SI9300365A - New alkenes and alkines phoshat derivates, process for their preparation and use thereof as medicine - Google Patents

Abstract

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

Description

European Patent Application 108 565 deals with compounds of general formula

R ¹ (O) _n - P - OCH2CH2N - R ³ I \ 4 and their pharmaceutically useful salts, wherein R 1 is an aliphatic hydrocarbon residue having 8 to 30 C atoms, the residues R2, R 3 and R 4 being the same or different lower alkyl residues or hydrogen, or wherein the NR 2 R 3 R 4 group is a cyclic ammonia group and n has a value of 0 or 1. For these compounds,

-2These anti-tumor and fungal inhibitory effects.

The invention relates to alkyl or alkene phosphates, the choline residue of which is part of a heterocyclic ring, a process for the preparation of a class of compounds as well as a therapeutic agent, and a method for the preparation of therapeutic agents containing these compounds as active constituents.

Surprisingly, the compounds of the invention have better anti-tumor activity than the open-chain derivatives described in EP-A108 565.

The invention also relates to the preparation and handling of new compounds.

The first stage of preparation is the reaction of phosphorous hydrochloride with long-chain alcohol into halogenated or aromatic hydrocarbons, saturated cyclic ethers or acyclic ethers.

The first stage of preparation A is the reaction of phosphorus oxychloride with long-chain alcohol into halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 C atoms, liquid aromatic hydrocarbons which may also be substituted by halogens (in particular chlorine) or in mixtures of the aforementioned solvents or solvents, optionally in the presence of the usual basic substances.

For example, halogenated hydrocarbons include hydrocarbons having 1 to 6 C atoms, with one, more or all of the hydrogen atoms being replaced by chlorine atoms. For example, methylene chloride, chloroform, ethylene chloride, chlorobenzene or dichlorobenzene may be used. In the case of halogen substituted aromatic hydrocarbons, these are preferably substituted by one or two

-3 halogen atoms.

For example, as a saturated cyclic ether, an ether having a ring size of 5 to 6 consisting of carbon and one or two oxygen atoms may be used. Tetrahydrofuran and dioxane are examples of this.

Acyclic ethers consist of 2 to 8 carbon atoms and are liquid. For example, diethyl ether, diisobutyl ether methyl-tetra-butyl ether, diisopropyl ether are considered.

As saturated hydrocarbons, unbranched and branched hydrocarbons consisting of 5 to 10 carbon atoms are liquid.

For example, pentane, hexane, heptane and cyclohexane are considered.

As aromatic hydrocarbons, for example, benzene and alkyl substituted benzenes are used, with alkyl substituents consisting of 1 to 5 carbon atoms.

As basic substances, amines, for example, aliphatic amines of the formula NR1R2R3, for which R1, R2 and R3 are the same or different and represent hydrogen or C1 - are suitable for the reaction of phosphorus oxychlorides with long-chain alcohols and the subsequent conversion to phosphorous acid diester. Ce-alkyl, but may also be aromatic amines such as pyridine, picoline, quinoline. When converted to phosphoric acid diester, the necessary basic substances may be added at the same time or before the amino alcohol or salt of the amino alcohol.

In any case, a solvent is required for this reaction, which means that a special solvent must be added later if the first step of the reaction has taken place without it. The mole conditions of phosphoroxychloride and long-chain alcohol are e.g.

-4 between 1.5: 1 and 0.8: 1. The amino alcohol or salt of the amino alcohol is optionally added in excess of the long-chain alcohol (about 1.1 to 1.5 molar excess). If the reaction of phosphoroxychlorindaav with long-chain alcohol takes place in the presence of a basic substance, the amount of the basic substance, for example, is 1 to 3 moles per 1 mole of POCI3. For conversion to the phosphoric acid diester that follows, an amount of basic substance, for example 1 to 5 moles per 1 mol, is used.

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

For example, the reaction time of this conversion is between 0.5 and 5 hours, preferably between 1 and 3 hours, and especially between 1.5 and 2 hours. If the reaction takes place in the presence of a basic substance, it generally expires faster (in about 30 minutes).

Subsequently, the amino alcohol or salt of the amino alcohol is added in part or in full.

Salts with mineral acids (such as sulfuric acid, hydrochloric acid) and salts with organic acids such as acetic acid, para-toluenesulfonic acid and the like are considered salts of aminoalcohols. This reaction step is carried out in an inert solvent. The solvents used herein are those of the same solvents as those used in the conversion of phosphorus oxychloride to long-chain alcohol, if this conversion took place in the solvent.

The basic substance is then dissolved in one of the solvents mentioned or liquefied without solvent. Preferably, they are solvents for basic substances

-5Here used here: halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 carbon atoms, liquid aromatic hydrocarbons or mixtures of the foregoing solvents.

These are the same solvents as can be used to convert phosphorous hydrochloride with long-chain alcohol.

The addition of the basic substance raises the temperature. Care must be taken to maintain the temperature between 0 ° C and 40 ° C, preferably between 10 ° C and 25 ° C, and most preferably between 15 ° C and 20 ° C.

The reaction mixture is then stirred at 5 ° C to 30 ° C, preferably between 15 ° C and 30 ° C (for example, 1 hour to 40 hours, preferably 3 to 15 hours.)

Hydrolysis of the initiation of the reaction occurs due to the addition of water, maintaining a temperature between 10 ° C and 30 ° C, preferably between 15 ° C and 30 ° C, and most preferably between 15 ° C and 20 ° C.

The hydrolysis fluids mentioned above may also contain basic substances. As such basic substances, carbonates and hydrogen carbonates of alkali and alkaline earth metals are considered.

For further hydrolysis, it is further stirred for 0.5 hours to 4 hours, preferably 1 to 3 hours, and preferably 1.5 to 2.5 hours at 10 ° C to 30 ° C, preferably 15 ° C to 25 ° C. and preferably at 18 ° C to 22 ° C.

The reaction solution is then washed with a mixture of water and alcohols (preferably aliphatic saturated alcohols of 1 to 4 carbon atoms), which may optionally contain a basic substance. The mixing ratio of water: alcohol may for example be between 5 and 0.5, preferably between 1 and 3 (V / V).

-6As basic alkaline substance substances, for example, are carbonates and hydrogen carbonates of alkali and alkaline earth metals, as well as ammonia (for example aqueous ammonia solution). Particular preference is given to a solvent of 3% sodium carbonate in water.

In this case, the reaction solution is then washed with an acid solution. Acidic rinsing is useful for removing the not yet converted basic portions of the reaction solution, especially when using methylene chloride as a solvent.

The spiral solution consists of a mixture of water and alcohols. In particular, aliphatic saturated alcohol mixtures of 1 to 4 carbon atoms may be considered, with an acidic substance optionally present. The mixing ratio of water: alcohol may for example be between 5 and 0.5, preferably between 1 and 3 (V / V).

Mineral and organic acids such as hydrochloric acid, sulfuric acid, tartaric acid, and citric acid, for example, may be considered acidic substances for a spiral fluid. In particular, 10% hydrochloric acid solution in water is preferred.

The compound is again washed with a mixture of water and alcohols. Preferably, mixtures of aliphatic saturated alcohols with 1 to 4 carbon atoms are preferred, with a basic substance being present, if appropriate. The mixing ratio of water: alcohol may be, for example, between 5 and 0.5, preferably between 1 and 3.

The washed phases are then combined and dried in the usual way and then the solvent is removed (preferably under reduced pressure, for example 5 to 100

-7mbar), optionally after the addition of 150-1000 ml, preferably 300-700 ml, and most preferably 450-550 ml of aliphatic alcohol (referring to 1 mole of the dry product weight). Alcohols, in particular, are saturated aliphatic alcohols with a chain length of between 1 and 5 carbon atoms. In particular, n-butanol and isopropanol are preferred as alcohols. This alcohol treatment is designed to completely remove the remaining water and to avoid foaming.

For example, further purification of the product, during which the crude product is hot dissolved in ethanol, may be followed by filtration and treated with an ion exchanger in a mixing layer, such as, for example, MB3 amberlite in ethanol solution. Instead of an ion exchanger in the mixing layer, all commercially available basic and acidic ion exchangers can be used simultaneously or one after the other.

The solution is then recrystallized from ketones such as acetone or methylethyl ketones, in some cases treatment with the solvents mentioned above is sufficient. It may be expedient to purify the products by column chromatography or flash chromatography on silica gel. For example, a mixture of chloroform, methylene chloride, methanol and 25% ammonia solution is used as the liquid agent.

The process according to variant B consists in the additional alkylation of the products, when they are replaced by amino alcohols with alkylating agents. For example, methylating p-toluenesulfonic acid or dimethylsulfate may be used as the alkylating agents. The solvents listed above are suitable as solvents.

For example, carbonates may be used as basic substances

-8 Alkali metals. The conversion occurs at elevated temperature, for example at the boiling point of the solvent.

Examples:

Example 1: designations (LUPAC nomenclature)

4 - ((((octadecyloxy) hydroxyphosphphenyl) oxy) -1,1-dimethylpyridine hydroxide in salt form

Short label:

octadecyl- (1,1-dimethylpyridin-4-yl) -phosphate C25H52NO4P (461.66) * 1/2 H ₂ O

Preparation according to variant A:

10.3 ml (0.11 mol) of phosphoroxychloride is added to 100 ml of chloroform and cooled to 5-10 ° C. In addition, 27.0 ml (0.10 mol) of 1-octadecanol dissolved in 100 ml of chloroform and 35 ml of pyridine were added dropwise over 30 minutes. After stirring for 30 minutes at 5-10 ° C, it is added

39.1 g (0.13 mol) of 4-hydroxy-1,1-dimethylpyridinium tosylate at a time. After the addition of 40 ml of pyridine and 30 ml of DMF, the mixture is stirred at room temperature for 24 hours. It is then hydrolyzed with 15 ml of water, stirred for a further 30 minutes and washed with an organic phase each time with 200 ml of water / methanol (1: 1), 3% Na2CO3 / methanol (1: 1) and then with water / methanol (1: 1). ). The volume of the organic phase is reduced and the residue is hot dissolved in 300 ml of ethanol and filtered after cooling. The filtrate was mixed with 80 g of MB3 amberlite ion exchanger, filtered off and then reduced in volume. The residue was recrystallized from 300 ml of methylethyl ketone, drained and evaporated

-9 Vacuum dry over P2O5. Yield: 4.71 g (10%)

Elemental analysis:

C H N ed: 65.26% 11,63% 2,62% Calc .: 64.38% 11,61% 2.73% 65,04% 11.80% 2.78%

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

Rf = 0.17 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.12

Melting point: 270-271 ° C (decomposition)

Preparation by variant B:

20.1 ml (0.22 mol) of phosphoroxy oxy chloride is added to 100 ml of methylene chloride, cooled to 5-10 ° C and stirred for 30 minutes in a solution of

54.1 g (0.20 mol) of octadecanol in 400 ml of methylene chloride and 70.5 ml of pyridine. After one hour of additional stirring, 29.9 g (0.26 mol) of 4-hydroxy-1-methylpyridine in 80 ml of pyridine are added dropwise. After stirring at 10 ° C for 3 hours, it is hydrolyzed with 30 ml of water in the cold state and stirred for an additional hour. Organic phase

-10was washed with 200 ml of water / methanol (1: 1), 3% hydrochloric acid / methanol (1: 1) and water / methanol (1: 1) each time. The organic phase, dried over Na2SO4, is reduced by volume to a turbidity by evaporation and mixed with 1 I methylethylketone. The crystallizate was recrystallized from 1 I methylethyl ketone, filtered off and dried over P2O5 in vacuo.

Yield: 54.1 g (60%) octadecyl-1- (1-methylpyridin-4-yl) -phosphate

98.1 g (0.22 mol) of octadecyl- (1-methylpiperidin-4-yl) -phosphate were suspended in 500 ml of abs. ethanol and heated to boiling. Eight parts were added under counter-flow to a total of 71.8 g (0.39 mol) of methyl ester of p-toluenesulfonic acid and 26.5 g (0.19 mol) of potassium carbonate over two hours. After the addition is complete, it is heated under counter-flow for another hour. After cooling, it is filtered off, the filtrate is reduced in half and mixed with a solution of 150 g of a wet MB III amberlite ion exchanger. After stirring for two hours, it is filtered off with silica foam / activated carbon, the filtrate is reduced in volume and crystallized over acetone. The crystalline cake was recrystallized from methylethylketone and dried in vacuo over P2O5.

Yield: 46.1 g (46%) octadecyl- (1,1-dimethylpyridin-4-yl) - phosphate

-11 Elemental Analysis:

C H N ed: 65.26% 11,63% 2,62% 65.18% 11,62% 2.68% 65,07% 11,71% 2.70%

Melting point: 271-272 ° C (decomposition)

Example 2: Hexadecyl-piperidin-4-yl-phosphate C21H44NO4P (405,558)

7.1 ml (77 mmol) of phosphoroxychloride were dissolved in 50 ml of dry tetrahydrofuran and, after cooling to 5-10 ° C, a solution of 17 g (70 mmol) of hexadecanol and 48 ml of triethylamine in 150 ml of tetrahydrofuran was added dropwise. After the addition is complete, the solution is stirred for an additional 30 minutes in an ice bath and then allowed to come 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 while stirring to the reaction solution so that the temperature does not exceed 40 ° C. After the addition is complete, it is cooked under counterflow for one hour. The still hot solution was filtered off over triethylammonium chloride and, after cooling, added ice-2M hydrochloric acid to the mixture while stirring. The product which fails to cool in the refrigerator is mixed into methylene chloride,

-12 dried over MgSO4 and, after volume reduction, chromatographed on silica gel with methylene chloride / methanol / 25% ammonia (70: 30: 5). The product-containing fractions are combined and the volume is reduced by evaporation. After recrystallization from methanol, it is dried in vacuo over P2O5.

Yield: 10.0 g (35%)

Elemental analysis:

C H N ed: 62.19% 10.94% 3.45% 65.15% 11,14% 3.54% 62,41% 11.19% 3.34%

Thin layer chromatogram: (chloroform / methanol / 25% ammonia 70:20:10)

Rf = 0.42 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.33

-13Example 3: Hexadecyl- (1,1-dimethylpiperidin-4-yl) -phosphate C25H52NO4P (461.64) * H ₂ O

5.7 g (14 mmol) of hexadecyl-pyridin-4-yl-phosphate were dissolved in 100 ml of methanol and mixed with 11.6 g (84 mmol) of potassium carbonate. 4.0 ml (42 mmol) of dimethylsulfate were added dropwise over 30 minutes with thorough stirring. The mixture was stirred for a further 4 hours at 40 ° C, filtered and reduced in volume after cooling. The residue was treated with acetone and dissolved in 100 ml of 96% ethanol after shaking. Next, 15 g of MB 3 amberlite ion exchanger is attached and stirred for 3 hours. After filtration, the volume is reduced and recrystallized twice from methyl ethyl ketone. Dry under vacuum over P2O5.

Yield: 3.70 g (61%)

Elemental analysis:

C H N ed: 61.17% 11,16% 3,10% 60.83% 11,14% 2.99% 60,92% 11,26% 3.00%

-14 Thin-layer chromatogram: (chloroform / methanol / 25% ammonia 70:20:10)

Rf = 0.28 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.13

Melting point: 230 ° C (decomposition)

Example 4: Erucyl- (1,1-dimethylpiperidin-4-yl) -phosphate C29H58NO4P (515.765) * H ₂ O

Add 50 ml of chloroform to 10.3 ml (0.11 mol) of phosphoroxychloride and mix dropwise at 5-10 ° C with a solution of 32.5 g (0.10 mol) of erucyl alcohol and 32 ml of pyridine in 100 ml of chloroform. After half an hour of additional stirring, 39.1 g (0.13 mol) of 4-hydroxy-1,1-dimethylpyridinium tosylate are added at once. After 40 ml of pyridine was added dropwise, the mixture was allowed to warm to room temperature and stirred for 3 hours. It is then hydrolyzed with 15 ml of water, stirred for another half hour and washed with each 100 ml of water / methanol (1: 1), 3% sodium carbonate / methanol solution (1: 1), 3% citric acid / methanol (1: 1) ) and water / methanol (1: 1). After reducing the volume, the organic phase of the residue is treated with acetone and then dissolved in 150 ml of 96% ethanol. This solution is stirred for 3 hours with 20 g of MB 3 amberlite ion exchanger and is filtered over silica foam. After volume reduction, chloroform is chromatographed on silica gel

-15 / methanol / 25% ammonia 70:40:10. The product containing the fraction was combined and the volume was reduced to dryness in vacuo.

Yield: 4.4 g (9%)

Elemental analysis:

C H N ed: 65.26% 11,63% 2,62% Calc .: 64.38% 11,61% 2.73% 65,04% 11.80% 2.78%

Thin layer chromatogram: (chloroform / methanol / 1 M sodium acetate in 25% ammonia 70:20:10)

Rf = 0.30

Example 5: Hexadecyl- (1,1-dimethylpiperidin-3-yl) -phosphate C23H48NO4P (433.616) * H2O

10.3 ml (0.11 mol) of phosphoroxychloride is added to 50 ml of chloroform and cooled to 0-10 ° C. Dissolve 24.2 g (0.10 mol) of n-hexadeca-nol in 100 ml of chloroform, mix 32 ml of pyridine and freeze in one hour

-16 drops of phosphoroxychloride solution. After half an hour of stirring, it is added at a time

39.2 g (0.13 mol) of 3-hydroxy-1,1-dimethylpyridinium tosylate were added dropwise at room temperature over 40 minutes 40 ml of pyridine. After stirring at room temperature for 16 hours, it is hydrolyzed with 15 ml of water, stirred for half an hour and washed with each 100 ml of water / methanol (1: 1), 3% sodium carbonate / methanol solution (1: 1), 3% citric acid / methanol (1: 1) and water / methanol (1: 1). After drying, the organic phase is reduced in volume over sodium sulfate. The residue was dissolved in 150 ml of 96% ethanol, filtered and the filtrate was mixed with an MB III ion exchange amberlite.

Yield: 13.5 g (31%)

Elemental analysis:

C H N ed: 61.17% 11,16% 3,10% calc .: 60.78% 11,41% 2.87% 60,85% 11,31% 2.86%

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

Rf = 0.37

-17Example 6: Octadecyl- (1,1-dimethylpyridin-3-yl) -phosphate

C25H52NO4P (461,670) * 1/2 H2O

The preparation is analogous to Example 5 of 10.3 ml (0.11 mol) of phosphoroxychloride, 27.0 g (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 39.2 g (0.13 mol) of 3-hydroxy- 1,1 - dimethipipyridine tosylate.

Yield: 18.7 g (40%)

Elemental analysis:

C H N ed: 63.80% 11,35% 2.98% Calc .: 63.38% 11,72% 2,63% 63,61% 11,98% 2.61%

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

Rf = 0.35

-18Example 7: Hexadecyl- (1,1-dimethylpyridin-2-yl) methyl phosphate

C24H50NO4P (447,643) * 1/2 H2O

The preparation is analogous to Example 5 of 10.3 ml (0.11 mol) of phosphoroxychloride,

24.2 g (0.10 mol) of hexadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol)

2-Hydroxymethyl-1,1 - dimethylpyridinium tosylate.

Yield: 22.9 g (51%)

Elemental analysis:

C H N changed: 63.13% 11,26% 3.07% Calc .: 63.69% 11,73% 3.04% 63,75% 11,71% 3.04%

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

25% ammonia 70:40:10)

Rf = 0.47

-19Example 8: Octadecyl- (1,1-dimethylpyridin-2-yl) methyl phosphate

C26H54NO4P (475,697) * 1/2 H2O

The preparation is analogous to Example 5 of 10.3 ml (0.11 mol) of phosphoroxychloride, 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- dimethylpyridinium tosylate.

Yield: 23.9 g (50%)

Elemental analysis:

C H N Ed. : 64,43% 11,44% 2.89% ex: 64.50% 11,61% 2.67% 64,11% 11,49% 2.77%

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

25% ammonia 70:40:10)

Rf = 0.47

-20Example 9: Hexadecyl- (1,1-dimethylpyridin-3-yl) methyl phosphate

C24H50NO4P (447,643) * 1 H2O

The preparation is analogous to Example 5 of 10.3 ml (0.11 mol) of phosphoroxychloride,

24.2 g (0.10 mol) of hexadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol)

3-Hydroxymethyl-1,1 - dimethylpyridinium tosylate.

Yield: 17.2 g (39%)

Elemental analysis:

C H N ed: 61.91% 11,26% 3,01% 62.32% 12,21% 2.86% 61,79% 11,96% 2.98%

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

25% ammonia 70:40:10)

Rf = 0.29

-21 Example 10: octadecyl- (1,1-dimethylpyridin-3-yl) methyl phosphate

C26H54NO4P (475.697) * H ₂ O

The preparation is analogous to Example 5 of 10.3 ml (0.11 mol) of phosphoroxychloride, 27.0 g (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol) of 3-hydroxymethyl- 1,1 - dimethylpyridine tosylate.

Yield: 16.7 g (35%)

Elemental analysis:

C H N ed: 63.25% 11,43% 2.84% 62.98% 12,21% 2.76% 63,67% 12,47% 2.80%

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

25% ammonia 70:40:10)

Rf = 0.30

-22Example 11: tetradecyl- (1,1-dimethylhexahydroazepin-4-yl) -phosphate

C22H46NO4P (419.54) * H2O

The preparation is analogous to Example 5 of 9.6 ml (45 mmol) tetradecanol, 4.6 ml (50 mmol) phosphoroxychloride, 10 + 20 ml pyridine and 21.3 g (67.5 mmol) hydroxy-1,1-dimethylhexahydroazepine tosylate . Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:40:10.

Yield: 2.70 g (15%)

Elemental analysis:

C H N changed: 60.40% 11.05% 3,20% calc .: 60.47% 11,29% 3,63% 60,78% 11.52% 3,68%

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

Rf = 0.30 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.08

-23Example 12: Hexadecyl- (1,1-dimethylhexahydroazepin-4-yl) -phosphate

C24H48NO4P (445,62)

The preparation is analogous to Example 5 of 10.8 g (45 mmol) of hexadecanol, 4.6 ml (50 mmol) of phosphoroxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1- dimethylhexahydroazepine tosylate. Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 5.0 g (25%)

Elemental analysis:

C H N ed: 64.69% 10,86% 3,14% Calc .: 63.90% 11.54% 3,22% 64,08% 11.59% 3.24%

Thin layer chromatogram: (chloroform / methanol / 25% ammonia 80: 25: 5)

Rf = 0.10 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.10

Melting point:> 250 ° C (decomposition)

-24Example 13: Octadecyl- (1,1-dimethylhexahydroazepin-4-yl) -phosphate

C26H54NO4P (475,695) * 1/2 H ₂ 0

The preparation is analogous to Example 5 of 12.1 g (45 mmol) of octadecanol, 4.6 ml (50 mmol) of phosphoxy oxy chloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol)

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

Yield: 5.5 g (26%)

Elemental analysis:

C H N ed: 64.43% 11,44% 2.89% ex: 64.54% 11,64% 2.82% 64,66% 11,58% 2.64%

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

Rf = 0.22

Melting point:> 250 ° C (decomposition)

-25Example 14: cis- A ⁹ -octadecenyl - (1,1

-Dimethylhexahydroazepin-4-yl) -phosphate

C26H52NO4P (473,679) * H2O

The preparation is analogous to Example 5 of 12.1 g (45 mmol) of cis-Δ ⁹ octadecenol, 4.6 ml (50 mmol) of phosphoroxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy- 1,1- dimethylhexahydroazepineoveatosilate.

Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 4.5 g (21%) Elemental analysis: C H N ed: 63.51% 11,07% 2.85% Calc .: 64.05% 11,21% 3,10% 63,80% 11,06% 3.06%

Thin layer chromatogram: (chloroform / methanol / 25% ammonia 70:40:10)

Rf = 0.28 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.10

-26Example 15: Eicosyl- (1,1-dimethylhexahydroazepino-4-yl) -phosphate

C28H58NO4P (503.754) * H2O

The preparation is analogous to Example 5 of 13.4 g (45 mmol) of eicosanol, 4.6 ml (50 mmol) of phosphoroxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1- dimethylhexahydroazepine tosylate.

Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 5.7 g (25%)

Elemental analysis:

C H N ed: 64.46% 11.59% 2.68% Calc .: 63.51% 11,48% 2.95% 64,00% 11,79% 2.91%

Thin layer chromatogram: (chloroform / methanol / 25% ammonia

70:40:10)

Rf = 0.12

-27Example 16: Erucil- (1,1-dimethylhexahydroazepin-4-yl) -phosphate

C30H60NO4P (529.789) * H2O

The preparation is analogous to Example 5 of 16.2 g (50 mmol) of erucyl alcohol, 5.1 ml (55 mmol) of phosphoroxychloride, 18 + 30 ml of pyridine and 20.5 g (65 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepine tosylate .

Purification by flash chromatography on silica gel with methylene chloride / methanol / 25% ammonia 70:30:10.

Yield: 4.1 g (15%)

Elemental analysis:

C H N ed: 65.78% 11,41% 2,56% 65.76% 12.01% 2.97% 65,82% 11,63% 2.96%

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

25% ammonia 70:40:10)

Rf = 0.30

-28Example 17: Octadecyl- (1,1-dimethylpyrrolidin-3-yl) -phosphate

C24H50NO4P (447,643) * 1/2 H2O

The preparation is analogous to Example 5 of 3.25 g (12 mmol) octadecanol, 1.21 ml (13 mmol) phosphoroxychloride, 3.7 + 4.8 ml pyridine and 4.31 g (15 mmol) hydroxy-1,1- dimethylpyrrolidine tosylate.

Purification of the residue of the product by dissolving in 96% ethanol and treating it with an MB 3 ion exchange amberlite.

Yield: 1.31 g (25%)

Elemental analysis:

C H N changed: 63.13% 11,26% 3.07% 62.99% 11,28% 2.80% 62,74% 11,27% 2.89%

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

25% ammonia 70:40:10)

Rf = 0.25

-29Example 18: Hexadecyl-2- (1,1-dimethylpyrrolidin-2-yl) ethyl phosphate C24H50NO4P (447,643) * H2O

The preparation is analogous to Example 5 of 9.21 g (38 mmol) of hexadecanol, 3.9 ml (42 mmol) of phosphoroxychloride, 13 + 16 ml of pyridine and 15.8 g (50 mmol) of 2- (2-hydroxyethyl) -1. 1- dimethylpyrrolidine tosylate.

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

Yield: 6.0 g (35%)

Elemental analysis:

C H N ed: 61.91% 11,26% 3,01% 61.82% 11,69% 3,21% 61,93% 11,86% 3.28%

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

25% ammonia 70:40:10)

Rf = 0.38

-30Example 19: Octadecyl-2- (1,1-dimethylpyrrolidin-2-yl) ethyl phosphate

C26H54NO4P (475,697) * 1/2 H ₂ O

The preparation is analogous to Example 5 of 10.3 g (38 mmol) octadecanol, 3.9 ml (42 mmol) phosphoroxychloride, 13 + 16 ml pyridine and 15.8 g (50 mmol) 2- (2-hydroxyethyl) -1. 1- dimethylpyrrolidine tosylate.

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

Yield: 7.8 g (43%)

Elemental analysis:

C H N ed: 64.43% 11,44% 2.89% Calc .: 64.69% 11,77% 2.64% 64,84% 11,88% 2,69%

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

25% ammonia 70:40:10)

Rf = 0.35

-31 Example 20: Hexadecyl- (1,1-dimethylpyrrolidin-2-yl) methyl phosphate

C23H48NO4P (433,616) * 1/2 H ₂ O

The preparation is analogous to Example 5 of 9.21 g (38 mmol) of hexadecanol, 3.9 ml (42 mmol) of phosphoroxychloride, 13 + 16 ml of pyridine and 15.1 g (50 mmol)

2-hydroxymethyl-1,1 - dimethylpyrrolidine tosylate.

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

Yield: 8.3 g (51%)

Elemental analysis:

C H N ed: 62.41% 11,16% 3,16% 62.09% 11,48% 3,01% 62,25% 11,66% 3.09%

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

25% ammonia 70:40:10)

Rf = 0.33

-32Example 21: Octadecyl- (1,1-dimethylpyrrolidin-2-yl) methyl phosphate

C25H52NO4P (461.67) * 1/2 H2O

The preparation is analogous to Example 5 of 10.3 g (38 mmol) octadecanol, 3.9 ml (42 mmol) phosphoroxychloride, 13 + 16 ml pyridine and 15.1 g (50 mmol) 2-hydroxymethyl-1,1-dimethylpyrrolidine tosylate .

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

Yield: 9.0 g (52%)

Elemental analysis:

C H N ed: 63.80% 11,35% 2.98% Calc .: 63.13% 11.57% 2.84% 63,55% 11,66% 2.82%

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

25% ammonia 70:40:10)

Rf = 0.35

-33Example 22: Hexadecyl- (1-methylquinuclidin-3-yl) -phosphate

C24H48NO4P (445.64) * 1.5 H2O

Dissolve 2.7 ml (30 mmol) of phosphoroxychloride in 25 ml of chloroform, cool to 5-10 ° C and mix dropwise within one hour with a solution of 6.4 g (26 mmol) of hexadecanol and 10 ml of pyridine in 50 ml of chloroform . After stirring at room temperature for half an hour, a solution of 4.5 g (35 mmol) of 3-hydroxyquinuclidine and 5 ml of pyridine in 10 ml of chloroform was added. After stirring for 5 hours at ambient temperature, it is hydrolyzed with 15 ml of water and stirred an additional half hour. It is then washed twice, each time with 100 ml of water / methanol (1: 1) and reduced the volume of the organic phase after drying over magnesium sulfate to dryness. The residue is chromatographed on silica gel with methylene chloride / methanol 80:25 and then methylene chloride / methanol / 25% ammonia 80: 25: 5. The product-containing fractions were purified, evaporated to dryness and crystallized with acetone. Vacuum drying over P2O5.

Yield: 4.95 (44%) hexadecyl- (quinuclidin-3-yl) -phosphate

4.95 g (11.5 mmol) of hexadecyl- (quinuclidin-3-yl) -phosphate is dissolved in 30 ml of methanol and mixed with 13.7 g (69 mmol) of potassium carbonate, 8.5 ml of water and dripped between mixing well with a solution of 3.3 ml (35 mmol) of dimethylsulfate in 5 ml of methanol. After stirring for 14 hours at room temperature

-34 is filtered through an organic salt, the filtrate is reduced to dryness and the residue is taken up in methylene chloride. After filtration, it is chromatographed on silica gel with methylene chloride / methanol / 25% ammonia 70: 30: 5. The product containing fractions were combined, evaporated to dryness and crystallized with acetone. Vacuum drying over P2O5.

Yield: 2.7 g (49%)

Elemental analysis:

C H N ed: 60.99% 10,88% 2.96% 61.38% 11,04% 3.29% 61,46% 11,22% 3.25%

Thin layer chromatogram: (chloroform / methanol / 25% ammonia 70:40:10)

Rf = 0.44

-35Example 23: Octadecyl- (1-methylquinuclidin-3-yl) -phosphate

C26H52NO4P (473.68) * 2 H ₂ 0

The preparation is analogous to Example 5 of 18.3 g (67.5 mmol) of octadecanol, 7.0 ml (75 mmol) of phosphoroxychloride, 18 + 20 ml of pyridine and 28.3 g (90 mmol)

3-hydroxy-1-methylquinuclidine tosylate.

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

Yield: 18.4 g (57%)

Elemental analysis:

C H N ed: 61.27% 11,07% 2.75% 61.27% 10.91% 2.45% 61,95% 11,23% 2.51%

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

Rf = 0.37 (1-butanol / ice acetic acid / water 40:10:10)

Rf = 0.13

-36Example 24: Hexadecyl- (1,1-dimethyltropanyl-4-yl) -phosphate

C25H50NO4P (459.654) * H ₂ 0

The preparation is analogous to Example 5 of 12.1 g (50 mmol) of hexadecanol, 5.1 ml (55 mmol) of phosphoroxychloride, 17 + 40 ml of pyridine and 21.3 g (65 mmol)

4-hydroxy-1,1-dimethyltropane tosylate.

Purification by dissolution in 96% ethanol, treatment with MB 3 ion-exchange amberlite and recrystallization with acetone.

Yield: 11.3 g (49%)

Elemental analysis:

C H N ed: 62.86% 10.97% 2.93% calc .: 62.45% 11.52% 2.82% 62,58% 11.52% 2.75%

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

Rf = 0.28

-37Example 25: Octadecyl- (1,1-dimethyltropanyl-4-yl) -phosphate

C27H54NO4P (487,708)

The preparation is analogous to Example 5 of 13.5 g (50 mmol) of octadecanol, 5.1 ml (55 mmol) of phosphoroxychloride, 17 + 20 ml of pyridine and 21.3 g (65 mmol) of 4-hydroxy-1,1-dimethyltropane tosylate .

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

Yield: 10.7 g (44%)

Elemental analysis:

C H N ed: 66.49% 11,16% 2.87% 65.72% 11,48% 2.64% 66,27% 11,78% 2.65%

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

Rf = 0.22

For:

ASTA MEDICA Aktiengesellschaft, Germany

Claims (5)

1. Compounds of general formula I R - X - A - P - O - (CH2) y - CH _X (CH2) m) R ¹ X (CteV X ² in which R is a straight or branched alkyl residue of 10 to 24 carbon atoms, which may also contain one to three double or triple bonds, R ¹ and R ² independently of one another contain hydrogen or each straight, branched a cyclic saturated or unsaturated alkyl radical having from 1 to 6 carbon atoms, which may also contain one group of CI-, OH or NH ₂ - and two of these residues may also be fused into a ring, A is a simple bond or one of a group of formulas -CH2-CH2-CH2-O- (II) CH ₂ - CH ₂ - O - (III) - CH ₂ - CH - O - (IV) I ch ₃ S- (CH ₂ ) 8-O- (V) - CH - CH - CH2 - O I \ H ₂ CO \ ch ₂ ^{x /} (VI) -39 wherein groups (II) to (VI) are oriented so that the oxygen atom is bonded to the phosphorus bond atom (I) and X is an oxygen or sulfur atom or NH if A is a simple bond or an oxygen or sulfur atom if A is one of groups (II) to (IV), which means that y is 0 or one integer between 1 and 3, m and n are independently integers defined by zm + n = 2 to 8. Compounds according to claim 1, characterized in that X represents an oxygen atom. Compounds according to claims 1 or 2, characterized in that A represents a simple bond. ⁴ Compounds according to claims 1 to 3, characterized in that R ¹ and R ^{2 are} each methyl groups. -405. Octadecyl - (1,1-dimethylpiperidin-4-yl) -phosphate, octadecyl- (1,1-dimethylhexahydroazepino-4-yl) -phosphate. A process for the preparation of a compound according to any one of claims 1 to 5, characterized in that the compound of the general formula R-X-A-H (VII) in which R, X and A have the meanings given in claim 1 is reacted with phosphoroxytrichloride in the presence of a suitable auxiliary base for reaction with or without solvent and then with a compound of the general formula HO - (CH 2) y - CH