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    • 专利摘要:
    The invention relates to 2-ammonium ethyl phosphate (AF) derivatives, in particular the preparation of compounds of the general formula RS (0) nR, -YP (0) (0®) -0- - (CHJ) ,,, where R is straight or branched, saturated or unsaturated C, -C, o-alkyl, in which there may be oxygen in the chain; R, - C cycloalkylene or straight or branched, saturated or unsaturated C —C alkylene, which may be monosubstituted by alkoxy, phenyl, lower (alkoxy) carbonyl or lower alkoxy, substituted by phenyl or lower alkoxy; Y is O or S; Rj - R, the same or different - H or lower alkyl; p - O or 2, which have antitumor activity and can be used in medicine. The goal is to create more active substances of the specified class. Synthesis of AF is carried out from POC and a compound of the formula R-S (0) h-R, -YH, where R, R ,, Y and n are indicated above, in an anhydrous solvent, when the temperature is raised from O to 20 ° C, preferably in the presence of pyridine. The resulting product is then hydrolyzed with aqueous NaOH followed by treatment with a compound of the formula HO- (CH,) 5-NR, R ,, where R ,, R3, R, and Y are indicated above, in pyridine in the presence of triisopropylbenzene sulfonyl chloride at 20 ° C , by transferring the resulting product to an internal salt using silver acetate and isolating the desired product. In the case of sulfone release, it is oxidized. New AFs exhibit better antitumor activity (phosphatase activity is reduced by 50% compared with the control substance) in the absence of irreversible aggregation of blood plates. 1 hp f-ly, 3 tab. i CO with O) from 4:00
    公开号:SU1376948A3
    申请号:SU833578351
    申请日:1983-04-20
    公开日:1988-02-23
    发明作者:Бозиес Эльмар；Галл Руди；Вайманн Гюнтер；Бикер Уве；Пальке Вульф
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:


    cm
    11376948
    This invention relates to the chemistry of organophosphorus compounds, and specifically to a process for the preparation of new derivatives of 2-ammonium ethyl phosphates of general formula I

    R-S (OV-Rr -P-0 (CH24-lj4 6® R4
    (I)
    where R is right or branched,
    saturated or unsweetened, -alkyl, which can be interrupted by an oxygen atom;
    R is C5 C-cycloalkylene or a straight or branched, nascent or unsaturated alkylene, which can be once or twice substituted by an alkoxy group, a phenyl, a lower (alkoxy) carbonyl or a lower alkoxy group substituted by a phenyl or a lower alkoxy group; oxygen or sulfur;
    20
    Y
    and K
    R
    same or different and denote hydrogen or lower 30 alkyl;
    n is an integer, O or 2, possessing antitumor activity, which can be applied in medicine.35
    The compounds of formula (I) and their properties are not described in the literature.
    The aim of the invention is to develop a simple and affordable method for the preparation of derivatives of 2-ammonium ethyl-40 phosphates, possessing antitumor activity.
    Example 1. Preparation of 3-hexadecyl-thio-2-pyridine monocholinic ester, 3.2 g (14 mol) of choline iodide and 4.2 g (14 mol) of triisopropylbenzenesulfonyl chloride are added to the solution successively and the mixture is stirred for 5 hours at 20 hours ° s Then 25 ml of 0.1 N is added to it. an aqueous solution of potassium chloride, stirred for 2 hours, acidified with 2N. hydrochloric acid and extraction is carried out from it with methylene chloride. The organic phase is separated, dried and evaporated. The residue is dissolved in 50 ml of methanol, filtered, the filtrate is mixed with 1.5 g of silver acetate, the mixture is stirred for 2 hours, sucked through the filter and the filtrate is evaporated. The residue is purified by passing it over 100 g of silica gel (mobile phase: a mixture of methylene chloride, methanol and water in a ratio of 65: 25: 4). The fractions containing the desired product are evaporated, the residue is dried and dissolved with acetone. The result is 0.54 g of the target product with a yield of 17% of theoretical. The resulting substance contains 3 mol of water of crystallization. M.p. 243-245 ° С (with decomposition).
    Example 2. Preparation of mono-choline. 2-methyl-hexadecylthiopropyl- (1) -phosphoric acid ester (compound No. 33).
    By adding hexadecyl mercaptan to methacrylic acid methyl ester in the presence of sodium methylate in methanol, oily methyl ester of 2-methyl-3-hexadecyl-thiopropionic acid is obtained in 80% yield, which is reduced using lithium aluminum hydrate in ether. The resulting 2-methyl-3-hexadecylthio-propanol- (1) (waxy mass), as in Example 1, is converted into a nomethoxymethyl-1-1-1 (1) -phosphoric acid 2-methyl-3-hexadetile (compound No. 62).
    At 0 C, 2 g (5.5 mol) of 3-hexacylthiopropyl- (1) -phosphoric acid is added to 0.6 ml of chloroxyphosphorus in 6 ml of absolute tetrahydrofuran. Yield 5%, so decomp. 235 ° C.
    Example 3. Preparation of 2-apkyl-3-hexa monozzoline ester
    decylthio-2-methoxymethylpropanol. ne-Dec Decylthiopropyl- (1) phosphoric acid
    - (compound number 82).
    stir the mixture for 1 hour at 1 hour at 20 ° C, then mix with 10 ml of 1N sodium hydroxide solution and stir for 2 hours at 20 ° C. The mixture is then acidified with 2N. hydrochloric acid and extraction is carried out from it with methylene chloride. The organic phase is washed with water, dried and evaporated. The residue is dissolved in 50 ml of absolutely analogous to Example 1 of 2-alkyl-3-hexadec1-thiopropanol- (1) (a waxy compound obtained 55 by reduction of allylmalonic acid diethyl ester using Alk lithium hydride, by reacting the obtained 2-alkyl-1,3-propanediol with benzenesulfonyl chloride in pyridine to
    0
    five
    0
    0
    five
    0
    pyridine, 3.2 g (14 mol) of choline iodide and 4.2 g (14 mol) of triisopropylbenzenesulfonyl chloride are added successively to the solution and the mixture is stirred for 5 hours at 20 ° C. Then 25 ml of 0.1 N is added to it. an aqueous solution of potassium chloride, stirred for 2 hours, acidified with 2N. hydrochloric acid and extraction is carried out from it with methylene chloride. The organic phase is separated, dried and evaporated. The residue is dissolved in 50 ml of methanol, filtered, the filtrate is mixed with 1.5 g of silver acetate, the mixture is stirred for 2 hours, sucked through the filter and the filtrate is evaporated. The residue is purified by passing it over 100 g of silica gel (mobile phase: a mixture of methylene chloride, methanol and water in a ratio of 65: 25: 4). The fractions containing the desired product are evaporated, the residue is dried and dissolved with acetone. The result is 0.54 g of the target product with a yield of 17% of theoretical. The resulting substance contains 3 mol of water of crystallization. M.p. 243-245 ° С (with decomposition).
    Example 2. Preparation of mono-choline. 2-methyl-hexadecylthiopropyl- (1) -phosphoric acid ester (compound No. 33).
    By adding hexadecyl mercaptan to methacrylic acid methyl ester in the presence of sodium methylate in methanol, oily methyl ester of 2-methyl-3-hexadecyl-thiopropionic acid is obtained in 80% yield, which is reduced using lithium aluminum hydrate in ether. The resulting 2-methyl-3-hexadecylthio-propanol- (1) (waxy mass) is analogously to example 1 converted into analogy to example 1 from 2-alkyl-3-hexadec1thiopropanol- (1) (a waxy compound obtained by reducing the allylmalonic acid diethyl ester with lk lithium hydride, by reacting the obtained 2-alkyl-1,3-propanediol with benzenesulfonyl chloride in pyridine to
    the corresponding monobenzene sulfonate, which is then treated with mercaptide hexadecyl sodium in ethanol), the desired product is obtained. Yield 20%, t.disq. 238 ° C.
    Example 4. Preparation of 2,2-bis-methoxymethyl-3-octadecylthiopropyl- (1) -phosphoric acid mono-choline ester (compound No. 64).
    Oily 2,2-bis-methoxymethyl-1,3-propyl diol monobenzenesulfonate is treated with the sodium salt of octadecyl-mercaptan, as a result of which

    69484
    pinyl) -3-hexadecylthiopropyl- (1) -phosphoric acid, yield 15%, t.rasl. .
    Example 7. Preparation of 2-isopropyl-3-hexa-decylthiopropyl- (1) -phosphoric acid mono-choline ester (compound No. 91).
    Analogously to Example 1, starting from 2-isopropyl-3-hex decylthiopropanol (mp. 28 ° C), obtained by reduction with diethyl isopropyl malonic acid diethyl ester using lithium aluminum hydride.
    to
    a waxy 2,2-bis-} 5 is formed by the formation of oily monobenzene 20
    25
    thirty
    . 35
    methoxymethyl-3-octadecylthiopropanol- (1), which is converted in Example 1 to 2,2-bis-methoxymethyl-3-octadecylthiopropyl- (1) -phosphoric acid monocholinate, yield 23%, t.p. 235-239 ° C.
    Example 5. Preparation of 2-methoxy-2-methyl-3-heptadecyl-propyl- (1) -phosphoric acid mono-choline ester (compound No. 65),
    The target product with so pl. 246-250 ° C and yield 1 5% is prepared analogously to example 1 from 2-methoxy-2-m-3-heptadecyl-thiopropanol- (1), which is formed upon reduction with lithium methyl ether 2-methoxy-2- methyl 3-heptadecy1Tiopropionic acid. The latter is obtained by the conversion of 2-methylglycidic methyl ester with heptagensidic sodium mercaptide and the methylation of 2-hydroxy-2-methyl-3 heptadecylthiopropionic acid methyl ester (mp. 45 ° C) with methyl iodide.
    Example 6. Preparation of 2- (2-propinsh1) -3-hexadecylthiopropyl- (1) -phosphoric acid mono-choline ester (compound No. 90).
    Analogously to example 1, it is obtained from 2- (2-propynyl) -3-hexadecylthiopropanol- (1), obtained from propargyl bromide by conversion with sodium-malonic acid diethyl ester and chromatographic separation of the resulting mono- and bis-compounds by reduction with 5 lithium aluminum hydride to oily 2- (2-propynyl) -1,3-propanediol, conversion into oily monobenzenesulfonate and chromatographic separation of the mono- and bis- 55 formed and conversion with hexadecylmercaptan, which also gives an oil, monoh Linova 2- (2-pro40
    45
    sulphonate from oleaginous 2-isopropyl propan-1,3-diol and by conversion with hexadecyl mercaptan in caustic potash in ethanol by stirring for 50 hours at room temperature, the desired product is obtained. Exit 19%, t.disl. 242 C.
    Example 8. Selection of monocholine ester of 3-hexadecylthio-2-methoxymethylpropyl- (1) -phosphoric acid (compound No. 62).
    To 0.6 ml of phosphorus oxychloride dissolved in 6 ml of absolute tetrahydrofuran are added with 0.5 ml of pyridine and 2 g (5.5 mol) of 3-hexadecylthio-2-methoxymethylpropanol, the mixture is stirred for 1 hour at 0 ° C and 1 hour at 20 ° C, after which 10 ml is added
    1n. caustic soda solution and stirring for 2 hours at 20 ° C. Then the mixture is acidified with 2N. hydrochloric acid and extraction from it with methyl chloride. The organic phase is still. washed with water, dried and evaporated. The residue is dissolved in 50 ml of absolute pyridine, 3.2 g (14 mmol) of choline iodide and g (14 mmol) of triisopropylbenzenesulfonic acid chloride are added successively to the resulting solution and the mixture is stirred for 5 hours at 20 ° C, after which it is added 25 ml Oh, 1N. an aqueous solution of potassium chloride, stirred for 2 hours, acidified with 2N. hydrochloric acid and extraction with methylene chloride. The organic phase is separated, dried and evaporated. The residue is dissolved in 50 ml of methanol, the solution is filtered, the filtrate is mixed with 1.5 g of silver acetate, the mixture is stirred for 2 hours, filtered off with suction and the filtrate is evaporated. The residue is subjected to chromatographic purification, passing it through a column filled with 100 g si} 5 to form oily monobenzene20
    25
    thirty
    35

    5 55
    40
    45
    sulphonate from oleaginous 2-isopropyl propan-1,3-diol and by conversion with hexadecyl mercaptan in caustic potash in ethanol by stirring for 50 hours at room temperature, the desired product is obtained. Exit 19%, t.disl. 242 C.
    Example 8. Selection of monocholine ester of 3-hexadecylthio-2-methoxymethylpropyl- (1) -phosphoric acid (compound No. 62).
    To 0.6 ml of phosphorus oxychloride dissolved in 6 ml of absolute tetrahydrofuran are added with 0.5 ml of pyridine and 2 g (5.5 mol) of 3-hexadecylthio-2-methoxymethylpropanol, the mixture is stirred for 1 hour at 0 ° C and 1 hour at 20 ° C, after which 10 ml is added
    1n. caustic soda solution and stirring for 2 hours at 20 ° C. Then the mixture is acidified with 2N. hydrochloric acid and extraction from it with methyl chloride. The organic phase is still. washed with water, dried and evaporated. The residue is dissolved in 50 ml of absolute pyridine, 3.2 g (14 mmol) of choline iodide and g (14 mmol) of triisopropylbenzenesulfonic acid chloride are added successively to the resulting solution and the mixture is stirred for 5 hours at 20 ° C, after which it is added 25 ml Oh, 1N. an aqueous solution of potassium chloride, stirred for 2 hours, acidified with 2N. hydrochloric acid and extraction with methylene chloride. The organic phase is separated, dried and evaporated. The residue is dissolved in 50 ml of methanol, the solution is filtered, the filtrate is mixed with 1.5 g of silver acetate, the mixture is stirred for 2 hours, filtered off with suction, and the filtrate is evaporated. The residue is subjected to chromatographic purification by passing it through a column filled with 100 g of silica gel. A mixture of methylene chloride, methanol and water in the ratio 65: 25: A is used as the mobile phase. The fractions containing the desired product are evaporated, the residue is dried and triturated with acetone. As a result, 0.54 g of the expected product is obtained. Yield 17%. The compound obtained contains 3 mol of water of crystallization. M.p. 243-245 C (with decomposition).
    In a similar manner, the following compounds were prepared:
    1-monocholinic 3-octa-decylthiopropyl- (1) -phosphoric acid ester, m.p. 238-240 ° C (decomp);
    2-monocholinic 3-octadecylsulfinylpropyl- (1) -phosphoric acid ester, m.p. (different);
    3-monocholine ether 3-octadecyl sulfonylpropyl- (1) -phosphoric acid, So pl. 240-242 C (p zl.);
    4- monocholine ether of 3- (octadec-9-enylthio) -propyl- (1) -phosphoric acid, m.p. 240-243 ° C, yield 9%;
    5- monocholinic 3- (octadec 9-ene-sulfonyl) -propyl- (1) -phosphoric acid ester;
    6-monocholinic 3-hexa-decylthiopropyl- (1) -phosphoric acid ester m.p. 240 ° C (decomp.);
    7-monocholinic 3-hexadecylsulfonylproyl- (1) -phosphoric acid ester;
    8- monocholinic 3- (3,7,11, 15-tetramethylhexadecylthio) propyl (1) -phosphoric acid ester;
    9- monocholinic 3- (3,7,11, 15-tetramethylhexadecylsulfonyl) propyl- (1) -phosphoric acid ester;
    10-monocholinic 3-heptadecylthiopropyl- (1) -phosphoric acid ester m.p. 246 ° C (decomp.);
    11-monocholinic 3-heptadecylsulfonyl 1-ShL- (1) -phosphoric acid ester;
    R
    12-monocholine ether of 3-eicosyl thiopropyl- (1) -phosphoric acid, m.p. 235-238 ° C (decomp.);
    13-monocholinic 3-aycoolyl sulfonyl-propyl- (1) -phosphoric acid ester, m.p. 210-229 ° C (decomp.);
    14-monocholinic phosphorus p 3-dodecyl thiopropyl- (1) -phosphoric acid,
    M.p. 229-2314 (decomp.);
    15-monocholine ether of 3-dodecyl sulfonylpropyl- (1) -phosphoric acid, m.p. 95-99 C (decomp.);
    76948
    Jq
    ds
    2 25
    -
    ZO
    ,, before

    dd

    five
    16 monocholinic ester of 3- (2-pentadecyloxyett thio) propyl- (1) -phosphoric acid, m.p. 231-233 C (decomp.);
    17- 3- (2-pentadecyloxy) ethylsulfonyl-propyl- (1) -phosphoric acid monocholine ester, t.
    18- hydroxide (octadecylsulfonyl) -propoxyphosphoryloxyhydroxy-propyltrimethylammonium, m.p. 226-229 C (decomp.);
    19-hydroxide 2-tЗ- (octadec-l-sulfonyl) -propoxy-phylophyroxy-x-2-methyl-ethyl-trimethylamine, m.p. 203 C (decomp.);
    20-monocholine 2-methoxy-3-octadecylthiopropyl- (1) -phosphoric acid ester, m.p. 251-252 ° C, yield 19%;
    21- - 2-methoxy-3-octadecylsulfonylpropyl- (1) -phosphoric acid monocholine ether, m.p. 270-272 С;
    22-monocholine 2-methoxy-3-octadecylsulfonyl-propyl- (1) -phosphoric acid ester;
    23-monocholine ether of 3- (2-pentadecylthioethylthio) -propyl- (1) -phosphoric acid, so cl. 237 ° C;
    24- hydroxide 3- (3-octadecyl-thiopropoxy) -phosphoryloxyhydroxypropyltrimethylammonium, t. 228- (decomp.);
    25-monocholine 2-methyl-3-0 ester ctadecylthyropyl- (1) -phophoric acid, m.p. 234-238 ° C;
    26,27 monocholinate 3- (2-methoxyoctadecyptio) propyl- (1) -phosphoric acid;
    28- 2- (3-octadecyl-thiopropoxyphosphoryloxyhydroxy) -2-methylethyltrimethylammonium hydroxide, m.p. bromine-free compound obtained by reaction with silver acetate, 61 ° C (sintering), (spreading), 200 ° C (decomposition);
    29-monocholinic 2-metsh1-3-octadecylsulfonylpropyzl- (1) -phosphoric acid, so pl. 59 ° С (sintering), 227-234 ° С (decomposition);
    30-monocholine ether of 3-tetradecylthiopropyl- (1) -phosphoric acid, m.p. spec., (In the form of monohydrate) 63 ° C, m.p. 231-233 C;
    31-monocholine ether 2-methyl-3-octadecylsulfinylprop-1 (1) -phos-; fororic acid, t. dec. 235-240 ° C;
    32A -. (3-Hexadecylthiopropoxyphosphoryloxyhydroxyethyl) -K, H-di-
    ethylamine, t. spec. 66 ° C, mp. 104-110 ° C;
    32B - (3-hexadecylthiopropoxyphosphoryloxyhydroxy) -ethyl-N, N-dimethylamine, m.p. spec. 84 ° C, mp. 145-150 ° C;
    32C - (3-hexadecylthiopropoxyphosphoryloxyhydroxy) -ethyl-N-methylamine, e.g. 91 C, m.p. 194 ° C;
    32D - 2- (3-Hexadecylthiopropoxyphosphoryloxyhydroxy) -ethylamine, m. Spec. 170 ° C, so pl. 195 ° C;
    33-monocholine 2-metsh1-3-hexadecylthiopropyl- (1) -phosphoric acid, t. Sinter, (monohydrate), t. Dec. 229-235 ° C;
    34-monocholinate 2,2-dimethyl-3-hexadecylthiopropyl- (1) -phosphoric acid, yield 14%, mp 238 ° C, m.p. 235-238 ° C;
    35-cis- or trans-3-octadecylthicyclohexyl- (1) - phosphoric acid monocholine ester; for cis compounds 5GS, m.p. 241-244 ° C (decomp.), For trans - t.sep. 45 ° C, mp. 239-24GS (decomp.);
    36- monocholine ether of 3- (14-methyloxytetradecylthio) -propyl- (1) -phosphoric acid; 76 ° C, mp. 238-244 ° C (decomp.);
    37- hydroxide (3-reKca-decylthiopropoxyphosphoryloxyhydroxy) ethyl3-N-methyl-N, N-diethylammonium,
    t. spec. 40 ° C, m.p. 119 ° C;
    38-monocholine 2-isopropyl-3-actadecylthiopropyl- (1) -phosphoric acid ester, t. Spec. 55 ° C, mp. 230 2334 (decomp.);
    39-monocholine ether 4-heptadecylthio-3-methyl-n-butyl- (2) -phosphorous knloty, t. Spec. 55 ° C, mp. 230-233 ° C (decomp.);
    40-monocholinic 3-octadecyl-thiobutyl- (1) -phosphoric acid ester, m. Spec. 58 C, t.d. 232 ° C;
    41-monocholinic 3- (9-oxytyloxynonylthio) -propyl- (1) -phosphoric acid ester, e.g. 50 ° C, t.rael. 221-224 ° C;
    42- monocholinic ester of 3- (4, -tridecyloxybutylthio) -propyl- (1) -phosphoric acid, yield 13%, that is, spec. 55 ° C. 218 C;
    43- 3-pentadecylthiopropsh1- (1) -phosphoric acid monocholine ester T. spec. 60 ° C, m.p. 237 ° C;
    0
    five
    0
    five
    0
    five
    0
    five
    44-monocholinate 5-hexa-decylthiopentsh1- (1) -phosphoric acid, t.sep. 58 C, t.razl, 228-230 C;
    45- monocholinic ester of 3- (10-n-butoxydecyloxyethylthio) -propyl- (1) -phosphoric acid, t.sec. 36 ° C
    tf 227-229 ° C;
    46- monocholinic ester of 3- (11-hexyloxyundecylthio) -propyl- (1) -phosphoric acid; diff. 226-229 ° C;
    47- monocholinic 3- (7-decyloxyhexylthio) -propyl- (1) -phosphoric acid ester, e.g. 53 ° C, mp. 244 ° C,
    In a similar manner, using 3- (3-tetradecyloxypropylthio) propanol as the starting material, the following is obtained:
    47a — 3- (3-tetradecyloxypropylthio) -propyl- (1) -phosphoric acid monocholinate, i.e. 52 C;
    48-3-hexa-decylthio-2-methoxypropyl- (1) -phosphoric acid monocholine ester, m.p. 255-256 C;
    49-monocholinic 3-heptadecylthio-2-methoxypropane 1- (1) -phosphoric acid ester, m.p. 255-257 ° C;
    50-monocholine 2-ethoxy-3-heptadecyl-thiopropyl- (1) -phosphoric acid ester, m.p. 225-230 ° C |
    51-monocholine 2-methoxy-3- (trans-octadec-9-enylthio) -propyl (1) -phosphoric acid ester, wax;
    52-monocholine 2-methoxy-3- (octadec-9,12-dienylthio) -propyl (1) -phosphoric acid ester, wax;
    53- 2-methoxy- 3- (1-methyl-octadecylthio) -propyl- (1) -phosphoric acid monocholine ester, m.p. 256-258 ° C;
    54- monocholinic 3- (3-heptadecylthio) -2-methoxypropyl- (1) -phosphoric acid ester, wax; .
    55-monocholine 2-methoxy-3- (3-tetradecyloxypropylthio) -propyl- (1) -phosphoric acid ester, m.p. 242-244 ° Cj
    56- monocholinic 3- (5-dodecyloxyamylthio) - (2-methoxypropyl) - (1) -phosphoric acid ester; 245-247 C;
    57-monocholine 2-methoxy-3- (8-nonyloxy-octylthio) -propyl- (1) -phosphoric acid ester, wax;
    58-monocholine 2-ethyl-3-hexadecylthiopropyl- (1) -phosphoric acid ester, mp, 236-238 ° C;
    59 - 3-hexa-decylthio-2-propyl- (1) -phosphoric acid monocholine ester, m.p. 239-242 C;
    60-monocholine 2-n-butyl 3-octadecylthiopropyl- (1) -phosphoric acid ester, mp, 232-238 0;
    61-monocholine 2-benzyloxy-3-octadecylthiopropyl- (1) -phosphoric acid ester, m.p. 210-212 ° C;
    63- 2-ethoxymethyl-3-hexadecylthiopropyl- (1) -phosphoric acid monocholine ester, m.p. 243-246 0;
    64-monocholinate 2,2-bis-methoxymethyl-3-octadecylthiopropyl- (1) -phosphoric acid, m.p. 237-23 C;
    65-monocholinic 3-hepta-decylthio-2-methoxy-2-methoxy-propyl- (1) -phosphoric acid ester, m.p. 244-251 ° C;
    66-monocholinate 4-hexadet of methylthiobutyl- (2) -phosphoric acid, wax;
    67-monocholine 4-octadecylthioamyl- (2) -phosphoric acid ester, m.p. 239-245 ° C;
    68-monocholinic 3-hexa-decylthiocyclo-amyl- (1) -phosphoric acid ester, m.p. 253-256 ° C;
    69-monocholinic ester of (S) -2-methanesulfonamido-octadecylthiopropyl- (1) -phosphoric acid, so pl. 212-215
    70- 0-monocholinic ester of S- (3- hexadecylthio-2-methoxymethylpropyl) - thiophosphoric acid, so pl. 230-235 ° C (decomp.);
    71- (N-dodecylcarboxyamido) monocholine ether-ethylthio -2-methoxypropyl- (1) -phosphoric acid, wax;
    72-monocholinic ester of 2-methoxy 3- (9-phenyloctadecylthio) -propyl- (1) - phosphoric acid, wax;
    73-monocholinic ester of (N-n-butylcarboxamido) -undecylthio -2-methoxypropyl- (1) -phosphoric acid, wax;
    74- 0-monocholine S- (2-methoxy-3-octadecylthiopropyl) (1) ester of thiophosphoric acid, m.p. 219-22GS (Raal.);
    75- 0-monocholinic 5- (4-oxtadecylno-2-amch1) -thiophosphoric acid ester, T.im. (decomp.), yield 9%
    76 - 2-methyl-2-methoxycarbonyl-3-hexadecylthio-propyl- (1) -phosphoric acid monocholinate, e.g., 65 ° C spec., M.p. 238-240 ° C, yield 13%;
    0
    five
    Q
    Q
    ,
    five
    five
    0
    77- 0-monocholine ester of S- (2-methyl-3-hexadecylthiopropyl) -thiophosphoric acid; 45 ° C, mp. 262 C (with foaming);
    78- 3-hexa-decylthio-2- (2-methoxy) -propyl- (1) -phosphoric acid monocholine ester, m.p. 257-258 C (decomp.);
    79-monocholine 2-hexadecyloxy-3-methylthiopropyl- (1) phosphoric acid ester;
    80-monocholine 2-benzyl ester of 3-hexadecylthiopropyl- (1) -phosphoric acid, so pl. 220-230 ° C (decomp.);
    81-monocholinic 3-hexadecylthio-2-phenylpropyl- (1) -phosphoric acid ester, m.p. (different);
    82- 2-allyl-3-hexadecylthiopropyl- (1) -phosphoric acid monocholine ester, m.p. 235-238 ° 0 (decomp.);
    83- 2-methylene-3-octadecylthiopropyl- (1) -phosphoric acid monocholine ester, mp. 235-237 C (decomp.);
    84-monocholine 3-tetradecylthiopropyl- (1) -phosphoric acid ester;
    85- (+) - or (-) - monocholine ether 2-methyl-3-hexadec1 thiopropyl- (1) -phosphoric acid, enantiomer A t.sec. 78 ° C, t.d. 241-245 0; enantiomer In t.pek. 55 ° C, t.d. 236-239 0;
    86-monocholine 4-hexadecylthio-n-butyl- (1) -phosphoric acid ester, yield 16% trihydrate, t.sep. , t, 224-224 ° C;
    87- 3-hexa-decylthio-2-methoxymethyl-propyl- (1) -phosphoric acid monocholine ester; 50 ° Oh,
    mp4 245 ° C}
    88-monocholinic 3-heptadecylthio-2-ethoxypropyl- (1) -phosphoric acid ester, yield 29%;
    89- monocholine ether of 3- (2-pentadecyloxyethylthio) -propyl- (1) -phosphoric acid, yield 35%, t.cl.
    90- monocholine ether of 2- (2-propinyl) -3-hexadecylthiopropyl- (1) -phosphoric acid, yield 15%, t.cl. 2394;
    91-monocholine ether of 2-isopropyl-3-hexadecylthiopropyl- (1) -phosphoric acid, yield 19%, m.p.
    In tab. 1 presents the data of elemental analysis of the compounds obtained. Determination of the antitumor activity of compounds of formula (I),
    eleven
    The effect of new 2-ammonium ethyl phosphate derivatives on mouse tumor cells is determined by screening. Methyl chloroanthrene (Math A) induced tumor cells were used as infected cells in mice as ascites, as well as lymphomatic cells A Belsen-8.1 (Av15), which are stored in vitro in a nutrient medium. For testing, 5x10 / ml of these cells in the DulBecco-modified Eagl medium containing, in addition, 10% fetal calf serum deactivated at high temperature, 5x10 mol of mercaptoethanol, 50 U of penptisillin and 50 µg / ml of streptomycin, as well as various Concentrations of new compounds of formula (I), phospholipids, are cultured for 24 hours in a thermostat with a relative humidity of 95%, and a CO content of 10%. The effect of the compounds is determined by comparing the growth of tumor cells in a medium containing new compounds of formula (I) and a control culture without the addition of test compounds. Monocholinate 2-methoxy-3-octadecyl-propane-1-ol-phosphoric acid is used as a control compound. The growth of Meth-A cells is assessed by the incorporation of N-thymidine into the DNA of the cells, and Av15-cells from the measurements of the alkaline phosphatase activity of an aliquot of the culture. For each test compound, the concentration at which the introduction of thymidine, respectively, alkaline phosphatase activity, is reduced by 50% compared to control, untreated tumor cells is determined.
    In tab. 2 shows compounds that are superior to the control compound. The effectiveness of the new compounds of the formula (I) of vyrgyken is a coefficient representing the ratio of the action of the control compound to the action of the test compound of the formula (I). The control compound is Compound No. 41.386.
    Definition of irreversible aggregation of blood plates.
    The compounds of formula (I), in addition to YOU HAVING an antitumor effect, do not detect aggregation of blood plates, as shown by anapogic
    J5 20 25 30 94812
    oxygen compounds (O instead of S).
    To determine the irreversible aggregation of blood plates, the blood of healthy donors is centrifuged at 100 g and the plasma-rich plasma is separated. Plate aggregation is determined by measuring the turbidity in the aggregometer. 1 ml of plate-saturated plasma is stirred at a few minutes. 0.2 ml of various concentrations of the test compounds are then added and the onset of turbidity is measured. Due to technical difficulties, it is not possible to test new compounds at a Bbmie concentration of 2 mg / ml.
    The data of irreversible aggregation of blood plates by compounds of formula (I) are presented in Table. 3
    Thus, the proposed method allows to obtain new derivatives of 2-ammonium ethyl phosphates of formula (T.), which are superior in their antitumor activity to known structural analogues.
    权利要求:
    Claims (2)
    [1]
    Invention Formula
    1. A process for the preparation of 2-ammonium ethyl phosphate derivatives of the general formula
    ABOUT
    R
    R-sioin-RrY-P-oim2V
    (I)
    ABOUT
    R,
    ,
    where R is straight or branched, saturated or unsaturated C-Cjg-alkyl, which can be interrupted by an oxygen atom;
    R, - C y-C-cycloalkylene or straight or branched, saturated or non-saturated, C-Cj-alkylene, which can be substituted once or twice by a lower alkoxy group, by phenyl, by a lower (alkoxy) carbonyl or by a lower alkoxy group, substituted phenyl or lower alkoxy; Y is oxygen or sulfur;
    Rj, Rj
    and Ri is the same or different hydrogen or lower alkyl;
    n is an integer, O or 2, concludes that the compound of the general formula
    R-S (0) -R, -YH
    (Ii)
    where R, R, n and Y have the indicated meanings,
    interact with chloro-CUY of phosphorus in an anhydrous organic solvent medium with an increase in temperature from 0 to, followed by selective hydrolysis with an aqueous solution of sodium hydroxide of the resulting compound of the general formula
    RC (ov-RrY-p:
    ci ci
    where R, R ,, n and Y have the indicated signs
    cheni
    by treating the resulting product of a compound of the general formula
    4./R1
    HO (PH2)
    Rt
    where R; j, R 4 and R have the indicated meanings
    neither
    in pyridine in the presence of tri-isopropylbenzenesulfonyl chloride with the subsequent transfer of the resulting product to the internal salt
    d. e
    20
    25
    -
    by treatment with silver acetate and the selection of the target product or the oxidation of its sulfone. ,
    [2]
    2. Method POP.1, characterized in that the reaction of the compound of formula (II) with phosphorus oxychloride is carried out in the presence of pyridine.
    Priority featured:
    10.21.80 when R is straight or branched, saturated or unsaturated C, -C-alkyl, which can be broken by an atom, oxygen, R is Cj-C-cycloalkylene or a straight or branched branched killen, which can be single or twice substituted by a C -C-alkoxy group, in turn, substituted by phenyl, Y is oxygen; and R is the same or different and is lower alkyl; n is an integer, O or 2;
    13.05.81 when R, is a straight or branched unsaturated; Eden C, -C-alkylen, which can be substituted once or twice by phenyl or C, -C-alkoxy, in the second with C: - alkoxy;
    10/20/81 with R, - unsaturated C,; - Cg-alkyl, once or twice substituted by lower (alkoxy) - carbonyl, Y - sulfur.
    cm
    g-mid
    1O
    Yu
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    see about
    VO
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    about
    ft
    vO
    about
    -
    in
    g-cm
    m
    one
    00 h00
    4f
    h
    cm
    cm
    CM
    C3
    CM
    CO
    CM
    -r-
    "
    inin
    00
    o
    - 00
    r cyi
    o
    rO
    a
    (CM
     -
    r- 00
    Vd beats
    in
    r
    vO
    in
    vO
    CO
    in
    CO
    00
    r in
    in
    VO
    vO
    in
    r
     in
    in
    M
    O in CO r- CM
    r 00
    v
    fO
    r
    CM
    MF
    CM
    MF
    r-i
    fO
    CM
    CM
    CM
    CM
    in
    vO
    (d
    h
    "F
    ABOUT
    tr o
    yo
    "F (U
    e
    S n)
    H
    w u
    about a
    tj "o ta
    but
    Yo
    371376948
    table 2
    control comparative)
    four
    five
    6
    7
    eight
    9
    10 11 16 17 18 20 29 32В 33 42 48 49 50 53 55 58 62 63
    1.0 1.6 2.0
    1.5
    1, “i 1 and 1.2 1.2
    1.1 1.6 1.6 1.7 1, A M 1.1 1.A
    M
    1 1.3
    2 About 1.5 1.1 1.5 1.2
    I
    38 Continued table. 2
    2
    1.5 1.1 1.1
    1.5 1.4
    1.2 J, 2 1.4 1.4 1.5 1.3
    Table E
    control comparative)
    12
    3
    6
    20 25 33 34 48 49
    0.05
    3
    2 0.1 2 3 2 2 2 1 1
    51 2790.1
    Note. The comparative compound is 55 2din-2-2 2-methoxy-3-octadecyl-propan-1-ol-mono-choline ester; phosphoric acid.
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