LT3113B - Novel phospholipide derivatives - Google Patents

Abstract

Novel phospholipid derivatives, preparation processes therefor and their use as medicaments are described.

Description

The invention relates to novel novel antitumor phospholipid derivatives, and to antifungal activity, their compositions and uses.

for the preparation and purification of pharmaceutical compositions containing these compounds

It is known from the European patent application 108565 that compounds of the general formula:

R _r (0) _n ~ P-OCH ₂ CH ₂ N ** R ₃ ,

and pharmaceutically acceptable salts thereof, wherein R 1 is an aliphatic hydrocarbon residue having from 8 to 30 C atoms: R ₂ , R ₃ and R ₄ are the same or different and are hydrogen or lower alkyl or NR ₂ R ₃ R ₄ is cyclic ammonium; group: n is 0 or 1, exhibits antitumor activity and antifungal activity.

The present invention includes a process for the preparation of this class of compounds, as well as a pharmaceutical composition, and alkyl-or alkenophosphates having a heterocyclic ring in the choline moiety, and a process for the preparation of said pharmaceutical composition comprising said compounds as active ingredient.

The compounds of the present invention unexpectedly exhibit better antitumor activity than the open-chain compounds described in EP-A 108565.

The invention also encompasses processes for the preparation and purification of novel compounds. The first step in the preparation of these compounds is the reaction of phosphorus oxychloride with long chain alcohols in halogenated or aromatic hydrocarbons, saturated cyclic or acyclic ethers.

First ways of receiving? Step A is the reaction of phosphorus oxychloride 5 with long chain alcohols on halogenated hydrocarbons. saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having from 5 to 10 carbon atoms, liquid aromatic hydrocarbons, including aromatic hydrocarbons containing halogens (particularly chlorine), or mixtures of the above solvents, where appropriate in the presence of conventional bases.

How. halogens .'t containing hydrocarbons, suitable for • i.

- hydrocarbons having from 1 to 6 carbon atoms and one or more of which are replaced by chlorine atoms. For example, methylene chloride, chloroform, ethylene chloride, chorobenzene, dichlorobenzene can be used. Of the halogenated aromatic hydrocarbons, the predominantly used is one or two halogenated hydrocarbons.

5 or 6-membered ethers consisting of carbon atoms and one or two oxygen atoms may be used as saturated cyclic ethers. Such ethers are, for example, tetrahydrofuran, dioxane.

Acyclic ethers can be liquid ethers with 2-8 carbon atoms, such as diethyl ether, diisobutyl ether, methyl tert. - butyl ether, diisopropyl ether.

Suitable saturated hydrocarbons are liquid straight or branched chain hydrocarbons having from ³ to 10 carbon atoms, such as pentane, heptane, cyclohexane.

hexane,

Suitable aromatic hydrocarbons are, for example, benzene and alkylbenzenes having from 1 to 5 carbon atoms in the alkyl substituent.

As bases, amines such as aliphatic amines of formula NR ₁ R ₂ R ₃ in which R _x , R ₂ and R ₃ are the same or different and are suitable for the reaction of phosphorus oxychloride with long chain alcohols and the preparation of phosphoric acid diester hydrogen aria alkyl having from 1 to 6 carbon atoms, as well as aromatic lamins such as pyridine, picoline, quinoline.

The bases required to obtain the phosphoric acid diester may be added at the same time or prior to the addition of the amino alcohol or the ammonium salt. /// = '.

* .This reaction requires in all cases a solvent, i.e. if the first step of the reaction can be carried out without any particular solvent, it must still be added.

'' T * '.

The molar ratio of phosphorus oxychloride to long chain alcohol should be, for example, between 1.5: 1 = and '0.8: 1.

To the reagent is added an excess of dihydroxide or '' '7' em © ni © alk © '' '4' compared to § long chain alcohol. in quantities (the excess in moles / mole is about 1.1-1.5). <''

When the reaction of phosphorus oxychloride with a long chain alcohol is carried out in the presence of a base, the amount of this base is from 1 to 3 moles and POCl ₃ is 1 mole. The amount of base used in the preparation of the phosphoric acid diester is 1 to 5 moles per mole of material.

1.13113 B '4

The reaction of phosphorus oxychloride with long chain alcohols is carried out at a temperature of -30 to + 30 ° C, usually -15 to + 5 ° C, in particular -1.0 ° C to -5 ° C.

o _e · This reaction is carried out for 0.5 to 5 hours at most for 1 to 3 hours, especially for 1.5 to 2 hours. If the reaction is carried out in the presence of a base, it is usually rapid (about 30 years).

Subsequently, the basic alcohol or the ammonium alcohol salt is added in portions or immediately. '.j __- r—

Ammonium alcohol alcohols * are suitable salts of mineral acids of ammonium alcohols, such as sulfuric acid, hydrochloric acid, or other salts.

15 .. organic acids (eg., _F is acetic acid, p-toluolsulf © acid), and similar salts.

: This reaction step _{: is} carried out in an inert solvent. The same solvents as the interaction of the phosphorus oxychloride with the long chain alcohols are suitable

reaction, in solvent. if the latter reaction is is being executed Added ba2e is soluble in one from specified 25th . solvents, mixture. or. drip without ' solvent A reactions

The most commonly used solvents for base dissolving are:

halogenated hydrocarbons, saturated cyclic ethers / saturated hydrocarbons having from 5 to 10 carbon atoms, liquid aromatic hydrocarbons or mixtures thereof. This means the same solvents which may be used in the reaction of phosphorus oxychloride with long chain alcohols.

With the addition of base, the temperature of the reaction mixture rises. Care should be taken to maintain the temperature between 0 ° C and 40 ° C, preferably 10-30 ° C, especially 15 ~ 20 ° C.

The reaction mixture is then stirred at 5-30 ° C, preferably 15-25 ° C (for example, 1 to 40 hours, preferably 3-15 hours),

The resulting reaction product is hydrolyzed by addition of water. The hydrolysis should be carried out at 10-30 ° C, preferably at 15-30 ° C, especially at 15-20 ° C. Basic substances may be added to the solution used for hydrolysis. Such base materials may be alkali and alkaline earth metal carbonates or hydrocarbons. A further 0.5-4 hours, preferably 1-3 hours, especially 1.52.5 hours, are needed for complete hydrolysis. ^C 10-30 C, preferably 15-25 ° C, especially 18-22 ° C. '. - '

The reaction mixture is then washed with a mixture of water and alcohol (preferably aliphatic saturated alcohol having 1 to 4 carbon atoms), which may also contain a base. The ratio of water: alcohol in the mixture, for example, may be between 5 and 0.5, preferably 1-3 (by volume). As a base material, such alkaline and earth alkaline carbonates and hydrocarbonates as well as ammonia (such as aqueous ammonia solution) may be used as the base material in such a wash. A 3% solution of sodium carbonate in water is particularly suitable.

7 '. . '

If necessary, the reaction mixture may be washed with an acidic solution.

Flushing. acid solution is required to remove the unreacted base from the reaction mixture, especially if methylene chloride was used as the solvent. The wash solution consists of water and alcohol.

- Mixtures containing an aliphatic alcohol containing 1-4 carbon atoms are preferred7 The acid may also be present. The water / alcohol ratio in this. in the mixture / - may: be, for example, between 5 and 0.5, preferably .1-37. (by volume) '. The acids in this blend may be: mineral or organic, such as -draze, sulfur, wine 'or lemon, especially suitable for 1®% -dryage' -the most acidic water. · <

1G / After /, 7 more - once - for / water / alcohol mixture ^ Best. / suitable - mixtures, .7 in which. is an aliphatic / alcohol # containing 1-4. carbon atoms; For this; /: ./ mixer /. '/ Can ·. /, be / / and / base /: '.material.,

The ratio of the ratios to the ratio in this mixture may be, for example ^: between -'5- and 0, 5, preferably 1 -3.

The portions of the washed -'-reaction-mixture> are combined together -and dried ^ in the usual manner. Then / solvent / evaporated / (preferably in vacuum 7 eg * from 5 - to -; / 100 mbar) plus 150-10OS ml, preferably: 300 - 100 ^ & l, y - 450550 ml aliphatic - ', alcohol <.:: -' - alcohol 'content' 7 / (based on 1 mole dried / product). For this goal . best suited to ./'sotus...-'aliphatic alcohols ·., whose, chain · consists of; / 1--5 / abglihs / atoms. -N25 butanol / isopropanol is particularly suitable. / This / addition of alcohol is required to completely remove water · and foam.

Further, the product may be purified as follows: The crude product is dissolved in hot ethanol, the insoluble residue is filtered off and treated with mixed-type ion exchangers such as amberlift in MB 3 ethanol solution. Other commercially available acidic or basic ion exchangers may be used in place of the mixed type / ion exchanger, or may be mixed first, followed by one.

The material is crystallized from solution »with the addition of ketones, e.g. .acetone or methylethylketone, and in some cases, the above solvents are sufficient.

>

_C Sometimes it may be appropriate to use the product to clean five column chromatography or express ^ by silica gel chromatography. The eluent may be, for example, a mixture of chloroform, methylene chloride, methanol and 25% ammonia.

Method B is a further alkylation of the products obtained by Method A by coupling an amino alcohol. Alkylating agents may be used, for example, toluene sulfuric acid methyl ester or dimethyl sulfate. Solvents may be those mentioned above.

As base materials, for example, alkali metal carbonates can be used. The reaction is carried out at elevated + / + temperatures, e.g., boiling the solvent

- / -temperature. '' / .: ++ ++ /. '

20 ... Examples'. z / +1 example. Name (IOPAC nomenclature):

, \; - 7. 7 J + + <(({(octadecyloxy) hyroxyphosphenyl) oxy) -i, 1-dimethylpiperidine hydroxide inner salt

Abbreviated, Name: 7 · '7' · +

Oktadecil- (1 _r 1-dimethylpiperidinium-4-yl) phosphate

C ₂₅ H5 ₂ SO ₄ P (461, 66) .1 / 2 H ₂ O

Method A:

LT3113.B • - 8 lflk, 3 ml <0.117. mol) of phosphorus afcsiehloride is added to ί & Θ

.. '/' / '®Γ ehloroform and cooled / to 5-10 ^a C7. Within 30 minutes

'-'aaBishant. · ..dripping. -.27.0 '· g <0.10 mol) 1-octadecanol dissolved in 100 / ml. of chloroform and 35 ml of pyridine.

· 'Plug in for another .30 degrees. 5t-1ºC and add

3-S, i - g <70 * 1.3 sol) '4' hydroxy-1,1-dimethylpiperidine

- - .. /; terilafcOi. Adding, else / -40 _; /7ϊ^ί.·.·,pyridine:-: and. 30 ml 'DMF, stirred at -.../ room / · - 7t.specification .. 24 · <hours, then <hydrolyzed- iS -.- ml // water,' / with stirring / for another 30 minutes.

10'- / Organic ', ..,:, Layer-washable // water / methanol (III),

- .3% · '· Hs ^ CSj / yrialio ^ / ^ Clii) and again water / methanol. (1: 1). Biol. · .... <po / 7200 / ml) , ^; Srgani ^ - / _: .fare. ' ..inhibiting, '

- -the residue -dissolved.:-.300./ml.<.hand-/'ethanol ,-./cooled and 'filtered'. . .Fil / fcratas' _/,: · stir with '80. g jonito ~ / afcerlito ffi '3' - nuf iltruo jamaš-. ion exchange and / or solvent evaporation, 'residue ../7 afferent is converted to 301 siylethylethylketone, - pressed, / / / / dried, - under vacuum over' IW. - '20 - Yield: · 4.71 7g f 10%),. ·

Blementic. analysis / - Excluded; 'C .65,2® ' • H . / 11 * 63% . · S. .. 2.62% Mail: / . 674 ^ 36% • 65, 04% · 11.61% - '- 7 2 * 13% . '2.70%

Thin layer ',. eferomatogramar ^?

7- ^: (Ciforoform / m.et.anol / 1. / H. Sodium 'acetate

25%. ammonia 70:40:10)

EU - 0, 17 (l-butanol / acetic acid / water 40:10:10) '

Melting point: 270-271 ° C (dec.).

Method B:

'

Add 20.1 ml (0.22 mol) of 'phosphorus oxychloride in 10 ml of methylene chloride, cool to 5-10 ° C for about 30 minutes. a solution of 54.1 g (0.20 mol) octadecanol in 400 ml of methylene chloride is added under stirring and

7.0.5 ml of pyridine. After stirring for another hour, a solution of 29.9 g (0.26 mol) of 4-hydroxy-1-methylpiperidine in 80 ml of pyridine is added dropwise. Stir in 3 or. At J0 ° C, 30 ml of water are then hydrolysed under ice-cooling with stirring for another hour. The organic layer was washed with water / methanol (1: 1), 3% hydrochloric acid / methanol (1: 1), and water / methanol (III) (200 mL each). The organic phase is dried over Na ₂ SO ₄ , evaporated to a precipitate, and mixed with 1 L of methylethylketone. From the 1 L of methylethylketone, the liberated .15 crystals are dried under vacuum over P ₂ O ₅ .

Yield: 54.1 g (60%) of octadecyl- (1-methylpiperidin-4-yl) phosphate. / ',' <

98.1 g (0.22 mol) of octadecyl (1-methylpiperidin-4-yl) phosphate are suspended in 500 ml of absolute ethanol and brought to boiling. During refluxing, add two portions of 8 hours in a total of 71.8 g (0.39 mol) of p-toluene sulfonic acid methyl ester and 26.5 g (0.19 mol) of potassium carbonate. / Add the above / materials and boil under reflux for another hour. Cool, filter, evaporate the filtrate to half volume and mix the solution with 150 g of wet ion (Amberlite MB 3). Stir for two hours, then filter through an adsorbent. Kieselguhr / activated carbon layer. / The filtrate is evaporated and the material / crystallized by the addition of acetone. Crystalline material /: recrystallized from methyl ethyl ketone. 'and dried // // in vacuo over P ₂ O ₅ . '^; ίο

I Seigo of 46 "1 g '(46%) octadecyl ~ (1 l ,. ~ ..- ^t dimetilρiperidinio 4-yl) phosphate * _r / 7'

Elemental Analysis .: / .. /.'ZC/7 7B ^;  N , _: Excludes:. ·. / - 65,, 26% /. n, 63% 2.62% / '' a7 Found:. '' € 5.18% ,. 11, <2% ^: 2.66% '· ?. ^; '65, m 11.71% 2.70%

'5 ...'. · Hydi temp-? Mp 272 ° C. . ^ rising) /.- : ^; example. +. .7-. '',. . Bexadecyl. ^. Iperidine74 ^ yl-phosphate / ;,; / / 7.1 (77 irides) 'fssf.oro: /ofeichIori.dor: Extracted with dry tetrahydrofuran and cooled to 5-110 ° C.

:. father-in-law Thou -; / - /. drop by drop:;: ^ / i7./;-/-.:g./-;.;;<7S7.;/m®oi) hexadecanol and 48 ml triethylamine in 150 ml tetrahydrofuran. After stirring for an additional 30 min, keep in an ice bath and allow to warm to room temperature at 10.1 g (100 mmol). Of 4-piperidinol

207 Dissolve;.! ®Ū '/' ffll '/ fcętrahidrdfwąhpįi /./ sBmaIšdma -' / with / 17 ^: ml of triethylamine and with stirring, add dropwise to the reaction mixture so that the temperature does not rise above 4G ° C. At the end of this time, drop the solution in a reflux condenser for one hour • Filter the still hot solution with triethylammonium

257 Chloride., Cooled filtrate, and stirring / pouring / into ice ·, and 2 / B ..; sprays.: 0./ acidic ./. ../: Freezing in refrigerator,. .dissolved product; .dissolved in methylene chloride / Z driedMgSG ₄ , / •• / spin / solvent, and chromatographed on silica gel using .30,. methylene ·. chloride / methanol / 25% ammonia + (7fl3030). ; The fractions containing '. / product, sn ^ pilafiKis together, 'evaporated; solvent and 'crystallized' from methanol. The product is dried under vacuum over P ₃ O ₅ ,

7 11 - Yield: 10.0 g (35%). Distance analysis: • c H '· ... N ··· Excluded: 62.19% 10.94% - 3; 45%  .Found: . 65.15% A ll, 14% ' 3.54% ..62.41% . '11.19% 3.34%

Thin layer chromatography:. - '.- (Ghloroform / methanol / 25% /...'ammoniac' • ..A '/ 7 30: .20: 10)'. ? a_ -. \ / '. a \?

'7-' A 7 · R _f . '0.42'. j, //.· / ll-batanol / vinegar. acidic s / water. 40:10,.: 10) ./

A,. . R, «0 ^ 33 '7' 7 7- A 7, /; '

10,. '. 'to,. -,. ./7. ;

. -.3 Example '...

7 ... Ββ'Ϊ5. · 3ΐ-βο11- (1 _Ύ · 1-ά1.! Ϋ́βίίΙρίρ · 8Χΐάΐηχο · 4 · “11) Phosphate 15 7 '7c _2S H ₅ 2WR-'<461 _? , € 4> .. I3 ₂ 0 'y ,. '·'' ^? '.., A' 5, -7 g'- / {-.mmol ii) heksadecii' pįperidiriįo ^i-4-yl "fosfafo - - 10-0 was dissolved in ml of methanol and mix? with. 11, _# .6 .g - (8.4.,, O - '.' A A d --- 7, / 7 ^! Imol) -.potassium / carbonate. Intensive .. with mixing, -, in 30 min »/ 2Q ^! - dripping. · '4,0' 7®! (42 mmol-) \ dimethylsulfate. / PoAio //. .mixture '4'. At 40 ° C, cool, filter ^: '. and eviscerated.— Remains / settles. / acetone, suction and dissolving 100..ml / ·· '$ 6% ethanol. ^: / Adds 15g / jon.it © (amberrito MB '3) and. stir 3

2/5 hours. Filter the yeast, evaporate the solution '

- and '/ product recrystallized ^: two. /..- once, 7 '/ of.

methyl ethyl ketone.

. Drying under vacuum over Ρ ₂ θδ · - '

30th Yield: 3.70 g (61%), '- Distance analysis:  C '7 • H7 A  r. A A -N 7 ' Excluding: - 61.17% ¹ 11.16% A. 3.10% Found in:. 60.83% 11.14% 2.99%

• 12

60, / 92%, 11, .26%. 3.0 ©% o-.

Thin-film-; cferotet ^ ogramr 7 '-, •' / - * / ' ⁷ <e & l © rofQXKias / ffletąSi0: llsZ2S%. amoni a what. // 70120: 10} <, '7' -7. ' / ¢ / 28/7 / .. =

3 ^ = - :: 4- ^ 7 .././:/^:^:= 4 ^ .3..3- 7 / ': .7 / -,.:

7- / - /230¾;Includes :),..- '' '· / 7: = 4.7' 7 --- 3 /. .7 /: - 3-- = 4: --./=. 7: 7 - .. 7-- .-.

: .4 / example /, ... 7.7: '' - '/; -grueil - (l ;,: l -dimethylplpetrldlnio-l-ii-j. Phosphate'.

iV '' 15 .- / ,, 02, ^^ 1 ^^: :( 515,7651 .h ₂ o · /// = - / i //:

'.10,3- kind :-( 07ΐ1: · «ο11 phosphorus oxychloride- / added to 5 © s., Chloroform and: 3- ~ to © ° C drip: 32 * S g (©, 1 © mole /.- aruc bay, alcohol, and ¹ 32 ml pyridine 7 solution

- = 100. no. : -ehi: OrQfox®G> / Pitched for half an hour ix pridsdsma, in - - fold 4 35, -2 '/ -g: (0.13 ssol) 4 ^ idroxy = 2 ^ i - ^ imefil ^

7-piporiciiaio-kpe ^ iiafco- ': This is followed by a drip of 40 ./faridino -.,. allowed to warm to room temperature and stir for a further 3 hours; ..: .- 7Bo. : tp.4., 4hydrolysed .. .15 / ml ./water,. 25 -. , s ^ shah7: else = pese // 'W / an ^ ds, = 4ir7? iiha ^ ama ;: vąnd ^ s /; mtahpl-io

4- (1.:11 - ^73%.; Pafcm / karkbhsto / ^ ^ tizp .įltįj;, -. 3% .7 .-: / -: ^c ± Tribe. (1 »1), and :: -; vahdmsZwfcaiB3lih: (1: 1) 4: siihihaisais47: / <p © /:: 1W:> ml 1 · Grgaa.inis - 4. ·· .layer '-.layer,:. 4;: i &':. to <3x7 precipitated material, 7 with addition of 'acetone, = and 7 / solubilized - ..: 150 =: solution: / 36% // alasol.7 Solution .mixed' for 3 hours: with 20 g of ion exchanger / RB3 ) and .cleared ;, -filtering through .'.- Beetroot. Evaporate 1 and chromatograph over silica gel eluting with chloroform / 70% ammonia (70:40:10). The fractions containing the product are combined and the solvent is evaporated to dryness in vacuo. ·

Yield 4.4 g (9%). · -

Elemental Analysis: 'c. H M Excluded: 65.26%. 11.63% 2.62% ^; <Found: · 64.38% 11.61% 2.73% + 65.04% 11.80% 2.78%

Thin layer chromatogram: 5 (chloroform / methanol / 1 M sodium acetate)

25% ammonia 70:20:10) r R _f = 0, 30, ......

example .. R.

io · '- ...... -' R /. : Heksadecil- (1, l-dimetilpiperidlnio-3-yl) phosphate 'Ο23Η ΝΟ ₄ @ Ρ ^, - (433.616) .H ₂ O. . *. // ++ .: +.

Add 15.3 ml (0.11 mol) of phosphorus oxychlotide + to / 50 ml of chloroform and cool to 0-10 ° C. 24.2 c + (0.10 REnol) n-hexadecanol is dissolved in 100 ml of chloroform, mixed with 32 ml of pyridine and added dropwise over half an hour under ice-cooling to a solution of phosphorus oxychloride +. of 39.2 g (0.13 mol) of 3-hydroxyethyl, dimethylpiperidine tosylate and 40 ml of pyridine are added dropwise at room temperature over 15 minutes. The mixture is stirred at room temperature for 16 hours, then hydro- 15 ml of water with stirring / for another half hour and washed with water / methanol (1: 1), 3% sodium carbonate solution / methanol (1: 1), 3% citric acid / methanol (1: 1) and water / methanol ( 1: 1-) (100 ml) R Dry the organic layer over sodium sulfate and evaporate to a residue, dissolve the residue in 150 ml - 96% ethanol, filter and mix the filtrate with ion exchanger (amberlite MB 3).

, -14.7 / - evaporated, added acetone and divorced fall for it vacuumed. Dried,. in a vacuum above P ₂ O ₅ . 7th - Yield- ::. I3.5 ·. g '<31% /. ·. ·,. Slice Analysis: '/ -t /' ^: - '/ {'. H N - '/ --Excluded.l ^: - 7- ^: 61, T7% ·. ' / 7 11.16% - 3.10% _: -./-. -..., / 7 /'('/../ Found in: '. '60, 76% ('/' 11X41% 2.87% 7 '' :( '-v'777: / ('_,. (. .-' y,. - Thin layer: chromatoc 60.35%. , // '- / / .. trema: - '{7 /. 11.31% 2 ₁ 86%

(- / (chloroformAethanolZl · - · Μ. sodium trioacetate / - '(' (7 <25% /. ammonia- · 70:40:10) ¹⁰ - / '(' i% / = X0.37. 7 ( / .- // 7 / · /

--c & example '-' // // -7. 7 / -7 'O kt Adici I - (i _T 1 ~ dimet i Iplper idini o-3 - j I) Phosphate' ¹⁵ {'(λ / 1 {// - {/ /-//.// {, / GaUnam ^; -7pages / 0 ./^ in the example- ·., Described'-tetodic ^ from TO, 3 ml <0, I1 '. / ^ 1>/' phosphorus <oxychloride:, / ·· .27,0 ' g (0.10 mol) of octadecanol, 722 + 40 / ml of pyridine and 39.3.2 g (0.13 mol) of 3-hydroxy-1,1-di-ethylpiperidine (thiazate).

. Yield: 18.7 g (40%);

Elemental Analysis:  /, 'Excluded:' (C 63.80% / H './' ' 11.25% N. 2.38% ../..·-·/-·--·-7 'Found in: 63.38% 11.72% 2.63 63.61% 11.38% 2.61%

/ Pore-layer chromatogram:

(EchloroformZmethaneIisZT M sodium acetate 25% ammonia 70:40:10)

R _f = »0, 35 .. · 'Example 7

Hexadecyl- (1,1-dimethylpiperidin-2-yl) phosphate

C ₂₄ H _5O N0 ₄ P (447.643) .1 / 2 H ₂ O

Prepared according to the procedure of Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 24.2 g (0.10, aol) of hexadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol).

2-hydroxymethyl-1,1-dimethylpiperidine tosylate.

Yield: 22.9 g (51%) Distance analysis: ^c ' . H / N Excluded: 63.13% 11.26% 3.0.7% Found: 63.69% 11.73% 3.04% 63.75% 11.71% 3.04%

Thin layer chromatogram:

(chloroform / methanol / 1 M sodium acetate 25% ammonia 70:40:10) R _f - 0.47.

Example 8

Octadecyl- (1,1-dimethylpiperidin-2-yl) phosphate

C ₂₆ H _m NO ₄ P (475, 697) .1 / 2 H ₂ O

Obtained according to the procedure described in Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g (0.13 mol) of octadecanol, 32-40 ml of pyridine and 41.0 g (0.13 mol).

2-hydroxymethyl-1,1-dimethylpiperidine tosylate.

Yield: 23.9 g (50%) '!

Stage Analysis:. C

Discount: 64.43%

H

11.44%

N

2, 89%

Found: 64.50% 11.61%, 64.11% · · / · 5/5 ′. ^; '7.

5 '·' '··' '- / ·' - '' '·? '·' 5 .. ·· ·

Thin-layer chrometogram:

2.67%

11.49%

2.77%

K. sodium acetate

..25%. saoniafe // 70r40 /: .Rf ~ 0.47; .. ii

BACKGROUND OF THE INVENTION 1- (1,1-Dimethylpiperidin-3-yl ·) phosphate

C ₂₄ H _S0 M) ₄ P (447, 643). 1

Incoming.;. By:;: 5- / in the example. the methodology described from l &, &. ml (0.11 mol) of phosphorus oxychloride, 24.2 g (0.10 mol) of h & a-xaephephenol, 324 ml of pyridine and 41.0 g (0.13 mol)

3-Hydrpfesim @ 1-ylmethyl-methylpiperidine-2-ylate. 'J: Yield; 17 * 2 _; g ..

7 · Rastat-analise; ·: Rastat

/ '// C'. ' H N 61.31% 11.26% 3.01% 62.32% 12.21% 2.86% 61.79% ' 11.96% . 2.89 -ama ·: ·· -. / 7 ./c

/ sodium ^ acetate '

'./,25%· .. ammonia .-. LOtMi R _f ® 0/29 Example

Octadecyl- (1,1-dimethylpiperldinyl-5-yl) phosphate

C ₂₆ H ₅₄ NO ₄ P (475,697) .H ₂ 0

, 17th .

Prepared according to the procedure of Example 5 from 10.3 ml (0.11 / mol) octadecanol, 32-40 'ml pyridine and 41.0 g / ml (13 mol) 3-hydroxymethyl-1,1-dimethylpiperidine tosylate.

Yield: 16.7 g (35%), -

Elementary Analysis: C k ·: / H ./ N ( /-7;-)',-.-Calculated:·-..'.·. 63.25% 11.43% 2y84% ) -.- / 7./-Found :,. / --.:62,.0-8% ... 12.21% .2.76% ) k 63.67%: -7 ((/ './12/12,47%/(7 /./.7-)2,60% Thin layer chromatogram:

. 10 / (chlotoform / methanol / 1 '' -: M / ./sodium----acetate'.'-'/7./Y(.(-k/(7..:.25% -'amoniake ') ..70: 40: -10) / y / y /'/./ '<

... (y /;) 'R _f «... 0, 30 .-.):, / (/ 171-1 -.- / example.' ////). -: -. 15) k /.(-. '' / '(/ ('('-.Y y, 7'. '/)' / - '' (. ('//: //' - / '(; kk y. Tetradecyl- (1,1-dimethylhexahydroazepin-4-yl) phosphate

Y.:,/ -: e ₂ sH4> D ₄ > / - '(410.54)'. B ₂ 0'-7. (') / .... :(. (/ c / k /.'

- / 20 - / - '/'/(Gaunaffias:-/pages::5:-':example)/written:://attetodi.ko(.of 9, 6 (9 /./- 7 (45 mmol) of tetradecanol, 4.6 ml (50 aimol) / phosphorus / 10- 20 ml of pyridine and 21.3 g (67.5 mmol) of hydroxy-1,1-dimethyltetrahydrodiazepine _tozilątoc; -7 - / '(Valomasekspres-chromatogiaf its /./būdu -. silica gel / (25 / gel / methylene chloride / metanoli0 / 25% / ammonia 70:40:10 mixture.

Yield: 2.70 g (15%)

Elementary. analysis: . Excluded: z * • v 60.40% -k ''. H ' 11.05% - 'N /: (. 3.20% Found: 60.47% 11.29% 3.63% 60.78% 11.52% 3.68%

Thin layer chromatogram:

- (Chloroform / methanol / 1 M sodium acetate

25% ammonia 70:40:10)> R _f = 0.30,. y ^: '·. · '·>. ^r ·> (1-butanol / acetic acid / water 40:10:10)

Rf - 0.08 * Hexadecyl- (1,1-dimethyl-1-hexa-hexahydro-2-pyriro-4-yl) -phosphate

C ₂₄ H _4e K04P (445.62)

Obtained according to the procedure described in Example 5 from 10.8 g (45 mmol) of hexadecanol, 4.6 ml (50 zanol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5: mm © i)

4-hydroxy-1,1-dimethylhexaphaideazepinyl tosylate ©. ..Cleared -express chromatographies. feodor over silica gel eluting with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 5.0 g (25%) Elemental analysis-:

Excluded:

Found:

C ·, H, - ·. · / S 64.69% , 10,> 6%. 3.14% 63.90% * 11.54% 3.22% 64.08% 11.59% 3.24%.

Thin layer chromatogram:

(chloroform / methanol / 25% ammonia

80: 25: 5) 7> 0.10 '(1-butanol / acetic acid / water 40:10:10)

R _f ® 0.10

Lyd. temperature: 250 ° C (decomposes)

EN 311 Example

Oct. decyl (1,1-dimethylhexahydroazepin-4-yl) phosphate '

C ₂₆ H ₅₄ NO 4 P; (475,695) .1 / 2 H ₂ 0

Prepared according to the procedure in Example 5 from 12/1 g / (45 mmol) octadecanol, 4.6 ml (50 mmol) phosphorus oxychloride, 10 + 20 ml pyridine and 21.3 g (67.5 mmol).

4-hydroxy-1,1-dimethylhexahydroazepine tosylate. Purify by silica gel flash chromatography eluting with 70:30:10 methylene chloride / methanol / 25% ammonia.

Yield: 5.5 g (26%) Elemental Analysis: / c 7 'H /// N '7 Excluded: 64/43% 11.44% / 2.89% / Found: 64, '54% 11.64% 2, 82% / // _: - // ^: 64.66% 11.58% , 2.64% Thin Film Chart: '

(chloroform / methanol / l M sodium acetate 20 25% ammonia 70:40:10) / '' R f = 0.22

Lyd. temperature: 250 ° C (Skyla)

Example 14.

cis-A ⁹ -OctBBdecenyl- (1,1-dimethylhexahydroazeplenio-4 'ii) phosphate 30 C ₂₆ H ₅₂ NO ₄ P (473, 679) .H ₂ 0

Is obtained according to the procedure described in Example 5 from 12.1 g / (45 mmol) of cis--oktadecenolio A ^s, 4.6 ml (50 mmol) of

EN 3113 JB Phosphorus oxychloride, 10 + 20 ml pyridine, 21.3 g (67 * 5 mmol) 4-hydroxy-1 * 1-dimethylhexahydroazepine tosylate * Purification by silica gel chromatography using methylene chloride / methanol as eluent / 25 %

-5. / ammonia 70: 30: 10./ ../,+7..+/. .

Yield: 4.5 g (21%)

Elementary. _: -anai:. / 7G - /, //// H N- / .Calculated: ' / • 63/51% / 4 / 11.07% 2.85%  4.-4 '//// + -. 7 of + Found: ' 64 * 05% / 11.21% 7  3 * 10% , · /. 7_ ^. -, - 7.- ·. '63.80%. 7 11.06% / 7 3.06%

/ Thin film ohrOmafe ogram: 7./7., / 7 -., + /.-.-: / 7 / / +. , -. (chloroform / methanol / 25% ammonia +. '+ - + 70:40:10) to 7/2'_; + / 7 7-- / 7 7 +

/.7//,- R _f ®0 * 28 '4 -: / 7 / - /7/../. .

. / -, 7 (1-Butanol / Acetic. Acid / Water 40:10:10) IS- '· / -' - ./ / R _f = 0.10 / - / '7 -, --'.-. 7 .- / Example 15 / '- / 7 ·'. . + # 4 / Sicosyl ^ (i * t-dimethylhexahydro-gaspepin-4-yl) phosphate

- · .½ ²⁰ 7. '

Cz ₈ H ₅₈ m ₄ P (503 * 754) .B ₂ P + '+

Obtained according to the procedure described in the example, + 4: 13/4 g (45 mmol) of eicosanol * 4 * 6 ml (50 mmol) of phosphorus oxychloride * 10 + 20 ml of pyridine and 21 * 3 g (67.5 mmol) of 4 -hydroxy! * 1-dimethylhexahydroazepine tosylate /

Purify by flash chromatography on silica gel using methylene chloride / methanol / + 25% ammonia 70: 30: 10 as eluent.

Yield: 5 * 7 g (25%)

Elemental analysis: + + C,

Discount: 64.46%

H N

11.59% - 2.68%

O 3113

Found: 63.51%

64.00%

11.48% 2.95%

11.79% 2.91%

Thin-layer chromogram:

+70: 40: 10) +. /, · · '. '

R _f = 0.12.

example. + + / './---,. . +. 10 + / +. + (grugll - + (1, l -Mmeti + lExahydro-azepine- * 4 ~; il) f os f atas y- '// / C^o® ^ + .(510, 789) .H ₂ 0 7,

Obtained according to the procedure described in Example 5 from 16.2 g of 15 +. (50 mmo-1) yerucil // + kgholi © .// · + 5.1 ml (55 mmol) phosphorus oxychloride, + 18 + + 30 ml pyridine and / 20.5 g (65 mmol)

4 ~ '+ hydroxyl-1,1'-dimethylhydroxyl + pentos tosylate. Cleaned by extras-chr omatogpafi - + method +. per si 1 i cage 1 in, eluent + '+' + -:. i + -6auidPjant - ++ · ./''.- throw + iffium chloride chloride / methanol / 25% ammonia / 70 / - + 30+ : +10 ... mix. +. +:

• to

Yield: 4.1 +. Morning + Female g (15%) analysis: +, '' '' C /. H -./// '' N . 7 -Yeah handmade: 65/78% 7 11.41% 2.56% Found: 65.76% 12.01% 2.97% 65.82% 11.63% 2/96%

+. Thin-layer clirbmatogram: + - 7.

'; (Chloroform / Methanol / L M Sodium; Acetate 25% in ammonia 70:40:10)

R _f = 0.30

-ii) Example of phosphate '

Gfetacfeci.1o

-Gamma ^ · pegal / 5'in the example .- ^ spelled ®ethodife 3.25% g - (I2 / '. ®b ^ l /./; aphaetenetenol, / -1,2.1.>1/113'to> 1 ) ..phosphorus © ksiefelorddo,; / 3/7. + 4, -8 µl; -pyridine and. 4.33-. g <15 lamol) 10. / Mdrofesi 'l> i ⁱ -difflethylpyrroliddnA.o / - tosylate. 'λ'.-Excluded -. ''product ^. 'cleansed,.'. / by dissolving -./95% / <in ethanol and> ·. trim; Jonita. (aafcerlifu HB 3) ...

Yield: / 1.31 / g (25%) /  Elegant ----, Analysis :. '/ -c 7. 'B '' .Ή · //./Deleted: 753, i 3% ... , / 11,253 // 3, 07A / Found: 762.39% <11.29% 2.80% Thin Film /..dkro&afce 62.74%. · jgraasa: /. ·. · .-. ' · ' . 11.27% - ; 2, m

(chloro-forates / «fam.liš / l: / M · sodium / acetate: _. /. -. 25% / ammonia 70,: 40-: 10) / 20 · 'iU / = 0/25 /,' . '' /.-Mache-adec ^^ 2 ^ .it _r TTdifflefąipirQlidinici ^ .2 - il: iet ± l: fo.sfatas

C ^ Bso ^ P <447,543). H ₂ 0

Incoming ..... by. 5 .. described in the example. methodology, of 9 »21 g

'..... (38: .mmoll'' ^{? -} hexadecanol.) // 3 .-, 9 ./ml (42mmol) phosphorus

Oxychloride, 13 + 16 ml of pyridine and 15, (8 g <50 mmol) of 2- <2-hydroxyethyl) -1,1-dimethyl-pyrrolidine-tosylate. The isolated product · is purified by dissolving in 96% ethanol and treating it with amberlite.

Yield: 6.0 g (35%). .B

E! Ewean analysis: . C H • B .... N ^ Excluded: 61.91% 11/26% 3.01%  Found: / 61.82% 7X1.69% ' 3/21% 61/93% 11.86% B 3.28%

> / -., · ..Bldnd slice chromatogram:. ''. * ^v ':. . . '· ·; λ '.

') ... (dfelorophoms / methanol / 1 .M. - sodium acetate //)'. ' / y) ^; 25% yamoniake · 70:40:10) / -y ..

- '. 7 /. ·. & £ / "0.38 '· / .. · /' • '• Example 19 ·. · / · ./.'- io. .b / '''. ·. ~ '/ B β.37) ^: β.β · β ·'. 'Β •: g-fefadegll ^ -ž'-l., 1 -dimethylplrolldinio-l-yl) ethylphosphate>. ^: . '{475/697}, 1/2. \ '///'

Method 1'5 of 10.3 g

- / y {38 m & olloct decanol,. ' 3 .j / · 9. /) Ml · ·· (42 mmol) phosphorus i / pxychioridoll3 · lO-mi-pyridine · jr · 15, · 8; · <// 50 ^? / ίΒ®ηο1) 2 ~

7: ₀ <, // ^; ; (2 '^ hydroxyethyl) ..-'- l., $' DimefiIpyrrolidine / '/ to.zilate. Purified by '') / - pfodu.ktas is made by dissolving .96% / eta »in ol- and ·

processed by jantyjbni you. (smfc erlitu '· .® .731 / 7 ///// Yield: 7/8 g / (43%). Elemental Analysis: / B ^: /..cB·· '/BH·'.·/ y / N B / B · /. / Calculated· .: ./'/64 of 43% ·· n, 4 to 4% - / 2.89% 'Found:' / 64.69% 11.77% 2/64% 64.84% 11/88% 2.69% Thin-layer chromogram: / - .. /// -

{chloroform / methanol /! M sodium acetate 25% ammonia 70:40:10)

R _f «0.35 '

o

Heksadecil- (I _r on the following one-to lpirol Idina-2-yl) met yl OSF report f

- / ą ₃ H ₄₈ M) ₄ P (433 * 616). 1/2 Hp

Obtained according to the procedure described in Example 75 / from 9.21 g (38 mmol) of hexa-deccanol *; 3.9 mL (42 mmol) of phosphorus oxychloride, 13 + 16 mL of pyridine 'and 15 * 1 g (50 mmol)

2-hydroxymethyl / l * l-dimethylpyrrolidine tosylate. The product is purified * by dissolution in 96% ethanol and treatment with ion exchanger (amberlite MB 3), 7 ..- 7 --- / 7 Yield: 8.3 / g (51%)

Elemental Analysis: // C /// '/' / /./ / N.

σ . Charged: 62.41% / 11.16% 3 * 16% Found: 7 62, 09% /// 7 : 711, 48% 7 / 7 3 * 01% 62/25% 11/66%; / . '/ 3, 09%

: ¹⁵ <// ////., /A.,·/ '

Thin layer chromatogram: /, (chloroform / methanol / 1 M sodium acetate in 25% ammonia 70:40:10) ·. : '

- <///, ///// lA = 0 * 33 ///// '··'. //. Example 21

Octadecyl- (1 * 1-dimethylpyrrolidin-2-yl) methyl phosphate · <· ^? / \ ';. 7 ^ · /// - -77 A / A; // · --- A · ... /-/.7/-. . // C ₂ 5H ₅₂ NO 4P (461 * 67). 1/2 H ₂ 0

Incoming / under 7; The procedure described in Example 5 was prepared from 10/3 g / (38 mmol) octadecanol * 3.9 ml / (42 / Bimol) ^ phosphorus oxychloride, 13 + 16 ml pyridine and 15.1 g (50 mmol) 2-. h.hydroxymethyl-1 * 1-dimethylpyrillide tosylate * The product is purified * by dissolution in 96% ethanol and treatment with ion exchanger (Amberlite MB 3). . ·

Eleuent analysis: C H

Calculated: 63.80% 11.35% / Found: 63.13% 11.57%

63.55% 11.66%

N

2.98% · 2.84%. 2, 82%

Thin layer chromatogram:

(chloroform / methanol / 1M sodium acetate)

25% ammonia 7 ©: 40: 101

- Rj. - 0, 35 '-. ... . ·. , ·

- Re xadeci 1- (1-Methyl Ilchinuclidine-3-11) Phosphate

- '/'.-..-,' n,

72, 7 ml <30 mmol) of phosphorus oxychloride is dissolved in 25 ml ./7 of chloroform; I cool ^{: to} 7 5-10¾ / titer / and // // one hour // drip 'solution /' From / 6,4 / g-. <26 mmol); :: Hexadecanol ^? and ml of pyridine in 50 ml of dichloroform.

Stir for half an hour / at room temperature - add /

-7/4,: 5. ^,: g // {35 /mmol)//-3^bydroxyquinuclidino'/.ir-.-.5. ml of pyridine

- '/. In 10 / ml: chloroform / · The mixture is stirred at 5 rpm / room / temperature and - hydrolysed at 15 / ml / runner: with stirring for another half hour. It is then washed twice with 100 ml water / methanol <1: 1 ) mixture: The organic layer is dried / magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with 80:25 methylene chloride / methanol and methylene chloride.

..., //. chloride / methane] 25/25% / ammonia 80: 25: 5 / The product-containing fractions are combined, evaporated to dryness and the product crystallized from acetone.

Vacuum drying over P ₂ O ₅ /

·

Yield: 4 * 95 g (44%) of hexadecyl- (quinuclidine-3 ii) phosphate, i, '7 - /' - ' _c

Dissolve 4.95 g (11.5 mmol) of hexadecyl * (quinuclide-35 → 1) phosphate in 30 ml of methanol containing

13.7 g (69 mmol) of potassium carbonate and 8.5 ml of Water #. and / or vigorously mixed with 3.3 ml (35 mmol) of dimethyl sulphate solution / 5 ml of methanol. Ma is rented for 14 hours- ^ / -. / IkaKberio.-.- /// -, - / fcéa ^ eratur, //: /../) ..-, not filtered

10. / inorganic salts, / / / dry evaporated.

The residue - ^ - is solubilized.// • imbibition //) ^: chloride *. / I / $ iltruo'j: aaaa - / and 7 is chromatographed on silica gel / eluent. methylene ..:.-....) /// cdiMri'do / methanclc / 25% /// - ^ ammonia -) //// 70: 30-: 5 '-...' / mixture:. '..// ^; 7 7 ^ - ... 7 / '' Product- '· - Containing // Fractions / Flasks // together, dry evaporated ./and product' ^ .crystallized - // from: .. acetone. J'oviiiama: / vacuum./op//.P^0 ₅ ./ '·. * ' _? '- ..7

Yield :: - · / z, '7 / g' .. 149%) .. /:.7 '' / '.'/-'Elementary-./analysis;.// ./--. CHH <-. Excluded:, / .---. 60.9 ^ - / - 7 -.-.- ^ - ^ 1.0 -,. ^ 8%. ---.-.--) 2 , 96% '..). Found :. .), 61, .36%. /.- _; -./11,04%- <.3,29 -61%, ^46% ./11,22%7- -.-) '7' 3.29%

Thin! Layer Chromatography;

(chloroform / methanol / 25% ammonia .25... '- 70:40:10)' '. · /. W "0, 4 4

2l7pavy2dys7

Octadecyl- (1-methylquinucl idlnio-3 - ii) phosphate

C _2e H ₅₂ NO ₄ P (473, 68) .2 H ₂ 0

- '27

Obtained according to the procedure described in Example 5 from 18.2 g (67.5 'mmol) octadecanol, 7.0 ml (75 mmol)'. Phosphorus oxychloride, 18-20 ml pyridine and 28.3 g (90 mmol).

3-Hydroxy-1-methylquinuclide tosylate. The product is purified by dissolution in 96% ethanol and treatment with ion exchanger (amberlite ffl 3).

Yield: 18.4 g (57%)

Elemental Analysis: C H N 'Calculated: 61.27% .... 11.07% 2.75%

Found: 61.27% 10.91% 2.45% '/ 61.95% 11.23%. 2.51%

Thin layer chromatogram:

{.chloroform / methanol / 1M sodium acetate. 25% ammonia 70:40:10)

R _f = 0.37. ¹ .. '+ .-. .. _: (l-butanol / 'iitb' acid. / water 'AOflOilO). ...

. . . R _f . = 0.13 '' ° 24-Example ·

Hexadecyl- (1,1-di | iffititropanio-4-lI) phosphate </ Λ. Obtained according to the procedure of Example 5 from 12.1 g of 25 (50 mmol) hexadecanol / 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 40 ml of pyridine and 21.3 g (65 mmol).

4-hydroxy-1,1-dimethyltropicane tosylate. The product is purified by dissolving in 96% ethanol and treating with ion exchanger (amberlite MB 3). Recrystallization from acetone.

R '...,'. '.

Yield: 11.3 g (49%)

Re-analysis: C K N

Calculated: 62.86% 10.97% 2.93¾

LT3113.B

Found: 62.45% 11.52% 2.82%

62.58% 11.52% 2.75%

Thin-layer chromogram:

(chioroform / methanol / 1M sodium acetate 5 25% ammonia 70:40:10}

Z //;'.,/ '. Rf = 0.28 77 / -7725 Example

Octadecyl- (1,1-άίιΚ6ΐί1ΐΓοραηίο-4-11} Phosphate

C ₂₇ H ₅₄ NO ₄ P (487,708)

Obtained according to the procedure described in Example 5 (13.5 g of 15 (50 mmol) octadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 20 ml of pyridine and 21.3 g (65 mmol)).

4-hydroxy-1,1-dimethyltropanyl tosylate. .. The product is purified by dissolving in 96% ethanol and treatment with ion exchanger (amberlite MB 3) »

7 /;

Yield: 10.7 g (44%)

E1emental Analysis: Excluded: 77C <., V / 66, 49% H 11.16% N 2.87% . '/ </ Found: 65.72% 7 11.48% 2.64% 66.27% 7 11.78% 2.65%

Thin layer chromatography:

(chloroform / methanol / 1M sodium acetate ~ 25% in ammonia 70:40; 10). R _f = 0.22.

Claims (17)

1.Fosf © lipids of general formula I (CH.) E-X-A-F-O- (CHj K-CH £ U \ t / H / \ a ⁴ wherein R is a straight or branched chain alkyl moiety / containing 10 to 24 carbon atoms, which may also be of the one to three double "or 15 triple connectors; , R _X and R ₂ independently of one another may be hydrogen or straight or branched cyclic saturated or unsaturated alkyl radicals having from T 20 to 6 carbon atoms which may contain C 1 -, OH - or MH ₂ - groups. , or two of these residues may be combined ⁰ into. ring; A is a single bond or groups of the formula: -CH.-GH-Gf nu iii) {IV -S-iGHpg-O (III), • (V), -GH-GH-GH.k-O1. \ * · (VI) wherein the groups (ii) to (VI) are so oriented 35 that oxygen is attached to the phosphorus atom of compounds (I) and X is oxygen or. sulfur atoms or HH when A is a single bond or represents a single oxygen or sulfur atom if A is a group of (II) to (IV); / + .-. ·· + 5 /. * ': y is 0' or an integer between .1. and 3; m and n are independent of each other + and are 0 or integers with values m ~ n = 2 through 8. c Compounds according to claim 1, characterized in that boiler K is an oxygen atom. , 7 /.----++ Compounds according to claim 1 or 2, characterized in that A is a single bond. . ¹⁵ '+''+7 + -' / 7- ^: · '// -. + </ F. Compounds according to claims 1-3, characterized in that R p and R ₂ may be methyl groups. / 5. Octo-de-ethyl (1,1-dimethyl-piperidin-4-yl) -phosphate, ok2O-tadecyl- (1,1-dimethyl-hexahydro-azepin-4-yl) -phosphate. Process for the preparation of compounds according to claims 1-5, characterized in that the compounds of the general formula 25; '' +. - \ 7 + ·. RXAH 7.7 (VII), wherein R, X, and A ^: are .-. Such as nuig & yU in Claim # # act f © s £ © r © © k§i © htaidu, are- · suitable for auxiliary bige, with or without solvent. solvent ©, from p © t © works 307 compounds of the general formula + BO-CCH ^ -CH «n v Z N '++ (VIII) wherein R _x and R ₂ , y, m and n are as defined in claim 1, and Y- is a halide, mesylate or tosylate. converts to compounds of formula (I), and thus ♦ compounds of general formula / ¾ -CH ' ^X u_ _s l \ / (ix). '10 / in which R _x , y,. -m and n are as given '! may be converted, if appropriate, into compounds of formula (I) wherein R _x and / or R ₂ is hydrogen; .. acts with alkylating agents R ₂ -X, wherein R ₂ has the meanings given in claim 1, and Y represents chlorine, bromine, iodine, tosyl or mesyl groups using known procedures. .7. A process for the purification of the compounds of the formula I, characterized in that the solution of the compounds of the formula I, obtained in known manner or as described in claim 6, is treated in a mixed solvent in an organic solvent. ionite, or first acidic followed by .basic 'tip © ionite, or. at the same time both acidic and basic Type 25 ion exchangers. Pharmaceutical composition, characterized in that as. the active substance is contained in one or more of the compounds mentioned in claims 1 to 5 or in them 30 pharmaceutically acceptable salts, which may also contain pharmaceutically acceptable carriers, excipients, excipients and solvents, and may be present in an amount of from 50 mg to 250 mg. ; 35 Pharmaceutical composition according to claim 8, characterized in that it contains as an active ingredient. octadecyl- (1,1-dimethylpiperidin-4-yl) phosphate, octa-decyl- (1,1-dimethylperhydroazepin-4-yl) phosphate ·, erucyl- (1,1-dimethylpiperidin-4-yl) phosphate, erucyl- (1,1-dimethyl-ylperhydroazepine-4-yl) phosphate, containing 50 to 250 mg of active ingredient. ' 5. -7 'A 7.' ž 'TO. Pharmaceutical composition according to claim 8, characterized in that it contains octadecyl- (1,1-dimethylpiperidin-4-yl) phosphate as an active ingredient in an amount of 50 mg to 250 10 'mg ·. Use of a pharmaceutical composition according to claim 8 or 9 for combating cancerous tumors. 15th Use of a pharmaceutical composition according to claim 8 or 9 for combating inflammatory or fungal diseases, in particular leishmaniasis. Pharmaceutical compositions according to claim 8 or 9 20 for use in the treatment of autoimmune diseases, particularly multiple sclerosis. Use of a pharmaceutical composition according to claim 8 or 9 for the treatment of skin diseases, in particular psoriasis 25 cases. .7 Use of a pharmaceutical composition according to claim 8 or 9 for the treatment of bone marrow lesions by treatment with cytostatics and other agents acting 30 bone marrow injuries. \ Use of a pharmaceutical composition according to claim 8 or 9 in the therapy of viral diseases including AIDS. v. · · '' ³⁵ 17. A process for the preparation of an antitumor drug, which comprises preparing a composition comprising as active ingredient one or more of the compounds as claimed in claims 1-5, which may contain pharmaceutically acceptable carrier excipients, J fillers and solvents.