IE41597B1 - Synthetic phospholipids a process for their manufacture and their use - Google Patents

Abstract

Synthetic phospholipids are prepared by A) reacting a polyhydroxy compound in which one hydroxyl group is in free form and the remaining hydroxyl groups are protected, with an omega -haloalkylphosphoryl dichloride of the formula I in which X denotes fluorine, chlorine, bromine or iodine and Alk denotes an alkyl or cycloalkyl radical having at least three carbon atoms; and B) reacting the resulting reaction product with an amine of the formula II in which R1, R2 and R3 independently of one another denote hydrogen or methyl groups. The products of the process can be employed in place of natural phospholipids in the entire range of intended purposes for which the latter are used. They are preferably used as stabilisers for enzyme preparations, as additives for foodstuffs and cosmetics, in particular for improving their resorption, and as emulsifiers for washing agents and detergents.

Description

The present invention relates to synthetic phospholipids, to a process for their manufacture and to their use.

Naturally occurring phospholipids are fat-like triglycerides containing two long-chained fatty acid radicals and a phosphoric acid radical to which a base is linked. They occur in all animal and vegetable cells, especially in the brain, heart, liver, yolk, as well as in soya beans. The most important of the naturally occurring phospholipids are the cephalins and lecithins, in which colamine or choline are present as bases.

Lecithins and cephalins are widely used since they have colloidal, surface-active, emulsifying, softening, antioxidizing, purifying and physiological properties.

Being natural products they are physiologically acceptable in foodstuffs and therefore superior to many synthetic substances of similar activity. They are, for example, added to margarine in order to assure a better linkage to water; when lecithin is used in chocolate and in coating preparations it brings about a better and quicker wetting of the mixing constituents, a reduction of viscosity and thus a considerable saving of expensive cacao butter. At the same time, the occurrence of rancidity and fat-bloom during storage are prevented.

Lecithin is used in sweets to help to emulsify the syrup with the fat; and at the same time, it prevents the fat from becoming rancid and the sugar from crystalliz41597 - 3 ing. Bakery goods can be more readily processed when lecithin is added owing to the improved wetting during the mixing operation. Up to 20% of the otherwise required fat can thus be saved, and the yield can be increased by up to 2% owing to the better linkage to water.

Large amounts of soya bean lecithin are also added to fodder material since this promotes the adsorption of the foodstuffs from the digestive tract and taken together with fish- and meat-flour, it counteracts the damaging effect of cholesterol.

When used for cosmetic purposes and in the manufacture of soap, small additions of lecithin improve the feel and absorption of, for example, ointments, creams, tooth pastes , and soaps.

In the leather and textile industries, lecithin emulsions are used as adjuvants in the processing operations because of their antioxidizing effect. In paints, lecithin prevents the pigments from settling and reduces the viscosity, thus improving the processing conditions. It is also possible to improve printing pastes and inks for paper and textiles using lecithin. Lecithin emulsions are also used in pesticides since this provides a good stability and adhesiveness.

Lecithins and cephalins have recently gained a particular importance since it was discovered that they have a role in cell oxidation and other cellular processes. The precise function of phospholipids in cell metabolism is little known and is particularly difficult to study since the compounds can be obtained only in small amounts, and their syntheses involve considerable difficulties, often requiring many steps. The desired products are then obtained in small yields only (cf.A.J.Slotboom and P.O. M. Bonsen, Chem.Phys.Liquids (1970) S.301).

Lecithin and cephalin are obtained from natural products, for example from yolk, cerebral matter, spinal marrow and soya beans. The commercial products have 41S97 widely differing properties and it is therefore difficult in many cases to use lecithin or .oephalin preparations for the various applications owing to the differing content of phospholipids.

The present invention provides a compound of the general formula XVI II p Αθ Alk - N — (XVI) in which Alk represents an alkylene or cycloalkylene radical having at least 3 carbon atoms, X^, X2 and X^, which may be the same or different each represents a hydrogen atom or a methyl group, and W is the residue of a polyhydroxy compound, the hydroxy groups of which may be protected, W being linked to the phosphorus atom via an oxygen atom.

The hydroxy groups of the radical W are preferably protected by groups which may be the same or different, selected from ester, ether and ketal groups.

The invention also provides a process for the manufacture of a compound of the general formula, which comprises: (a) reacting a polyhydroxy compound W-H having one free hydroxy group, the other hydroxy groups of which are protected, with an ω-halogenalkylphosphoric acid dichloride of the general formula Cl 0 \ll P - 0 - Alk - X S' Cl in which X stands for a fluorine, chlorine, bromine or iodine atom, and Alk stands for an alkylene or cycloalkylene group having at least 3 carbon atoms to give, after hydrolysis, a compound of the general formula II W -P - 0 - Aik - X, I OH and (B) reacting the resulting reaction product with an amine of the formula N—X2 in which X2 and X^, which may be the same or different, each stands for a hydrogen atom or a methyl group.

The compounds of the invention may be used for the same purposes as the natural phospholipids.

The invention accordingly provides a pharmaceutical preparation which comprises a compound of the invention in admixture or conjunction with a pharmaceutically suitable carrier. The preparation may also comprise one or more other pharmacologically active substances.

Other aspects of the invention are cosmetic preparations and soaps, detergent preparations and foodstuffs, especially margarine, each of which comprises a compound of the invention The compounds of the invention have valuable pharmacological properties. The compounds which are analogous to lecithin are patent surfactants and as such have a great influence on natural cell membranes and on the permeability conditions in biomembranes. By selectively varying the phosphate-nitrogen distance in compounds of the invention used, the properties of the cell membranes can be modified in a selective manner. This variation of the phosphate-nitrogen distance results from the selection of the number of carbon atoms in the Aik radical.

When the surface activity of cell membranes is influenced by means of a compound of the invention, the activity of a pharmaceutical composition comprising that compound and an active substance is modified e.g. with regard to the absorbability with the distribution of the active substance in the organism.

Owing to the marked surface activity, the compounds of the invention cause a change of the properties of cell membranes when administered to warm-blooded animals, for example, by the oral or intraperitoneal route. When administered in even higher concentrations, cytolytic phenomena are observed. The administration of sublytic doses causes changes in the cellular membranes.

Compounds having saturated fatty acid esters of 16 and more carbon atoms, for example palmitic acid, are immunological adjuvants, whilst compounds having chain lengths of less than 14 carbon atoms were found to cause an inhibition (immuno-suppressant action) of the immunoapparatus. These results were observed with phosphoric acid choline esters. The immunological adjuvant effect reveals itself in a general increase of the antibody level.

The comprehensive variants of structure of the lysophospholipid molecule which can now be achieved leads to more efficient adjuvants.

Enzymes in the cellular membranes which are dependent on phospholipids contain natural phospholipid mixtures having a large number of unsaturated fatty acids.

Due to the instability of unsaturated fatty acids in the presence of oxygen, stabilisation of such enzyme compositions is difficult. Enzyme compositions of this kind, however,may be delipidized, thus losing their enzymatic activity. A reactivation of the enzyme can be obtained using a phospholipid of the invention that does not contain an unsaturated fatty acid radical. Reactivation 41S97 may be brought about by mixing the enzyme in a suitable ratio with a compound of the invention. It is thus possible to reactivate and stabilize enzymes which require the presence of phospholipids.

According to the concept of various authors, hybrid-formation and the cell fusion are induced by lysolecithin. Thus it is possible to produce cell hybrids in a manner similar to that using the sendai virus. A disadvantage of the use of natural lysolecithin is the great cytolytic activity of the lysolecithins obtained from egg lecithin, which are used for these investigations. The compounds of this invention have a finely varying cytolytic activity, which allows the experiments on cell fusion to be optimised, that is to say, cytolysis can be avoided by selection of a phospholipid of the invention having low cytolytic activity.

As already mentioned above, the compounds of the invention are good emulsifiers owing to the combination of lipophilic and hydrophilic as well as of acidic and basic groups in the same molecule, and they form stable emulsions at a pH ranging from 0 to 11. They may therefore advantageously be used in detergents. In addition they have the further advantage that, owing to their close relation to natural phospholipids, they can be degraded biologically, thus avoiding ecological problems. Moreover, the compounds of the invention having more than 6 carbon atoms between the phosphorus and the nitrogen atoms are found to be stable against the attack of phospholipases C and D, so that their bactericidal and bacteriostatic activities cannot be destroyed by these enzymes produced in the cells.

According to the process of the present invention, a polyhydroxy compound having a free hydroxy group is reacted with a halogenalkylphosphoric acid dichloride.

The protection of the hydroxy groups in the polyhydroxy compounds may be effected by etherification, esterification or ketalization or by any combination of these tech41S97 -8-. niques. For the process of the invention, a polyhydric aliphatic alcohol, for example, erythritol, a penitol or a hexitol, or a 1,2- or 1,3-diglyceride or another glycerol derivative is generally used as the polyhydroxy compound. ExamjiES of polyhydroxy compounds which may be reacted according to the invention are illustrated in detail later on in connection with the compounds of the invention.

The polyhydroxy compound is reacted with a halogenalkylphosphoric acid dichloride of the general formula CL 0 \ll XP - 0 - Alk - X z Cl in which X stands for a fluorine, chlorine, bromine or iodine atom and Alk stands for an alkylene or cycloalkylene group having at least 3 carbon atoms. Preferably an ω-bromo alkylphosphoric acid dichloride is used. In the above formula, Alk preferably contains 3 to 25 carbon atoms, more preferably 3 to 16, and most preferably 3 to 12 carbon atoms, in the case of alkylene groups, or 6 carbon atoms in the case of cycloalkylene groups if Alk represents a cyclohexylene group. The halogenalkylphosphoric acid dichlorides of the desired chain length may be obtained by reacting a halogenated alcohol of the following formula HO - Alk - X of a corresponding chain length, that is to say, Alk has the same meaning as given above, with phosphorus oxytrichloride. The halogenated alcohol may be obtained from the corresponding diol. For example a brominated alcohol may be prepared by introducing one bromine atom per molecule of diol according to a simple process. The reaction product having one bromine atom is removed from the reaction medium by extraction and thus the possibility of further bromination is excluded.

The reaction of the halogenalkylphosphoric acid dichloride with the polyhydroxy compound is preferably carried out in an inert organic solvent, for example, in a halogenated hydrocarbon, for example, chloroform, or carbon tetrachloride, or benzene, toluene, or petroleum ether.

The reaction should be carried out with the exclusion of moisture. The reaction temperature generally ranges from -10 to +50°C, preferably from 0 to 20°C. The reaction is preferably carried out in the presence of an inert base, for example triethylamine or pyridine. The halogenalkylphosphoric acid dichloride is generally dissolved in the inert solvent, and the base is added. Whilst stirring, the polyhydroxy compound, likewise dissolved in an inert solvent, is added dropwise to the phosphorylation agent, where required while cooling.

Under these conditions, the reaction is smooth.

It is generally complete within a short time,but it is recommended to continue stirring for some time to ensure complete reaction. Reaction periods ranging from half an hour to five hours are usual.

The reaction may be checked, for example, by thin layer chromatography. When the reaction is complete, the solvent and excess base are eliminated at a low temperature, and the reaction product may be separated by usual methods, for example by extraction.,It is not necessary generally to purify the reaction product but it may be reacted immediately with the desired amine without further purification.

For this purpose, the reaction product is dissolved in a suitable solvent, and an ethanolic or an aqueous solution of the corresponding amine is added thereto. This reaction may be carried out at room temperature or at a slightly elevated temperature, for example at 55°C , for 5 to 20 hours, or for 1 to 6 hours. The reaction can be followed by thin-layer chromatography.

Care should be taken that the necessary reaction time is not exceeded since, after the reaction is complete, the reaction product decomposes.

After ensuring that the reaction is complete, the reaction product may be isolated in a known manner, for example it may be purified by column chromatography.

The yield of the products, which is analytically 5 pure, generally ranges from 10 to 25% of the theoretical yield, calculated on the diglyceride used or on the other starting materials.

Examples of compounds which may be prepared according to the process of the invention are the following: 1. Lecithins and cephalins of the following formulae it H^C-O-CHC-0 C- Rn H-C-O-P-O-Alk-N 2 la (IV) II H2C-0-C-R1 ? · i HC-O-P-O-Alk-N — X_ 'Θ \ 2 0® \x, (V) H2C-O-C“R2 Starting materials are racemic or optically active 1,2- or 1,3-diglycerides preferably having unsaturated, saturated or branched fatty acids or fatty acids substituted by a cycloalkyl or aromatic ring.

In the above formula, X^,X2ant^ X3' independently of one another, each stands for a hydrogen atom or a methyl group, alk is defined as above, R^ and R2 each stands for a straight-chain or branched saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a cycloalkyl group or an aromatic group. The aliphatic hydrocarbon groups each contain from 9 to 25 carbon atoms, preferably 12 to 18 carbon atoms, and most preferably 14 to 18 carbon atoms. The cycloalkyl groups may contain from 5 to 7, preferably 5 to 6, carbon atoms. As aromatic groups, for example phenyl groups and substituted phenyl groups may be mentioned. and R2 may preferably stand for fatty acid radicals, for example radicals of palmitic acid and stearic acid . 2. Lyso analogues of compounds of the general formula IV or V.

The starting material for the manufacture of a lyso analogue of a compound of the general formula IV or V is for example, l-acyl-2-benzyletherglycerol or 1-benzylether-2-acylglycerol. The starting material may be prepared biochemically from a lecithin or cephalin by enzymatic splitting with phospholipase A 1 and/or A 2. 3. Analogues with saccharic alcohols h2c - 0 - CO - R (HC - 0 - CO - R) ,, X.

I 9 2 ®/ 1 H-C - 0 - P - 0 - Aik - N—X- (VI) in which Aik, X^, X2 amd X3 are defined as above, 2' is an integer of from 1 to 5, and R has the same meaning as given for R^ and R2· The starting materials are acylated saccharic alcohols containing z-1 acyl radicals in the case of z hydroxy groups, z being an integer of from 3 to 7, preferably 3 to 6, most preferably 4, 5 or 6. Cyclic saccharic alcohols may be used. 4. Ether analogues and ether-ester analogues of the compounds of Groups 1 to 3 . For example (VII) H2C -0I ° 1 Ii H - C - 0 - C- Alk - N —— X„ (VIII) in which R , R2, Alk, X^, X2 and X3 are defined as above.

Starting materials are the 1,2- and 1,3-dialkyl glycerol ethers or acyl glycerol alkyl ethers. . 0-Mono- and Di-(alkyl, alkenyl- and alkynyl)methylidene glycerol phospholipids (IX) (IXa) 415 9 7 Alk - Ν (xa) H.C - 0 R. 1 x, H -C - 0 H ® /“] 1 II X H2C - 0 - P - 0 - Alk - N —X2 (X) In the above formula IX and X, R , R2, Alk, X^, X2 and X3 are defined as above.

Starting substances are mono or di(alkyl, alkenyl or alkynyl)-O-methylidene 1,2- and 1,3-glycerols which may be obtained from glycerol or its 2-benzylether by reacting with a ketone or aldehyde. The ketone or aldehyde may be substituted by a cycloalkane or aromatic ring in the lateral chain. 6. Other O-methylidene glycerol phospholipids (XI) (XII) In the above fonnula XI and XII, Alk , X^, X^ and X3 are defined as above, y stands for an integer of from 5 to 32, preferably 5 to 18, more preferably from 5 to 16, most preferably from 5 to 12, i.e., 5,6,7,8,9,10,11 or 12. In the above formula, Alk may also contain 2 carbon atoms.

Starting substances are 0-1,2- and 1,3-dycloalkylidene glycerols which may be obtained from glycerol or 2-benzyl glycerol by a reaction with the corresponding cycloalkanone. 7.

Desoxy lysophosphatides.

H,C - 0 II C - R »2C II P - 0 - Alk ®/Xl N — X„ (XIII) (CH,) ι 2 m H -C - 0 h2c - 0 II C - R (XIV) II3C il C - R (CH ) I 2 H H2C0 ϋ P - 0 - Alk ¢/ X1 (XV) In the above formulae, Alk, X , X2, X3, R are defined as above, m stands for zero or for an integer of from 1 to 14, preferably 1 to 8, most preferably 2 to 6. The sum of p and q makes m.

Starting substances for the compounds of the general formula XIII, XIV and XV are the corresponding monoacyl alkane diols, preferably ω,ω'-monoacyl alkane diols. The alkane diols may be saturated, unsaturated or branched and may be substituted by a cycloalkane or an aromatic ring. 8. Ether analogues of the compounds of Group 7.

The above classes of compounds (Groups 1 to 8) are examples of compounds of the invention. The process of the invention is generally applicable and may be used for the synthesis of many compounds.

The compounds obtained according to the process of the invention may be isolated generally by column chromatography on silica gel. The analytically pure products are white, amorphous powders having an intermediate melting point, so, characterisation is generally made by thin-layer chromatography and elementary analysis.

The following Example 2 illustrates the invention, Example 1 illustrating the preparation of a starting material.

EXAMPLE 1 Preparation of brominated alcohols of different chain lengths according to a simplified method: The compounds of the following type were synthesised: Br - (CH_) - OH 2'n where n is an integer of 4 to 10.

Starting products were diols of the corresponding chain length. Since in each case,only one bromine atom per diol molecule was to be introduced, a process had to be found wherein the reaction product was eliminated Immediately from the reaction medium and thus further reaction was excluded. For this purpose, an extraction method was found to be suitable.

The diol and hydrobromic acid were placed in a round flask. The starting materials were overlaid with petroleum benzine or with benzene/petroleum benzine.

The selection of the extraction agent depended on the insolubility of the diol and the good solubility of the reaction product therein. The round flask was equipped with a reflux condenser. While stirring very vigorously by means of a magnetically operated stirrer, the mixture was refluxed by means of an adequate heating device until the reaction was complete. The progress of the reaction was checked by means of thin-layer chromatography.

The extraction medium phase was then separated and dried with calcium sulfate. After the siccative had been filtered off, the extraction medium was eliminated in a rotary evaporator. The residue was subjected to fractional distillation under vacuum.

The yield ranged from about 80 to 95 percent of the theoretical yield, calculated on the diol used. 4Bromo-butanol-(1) and 5-bromo-pentanol-(1) were prepared as follows: 22.5 g (0.25 mol) of 1,4-butane diol or g of 1,5-pentane diol (0.025 mol) were refluxed together with g of hydrobromic acid (47 percent strength, 0.48 mol), 500 ml of benzene and ml of petroleum benzine (boiling point 100 5 to 140°C) for 6.5 and 6 hours, respectively.

The rest Of the brominated alcohols were prepared as follows: 29.6 g (0.25 mol) of the corresponding diol were refluxed together with g (0.48 mol) of hydrobromic acid (47 percent strength), 1500 ml of petroleum benzine (boiling point 100 to 140°C).

The following reaction products were prepared: Reaction product 4- bromobutanol-(1) - bromopentanol-(1) 6- bromohexanol-(1) 7- bromoheptanol-(1) 8- bromooctanol-(1) 9- bromononanol-(1) - bromodecanol-(1) TABLE Reaction period 6.5 hours hours 1.5 hours 1.5 hours hour hour minutes Physical constants boiling point (0.7 mmHg) 58-6O°C boiling point (0.5 mmHg) 72-74°C boiling point (0.6 mmHg) 85-87°C boiling point (0.5 mmHg) 87-89°C boiling point (0.5 mmHg) 110-112°C boiling point (0.4 mmHg) 112-114°C boiling point 10.3 mmHg) 124-126°C Up to 8-bromooctanol-(1),the reaction products are colorless liquids. 9-bromononanol-(1) and 10-bromodecanol(1) are white solid products at room temperature. Brominated alcohols of greater chain length may in principal be prepared according to this method. Since all these reaction products are solid substances, they are purified by recrystallization.

EXAMPLE 2 Preparation of lecithins having a modified phosphorus-nitrogen distance in the polar head: A. ω-bromoalkylphosphoric acid dichloride: mmols = 30 ml of phosphorus oxytrichloride (freshly distilled, boiling point 105 to 107°C) in ml of absolute chloroform (distilled for minutes with circulation over were placed in a round flask. At room temperature, nitrogen was fed into this solution for a short time to expel air.

The flask was equipped with a dropping funnel and was sealed airtight. While stirring with a magnetically operated stirrer, 20 mmols of the brominated alcohol of desired chain length in 50 ml of absolute chloroform were slowly added dropwise at room temperature with the exclusion of moisture. Stirring was continued for about 12 hours.

The hydrogen chloride resulting from the reaction as well as excess phosphorus oxytrichloride and chloroform were eliminated at 30°C in a rotary evaporator. To eliminate any trace of phosphorus oxytrichloride, toluene was added and likewise evaporated.

The conversion rate was 95 to 100%, and the reaction was checked by means of thin-layer chromatograms.

B. Phosphorylation: The ω-bromoalkylphosphoric acid dichloride obtained sub A. was taken up in 60 ml of absolute chloroform, and the solution was cooled to 0°C. While stirring by means of a magnetically operated stirrer, 10 ml of triethylamine (dried over lithium-aluminium-hydride and freshly distilled) - 19 were added. 14 mmols of the corresponding diglyceride, J or example SN-1,2-dipalmitoylglycerol, SN-1,2-dimyristoylglycerol, 1,2-0-dipentadecylmethylideneglycerol or another of the above-mentioned starting substances in 60 ml of absolute chloroform were slowly added dropwise at 30 to 35°C while stirring by means of a magnetically operated stirrer and with the exclusion of atmospheric moisture.

(SN is a prefix indicating that the relevant compound can exist in a number of stereoisomeric forms.).

It was ascertained by thin-layer chromatography that the reaction was almost complete during the dropwise addition. During the reaction, the light yellow solution turned a dark-brown colour. Stirring was continued for another 3 to 5 hours. Chloroform and triethylamine were then eliminated at 35°C in a rotary evaporator. The reaction product was taken up in 100 ml of tetrahydrofuran. While stirring 1M sodium acetate solution of pH 8.4 was added until the solution remained weakly alkaline. 100 ml of diisopropyl ether were then added to the reaction product thus hydrolysed, and the mixture was stirred for 1 hour. After the phases had been separated, extraction was repeated using 50 ml of ether. The combined ether phases were stirred over sodium carbonate for 1 hour, filtered, and ether was then eliminated in the rotary evaporator.

The subsequent reactions were carried out without further purification of this reaction product.

C. Reaction with an amine The reaction product obtained sub B. was taken up in 150 ml of butanone for further reaction yielding lecithins. When a cephalin was to be prepared, it was dissolved in 50 ml of chloroform and in 100 ml of methanol. 100 ml of acetonitrile and 100 ml of an ethanolic or aqueous solution of the required amino base were added thereto. 415θ7 - 20 The reaction vessel was sealed airtight and maintained for 1 to 6 hours at 55°C, or for 5 to 20 hours at room temperature. The reaction procedure was checked by thin-layer chromatography. If the necessary reaction time was exceeded, the reaction product decomposed, which was manifested by a considerable reduction in yield. The volatile constituents of the reaction mixture were then eliminated at 50°C in a rotary evaporator. The residue was taken up in 150 ml of chloroform, 100 ml of 2% formic acid, and 200 ml of methanol were added, and the mixture was shaken. The reaction product was in the chloroform phase and was treated with 100 ml of 0.1M sodium acetate solution of pH 5.6 and 200 ml of methanol for neutralisation purposes. Upon repeated separation of the phases, the chloroform phase was dried over 10 g of sodium sulfate and the chloroform was eliminated in a rotary evaporator.

The so-obtained crude product was purified by means of column chromatography. For this purpose, a column was charged with a suspension obtained from 100 g of silica gel (Mallinckrodt AR p.a.) in a solvent system of chloroform/methanol/ammonia = 200/15/1. The product dissolved in 10 to 15 ml of solvent was then applied to the top of this column, and contaminants were then eluted by means of the above-said system. The reaction product was then eluted with chloroform/methanol/ammonia = 65/15/1 and 65/30/3, respectively. The fractions were checked by thinlayer chromatography as for their purity.

The yields of the analytically pure products ranged from 10 to 25% of the theoretical yield, calculated on the diglycerides used or on other corresponding starting substances.

The compounds cited below with their individual analytical data were prepared: Group 1: SN-l,2-dipalmitoylglycerol-3-phosphoric acid5-trimethylamino-pentylester C43W mol weight: 794.15 calculated: C 65.03¾ H 11.17% N 1.76% P 3.90% Found: C 64.36% H 11.04% N 1.84% P 3.91% Group 2: SN-l-palmitoylglycerol-3-phosphoric acid -5-tri5 methylaminopentylester C27H5qNO8P mol weight: 537.72 calculated: C 58.35% H 10.52% N 2.52% P 5.57% The analytical data obtained complied with the calculated values.

Group 3: 1,2,3,4,5-pentamyristoyl-D-mannitol-6-phosphoric acid-7-trimethylaminoheptylester cg2Hi68NO14P mol. weight: 1,541.31 calculated: C 71.69% H 10.86% N 0.91% P 2.01% The analytical data obtained complied with the calculated values.

Group 4: a) l-palmitoyl-2-hexadecyletherglycerol-3-phosphoric acid-9-trimethylaminononylester C^yHggNOgP mol weight: 836.27 calculated: C 67.50% H 11.81%, N 1.67%, P 3.70% The analytical data obtained corresponded to the calculated values. b) l,3-dioctyletherglycerol-2-phosphoric acid-6-tri25 methylaminohexylester C28H62NO7P mol weight: 555.78 calculated: C 60.51%, H 11.24%, N 2.52%, P 5.57% The analytical data obtained corresponded to the calculated values. 41S9? Group 5: 1,2-0-dipentadecylmethylideneglycerol-3-phosphoric acid-6-trimethylaminohexylester Ο^ΗθθΝΟ^Ρ mol.weight: 750.12 calculated: C (67.25%, H 11.83%, N 1.87%, P 4.13% found : C 67.28%, H,11.87%, N 1.82%, P 4.14% Group 7: l-myristoylpropanediol-3-phosphoric acid-4-trimethylaminobutylester mol weight: 497.65 calculated: c 57.92%, H 10.53%, N 2.81%, P 6.22%.

The analytical data obtained corresponded to the calculated values.

Group 8: l-tetradecyletherpropanediol-3-phosphoric acid-4trimethylaminobutylester C-^Hj-^NOgP mol.weight: 483.67 calculated: C 59.60%, H 11.25%, N 2.90:, P 6.40% The analytical data obtained corresponded to the calculated values.

Group 1: SN-1,2-dipalmitoylglycerol-3-phosphoric acid-6trimethylaminohexylester, mol. weight: 808.18.

C44H9ONO9P calculated: C 65.39%, H 11.23%, N 1.73%, P 3.83% found: C 66.66%, H 11.45%,,N 1.80%, P 4.08% SN-1,2-dipalmitoylglycerol-3-phosphoric acid-7-trimethylaminoheptylester, mol. weight: 822.20 C45H92NO9P calculated: C 65.74%, H 11.28%, N 1.70%, P 3.77% found: C 64.90%, H 11.16%, N 2.02%, P 4.59%.

SN-1,2-dipalmitoylglycerol-3-phosphoric acid-8-trimethylaminooctylester, mol. weight: 836.23 C46H94NO9P calculated: C 66.07%, H 11.33%, N 1.68%, P 3.70% found: C 64.15%, H 10.91%, N 2.30%, P 4.60% SN-l,2-dipalmitoylglycerol-3-phosphoric acid-9-trimethylaminononylester, mol. weight: 850.26 C47H96NO9P calculated: C 66.39%, H 11.38%, N 1.65%, P 3.64% found: C 66.28%, H 11.43%, N 1.85%, P 3.85% Group 5: 1,2-0-dipentadecylmethylideneglycerol-3-phosphoric acid-5-trimethylaminopentylester, mol. weight: 736.11 C42H88NO7P calculated: C 66.90%, H 11.78%, N 1.90%, P 4.21% found: C 67.06%, H 11.78%, N 2.06%, P 4.22% l,2-0-dipentadecylmethylideneglycerol-3-phosphoric acid-8-trimethylaminooctylester, mol. weight: 778.19 C45H94N97P calculated: C 67.91%, H 11.92%, N 1.80%, P 3.98% 20 found: : C 68.21%, H 11.93%, N 1.89%, P 3.95%.

Claims (26)

1. CLAIMS:1. - 24 A compound of the general formula XVI • X, W - P - 0 - Alk - Ν — X 0® ^ X 3 (xvi) in which Alk represents an alkylene or cycloalkylene radical having at least 3 carbon atoms, X^, X 2 and X 3 which may be the same or different each represents a hydrogen atom or a methyl group, and W is the residue of a polyhydroxy compound, the hydroxy groups of which may be protected, W being linked to the phosphorus atom via an oxygen atom.

2. A compound as claimed in claim 1, wherein the hydroxy groups are protected by groups, which may be the same or different, selected from ester, ether and ketal groups.

3. sents A compound as claimed in claim 1, wherein W repreH-C-O-CO-R, 2| 1 H C-O-CO-RI 2 h 2 c -°H,C-O-CO-R n Ί x H C-0h 2 c-o-co-r 2 wherein R and R^ which may be the same or different, each stands for a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain of 9 to 25 carbon atoms which may be substituted by a cycloalkyl or aromatic group, the ether analogues thereof wherein W represents H-C-O-R. 2 ι· 1 H C-O-R. I 2 h 2 c-oH„C-O-R. 2 | 1 H C-0I H C-O-R the mixed ether/ester analogues thereof, and the lyso analogues of any one of the aforementioned compounds and analogues.

4. A compound as claimed in claim 1, wherein W rep5 resents H-C-O-CO-R 4 I (H C-O-CO-R) , I z h 2 c -°wherein R has the same meaning as R^ or R 2 as 10 defined in claim 3, z 1 is an integer of from 1 to 5, the ether analogues thereof, and the mixed ether/ester analogues thereof.

5. A compound as claimed in claim 1, wherein W represents H,C-O 2 I H C-O' • R, H 2?-°\CH C-0' h 2 c-oh 2 c-o H 2 C_0 ' h 2c-o.

6. resents H C-0 I h 2 c-0 H C-i H 2 C ° the meaning of R^ and R 2 being as in claim 3. A compound as claimed in claim 1, wherein W rep- (CH 2 )y or H C-i h 2 c-o °/ C -^(CH 2 ) y wherein y is an integer of from 5 to 32. 415 9 7

7. Λ compound as claimed in claim 1, wherein W represents H.C-O-CO-R z I (CH.) I z m H 2 c-oH-C 3 I (CH.) H C-O-CO-R h 2c-°H-C J I (CH.) I 2 P H C-O-CO-R(CH.), 2'9 h 2 c-°whcrein R has the meaning given in claim 4, m is zero or an integer of from 1 to 14 and p+q=m, and ether analogues thereof. A compound of the general formula ° ®/ x i W-P-O-Alk’-N - X. Ιθ \ v Οθ X 3 in which X^, X 2 and X 3 are defined as in claim 1, W is defined as in claim 6 and Alk' represents an ethylene radical.

8. 9. l,2-Dipalmitoylglycerol-3-phosphoric acid-5-trimethylaminopentylester,

9. 10. l-Palmitoylglycerol-3-phosphoric acid-5-trimethylaminopentylester.

10. 11. 1,2,3,4,5-Pentamyristoyl-D-mannitol-6-phosphoric acid-7-trimethylaminoheptylester.

11. 12. l-Palmitoyl-2-hexadecyletherglycerol-3-phosphoric acid-9-trimethylaminononylester.

12. 13. l,3-Dioctyletherglycerol-2-phosphoric acid-6-trimethylaminohexylester.

13. 14. 1,2-0-dipentadecylmethylideneglycerol-3-phosphoric acid-6-trimethylaminohexylester.

14. 15. l-Myristoyl-propanediol-3-phosphoric acid-4-trimethylaminobutylester.

15. 16. l-Tetradecyletherpropanediol-3-phosphoric acid-4trimethylaminobutylester. 5

16. 17. A compound as claimed in claim 1 and which is des cribed in Example 2 Part C.

17. 18. A process for the manufacture of a compound as claimed in claim 1, which comprises A) reacting a polyhydroxycompound W-H having one free hydroxy group, the other hydroxy groups of which are protected, with an ω-haloalkylphosphoric acid dichloride of the general formula Cl Cl II P 0 - Alk - X in which X stands for a fluorine, chlorine, bromine or iodine atom, and Alk stands for an alkylene or cycloalkylene radical having at least 3 carbon atoms to give, after hydrolysis, a compound of the general formula II W —P - 0 - Alk - X, OH and

18. 20 B) reacting the amine of the resulting reaction product with an formula N-X, II \ 2 in which X^, X 2 and Xg, which may be the same or different, each stands for a hydrogen atom or a methyl group. 415 9 7 - 28 19. A process as claimed in claim 18, wherein the reaction A) is carried out in the presence of an inert solvent. 20. A process as claimed in claim 19, wherein the 5 reaction A) is carried out with the exclusion of moisture.

19. 21. A process as claimed in claim 19 or claim 20, wherein the reaction A) is carried out in the presence of a base.

20. 22. A process as claimed in claim 18, carried out sub10 stantially as described in Example 2.

21. 23. A compound as claimed in any one of claims 1 to 7 or 9 to 17, whenever prepared according to a process as claimed in claim 18.

22. 24. A pharmaceutical preparation which comprises a com15 pound as claimed in any one of claims 1 to 17, in admixture or conjunction with a pharmaceutically suitable carrier.

23. 25. A pharmaceutical preparation as claimed in claim 24, which also comprises one or more pharmacologically active substance(s) 20

24. 26. A cosmetic preparation or a soap which comprises cosmetic material or a soap and a compound as claimed in any one of claims 1 to 17.

25. 27. A detergent preparation which comprises a detergent and a compound as claimed in any one of claims 1 to 25 17.

26. 28. A foodstuff composition which comprises a feedstuff and a compound as claimed in any one of claims 1 to