen acom, NH or NRjs n signifies a whole number of 0 to 10s is a CpCgalkyl group or wherein represents a C2-Cg-alkyl group which is unsaturated and/or substituted with halogen, amino, C^-Cg-alkyalmino» di-Cp-C,-alkylamino, tri-CpCg-alkylamino» hydroxyl., carboxyl., CpCg-cycloalkyl or phenyl and wherein R^ can furthermore also signify 2=tert,-butyloxycarbonylaminoethyl5 2-tert.butyloxycarbonylethyl, 2,3-isopropylidenedioxypropyl-(1), 2»3-dibenzyloxypropyl-(1), 1„3-dibenzyloxypropyl-(2) or N~CpCg-alkylamino-C2~CL-alkyl when X is an oxygen atom or wherein R^ can furthermore also signify 2,3dihydroxypropyl-(1) when X is the NH group and R2 represents a 2s3-dihydroxvpropyl-(1) group,, a CpCgalkyl group or a C2"Cg-alkyl group which is unsaturated and/or substituted with halogen., amino» CpCg-alkylaminos -8di-C-^-C,-alkylamino,, tri-C-^-C,-alkylamino 5 hydroxyl, carboxyl^ C^-Cg-cycloalkyl or phenyl» and of their physiologically acceptable salts, which is characterised in that one reacts in an inert solvent a compound of the formula II CH0 - 0 -· R I CH - 0P0Clo I 2 (CH0) I Z H CH3 wherein R and n have the given meanings» with a compound of the formula III HX - Rj wherein X and R^ have the given meanings» hydroxyl groups, carboxyl groups» amino groups and C^-C,-alkylamino groups present can also contain a usual protective group or 2 neighbouring hydroxyl groups can also be acetalised by an aliphatic C^-C,-ketone, whereby, for the case that Rj contains a free hydroxyl group or a free amino group on the C-atom which is adjacent to the C-atom which is linked with the group X» the reaction mixture obtained or the reaction product obtained is,„ for the complete ring closures, possibly heated to 60 co 80°C. and subsequently possibly treated in an inert solvent with water,» an inorganic or organic acid or with alkaline agents» in the other cases the reaction mixture obtained or the reaction product obtained reacted with benzyl alcohol» a C^-Cg-alkanol or an unsaturated C2-Cg-alcohol and subsequently the so obtained reaction product is created with alkali metal bromides» alkali metal iodides» lower alkyl magnesium halides or amines» possibly splits off protective groups present in the compounds obtained» possibly reacts reaction products obtained» in which R^ contains a halogen atom» with ammonia or an amine of the formula NR^R^R^» whereby the radicals R^» R^ and R^ are the same _9or different and signify hydrogen or -C^-alkyl9 and/ or in products obtained with an amino group, this amino group is alkylated by C^C^-alkyl groups and the products obtained possibly converted into the salts.

The preparation of the compounds according to general formula I can take place according to per se known methods, e.g. by reaction of: H?C - OR 2 I CH - OH I (CH9) I 2 n CH3 or a functional derivative thereof with phosphorus 10 oxychloride and triethylamine, reaction of the product with a compound HXR^ and acidic cleavage, whereby R, R^ and X possess the meanings already given.

The process is explained schematically in the following reaction equations, whereby A signifies the radical h2c OR CH(CH2)n i 2 n CH-10" ο IS AG-P-O™(CH2Sx-CK3 0Ctt3 LxBr " -ro-p-o- ( ch2 } x-ch3 QLi alkylohosbhoalkvl ester (x « I ~ 7} 2) ao-p-0~(ch.,) -Br ft * 1 OCK3 -> AQ-P-Q- ( CH2 ~Br a) LiBr OLi aikylphosphobromalkyl ester (y a 2 - 12) w 4· -A0-F-©- ( CH2 ϊ w-N( ch3j 2S aj N0 alkylphospho-(S.N>diiBefchylaikanolaraine 6fi «4* -> AO-P-G-C CH^)yM(CK3>H2 &2)n3Sb2 ° alkylphospho-N-ssathyl alkanol arsine 1-> alkylphosphoalkanoiaiaine a3) «®3 fo> N(CH3)30 AO-P-0~(CS22) y"®< CH3>3 q~ phosphatidylcholine -ΧΙ3) -Tr » 2-y ©CH~ -> a) Li3r a^,) acid hydrolysis* NaHCO3 AO-P-0-(CH,) -OH ONa alkylphosphohydroxyalkyl ester Cy " 2 - 20)7 Tr trityl 4) AO-P-0-(CH,) -C o-c'ca.)3 -> a) LiBr a,> acid hydrolysis? A N«HCO3’ AO-P-0-(CH,)„~C & is ONa OH alkvlphosphocarboxyalkyl ester (2 « 1 - 20) NH-30C ) AO-P-0-CH,-CH s 2 OCH3 O-C(CH3)3 a) LiBr a7) acid hydrolysis; A NaHCO3 AO-P~0~CH,-CK^ ONa A COO alkylphosphosezine (BOC » tert.-butoxycarbonyl ) 6) AO-P—0-CK--CH - CH, I! " | | och3 oCx CH3 Cr3 --> a) LiBr a,) acid hydrolysis; ~ NaHCQ,' AQ-P-0-CH2-CH-CH2 ONa OH ii alkylphosphoglycerol 7) -12-τ AO-P-O-(CH-) -NH-BOC « y OCH3 a) LiBr* a.j,) acid hydrolysis OB T Αθ~Ρ«0«(υΗ2)ν-^3 0~ alkylphosphoefch anolaroxne Cy =» 2 - 20); 30C ~ foutoxycarbonyl 8) AO-P-0-(CH-) -N-BOC ® λ it* OCH3 CH3 a Is V >5 Q«— CR g &&) *"a «-? OUt g a,) acid hvdrolysis - * > alkylpho3pho~N-ro©thyl' ethanol anti ne (y » 2 — 20) BOC = bufcoxycarboayl -130 alkylphosptoo-N, W,»Ν-trims thylami noalkylamide -1410) ο (Μ ΑΟΡ-ΝΗ- (GH2) g-OTri tyl GCH-, a) Li3r; a«) acid hydrolysis; x NaHCO3 Q AO-P-NH-(CH2)Z-OH ON'S alkylphosphohvdrosey alkylamide 11) - 'O-CJCHjSj -> a) Liar? a,) acid hydrolysis; 1 HaHCOj AO P- NH- ( CH 2 ) Z-C; 0N& ©Ha alkylphosphcscarboxyaIky1amid© 12) AO-P-NK-CH^-CK - CE^ OCH, 1 1χ __--> a) Li3r; a,) acid hydrolysis; NaHCO3 w ao-p-nh-ch,-ch»ch» « / 111 It / ONa OH OS alkylpho^hodihydroxypropyI amid© -15Further statements to the process according to the invention: In the starting materials of the formula III, hydroxyl groups, carboxyl groups., amino groups or C.-C,-alkylamino groups present which occur in the ° i 2 radical R or also in the radical R (if X is the group 2 NR ) can be protected by usual protective groups.

Neighbouring hydroxyl groups can be protected by ketalisation with an aliphatic saturated CQ-C.-ketone. * j o It is hereby a question of radicals which can easily be split off by hydrolysis or hydrogenolysis and are split off during or after the reaction. If such protective groups are not split off in the case of the process reaction, then a splitting off takes place after the reaction. The starting compounds frequently contain such protective groups on the basis of their preparation In the case of these protective groups, it is, for example, a question of acyl groups which can easily be split off solvolytically or groups which can be split off by hydrogenation. The protective groups which can be split off solvolytically are, for example, split off by saponification with dilute acids (for example acetic acid, perchloric acid, hydrochloric acid, sulphuric acid, formic acid, trifluoroacetic acid) or by means of basic substances (potash, soda, aqueous alkali solutions alcoholic alkali solutions, NH^) at temperatures between -50 and 150°C., especially between 0 and 1OO°C. Groups which can be split off by hydrogenation, such as arylalkyl radicals (benzyl radical) or hydroxycarbonyl radicals (carbobenzoxy radical), are expediently split off by catalytic hydrogenation in the presence of usual hydrogenation catalysts (noble metal catalysts), especially palladium catalysts or also platinum catalysts (platinum oxide), Raney nickel, in a solvent or suspension agent, possibly under elevated pressure (for -16example 1-50 bar) at temperatures between 20 - 150°C.® especially 30 - 100°C„® preferably 40 - 80°C.

As solvent or suspension agents for the splitting off of such protective groups® there come into consideration® for example? water® lower aliphatic alcohols® cyclic ethers® such as dioxan or tetrahydrofuran® aliphatic ethers® halogenated hydrocarbons® dimethylformamide and so forth® as well as mixtures of these agents. As protective groups which can be split off by hydrogenolysis® there come into question® for example? benzyl radical® cc-phenylethyl radical® benzyl radicals substituted in the benzene nucleus (p-bromo- or p-nitrobenzyl radical)® carbobenzoxy radical® carbobenzthio radical® tert.-butyloxycarbonyl radical. Examples of radicals which can be split off hydrolytically? trifluoroacetyl radical® phthalyl radical® trityl radical® p-toluenesulphonyl radical® tert.-butyloxycarbonyl radical® tert.-butyl radical® dimethyImethylene radical and the like® as well as lower alkanoyl radicals® such as acetyl radical® formyl radical® tert.-butylcarboxy radical and the like.

In particular, there come into question the protective groups usual in the peptide syntheses and the splitting off processes there usual. Inter alia® in this regard® reference is made to the book of 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 the following. The carbalkoxy group (for example low molecular) also comes into question.

The reaction of compounds of the formula II with a compound of the formula III takes place at temperatures between 0 and 200® preferably 20 and 150°C. or also between 50 and 100°C. in a solvent or suspension agent.

As such agents® there come into question? aromatic -17hydrocarbons» such as» for example, pentane» hexane» heptane» benzene» mesitylene. toluene» xylene; lower aliphatic ketones» such as» for example» acetone» methyl ethyl ketone; halogenated hydrocarbons, such as» for example» chloroform» trichloroethylene» carbon tetrachloride» chlorobenzene» methylene chloride; cyclic ethers» such as» for example» tetrahydrofuran and dioxan; 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^-C^-carboxylic acids (dimethylformamide» dimethylacetamide); Cj-Cg-dialkyl sulphones (dimethyl sulphone» tetramethylsulphone); C^-C,-dialkyl sulphoxides (dimethyl sulphoxide)» as well as further aprotic agents» such as Ν-methylpyrrolidone» tetramethylurea» hexamethylphosphoric acid triamide» acetonitrile. _The individual alkyl radicals of the above-mentioned solvents contain» for example» 1-6» especially 1-4 carbon atoms. Mixtures of these agents» as well as mixtures with water» also come into question as reaction medium.

If a solvent or dispersion agent is used» one frequently works at the reflux temperature of this agent.

This process is expediently carried out in the presence of basic materials. Such basic materials 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 reacted in which R1 (or also R^» if X is NR^) contains a hydroxyl group or an amino group on the C-atom which is adjacent to -18the C-atom which is linked with the group Xs these groups also react with the second chlorine atom of the compound I with ring formation. For the completion of the ring closure, it is possibly heated to 60 to 80°C.

The splitting of this ring takes place by treatment with an inorganic or organic acid, with alkaline agents or possibly also only by the addition of water at temperatures between 10 and 100, preferably 15 to 80°C., especially 30 - 60°C. As acids herefor there come into question, for example? formic acid® acetic acid, trifluoroacetic acid, perchloric acid, mineral acids (hydrochloric acid, sulphuric acid, phosphoric acid).

For this ring opening, there is expediently used the reaction mixture obtained. The acid used is expediently employed in diluted form, for example there are used aqueous acids in concentrations between 0.1 and 2N„ As alkaline agents, there come into question, for example: 0.1 to 1 molar aqueous solutions of sodium carbonate, potassium carbonate or ammonia. If, in the case of the ring formation, rings result which contain two phosphorus-oxygen bonds, the ring opening takes place only with water; if the ring contains a phosphorusnitrogen bond and a phosphorus-oxygen bond, in the case of treatment with acids there preferably takes place a cleavage of the phosphorus-nitrogen bond, whereas in the case of the alkaline treatment, a cleavage of the phosphorus-oxygen bond takes place.

In the cases where, in the case of che reaction of a compound of the formula II with a compound of the formula III, two chlorine atoms of the compound II react in each case with 2 mole of the formula III (that is where no ring closure of functional groups of or R cakes place with the second chlorine atom of the phosphoric acid dichloride), a subsequent treatment with -19benzyl alcohol or a C^-C^-alkanol or a preferably singly unsaturated aliphatic C2"C^-alcohol (especially Co-C,-alcohol where the double bond stands in the β3 o position to the hydroxyl group, such as, for example, allyl alcohol) is necessary. Ope preferably uses methanol.

This treatment takes place at temperatures between 10 and 100°C.s preferably 15 to 80°C., whereby, in general, the reaction mixture obtained is also used. The amount of alcohol can lie, for example, between 1 and 50 mole, referred to 1 mole of the compound I.

This reaction is expediently also carried out in the presence of basic materials, such as, for example, Cj-CL-alkylaniines, especially tertiary Cj-CL-alkylamines (triethylamine, tripropylamine, pyridine). Compounds of the formula I result in the case of this reaction with alcohols, wherein the free hydroxyl group of the phosphoric acid part is replaced by the corresponding alkoxy group, benzyloxy group or alkenoxy group. The subsequent splitting off of these alcohol groups takes place, for example, with alkali metal bromides, alkali metal iodides, lower alkyl magnesium halides or with primary, secondary or tertiary amines, especially the corresponding lower alkylamines, such as, for example, tertiary C^-C,-alkylamines (triethylamine). As alkali metal bromides or alkali metal iodides, there come into question, for example: lithium bromide, sodium bromide, lithium iodide, sodium iodide. As lower alkyl magnesium halides, there come into question, for example: methyl magnesium iodide, methyl magnesium bromide (solvents in this case are lower aliphatic ethers, such as diethyl ether).

This treatment takes place at temperatures between and 200, preferably 50 and 150°C., especially 50 and 80°C., whereby one dissolves the reaction product »20obtained up to then, after removal of the solvent, in an inert agent. As such inert agents, there come into question: saturated aliphatic C^-Cg-ketones (ethyl methyl ketone, diethyl ketone, acetone), cyclic ethers, non-cyclic lower aliphatic ethers (for example diethyl ether)» Per 1 mole of the compound II employed, there are, in general, used 1.5 to 3 mole of the previouslymentioned cleavage agents, preferably 2 mole.

The reaction of products obtained (for example 1 2 compounds in which R and/or R signifies haloalkyl) 4 5 with ammonia or an amine of the formula NR R R takes place at temperatures between 10 and 200, preferably 20 and 180°C., especially 40 and 150°C„, with or without solvents. If a solvent or suspension agent is used, for this there come into question: lower aliphatic C^-C^-alcohols, halogenated hydrocarbons (chloroform, carbon tetrachloride), as well as the agents which have already been mentioned for the reaction of a compound of formula II with the compound of formula III.

This aminisation reaction is expediently carried out in the presence of basic materials. As basic materials, there come into question, for example: alkali metal hydroxides, alkali metal carbonates, tertiary amines.

The alkylation of free amino groups in the i 2 radicals R and/or R takes place at temperatures between 0 and 200, preferably between 20 and I50°C., especially 20 and 80°C. This alkylation takes place, for example, by reaction with compounds of the formula R’Hal, ArSO2OR' and SO2(OR'g)2, whereby Hal is a halogen atom (especially chlorine, bromine or iodine) and Ar an aromatic radical (for example a phenyl or naphthyl radical possibly substituted by one or more lower alkyl radicals) and R’ is a C^-C,-alkyl group. Examples are p-toluenesulphonic acid C^-C^-alkyl esters, (3η-0θ-21dialkyl sulphates, Cj-C^-alkyl halides. The alkylation reaction is possibly carried out with the addition of usual acid-binding agents, such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal carbonates, alkali metal acetates, tertiary amines (for example trialkylamines, such as triethylamine), pyridine or also alkali metal hydrides, in inert solvents or suspension agents. As solvent or dispersion agents, there come into consideration, for example: aromatic hydrocarbons, such as for example benzene, toluene, xylene; aliphatic ketones, such as for example acetone, methyl ethyl ketone; halogenated hydrocarbons, such as for example chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; aliphatic ethers, such as for example butyl ether; cyclic ethers, such as for example tetrahydrofuran, dioxan; sulphoxides, such as for example dimethyl sulphoxide; tertiary acid amides, such as for example dimethylformamide, N-methylpyrrol idone, hexamethylphosphoric acid triamide; aliphatic alcohols, such as methanol, ethanol, isopropanol, amyl alcohol, tert.-butanol, cycloaliphatic hydrocarbons, such as cyclohexane and the like.

Aqueous mixtures of the mentioned solvents can also be used. One frequently works at the reflux temperature of the solvent or dispersion agent used. The alkylation reaction components are frequently used in excess. The alkylation can also be carried out in the presence of tetraalkylammonium salts (especially the halides) in combination with alkali metal hydroxides at temperatures between 0 - 100°C., preferably 20 - 80°C., in an aprotic solvent or also in chloroform or methylene chloride. As aprotic solvents, there come into consideration especially: tertiary amides (dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric acid triamide). -22dimethyl sulphoxide» acetonitrile» dimethoxyethane» acetone» tetrahydrofuran.

The medicaments according to the invention which» as active materials» contain a compound of the general formula I possess an outstanding cytotoxic effectiveness which was demonstrated not only in vivo on chemically-induced mammary carcinoma of the rat but also in vitro on leukaemia cells in the cell culture. Furthermore» in a clinical pilot study» in the case of female patients with mammary carcinoma» skin metastases were brought to complete healing in the case of topical used.

Especially for the topic administration but also for the preparation as medicaments for other types of administration» it has proved to be especially favourable to use the compounds of general formula I together with at least one alkyl glycerol with 3 to 12. carbon atoms in the alkyl radical» which can be present bound in the form of an ether group to one of the primary or secondary OH groups of the glycerol. Such alkylglycerols can improve the action of the compounds of general formula I synergistically and by increased penetration of the tissue. There are hereby preferably used alkylglycerols with 3 to 9 C-atoms» alone or in mixture. Quite especially preferred is a mixture which contains nonylglycerol» hexylglycerol and propylglycerol» which are expediently present in about the same amounts by weight» whereby the mixture expediently also contains water in about the same amount as each of the individual components. Such a mixture of nonylglycerol» hexylglycerol» propylglycerol and water in a weight ratio of 1:1 to 1:1 is» in the following» referred to as a cascade. The content of the compound of general formula I in mg./ml. of cascade is indicated by a following index in such a manner that a cascade mixture containing 5 mg./ml. of compound of formula I is -23referred to as cascade^, a mixture containing 200 mg. of compound of formula I per ml. of cascade as cascade2QQ. The preparation of the alkylglycerols is known, for example, from DE-OS 33 43 530.8.

The medicaments according to the invention are suitable for topical administration to an especial degree. In order to treat skin tumours or skin metastases with this medicament, the skin region in question has rubbed into it three times daily for example cascade^ to cascade2QQ. Hitherto, harmful side effects could not be observed even in the case of patients who had been treated over a period of time of 3 months. The remission of the skin metastases is accompanied by a normalisation of the skin which could be clearly demonstrated by tissue sections. Several female patients with skin metastases were treated in this way and a complete disappearance of the mammary carcinoma skin metastases hereby observed.

The topical treatment with che preferred agents according to the invention in the formulation cascade to cascade2QQ can also be used for the treatment of internal tumours or metastases by large surface rubbing into the skin. Therapeutically effective blood levels are hereby achieved via the resorption through the skin. An advantage of this type of administration lies in che fact that the compositions cascade^ to cascade2QQ are tolerated by the skin without problems.

This preferred type of composition of the medicament according co the invention in the form of the solutions of cascade^ to cascade2gg is also well suited for the preparation of suppositories for rectal insertion. Internal tumours or internal metastases can also be well treated herewith.

Another form of use of the medicament according to the invention consists in the instillation into -24pre-formed body cavities. This type of administration is especially suitable for pleural carcinoses, malign ascites, malign pericardial discharges and bladder carcinomas. In this case, the anti-tumour agents of general formula I according to 'the invention are used either alone or in combination with usual carrier and dilution agents, especially also with cascade.

For the systemic administration, oral and intravenous administration comes into consideration.

For the oral administration, the compounds of the general formula I are expediently used in the form of a drinking solution. As carriers, there are suitable, for example, milk, cocoa, fruit juice or drinking water. In the case of rats, daily doses of 20, 40 and 60 mg./kg. body weight led, in the case of the use of hexadecylphosphocholine and olelylphosphocholine, to a complete remission of chemically-induced mammary carcinomas. These compounds hereby proved to be better effective and better compatible than l-octadecyl-2methyl-rac-glycero-3-phosphocholine. In the case of the tumour model used for these experiments, it is a question of a so-called hard model. This means that the findings obtained on this model can, in most cases, also be transferred to the human situation.

For the intravenous administration via an intravenous infusion therapy, the compounds of formula I according to the invention are expediently used in physiological common salt solution. Other infusion solutions can hereby also be used.

Finally, several types of administration of the medicament according to the invention can be used combined, whereby the especial topical compatibility has the result that, on the one hand, a rubbing in of the skin is combined with another form of administration. -25A further carrier mixture for the compounds of formula I9 which has proved to be especially useful» consists of a mixture of about 4 parts by weight of water» 4 parts by weight of propylglycerol and» in each case» 2 parts by weight of, hexylglycerol and nonylglycerol .

The topical use of the medicament according to the present invention in the especially preferred form of composition of cascade^ to cascade2QQ over a period of time of several months showed that the local toxicity is limited to an increased desquamation of the skin» similar to the case of the local use of acetylsalicylic acid.

The compounds according to the invention show» for example» a good action on 7,12-dimethylbenzanthracene induced mammary cancer of the rat: also on the methylnitrosourea-induced mammary carcinoma of the rat.

For example» in the case of the above-mentioned experimental method» at a dose of 10 mg»/kg. body weight of rat there is achieved a cessation of growth of the tumours, in the case of higher doses also a complete disappearance of the tumour.

The lowest» already effective dose in the abovementioned animal experiment» is for example mg./kg. orally 5 mg./kg. intravenously.

As general dose range for the action (animal experiment as above)» there comes into question» for example : -50 mg./kg. orally» especially 15 - 32 mg./kg. -50 mg./kg. intravenously» especially 15 - 32 mg./kg.

The direction of action of the compounds according to the invention is comparable with the action of the known medicament active material TAMOXIFEN but the following differences hereto exist: The action is -26stronger and of longer duration than that of TAMOXIFEN.

Indications for which the compounds according to the invention come into consideration: mammary cancer and other types of human cancer.

In general, the pharmaceutical compositions 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, cones, salves, gels, creams, powders, dusting powders, aerosols or in liquid form. As liquid forms of use, there come into question, for example: oily or alcoholic or aqueous solutions, as well as suspensions and emulsions. Preferred forms of use are tablets which contain between 40 and 400 mg. or solutions which contain between 0.1% to 5% of active substance.

The individual dose of the active componentsaccording to the invention can, for example, lie a) in the case of oral medicinal forms between 5 100 mg./kg. body weight, preferably 15 - 50 mg./kg. body weight, b) in the case of parenteral medicinal forms (for example intravenous, intramuscular) between 5 100 mg./kg. body weight, c) in the case of medicinal forms for local administration to the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, salves and so forth) between 50 - 2000 mg., preferably 80 - 1500 mg.

(In each case, the doses refer to the free base).

For example, 1 tablet with a content of 40 400 mg. of effective substance can be recommended 3 times daily or, for example, in the case of intravenous injection, 1-5 times daily one ampoule of 1 - 5 ml. content with 50 - 250 mg. of substance. In the case of -27oral administration, the minimum daily dose is, for example, 120 mg.; the maximum daily dose in the case of oral administration is not to lie above 100 mg./kg. body weight.

The acute toxicity of the' compounds according to the invention on the mouse (expressed by the LD 50 mg./kg.; method according to Miller and Tainter: Proc. Soc. Exper. Bio. a. Med. 57 (1944) 261) lies, for example, in the case of oral administration, between 200 and 450 mg./kg. body weight.

The medicaments can be used in human medicine, veterinary medicine, as well as in agriculture, alone or in admixture with other pharmacologically-active materials.

Thus, the invention makes available new compounds and a new medicament for the treatment of tumours and hereby provides not only a further anti-tumour agent but also provides, for the first time, an agent which, as has been demonstrated in the clinical trial, is effective for the first time in the case of topic use. New possibilities for the treatment of tumour patients are hereby opened.

The invention is explained by the following Examples.

Example 1 1-Hexadecylpropanediol-(1,2)-phosphoethanolamine (phosphorylation with phosphorus oxychloride, ring closure of the phosphoric acid dichloride with ethanolamine and ring opening) 1-Hexadecylpropanediol-(1,2) (1 mole) and triethylamine (1.8 mole) are dissolved in 1.5 1. tetrahydrofuran (THF) and added dropwise, with stirring, to a solution of phosphorus oxychloride (1.2 mole) in 120 ml. THF in such a manner that the temperature does not exceed 25°C. (cooling with icebath). The reaction -28is concluded 30 minutes after the dropping in and maintenance of a temperature of 25°C. (detection via TLC in ether: Rf value of 0.9 for the starting product and of 0.0 for the reaction product after hydrolysis with water). One removes the icebath and drops into the reaction mixture» with vigorous stirring» a solution of ethanolamine (1.5 mole) and triethylamine (1.8 mole) in such a manner that the temperature in the reaction vessel increases to 65 to 70°C. The ring formation is then concluded (detection by TLC in ether: Rf value of 0.2). One filters off from the precipitated triethylamine hydrochloride and mixes the filtrate at 40 to 50°C. with 1.5 1. 2N formic acid. After 15 minutes» the ring opening is concluded (detection via TLC in ether: Rf value 0.0; Rf value in chloroform/ methanol/acetic acid/water 100:60:20:5 in vol.» 0.8).

One cools to -20°C. and filters off the product with suction» which is mostly obtained pure. The yield of 1-hexadecylpropanediol-(1»2)-phosphoethanolamine amounts to 907o» referred to the starting alcohol.

Analysis data: 1-hexadecylpropanediol-(1,2)-phosphoethanolamine (M.W. 423.6) calc./found (%) C, Hs 59.55/59.43 .95/10.86 N, 3.31/3.26 Ρ» 7.31/7.21 1-oleylpropanediol-(1»2)-phosphoethanol amine (M.W.449.6) calc./found (%): C» 61.44/61.29 Η» 10.76/10.62 Ν» 3.12/3.03 P, 6.89/6.59 Furthermore» the following compounds were prepared analogously: -291-tetradecylpropanediol-(1, 2)-phosphocholine 1-octadecylpropanediol-(1,2)-phosphocholine 1-eicosylpropanediol-(1,2)-phosphocholine 1-cis-11-hexadeceny1propanediol- (1,2)-phosphocholine. Example 2. 1-Hexadecylpropanediol-(1,2)-phosphocholine + 1 1^0 (methylation of 1) The crystals from Example 1 (1 mole) are taken up in 1.2 1. 2-propanol and 0.4 1. dichloromethane.

One mixes the resulting suspension, with vigorous stirring, with potassium carbonate (4 mole) in 1 1. of water. The two-phase reaction mixture is mixed dropwise and with stirring with dimethyl sulphate (4 mole) in such a manner that the temperature does not exceed 40°C. The reaction is finished 60 minutes after the dropping in has ended (detection by TLC in chloroform/ methanol/257o ammonia 50:50:5 in vol., Rf value 0.3).

After phase separation at 20°C., the upper phase contains the product. One removes the solvent under vacuum and chromatographs the viscous residue on silica gel (Merck Art. 7733, silica gel 60, grain size 0.2 to 0.5 mm.). Chromatography Silica gel, 2 kg., are mixed with chloroform/ methanol/25% ammonia (200/15/1 in vol.) and filled into a chromatography column. One dissolves the viscous oil in 800 ml. of the above solvent mixture and applies the crude product to the column (insoluble components are previously filtered off). One elutes with elution agents of increasing polarity until the impurities are washed out. The product is finally eluted with chloroform/methanol/25% ammonia (50/50/5 in vol.). The combined eluates are rotary evaporated and the residual water removed with toluene. The residue is taken up in 600 ml. dichloromethane and mixed with 4 1. of acetone. The crystals separating out at -20°C. are washed with -30cold acetone, then with pentane and dried in a vacuum.

Analysis data: 1-hexadecylpropanediol-(1,2)-phosphocholine (M.W.483.7) calc./found (%): C, 59.60/59.47 H, 11.25/11.18 N, 2.90/2.73 P, 6.40/6.31 1-oleylpropanediol-(1 509.7) calc./found (X): C, H, N, P, 2)-phosphocholine + 1^0 (M.W. 61.27/61.18 11.07/11.03 2.75/2.65 6.08/6.05 Corresponding compounds were obtained as tetradexyl, octadecyl and eicosyl derivatives.

Example 3 1-Hexadecylpropanediol-(1,2)-phospho-(N-methy1)ethanolamine (phosphorylation with phosphorus oxychloride, 2nd phosphorylation with the phosphoric acid dichloride formed, methanolysis, LiBr cleavage, amination) in 1.5 1. THF. with continuous The 1st phosphorylation takes place as described in Example 1. The reaction mixture, about 1 mole of 1-hexadecylpropanediol-(1,2)-phosphoric acid dichloride, is further reacted directly with the dropwise addition of bromoethanol (1.5 mole) and triethylamine (1.8 mole) The temperature is increased to 30°C. stirring. After two hours at 30°C., the reaction is concluded. For the methanolysis, the reaction mixture is mixed with methanol (10 mole) and worked up after 30 minutes. For this purpose, one mixes with 1.5 1. hexane and 1.5 1. water, shakes up well and, after phase separation, separates off the upper hexane phase. One removes the solvent in a vacuum and mixes the oily residue with a solution of 2 mole LiBr in -311.5 1. ethyl methyl ketone. One boils under reflux for 30 minutes, the demethylation then being concluded.

One removes the solvent and mixes the residue with a mixture of, in each case. 1 1. methanol/water/ chloroform, shakes up well and uses the lower chloroform phase which contains the product. One removes the solvent» mixes with 500 ml. chloroform and then with 500 ml. ethanol which contains 1 mole methylamine. One heats to 50°C.» closes with a ground stopper and works up the reaction mixture after 24 hours. The solvent is first removed in a vacuum and the residue shaken up well with a mixture of, in each case» 1 1. chloroform/ methanol/water. After phase separation» the lower chloroform phase is removed and freed from solvent in a vacuum. The purification of the product takes place by chromatography (see Example 2).

Analysis data: 1-hexadecylpropanediol-(1»2)-(N-methyl)-ethanolamine (M.W. 437.6) calc./found (%) C, 60.39/60.34 H, 11.06/10.93 Ν» 3.20/3.14 P, 7.08/7.00 The tetradecyl» octadecyl» oleyl and eicosyl derivatives were also prepared according to this process Example 4. 1-Hexadecylpropanediol-(1»2)-phospho-(N»N-dimethyl)ethanolamine (phosphorylation with phosphorus oxychloride» 2nd phosphorylation with the phosphoric acid dichloride formed» methanolysis» LiBr cleavage» amination).

The reaction sequence» working up and purification is as described for Example 3. However» the amination takes place in the presence of 2 mole diethylamine.

Analysis data: -321-hexadecylpropanediol-(1.2)- (N 9N-dimethyl)-ethanolamine (M.W. 451.6) calc./found (%): Cs H, N, P, The tetradecyl, derivatives were also Example 5 1-Hexadecylpropanediol-(1,2)-phospho-(N,N,N-trimethyl)alkanolamine + 1 Η£θ The reaction sequence, working up and purification is as described in Example 3» However, in the second phosphorylation step, instead of bromoethanol there are used the corresponding bromoalkanols, thus bromobutanol, bromohexanol or bromooctanol, in order to obtain the desired structures with changed phosphorus-nitrogen distance in the amination step. In the amination step, in the case of the synthesis of the trimethylammonium compounds, the reaction is carried out in the presence of 2 mole trimethylamine. For the preparation of the alkanolamines, to the mixture of, in each case, 500 ml. chloroform/ethanol is added a solution of 25% ammonia (150 ml.). It is worked up and purified as discussed in Example 3.

Analysis data: 1-hexadecyIpropanediol-(1,2)-phospho-(Ν,Ν,Ν-trimethyl)butanolamine + 1 Η£θ (M calc./found (7O)°. C, H, N, ps 1-hexadecyIpropanediol-(1,2)-phospho-(N,Ν,Ν-crimethyl)hexanolamine + 1 H2O (M.W. 539.8) 61.17/61.09 11.16/11.04 3.10/3.02 6.86/6.75 octadecyl9 oleyl and eicosyl prepared according to this process.

.W. 511.7) 61.03/60.87 11.42/11.29 2.74/2.69 6.05/5.94 -331 h2o C Hi N; P calc./found (%)s C. 62.31/62.24 H, 11.58/11.49 Ns 2.58/2.42 P, 5.74/5.59 1-hexadecylpropanediol-(1s 2)-phospho-(N,. N,N-trimethy1) octanolamine calc./found (%): C, 61.17/61.05 11.16/11.09 3.10/3.03 6.86/6.79 1-oleylpropanediol-(1 s,2)-phosphobutanolamine (M.W. 477.7) calc./found (%): C, 62.86/62.79 H, 10.97/10.84 2.93/2.89 P„ 6.48/6.29 1-oleylpropanediol-(1,2)-phosphohexanolamine (M.W.505.7) calc./found (%): C, 64„l3/64.05 H, 11.16/11.03 N, 2.77/2.71 P, 6.12/6.02 1-oleylpropanediol-(1»2)-phosphooctanolamine (M.W.533.8) calc./found (%) C, H, Ns P 65.26/65.19 11.33/11.21 2.62/2.59 .80/5.73 1-oleylpropanediol-(1,2)-phospho-(N,N,N-trimethyl)butanolamine -fcalc./found (7O) h2o : C, H, N, P, (M.W. 537.8) 62.54/62.42 11.25/11.21 2.61/2.53 .76/5.69 1-oleylpropanediol-(1,2)-phospho-(N ?N,N-trimethyl)hexanolamine + H20 (M.W. 565.8) calc./found (%): C, 63.68/63.52 H, 11.40/11.37 64.72/64.63 11.54/11.49 2.36/2.29 .22/5.14 octadecyl and eicosyl derivatives cording to this process. -34N, 2.48/2.35 P, 5.47/5.33 1-oleylpropanediol-(1,2)-phospho-(N,N,N-trimethyl)octanolamine + 1 1^0 calc./found (%) : C, H, Ns Ρ» The tetradecyl, were also prepared ac Example 6 1-Oleylpropanediol-(1 ,2)-phosphoglycerol „ sodium salt ? H^O (phosphorylation with phosphoric oxychloride, phosphorylation with the phosphoric acid dichloride formed, 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 step is taken up in 2 1. of 70% acetic acid and heated to 60°C. The resultant acetone is removed under a slight vacuum. The reaction is concluded after 2 hours. One mixes with 2 1., of water and 2 1. of chloroform and shakes up well. The chloroform phase is treated with 2 1. 0.5M sodium carbonate solution and separated off after phase separation. One removes the solvent and chromatographs on silica gel. Analysis data: 1-oleylpropanediol-(1,2)-phosphoglycerol, sodium salt + 1 H20 (M.W. 520.6) calc./found (%): C, H, P, Furthermore, the and eicosyl derivatives were prepared analogously. 55.37/55.22 9.68/9.57 .95/5.89 tetradecyl, hexadecyl, octadecyl -35Example 7 1-Oleylpropanediol-(1»2)-phosphoglycol ester, sodium salt + 1 H^O (phosphorylation, ring closure» ring opening).

The phosphorylation takes place as described under Example 1. The reaction mixture» about 1 mole 1-oleylpropanediol-(1,2)-phosphoric acid dichloride» is further reacted directly with the dropwise addition of ethylene glycol (1.5 mole) and triethylamine (1.8 mole) in 1.5 1. THF. For the completion of the ring formation» the temperature is increased to 60°C„ After two hours at this temperature» the reaction is concluded. One filters off the precipitated triethylamine hydrochloride over a porcelain frit and mixes the filtrate» with vigorous stirring at 20°C.» with 1.5 1. of water. After two hours» the hydrolysis is ended. One removes the solvent from the upper THF phase by rotary evaporation in a vacuum. The residue is mixed with a mixture of» in each case» 1 1» chloroform/methanol/half saturated NaCl solution» well shaken and the phase separation awaited. The lower chloroform phase contains the product» is freed from solvent in a vacuum and the residue purified by chromatography on silica gel.

Analysis data: l-oleylpropanediol-(l»2)-phosphoglycol» sodium salt + H20 (M.W. 490.6) calc./found (%): C 56.31/56.26 9.86/9.79 6.28/6.23 The tetradecyl» hexadecyl» octadecyl and eicosyl derivatives were prepared correspondingly.

Example 8 1-Oleylpropanediol-(1,2)-phosphomethyl» sodium salt + H20 (phosphorylation» methanolysis and LiBr cleavage) -36The phosphorylation takes place as described in Example 1. For the methanolysis, the reaction mixture, about 1 mole, is mixed with methanol (10 mole) and triethylamine (1.8 mole) at 20°C. The methanolysis is concluded after 30 minutes. One mixes with 1.5 1. hexane and 1-5 1» of water, shakes up well and frees the upper hexane phase from solvent. The oily residue is boiled under reflux with LiBr (2 mole) in 1.5 1. ethyl methyl ketone. The demethylation is complete after one hour. One removes the solvent, takes up in a mixture of, in each case, 1 1. chloroform/methanol/ water, shakes up well and treats the lower chloroform phase with 1 1. saturated NaCl solution for conversion into the sodium salt. The lower chloroform phase is rotary evaporated and the product purified by chromatography on silica gel.

Analysis data: l-oleylpropanediol-(l,2)-phosphomethyl, sodium salt + H20 (M.W. 460.6) calc./found (%): C, H, 57.38/57.25 .07/9.94 P, 6,69/6.43 The tetradecyl, hexadecyl, octadecyl and eicosyl derivatives are prepared correspondingly.

Example 9 1-Oleylpropanediol-(1,2)-phosphopenty1, sodium salt * 1 H20 (phosphorylation, 2nd phosphorylation with the phosphoric acid dichloride formed, methanolysis, LiBr cleavage) One proceeds as described in Example 3. However, the second phosphorylation takes place with pentyl alcohol instead of bromoethanol. The product of the demethylation with LiBr is taken up in a mixture of, in each case, 1 1. chloroform/methanol/semi-saturated NaCl solution for the exchange of Lir against Na ’ , vigorously -37shaken and the lower chloroform phase rotary evaporated The residue is chromatographed on silica gel.

Analysis data: l-oleylpropanediol-(1,2)-phosphopentyl» sodium salt + H20 (M.W. 516.7) c a 1 c. / f ound (7») : C» 60.44/60.13 Η» 10.53/10.39 P, 5.99/5.87 Analogous compounds were prepared as tetradecyl, hexadecyl» octadecyl and eicosyl derivatives.

Example 10 1-Oleylpropanediol-(1,2)-phosphoserine» sodium salt (phosphorylation» 2nd phosphorylation with the phosphoric acid dichloride formed» methanolysis,. LiBr cleavage» acid hydrolysis) The first four reaction steps are carried out as described in Example 3. However, in the 2nd phosphoryl ation step, N-cert»-butyloxycarbonylserine tert.-butyl ester is used instead of bromoethanol. The acid hydrolysis of the serine protective group takes place in a mixture of 2 1. methylene chloride, 1 1. trifluoro acetic acid and 500 ml. 70¾ perchloric acid in an icebeth at temperatures below 10°C. After 30 minutes, one mixes with 4 1. of water» 2 1. of chloroform and 4 1. of methanol. One shakes up well and separates off the lower chloroform phase. For neutralisation» one furthe shakes the chloroform phase with 2 1. 0.5 M solution. The chloroform phase is rotary evaporated and the product chromatographed on silica gel.

Analysis data: l-oleylpropanediol-(1,2)-phosphoserine (M.W. 515.6) sodium salt calc./found (¾) C, 55.91/55.73 H, 9.19/9.08 N, 6.01/5.92 Ps 2.72/2.51 -38Analogous compounds were obtained as tetradecyl hexadecyl, octadecyl and eicosyl derivatives.

Claims (19)

1. Patent Claims:

1. Compounds of the general formula CH 9 - 0 - R I z CH - 0 - PO ® - X - R-, I 2 1 i ch 3 in which R signifies a saturated or unsaturated hydrocarbon radical with 12 to 24 C-atoms® which can also be halogen-substituted® X is an oxygen atom® NH or NR 2 ® n signifies a whole number from 0 to 10® R^ is a C-pCg-a’lky 1 group or wherein Rg represents a C 2 -Cg-alkyl group which is unsaturated and/or substituted with halogen® amino® Cg-C^-alkylamino® di-C^-C,-alkylamino, tri-C^-Cg-alkylamino® hydroxyl® carboxyl® Cg-Cg-cycloalkyl or phenyl® and wherein Rg can also signify 2-cert.butyl oxycarbonylaminoethyl» 2-tert.-butyloxycarbonylethyl® 2®3-isopropylidene-dioxypropyl-(1), 2®3dibenzyloxypropyl-(1)® 1®3-dibenzyloxypropyl~(2) or N-C 3 “Cg-alkylamino-C 2 -Cg-alkyl when X is an oxygen atom and wherein Rg can also signify 2®3-dihydroxypropyl-(1) when X is che NH group® and R 2 represents a 2® 3dihydroxypropyl-(1) group® a Cg-Cg-alkyl group or a C 2 ~Cg-alkyl group which is unsaturated and/or substituted with halogen, amino. Cg-C^-alkylamino. di-C 1 -C.-alkylamino, tri-Cg-C^-alkylamino® hydroxyl® carboxyl® Cg-Cgcycloalkyl or phenyl® and their physiologically compatible salts .

2. Compounds according to claim 1® characterised in that R is an alkyl or alkenyl radical with 14 to 20 C-atoms® X = 0 and = trialkylammonium methyl with 1 to 3 C-atoms per alkyl group.

3. 1-Hexadecylpropanediol-(1,2)-phosphocholine. -404. 1-Oleylpropanediol-(1»2)-phosphocholine.

4. 5. 1-Hexadecylpropanediol-(1»2)-phospho-(N»N.Ntrimethyl)-propanolamine.

5. 6. 1-Oleylpropanediol-(1,2)-phospho-(N,N»N-trimethyl)propanolamine.

6. 7. 1-Oleylpropanediol-(1,2)-phospho-(N»N»N-trimethyl )butanolamine.

7. 8. 1-Hexadecylpropanediol-(1,2)-phospho-(N »N »Ntrimethyl)-butanolamine.

8. 9. 1-Oleylpropanediol-(1 »2)-phospho-(N s N»,N-trimethyl )pentanolamine.

9. 10. 1-Hexadecyl propanediol - (1 »2)-phospho-(N»N»Ntrimethy1)-pentanolamine.

10. 11. Medicament» characterised in that it contains at least one compound of the general formula I of claim 1 as active material» possibly together with usual pharmaceutical additive and dilution agents.

11. 12. Medicament according to claim 11, characterised in that» apart from the compound of formula I» it contains at least one alkylglycerol of the general formula II H 0 C - 0 - R, 21 o HC - 0 - R 7 I ' H 2 C - OH in which one of the radicals R^ and R? signifies an alkyl group with 3 to 12 C-atoms and the other radical an H-atom.

12. 13. Agent according to claim 11 or 12» characterised in that» for the topical treatment of skin tumours» it contains 5 to 200 mg. of compound according to claim 1 per ml. of alkylglycerol. -4114. Agent according to claim 13, characterised in that it contains equal parts by weight of nonylglycerol, hexylglycerol, propylglycerol and water.

13. 15. Agent according to one of claims 11 or 12, 5 characterised in that, for the oral treatment of tumours, it is formulated as drinking solution with a daily dose of between 5 and 100 mg./kg. body weight.

14. 16» Agent according to one of claims 11 or 12» characterised in that, for the intravenous treatment 10 of tumours, it contains a compound according to claim 1 in an amount of 5 to 100 mg./kg. body weight in physiological common salt solution.

15. 17. Process for the preparation of compounds of the formula CH 9 - 0 - R I z CH - 0 - PO © - X - R in which R signifies a saturated or unsaturaced hydrocarbon radical with 12 to 24 C-atoms, which can also be halogen-substituted,, X is an oxygen atom, NH or NR 2 » n signifies a whole number of 0 to 10, R^ is a C^-Cg20 alkyl group or wherein R^ represents a C 2 -Cg-alkyl group which is unsaturated and/or substituted with halogen, amino, C^-C,-alkylamino, di-C^-C^-alkylamino, tri-C^-C^-alkylamino, hydroxyl, carboxyl, Cg-Cg-cycloalkyl or phenyl, and wherein Rj, can also signify 225 tert.-butyloxycarbonylaminoethyl, 2-tert.-butyloxycarbonylethyl , 2,3-isopropylidenedioxypropyl-(1), 2,3-dibenzyloxypropyl-(1), 1,3-dibenzyloxypropyl-(2) or N-C^-C^-alkylamino-C 2 -C^-alkyl when X is an oxygen atom or wherein R^ can also signify 2,3-dihydroxypropyl 30 (1) when X is the NH group, and R 2 represents a 2,3-42dihydroxypropyl-(1) group, a C^-Cg-alkyl group or a C2~Cg-alkyl group which is unsaturated and/or substituted with halogen, amino, C-pC,-alkylamino, di-C^-C^-alkylaminos tri-C^-Cg-alkylamino, hydroxyl, carboxyl, Cg-Cg-cycloalkyl or phenyl, and of their physiologically acceptable salts, characterised in that one reacts a compound of the formula II CH 9 - 0 - R I Z CH - OPOC1 2 CH, wherein R and n have the given meanings, with a compound of the formula III HX - R x wherein X and Rj have the given meanings, hydroxyl groups, carboxyl groups, amino groups or CpC,-alkylamino groups present can also contain a usual protective group or 2 neighbouring hydroxyl groups can also be acetalised by an aliphatic Cg-C,-ketone, in an inert solvent, whereby, for the case in which contains a free hydroxyl group or a free amino group on the C-atom which is adjacent to the C-atom which is linked with the group X, possibly heats the reaction mixture obtained or the reaction product obtained to 60 to 80°C. for the complete ring closure and subsequently possibly treats in an inert agent with water, an inorganic or organic acid or with alkaline agents, in the other cases reacts the reaction mixture obtained or the reaction product obtained with benzyl alcohol, a C^-Cgalkanol or an unsaturated C2’Cg-alcohol and subsequently treats the so obtained reaction product with alkali metal bromides, alkali metal iodides, lower alkyl magnesium halides or amines, splits off protective -43groups possibly present in the compounds obtained, possibly reacts the reaction products obtained, in which contains a halogen atom, with ammonia or an amine of the formula NR^R^R^, whereby the radicals 5 R^, and R^ are the same or .different and signify hydrogen or C^-CA-alkyl„ and/or, in products obtained with an amino group, alkylates this amino group by C^-C,-alkyl groups and possibly converts the products obtained into the salts. 10

16. 18. A compound according to claim 1, substantially as hereinbefore described and exemplified.

17. 19. A process for the preparation of a compound according to claim 1, substantially as hereinbefore described and exemplified . 15

18. 20. A compound according to claim 1, whenever prepared by a process claimed in a preceding claim.

19. 21. A medicament according to claim 11, substantially as hereinbefore described. F. R. KELLY & CO.