FI111262B - Process for the preparation of therapeutically useful phospholipid derivatives - Google Patents

Abstract

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

Description

111262 ./

A process for the preparation of therapeutically useful phospholipid derivatives EP-A-108 565 relates to compounds of the general formula 0R2. Il ♦ / 3

R 1 (O) n P-OCH, CH 0 N-R 3 10 10 "R 4 and pharmaceutically acceptable salts thereof, wherein R 1 is an aliphatic hydrocarbon residue of 8 to 30 C atoms, R 2, R 3 and R 4 are the same or different and 15 are hydrogen or lower alkyl residues, or wherein NR2R3R4 represents a cyclic ammonium group and n has a value of 0 or 1. These compounds are reported to have anti-tumor activity and antifungal activity.

The invention relates to a process for the preparation of alkyl or alkene-20 phosphates having a choline moiety as part of a heterocyclic ring.

Surprisingly, the compounds of the invention have better antitumor activity than the open-chain derivatives disclosed in EP-A-108 565. The invention also relates to methods for purifying new compounds.

The first step of the process is the reaction of phosphorus oxychloride with a long chain alcohol in halogenated or aromatic hydrocarbons, saturated cyclic ethers or acyclic ethers.

The first step of Method A is the reaction of phosphorus oxychloride with a long chain alcohol in halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 carbon atoms, halogen (especially chlorine), or in mixtures of the abovementioned solvents, or a solvent, optionally in the presence of a common basic substance.

Suitable halogenated hydrocarbons include, for example, hydrocarbons having from 1 to 6 carbon atoms, wherein one or more or all of the hydrogen atoms are replaced by chlorine atoms. For example, methylene chloride, chloroform, ethylene chloride, chlorobenzene, dichlorobenzene can be used. In the case of halogen-substituted aromatic hydrocarbons, they are preferably substituted with one or two halogen atoms.

As saturated cyclic ethers, for example, ethers having a ring size of 5 to 6 atoms with carbon atoms and one or two oxygen atoms may be used. Examples of these are tetrahydrofuran, dioxane.

Acyclic ethers have 2 to 8 carbon atoms and they are liquid. Examples include diethyl ether, diisobutyl ether, methyl tert-butyl ether, diisopropyl ether.

Suitable hydrocarbons are straight or branched hydrocarbons having from 5 to 10 25 carbon atoms and which are liquid.

1 'Examples include pentane, hexane, heptane, cyclohexane.

Suitable aromatic hydrocarbons are, for example, benzene and alkyl-substituted benzenes, wherein the alkyl substituents have from 1 to 5 carbon atoms.

As basic substances and for the reaction of phosphorus oxychloride with a long chain alcohol as well as for subsequent reaction, amines of formula NR 1 R 2 R 3 wherein R 1, R 2 and R 3 are the same or different and denote hydrogen or C 1-6 are suitable. alkyl, or also aromatic amines such as pyridine, picoline, quinoline. In the reaction to the phosphoric acid ester, the basic substance required for this can be added simultaneously or also before the amino alcohol 5 or the ammonium alcohol salt.

In any case, a solvent is required for this reaction; that is, if the first reaction step takes place without a particular solvent, one must now be added. The molar ratio of phosphorus oxychloride to long chain alcohol 10 is, for example, between 1.5: 1 and 0.8: 1.

For example, an amino alcohol or an ammonium alcohol salt is used in excess with respect to the long chain alcohol (about 1.1 to 1.5 moles excess).

If the reaction of phosphorus oxychloride with a long chain alcohol occurs in the presence of a basic substance, the amount of basic substance is, for example, 1-3 moles per mole of POCl3. For the next reaction, the amount of basic substance used as the phosphoric acid ester is, for example, 1-5 moles per mole.

The reaction temperature of the reaction between phosphorus oxychloride and the long chain alcohol is between -30 ° C and +30 ° C, preferably between -15 ° C and +5 ° C, in particular between -10 ° C and -5 ° C.

The reaction time for this reaction is, for example, 0.5 to 5 to 25 hours, preferably 1 to 3 hours, especially 1.5 to 2 hours. If the reaction occurs in the presence of an alkaline agent, it is usually rapid (about 30 minutes).

The amino alcohol or the ammonium alcohol salt is then added portionwise or at once.

Salts of ammonium alcohol include salts with inorganic acids (such as sulfuric acid, hydrochloric acid), further salts with organic acids such as acetic acid, para-toluenesulfonic acid and the like. This reaction step 35 takes place in an inert solvent. As solvents, the same solvents as used in the reaction of phosphorus oxychloride with a long chain alcohol are contemplated if this reaction occurs in a solvent.

The basic material is then added by dropwise addition of one of the solvents mentioned or the solvent. Preferred solvents for the basic substance are, for example: halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having from 5 to 10 carbon atoms, liquid aromatic hydrocarbons or mixtures of the abovementioned solvents.

These are the same solvents that can be used in the reaction of phosphorus oxychloride with a long chain alcohol. The temperature increases to 15 by addition of the alkaline agent. It is ensured that the temperature is maintained in the range of 0 to 40 ° C, preferably in the range of 10 to 30 ° C, in particular in the range of 15 to 20 ° C.

The reaction mixture is then stirred for an additional 5 ° C to 30 ° C, preferably 15 to 25 ° C (e.g. 1 to 20 to 40 hours, preferably 3 to 15 hours).

The reaction batch is hydrolyzed by the addition of water, whereby the temperature must be maintained between 10 and 30 ° C, preferably between 15 and 30 ° C, in particular between 15 and 20 ° C.

The above hydrolysis fluids may also contain basic substances. Carbonates and hydrogen carbonates of the alkali and alkaline earth metals are suitable as such basic substances.

Thereafter, for a further period of 0.5 to 4 hours, preferably 1 to 3 hours, in particular 1.5 to 2.5 hours at 10 to 30 ° C, preferably 15 to 25 ° C, in particular 18 to 20 minutes, to complete the hydrolysis. At 22 ° C.

The reaction solution is then washed with a mixture of water and alcohols (preferably aliphatic saturated alcohols having from 1 to 4 carbon atoms), which may possibly contain more basic material. Water: The mixture ratio of alcohol to alcohol may be, for example, from 5 to 0.5, preferably from 1 to 3 (v / v).

The alkaline substances for the washing liquid include, for example, carbonates and bicarbonates of the alkali and alkaline-earth metals and ammonia (for example, aqueous ammonia). Particularly preferred is about 30% aqueous sodium carbonate solution.

Thereafter, washing of the reaction solution may optionally be performed with an acidic solution. Acid washing is preferred to remove any unreacted basic moieties still present in the reaction solution, especially when using methylene chloride as solvent.

The washing solution is a mixture of water and alcohols. Mixtures of aliphatic saturated alcohols having from 1 to 4 carbon atoms are optionally preferred, whereby an acidic substance may still be present. The water: alcohol to alcohol ratio of the mixture may be, for example, between 5 and 0.5, preferably between 1 and 3 (v / v).

As the acidic substance for the washing liquid, there are, for example, inorganic and organic acids, for example hydrochloric acid, sulfuric acid, tartaric acid or citric acid. A 10% aqueous hydrochloric acid solution is particularly preferred.

25 Then wash again with a mixture of water and alcohols. Preferred are mixtures of aliphatic saturated alcohols having from 1 to 4 carbon atoms, whereby a basic substance may still be present. The water: alcohol to alcohol ratio of the mixture may be, for example, from 5 to 0.5, preferably from 1 to 3.

The washed phases are then combined and dried in the usual manner, and then the solvent is removed (preferably under reduced pressure, for example 5-100 35 mbar), possibly after the addition of 6111262 150-1000 ml, preferably 300-700 ml, especially 450-550 ml. ml of aliphatic alcohol (per mole of dry product). As alcohols, preference is given to saturated aliphatic alcohols having from 1 to 5 carbon atoms in the carbon chain. Particularly preferred alcohol is n-butanol, iso-propanol. The purpose of this alcohol treatment is to completely remove residual water and prevent foaming.

Further purification of the product may be accomplished, for example, by dissolving the crude product hot in ethanol, filtering the residue, and treating with a mixed ion exchanger such as Amberlite MB3 in ethanol solution. The blend-based ion exchanger gun-15 can also be used simultaneously or sequentially with any conventional commercial acidic and basic ion exchanger.

The solution is then recrystallized from ketones, such as acetone or methyl ethyl ketone, in some cases sufficient digestion with the solvents mentioned above. Purification of the products by column chromatography or flash chromatography on silica gel may be appropriate. Mixtures of, for example, chloroform, methylene chloride, methanol and 25% ammonia solution are used as solvents.

Process variant B is the subsequent alkylation of the products obtained by Method A using amino alcohols. As alkylating agents, for example, p-toluenesulfonic acid methyl esters or dimethyl sulfate can be used. As solvents, the aforementioned solvents are in question.

For example, alkali metal carbonates are used as basic substances. The reaction takes place at elevated temperature, for example at the boiling point of the solvents.

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examples

Example 1

Labeling method (IUPAC nomenclature) 4 - (((octadecyloxy) hydroxyphosphenyl) oxy) -1,1-5 dimethylpiperidinium hydroxide, inner salt

Short notation:

Octadecyl (1,1-dimethylpiperidinio-4-yl) phosphate

C25H52N04P (461.66) ♦ 1/2 H20 10 Preparation A

10.3 ml (0.11 mol) of phosphorus oxychloride are first added to 100 of any chloroform and cooled to 5-10 ° C. 27.0 (0.10 mol) of 1-octadecanol dissolved in 100 of any chloroform and 35 ml of pyridine are added dropwise over 30 minutes. After stirring for 30 minutes at 5-10 ° C, 39.1 g (0.13 mol) of 4-hydroxy-1,1-dimethylpiperidinium tosylate are added in one portion. After addition of 40 ml of pyridine and 30 ml of DMF, the mixture is stirred for 24 hours at room temperature. The mixture is then hydrolyzed with 15 ml of water, then stirred for 30 minutes and the organic phase is washed with 200 ml of water / methanol (Iti), 3% Na 2 CO 3 / methanol (Iti) and finally with water / methanol (Iti). The organic phase is evaporated to dryness, the residue is dissolved in 300 of any hot ethanol and, after cooling, filtered. The filtrate is mixed with 80 g tn ion exchanger Amberlite MB3, filtered and evaporated to dryness. The residue is recrystallized from 300 ml of methyl ethyl ketone, filtered off with suction and dried under reduced pressure over P 2 O 5.

Yields 4.71 g (10%)

Elemental Analysis t Calculated C 65.26% H 11.63% N 2.62% Found: 64.38% 11.61% 2.73% 35 65.04% 11.60% 2.78% 8 111262

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10), Rf = 0.17; (1-butanol / glacial acetic acid / water 40:10:10), Rf = 0.12. Melting point: 270-271 ° C (with decomposition).

5 Manufacturing Option B

20.1 ml (0.22 mol) of phosphorus oxychloride are first added to 100 ml of methylene chloride, cooled to 5 to 10 ° C and, with stirring, a solution of 54.1 g (0.20 mol) of octadecanol in 400 ml is added: of methylene chloride and 70.5 ml of pyridine. After stirring for one hour, 29.9 g (0.26 mol) of 4-hydroxy-1-methylpiperidine in 80 ml of pyridine are added dropwise. After stirring for 3 hours at 10 ° C, the mixture is hydrolysed with ice with 30 ml of water and then stirred for 1 hour. The organic phase is washed with 200 ml portions of water / methanol (1: 1), 3% hydrochloric acid / methanol (1: 1) and water / methanol (1: 1). The organic phase dried over Na 2 SO 4 is concentrated to cloudiness and 1 liter of methyl ethyl ketone is added. The crystallization is recrystallized from 1 liter of methyl ethyl ketone, filtered off with suction and dried under reduced pressure over P 2 O 5.

Yield: 54.1 g (60%) of octadecyl (1-methylpiperidino-4-yl) phosphate.

98.1 g (0.22 mol) of octadecyl (1-methylpiperidinio-4-yl) phosphate are suspended in 500 ml of abs. ethanol and bring to the boil. Under reflux, a total of 71.8 g (0.39 mol) of p-toluenesulfonic acid methyl ester and 26.5 g (0.19 mol) of potassium carbonate are added in eight portions over 2 hours. After the addition is complete, reflux for an additional hour. After cooling, it is filtered, the filtrate is evaporated to half its volume and 150 g of the Amberlite MB3 wet ion exchanger are added to the solution.

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After stirring for 2 hours, the diatomaceous earth is filtered through charcoal, the filtrate evaporated to dryness and crystallized with acetone. The crystal cake is recrystallized from methyl ethyl ketone and dried over P 2 O 5 under reduced pressure.

Yield: 46.1 g (46%) of octadecyl (1,1-dimethylpiperidin-4-yl) phosphate.

Elemental Analysis: Calculated: C 65.26% H 11.63% N 2.62% 10 Found: 65.18% 11.62% 2.68% 65.07% 11.71% 2.70%

Melting point: 271-272 ° C (with decomposition).

Example 2

Hexadecylpiperidinio-4-yl-phosphate C21H44NO4P (405,558) 7.1 ml (77 mmol) of phosphorus oxychloride is dissolved in 50 ml of dry tetrahydrofuran and after cooling to 5-10 ° C, a solution of 17 g (70 mmol) of hexadecanol is added dropwise and 48 ml of 20 triethylamine in 150 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 30 minutes in an ice bath and then allowed to return to room temperature. 10.1 g (100 mmol) of 4-piperidinol are dissolved in 100 ml of tetrahydrofuran, mixed with 17 ml of triethylamine and added dropwise to the reaction mixture under stirring so that the temperature does not rise above 40 ° C. After the addition is complete, reflux for one hour. The triethylammonium chloride is filtered off from the still hot solution and, after cooling, poured into an ice / 2 mol mixture. hydrochloric acid. Upon cooling in a refrigerator, the product obtained is dissolved in methylene chloride, dried over MgSO 4 and, after evaporation to dryness, is chromatographed on silica gel with methylene chloride / methanol / 25% ammonia (70: 30: 5). The product-containing fractions are combined and evaporated to dryness. After recrystallization from methanol, it is dried under reduced pressure over P 2 O 5.

Yield: 10.0 g (35%)

Elemental Analysis: Calculated: C 62.19% H 10.94% N 3.45% Found: 65.15% 11.14% 3.54% 62.41% 11.19% 3.34%

Thin Chromatography: (Chloroform / Rethanol / 25% Ammonia 70:20:10) Rf = 0.42; (1-butanol / glacial acetic acid / water 10 40:10:10) Rf = 0.33.

Example 3

Hexadecyl (1,1-dimethyl-piperidin-4-yl) -phosphate C25H52NO4P (461.64) · H2O 15 Dissolve 5.7 g (14 mmol) of hexadecyl-piperidin-4-yl phosphate in 100 ml of methanol and mix 11.6 g (84 mmol) of potassium carbonate. With vigorous stirring, 4.0 mL (42 mmol) of dimethyl sulfate is added dropwise over 30 minutes. The mixture is then stirred for 4 hours at 40 ° C, after cooling, filtered and evaporated to dryness. The residue is digested with acetone and, after filtration, dissolved in 100 ml of 96% ethanol. Add 15 g Amberlite MB 3 ion exchanger and stir for 3 hours. After filtration, the crystals are evaporated to dryness and recrystallized twice from methyl ethyl ketone. Drying on P205 under reduced pressure. Yield: 3.70 g (61%)

Elemental Analysis: Calculated: C 61.17% H 11.16% N 3.10% 30 Found: 60.83% 11.14% 2.99% 60.92% 11.26% 3.00%

TLC: (chloroform / methanol / 25% ammonia 70:20:10) Rf = 0.28; (1-Butanol / glacial acetic acid / water 40:10:10) Rf = 0.13 35 Melting point: 230 ° C (with decomposition).

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Example 4

Erucyl (1,1-dimethylpiperidinio-4-yl) phosphate C29H58NO4P (515,765) · H2O 10.3 ml (0.11 mol) of phosphorus oxychloride are first added to 50 ml of chloroform and added dropwise at 5 to 10 ° C. A solution of 32.5 g (0.10 mol) of erucyl alcohol and 32 ml of pyridine in 100 ml of chloroform. After stirring for half an hour, 39.1 g (0.13 mol) of 4-hydroxy-1,1-dimethylpiperidine-10-nium tosylate are added in one portion. After adding 40 ml of pyridine dropwise, the mixture is allowed to return to room temperature and stirred for 3 hours. It is then hydrolysed with 15 ml of water, then stirred for half an hour and washed with 100 ml portions of water / methanol (1: 1), 3% sodium carbonate / methanol (1: 1), 3%: citric acid / methanol (1: 1) and water / methanol (1: 1). After evaporation of the organic phase, the residue obtained is digested with acetone and then dissolved in 150 ml of 96% ethanol. This solution is stirred for 3 hours with 20 g of the Amberlite MB 3 ion exchanger and filtered with diatomaceous earth. After evaporation to dryness, silica gel chromatography is performed with chloroform / methanol / 25% ammonia 70:40:10. The product-containing fractions are combined and evaporated to dryness under reduced pressure.

Yield: 4.4 g (9%)

Elemental Analysis: Calculated: C 65.26% H 11.63% N 2.62% Found: 64.38% 11.61% 2.73% 30 65.04% 11.80% 2.78%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia (70:20:10) Rf = 0.30.

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Example 5

Hexadecyl (1,1-dimethyl-piperidin-3-yl) -phosphate C23H48NO4P (433.616) · H2O. 10.3 ml (0.11 mol) of phosphorus oxychloride are first added to 50 ml of chloroform and cooled to 0-10 ° C. 24.2 g (0.10 mol) of n-hexadecanol are dissolved in 100 ml of chloroform and 32 ml of pyridine-10 are dropped into the phosphorus oxychloride solution under ice-cooling for one hour. After stirring for half an hour, 39.2 g (0.13 mol) of 3-hydroxy-1,1-dimethylpiperidinium tosylate are added in one portion and 40 ml of pyridine is added dropwise at room temperature over 15 minutes. After stirring for 16 hours at room temperature, hydrolyze with 15 ml of water, stir for half an hour and wash with 100 ml portions of water / methanol (1: 1), 3% sodium carbonate solution / methanol (1: 1), 3% citric acid / methanol (1: 1) and water / methanol (1: 1). After drying over sodium sulfate, the organic phase is evaporated to dryness. The residue is dissolved in 150 ml of 96% ethanol, filtered and the filtrate is mixed with the Amberlite MB 3 ion exchanger. After filtering off the ion exchanger, evaporate to dryness, crystallize the residue with acetone and, after filtration, dry over P 2 O 5 under reduced pressure. Yield: 13.5 g (31%)

Elemental Analysis: Calculated: C 61.17% H 11.16% N 3.10% Found: 60.78% 11.41% 2.87% 60.85% 11.31% 2.86% 30 Ohm Chromatogram: (Chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.37.

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Example 6

Octadecyl (1,1-dimethylpiperidinio-3-yl) phosphate C25H52NO4P (461,670) · 1/2 H2 O Preparation according to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g (0). , 10 mol) octadecanol, 32 + 40 ml pyridine and 39.2 g (0.13 mol) 3-hydroxy-1,1-dimethylpiperidinium tosylate.

Yield: 18.7 g (40%)

Elemental Analysis: Calculated: C 63.80% H 11.35% N 2.98% Found: 63.38% 11.72% 2.61% 63.61% 11.98% 2.61% 15 / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.35.

Example 7

Hexadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate 20 C 24 H 50 NO 4 P (447,643) · 1/2 H 2 O

Preparation according to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 24.2 g (0.10 mol) of hexadecanol, 32 + 40 ml of pyridine and 41.0 g of , 13 mol) 2-hydroxymethyl-1,1-dimethylpiperidiniumto-25-ylate.

Yield: 22.9 g (51%)

Elemental Analysis: Calculated: C 63.13% H 11.26% N 3.07% Found: 63.69% 11.73% 3.04% 30 63.75% 11.71% 3.04%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.47.

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Example 8

Octadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C26H54NO4P (475,697) · 1/2 H2 O Preparation according to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g. (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol) of 2-hydroxymethyl-1,1-dimethylpiperidinium tosylate.

Yield: 23.9 g (50%)

Elemental Analysis: Calculated: C 64.43% H 11.44% N 2.89% Obtained: 64.50% 11.61% 2.67% 64.11% 11.49% 2.77% 15 Ohm Chromatogram: (Chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.47. Example 9

Hexadecyl (1,1-dimethylpiperidinio-3-yl) methylphosphonate 20 C24H50NO4P (447,643) · 1H2O

Preparation according to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 24.2 g (0.10 mol) of hexadecanol, 32 + 40 ml of pyridine and 41.0 g of , 13 mol) 3-hydroxymethyl-1,1-dimethylpiperidiniumto-25-ylate.

Yield: 17.2 g (39%)

Elemental Analysis: Calculated: C 61.91% H 11.26% N 3.01% Found: 62.32% 12.21% 2.86% 30 61.79% 11.96% 2.98%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.29.

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Example 10

Octadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C26H54NO4P (475, 697). H 2 O Preparation according to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 41.0 g of , 13 mol) 3-hydroxymethyl-1,1-dimethylpiperidinium tosylate.

Yield: 16.7 g (35%)

Elemental Analysis: Calculated: C 63.25% H 11.43% N 2.84% Found: 62.98% 12.21% 2.76% 63.67% 12.47% 2.80% 15 / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.30. Example 11

Tetradecyl (1,1-dimethylhexahydroazepinio-4-yl) phosphate C22H46NO4P (419.54). H20

Preparation according to Example 5 from 9.6 g (45 mmol) of tetradecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of hydroxy- 1,1-dimetyyliheksahydroatsepiniumtosylaattia.

Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:40:10).

Yield: 2.70 g (15%)

Elemental Analysis: Calculated: C 60.40% H 11.05% N 3.20% 30 Found: 60.47% 11.29% 3.63% 60.78% 11.52% 3.68%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.30; (1-butanol / glacial acetic acid / water 40:10:10) Rf = 0.08.

35 16 111262

Example 12

Hexadecyl (1,1-dimethylhexahydroazepinio-4-yl) phosphate C24H48NO4P (445.62) 5 Preparation according to Example 5 from 10.8 g (45 mmol) of hexadecanol, 4.6 ml (50 ramol) of phosphorus oxychloride, 10 ml. + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. Purification by flash chromatography on silica gel with 10% methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 5.0 g (25%)

Elemental Analysis: Calculated: C 64.69% H 10.86% N 3.14% 15 Found: 63.90% 11.54% 3.22% 64.08% 11.59% 3.24%

Thin chromatogram: (chloroform / methanol / 25% ammonia 80: 25: 5) Rf = 0.10; (1-butanol / glacial acetic acid / water 40:10:10)

Rf = 0.10 Melting point:> 250 ° C (with decomposition).

Example 13

Octadecyl (1,1-dimethylhexahydroazepinio-ethyl) phosphate C26H54NO4P (475,695). Preparation according to Example 5 from 12.1 g (45 mmol) of octadecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. Purification by flash chromatography on silica gel; With this mixture of methylene chloride / methanol / 25% ammonia 70:30:10.

// Yield: 5.5 g (26%)

Elemental Analysis: Calculated: C 64.43% H 11.44% N 2.89% 35 Found: 64.54% 11.64% 2.82% 64.66% 11.58% 2.64% 17 111262

Thin chromatogram: (chloroform / methanol / 1 mole sodium acetate in 25% ammonia 70:40:10) Rf = 0.22 Melting point:> 250 ° C (with decomposition).

Example 14 5 cis -Δ 9 -octadecenyl- (1,1-dimethylhexahydroazepinio-4-yl) phosphate C26H52NO4P (473, 679). H20

Preparation according to Example 5 from 12.1 g (45 mmol) of cis-? 9-octadecenol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g ( 67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydrotazepinium tosylate. Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonium acetate 70:30:10.

Yield: 4.5 g (21%)

Elemental Analysis: Calculated: C 63.51% H 11.07% N 2.85% Obtained: 64.05% 11.21% 3.10% 63.80% 11.06% 3.06% 20 Bar chart: (Chloroform (methanol / 25% ammonia 70:40:10) Rf = 0.28; (1-Butanol / glacial acetic acid / water 40:10:10) Rf = 0.10.

Example 5

Eicosyl- (1,1-dimethylhexahydroazepinio-4-25-yl) phosphate C28H58NO4P (503,754). H 2 O Preparation according to Example 5 from 13.4 g (45 mmol) of eicosanol, 4.6 ml (50 mmol) of phosphorus oxy. chloride, 10 + 20 ml of pyridine and 21.3 g of 30 (67.5 mmol) 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 5.7 g (25%) 18111262

Elemental Analysis: Calculated: C 64.46% H 11.59% N 2.68% Obtained: 53.51% 11.48% 2.95% 64.00% 11.79% 2.91% 5 Ohm Chromatogram: (Chloroform / methanol / 25% Ammonia 70:40:10) Rf = 0.12.

Example 16

Erucyl (1,1-dimethylhexahydroazepinio-4-yl) phosphate 10 C 30 H 60 NO 4 P (529, 789). H20

Preparation according to Example 5 from 16.2 g (50 mmol) of erucyl alcohol, 5.1 ml (55 mmol) of phosphorus oxychloride, 10 + 30 ml of pyridine and 20.5 g (65 mmol) of 4 hydroxy-1,1-dimethylhexahydroazepiniumto-15 cylate. Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 4.1 g (15%)

Elemental Analysis: Calculated: C 65.78% H 11.41% N 2.56% Found: 65.76% 12.01% 2.97% 65.82% 11.63% 2.96%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.30.

Example 17

Octadecyl (1,1-dimethylpyrrolidin-3-yl) phosphate C24H50NO4P (447,643) - 1/2 H2 O

Preparation according to Example 5 from 3.25 g of 30 (12 mmol) octadecanol, 1.21 ml (13 mmol) of phosphorus oxychloride, 3.7 + 4.8 ml of pyridine and 4.31 g ( 15 mmol) of hydroxy-1,1-dimethylpyrrolidinium tosylate. Purification of the crude product by dissolving in 96% ethanol and treating the ion exchanger with Amberlite MB 3. 35 Yield: 1.31 g (25%) 19111262

Elemental Analysis: Calculated: C 63.13% H 11.26% N 3.07% Obtained: 62.99% 11.28% 2.80% 62.74% 11.27% 2.89% 5 Ochromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.25 Example 18

Hexadecyl 2- (1,1-dimethylpyrrolidin-2-yl) -ethylphosphate 10 C 24 H 50 NO 4 P (447,643) · H 2 O

Preparation according to Example 5 from 9.21 g (38 mmol) of hexadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.8 g (50 mmol) of 2 (2-hydroxyethyl) -1,1-dimethylpyrrolidinium tosylate. Purification by dissolving in 96% ethanol and treating the ion exchanger with Amberlite MB 3.

Yield: 6.0 g (35%)

Elemental Analysis: Calculated: C 61.91% H 11.26% N 3.01% Found: 61.82% 11.69% 3.21% 61.93% 11.86% 3.28%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.38.

25 Example 19

Octadecyl 2- (1,1-dimethylpyrrolidin-2-yl) -ethylphosphate C26H54NO4P (475,697) · 1/2 H2O

Preparation according to Example 5 from 10.3 g of 30 (38 mmol) octadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.8 g (50 mmol) of 2 - (2-hydroxyethyl) -l, 1-dimethyl-pyrrolidin-niumtosylaattia. Purification by dissolving in 96% ethanol and treating with ion exchanger Amberlite MB 3 35.

20 111262

Yield: 7.8 g (43%)

Elemental Analysis: Calculated: C 64.43% H 11.44% N 2.89% Found: 64.69% 11.77% 2.64% δ 64.84% 11.88% 2.69%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.35.

Example 20

Hexadecyl (1,1-dimethylpyrrolidin-2-yl) methyl-10-phosphate C23H48NO4p (433,616) · 1/2 H2O

Preparation according to Example 5 from 9.21 g (38 mmol) of hexadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.1 g of 15 (50 mmol) of 2-hydroxymethyl -1,1-dimethylpyrrolidinium tosylate. Purification by dissolving in 96% ethanol and treating the ion exchanger with Amberlite MB 3. Yield: 8.3 g (51%).

Elemental Analysis: Calculated: C 62.41% H 11.16% N 3.16% Found: 62.09% 11.48% 3.01% 62.25% 11.66% 3.09%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.33.

25 Example 21

Octadecyl (1,1-dimethylpyrrolidin-2-yl) methyl phosphate C25H52NO4P (461.67) · 1/2 H2O

Preparation according to Example 5 from 10.3 g of 30 (38 mmol) octadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.1 g (50 mmol) of 2 hydroxymethyl-l, 1-dimetyylipyrrolidiinium-tosylate. Purification by dissolving in 96% ethanol and treating the ion exchanger with Amberlite MB 3. 35 Yield: 9.0 g (52%) 21111262

Elemental Analysis: Calculated: C 63.80% H 11.35% N 2.98% Found: 63.13% 11.57% 2.84% 63.55% 11.66% 2.82% / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.35. Example 22

Hexadecyl (1-methylquinuclidinio-3-yl) phosphate 10 C24H48NO4P (445.64) ♦ 1.5 H2O 2.7 ml (30 mmol) of phosphorus oxychloride are dissolved in 25 ml of chloroform, cooled to 5-10 ° C for one hour. a solution of 6.4 g (26 mmol) of hexadecanol and 10 ml of pyridine in 50 ml of 15 chloroform is added dropwise. After stirring for half an hour at room temperature, a solution of 4.5 g (35 mmol) of 3-hydroxyquinuclidine and 5 ml of pyridine in 10 ml of chloroform is added. After stirring for 5 hours at room temperature, hydrolyze with 15 ml of water and then stir for half an hour. It is then washed twice with 100 ml portions of water / methanol (1: 1) and, after drying over magnesium sulphate, the organic phase is evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride / methanol 80:25 followed by 25% methylene chloride / methanol / 25% ammonia 80:25: 5. The product-containing fractions are combined, evaporated to dryness and crystallized by the addition of acetone. Drying on P205 under reduced pressure.

Yield: 4.95 g (44%) of hexadecyl (quinuclidin-3-yl) -30 phosphate.

Dissolve 4.95 g (11.5 mmol) of hexadecyl (quinuclidinio-3-yl) phosphate in 30 ml of methanol, add 13.7 g (69 mmol) of potassium carbonate, 8.5 ml of water, and dropwise add a solution of 3.3 mL of 35 (35 mmol) dimethyl sulfate in 5 mL of methanol. After stirring for 14 hours at room temperature, the inorganic salts are filtered off, the filtrate is evaporated to dryness and the residue is dissolved in methylene chloride. After filtration, it is chromatographed on silica gel with methylene chloride / methanol / 25% ammonia 70: 30: 5. The product-containing fractions are combined, evaporated to dryness and mixed with acetone for crystallization. Drying over P2C> 5 under reduced pressure.

Yield: 2.7 g (49%) Elemental analysis: Calculated: C 60.99% H 10.88% N 2.96% Found: 61.36% 11.04% 3.29% 61.46% 11, 22% 3.25%

Thin chromatogram: (chloroform / methanol / 25% ammonia 70:40:10) Rf = 0.44.

Example 23

Octadecyl (1-methylquinuclidinio-3-yl) phosphate C26H52NO4P (473, 68). Preparation according to Example 5 from 18.3 g (67.5 mmol) of octadecanol, 7.0 ml (75 mmol) of phosphorus oxychloride, 18 + 20 ml of pyridine and 28.3 g of 90 mmol) of 3-hydroxy-1-methylquinuclidine neurosylate. Purification by dissolving in 96% ethanol and treating with ion exchanger Amberlite MB 3.

Yield: 18.4 g (57%)

Elemental Analysis: Calculated: C 61.27% H 11.07% N 2.75% Found: 61.27% 10.91% 2.45% 30 61.95% 11.23% 2.51%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.37; (1-Butanol / glacial acetic acid / water 40:10:10) Rf = 0.13.

23 111262

Example 24

Hexadecyl (1,1-dimethyltropanio-4-yl) phosphate C25H50NO4P (459,654) 54 H2 O Preparation according to Example 5 from 12.1 g (50 mmol) of hexadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, + 40 ml of pyridine and 21.3 g (65 mmol) of 4-hydroxy-1,1-dimethyltropananosylate. Purification by dissolution in 96% ethanol, treatment with Amberlite MB 3 ion exchanger and recrystallization from acetone.

Yield: 11.3 g (49%)

Elemental Analysis: Calculated: C 62.86% H 10.97% N 2.93% 15 Found: 62.45% 11.52% 2.82% 62.58 £ 11.52% 2.75%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.28. Example 25 20-Octadecyl (1,1-dimethyltropanio-4-yl) phosphate C27H54NO4P (487,708)

Preparation according to Example 5 from 13.5 g (50 mmol) of octadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 20 ml of pyridine and 21.3 g of 25 (65 mmol) of 4-hydroxy -l, 1-dimetyylitropaaniumtosylaattia.

Purification by dissolving in 96% ethanol and treating the ion exchanger with Amberlite MB 3.

Yield: 10.7 g (44%)

Elemental Analysis: Calculated: C 66.49% H 11.16% N 2.87% 65.72% 11.48% 2.64% 66.27% 11.78% 2.65%

Thin chromatogram: (chloroform / methanol / 1 mol sodium acetate in 25% ammonia 70:40:10) Rf = 0.22.

Claims (6)

24 111262 A process for the preparation of therapeutically useful compounds of the general formula I: O-O-CH-CH- (CH 2) -R-X-A-P-O- (CH 2) y -CH. N. (I) 1 - (CH 2) n - \ R 2 O - wherein R represents a straight or branched alkyl radical of 10 to 24 carbon atoms and which may also have 1 to 3 double or triple bonds, R 1 and R 2 independently represent hydrogen. or each of a linear, branched, cyclic saturated or unsaturated alkyl radical having from 1 to 6 carbon atoms and which may also have a C1-, OH- or NH2-15 group, wherein two of these residues may also be bonded to a ring, A represents a single bond or a group of the formula -CH 2 -CH 2 -CH 2 -O- (II) -CH 2 -CH 2 -O- (III) -ch 2 -ch-o- (IV) -S- (CH 2) q -O- (V) ch3 -CH-CH-CHo-O-lH2CO (VI) wherein the groups (II) to (VI) are arranged such that the oxygen atom is bonded to the phosphorus atom of compound (I), and X is an oxygen or sulfur atom or NH when A is a single bond, or is an oxygen or sulfur atom when A is one of groups (II) to (IV); y is 0 or an integer from 1 to 3, 5 and n are independently 0 or an integer provided that m + n = 2 to 8, characterized in that the compound of the general formula RXAH (VII) 10 wherein R X and A have the above meanings, are reacted with phosphorus oxychloride in the presence or absence of a suitable auxiliary base in a solvent, and then allowed to react with 15 a) a compound of the general formula HO- (CH 2) y -CH 2 O 2 N 2 H 2) n // X ^ \ r2. wherein R 1 and R 2, y, m and n have the meanings mentioned above and y "represents a halide, mesylate, ·>, or tosylate, compounds of general formula I, or ) with compounds of the general formula H0- (CH2) y-Cl <^ - r1 (IX) wherein R1, y, m and n have the meanings given above, wherein the compounds of the general formula (I) the compounds wherein R 1 and / or R 2 are hydrogen are then reacted in a known manner with the alkylating agents R 2 -Y where R 2 has the meaning given above and Y is Cl, bromine, iodine, tosyl or mesyl. Process according to Claim 1, characterized in that X represents an oxygen atom. A process according to claim 1 or 2, characterized in that A represents a simple bond. Process according to claims 1-3, characterized in that R 1 and R 2 are in each case methyl groups. Process according to Claim 1, characterized in that the compound octadecyl (1,1-dimethylpiperidino-4-yl) phosphate or octadecyl (1,1-dimethylhexahydroazepinio-4-yl) phosphate is prepared. 6. A process for the purification of the compounds of the formula I, characterized in that a solution of the compounds of the formula I prepared by the known method or the method according to claim 1 is treated in an organic solvent with a mixed medium ion exchanger, or sequentially or simultaneously with an acidic or basic ion exchanger. 27 111262