PL172291B1 - Method of obtaining octadecyl-[2-(n-methylopiperydine)-ethyl]-phosphate and of urifying it - Google Patents

Abstract

A method for producing a new octadecyl-[2-(N-methylpiperidino)-ethyl]-phosphate, characterized in that the compound of the formula 1 is subjected to a methylation reaction. Pattern 1 PL PL

Description

The subject of the invention is a process for the preparation of a novel octadecyl- [2- (N-methylpiperidine) ethyl] -phosphate.

European patent application No. 108 565 relates to compounds of general formula 16 and their salts suitable for pharmaceutical use, where R1 is an aliphatic hydrocarbon radical of 8-30 carbon atoms, the radicals R2, R3 and R4 are the same or different and represent a hydrogen atom or low alkyl radicals, or the group NR2R3R4 is a cyclic ammonium group and n is 0 or 1. These compounds have antitumor activity and fungus inhibitory activity.

The novel octadecyl- [2- (N-methylpiperidine) ethyl] -phosphate produced by the process according to the invention is suitable for use as an active ingredient of medicaments. Surprisingly, it exhibits significantly better or more favorable anti-tumor activity than the compounds described or mentioned in European Patent Application No. 108,565.

In addition, the compounds according to the invention inhibit platelet aggregation, exhibit phospholipase A 2 inhibitory activity and lipoxygenase inhibitory activity.

In the process of the invention, the compound of formula I is methylated, the methylation being carried out, for example, by reaction with compounds of the formula CHbHal ArSO2OCH3 and SO2 (OCH3) 2, Hal being a halogen atom, in particular chlorine, bromine or iodine, and Ar being aromatic a radical, for example an optionally substituted phenyl or a naphthyl radical optionally substituted with one or more low alkyl radicals. Examples are p-toluenesulfonic acid methyl ester, dimethyl sulfate, methyl halides. The methylation reaction is optionally carried out by adding customary acid binders such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, alkali metal acetates, tertiary amines, for example trialkylamines such as triethylamine, pyridine or also alkali metal hydrides at a temperature of 0-200 ° C, preferably 40-140 ° C, in inert solvents or dispersing agents. Suitable solvents or dispersants are, for example: aromatic hydrocarbons, such as, for example, benzene, toluene, xylene, aliphatic ketones, such as, for example, acetone, methyl ethyl ketone, halogenated hydrocarbons, such as, for example, chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; aliphatic ethers such as, for example, butyl ether; cyclic ethers such as, for example, tetrahydrofuran, dioxane; sulfoxides, such as, for example, dimethyl sulfoxide; tertiary acid amides such as, for example, dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide; aliphatic alcohols like methanol, ethanol, isopropanol, amyl alcohol, tert-butanol, cycloaliphatic hydrocarbons like cyclohexane and the like. It is also possible to use aqueous mixtures of the solvents mentioned. Often the reaction is carried out at the reflux temperature of the solvent or dispersant used.

Often the components of the methylation reaction are used in excess. The methylation can also be carried out in the presence of tetraalkylammonium salts, especially halides, in combination with alkali metal hydroxides at a temperature of 0-100 ° C, preferably

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20-80 ° C in an aprotic solvent or also in chloroform or methylene chloride. Suitable aprotic solvents are, in particular, tertiary amides, such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, dimethoxyethane, acetone or tetrahydrofuran.

Optionally, the methylation can also be carried out so that an alkali metal compound, for example a sodium, potassium or also lithium salt, is first produced from the compound to be methylated by reacting it in an inert solvent such as dioxane, dimethylformamide, benzene or toluene. with an alkali metal, alkali metal hydride or alkali metal amides, especially sodium or sodium compounds, or with butyllithium at a temperature of 0-150 ° C and then the methylation reagent is added.

Instead of the methylating agents cited, other chemically equivalent agents used in chemistry can also be used, see for example also L.F. and Mary Fieser Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, 1967, Vol. 1, pages 1303-4 and Vol. 2, page 471.

The WHI growth inhibition index is determined on a human KB tumor cell line that has been transplanted into nude mice. The growth inhibition index is determined by the formula:

a treatment group or a control group 14 days after treatment with respect to the values of the application day. A WHI of greater than 100% indicates that tumors have shrunk due to treatment, while a WHI of less than 100% indicates only treatment-induced slowing of tumor growth versus control. The higher the WHI index, the stronger the antitumor efficacy of the test substance.

EC90 is determined on the same cell line in vitro. EC90 is the concentration of anti-tumor active substance in weeks / ml which inhibits the growth of cancer cells in vitro by 90% compared to the control without the addition of anti-tumor active substance.

The Cape Index, or the cancer inhibitory effect coefficient, is a measure of the high selectivity and specificity of a chemical to anticancer agents. This Cape index is obtained by dividing the WHI index by the EC90 index.

That is, the action on an animal (in vitro) is related to the action in an in vitro system. It turned out that the higher the coefficient thus formed, the more selective and effective the substance is in its antitumor activity.

Test results for the compound according to the invention and for compounds with * T »Ł * 1tr'U ^T and ^a nreprletdynAnp to tv toTtzili iiV | ouuiviuizjv »τ j luocui,

Table

Substance WHI Growth Inhibition Index in% in vivo / human KB tumor cell line transplanted into nude mice EC90 in mg / ml in vitro / kB-mouse tumor cell line Cape index 1 2 3 4 Compound of formula 2 D 20133, prepared by the method of the invention 121 0.3 403 Compound with a similar structure Compound of formula 3 D21545 13.7 1.3 10

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Table (continued)

1 2 3 4 | Compound of formula 4 D21033 7 0.3 23 Compound of formula 6 D21052 0 3.2 0 Compound of formula 7 D20813 76 2 38 Compound of formula 8 D20317 38 1.4 27 Compound of formula 9 D20110 25 1 25 Compound of formula 10 D20931 13 1 13 Compound of formula 11 D 20680 0 > 10 0 Compound of formula 12 D19862 0 > 1 0 Compound of formula C ₁₈ H ₃ 7-AN * (CH 3) 3 D19391 11 0.31 36 Compound of formula 13 D20918 0 1 0 Compound of formula 14 D20706 0 3.1 0 Compound of formula 15 D 20745 twenty 10 2

A - in all relationships quoted in the table it is represented by the formula 5

The compounds according to the invention show good antitumor activity on KB tumor (human oral carcinoma, transplanted into nude mice) and on indigenous, chemically induced rat DMBA breast cancer. For example, a dose of a compound according to the invention of 2 x 316 mg / kg body weight, given one week apart, regression of the KB tumor is achieved. After 14 days of oral treatment with a dose of the compound according to the invention of 21.5 mg / kg of body weight per day, DMBA tumors of 5 g have regressed to the limit of palpation.

As shown in the table above, the compound according to the invention exhibits several times higher and more specific antitumor efficacy than compounds of a similar structure. This effect did not materialize.

Examples for the preparation of octadecyl- [2- (N-methylpiperidine) ethyl] phosphate and the starting materials are shown below.

Example I. Preparation of octadecyl- [2- (N-methylpiperidine) ethyl] -phosphate, methylation.

3.7 g (8.00 mmol) octadecyl-2-piperidineethylphosphate and 0.63 ml (10.0 mmol) methyl iodide are dissolved in 20 ml acetonitrile and heated in an autoclave for 6 hours at 100 ° C. It is cooled to room temperature, the precipitate formed is filtered off with suction, dissolved in 140 ml of 96% ethanol and stirred for 1.5 hours with 50 g of the Amberlite MB® 3 ion exchanger. After filtering off the ion exchanger, it is concentrated by evaporation. The residue is mixed with 20 ml of butanol and dried at 40 ° C under reduced pressure over P2 O5.

Yield: 0.96 g (2.02 mmol) of the amorphous product D-20133.

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The starting material is prepared, for example, as follows.

27.3 g (60.0 mmol) octadecyl-2-bromoethylphosphate is dissolved in 90 ml (900 mmol) piperidine and refluxed for 1.5 hours. After cooling, concentrated, the residue dissolved in 150 ml of methanol was added 25.2 g (90.0 mmol) of ₃ Ag2CO and maintained at reflux for 1.5 hours. It is then filtered while hot under reduced pressure through a membrane filter and concentrated. The black oil obtained is chromatographed on silica gel using CHCl 3 (methanol) 25% ammonia (80: 25: 5) as eluent. Fractions containing octadecyl-2-piperidineethylphosphate are concentrated and the residue is recrystallized from 200 ml of butanol.

Yield: 13.2 g (28.6 mmol, 48%) octadecyl-2-piperidine ethyl phosphate.

C18H37-OPO (OH) -O-CH2-CH2-22> Formula 1

C18H37-A-N ^}

CH3

Formula 2 a = o-the-CH ₂ -CH ₂ O®

Formula 5

C22Hi5'A- ^ 2) ch ₃

Formula 6

C19H39'A-N ^ 2>

CH3 Formula 3 / ^ - ⁷

CH ₃

Pattern Ί

CH ₃

Formula 4

CH ₃ Formula 8

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C 18 H37-A- ^ 3

Formula 9

C18H37-AN (2) ch ₃

Formula 13

C 18 H ₃₇ -A'N ^ 3

Co H5 Formula 10 ® / = - N

CiaH ₃ 7-AN \ = J

Formula 14

Ci8H37 ~ AN _x _0

CH ₃

Formula 11

S-NH

Cl8H ₃ 7 ~ A-NH> 0

C 18 H ₃ 7-AN ^) Formula 12

Formula 15

II • Z

R ¹ (O) _n -P-OCH _o CH _Q N -r ^{3 1}

0 “R ⁴

PATTERN16

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Claims (1)

Patent claim A process for the preparation of the novel octadecyl- [2- (N-methylpiperidine) ethyl] -phosphate, characterized in that the compound of formula I is subjected to a methylation reaction.