Phosphorylated serine

 

(57) Abstract:

Usage: in medicine as a cytostatic and vironostika drugs. The inventive products-phosphorylated serine f-crystals: RP(O)(OH) - OCH2CH(NH2)COOH, where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing from 6 to 30 carbon atoms which may be substituted with halogen, OR, SR or NRR, where R and R are lower alkali. Reagent 1: RP(O)(OH), where R is described above. Reagent 2: HOCH2CH(NHY) - C(O) - OX, where X is benzyl, tert-butyl, phthalimidomethyl, isopropyl, benzhydryl, Y - N-benzyloxycarbonyl, N-tertbutoxycarbonyl, N-phthaloyl. Reaction conditions: in the presence of a condensing means, with the subsequent elimination of the protective groups. 2 S. and 1 C. p. F.-ly, 1 table.

The invention relates to new phosphorylated to Surinam General formula

R-- OCH2-COOH,

(I) where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing 6-30 carbon atoms which may be substituted with halogen, -OR, - SR1or-NR1R2group, where R1and R2lowest alkali.

We offer possess cytotoxic and Obedinenie formula (2)

R-

(II) where R has the above meaning, is subjected to the interaction of the serine derivative of General formula

HO-CH2-C

(III) where X is benzyl, tert-butyl, phthalimidomethyl, isopropyl, benzhydryl or other tsepliaeva usual protective group Y-N-benzyloxycarbonyl, N-tertbutoxycarbonyl, N-phthaloyl or other tsepliaeva usual protective group, if necessary, in the presence of a condensing means with subsequent removal of the protective group from the resulting compounds of General formula

R-- O-CH2-

(IV) where R,X and Y have the above significance, or its salt, with subsequent isolation of the product or its transfer, if necessary, in salt.

The conversion of compounds of General formula (II) occurs in such a way that the connection is transferred to the salt of the base, for example pyridine, and this salt then turn derived from serine. The transformation occurs in the presence of a condensing means, for example in the presence of 2,4,6-triisopropylbenzenesulfonyl under anhydrous conditions and in the presence of an inert organic solvent. The solvent take, for example, pyridine.

Components of the reaction are usually used in equimolar the Transformation occurs at temperatures of about 5-60aboutC, preferably at room temperature.

Upon completion of the reaction the remaining acid chloride acid destroy in the reaction solution in the usual manner, for example by addition of water, and the product emit the usual manner, for example by extraction with a simple diethyl ether. If necessary, the thus obtained compounds of General formula (IV), before removal of the protective groups to be clear on, for example, by chromatography on a column of silica gel. But they can also without further purification translate into compounds of General formula (I).

This protective group otscheplaut in the usual way, for example, by catalytic hydrogenolysis, hydrazinolysis, treatment with Hcl or formic acid, preferably in an inert solvent. Compounds of General formula (I) can then allocate a known manner and, if necessary, be clear on, for example, chromatography.

New phosphoserine have strong cytotoxic and virusstatus action. To determine the cytotoxic actions investigated the antiproliferative activity in tumor cells of Ehrlich Ascites. It appeared that the proposed compounds have an excellent cytostatic effect in contrast to fo olewig cells Ehrlich ascites (eat) alkylphosphocholine, and data output (q) presented in the table.

P R I m e R 1. n-hexadecylamine-L-serine

n hexadecylphosphocholine acid.

A mixture of n-hexadecylamine (4,89 g, 16 mmol) and swietojanska of trimethylphosphite (2,48 g, 20 mmol) is stirred for 24 h at 116aboutC. Then the excess trimethylphosphite distilled off in vacuum, the residue is stored 24 h over propeciacost phosphorus in vacuum. The corresponding complex of dimethyl ether n-hexadecylphosphocholine acid isolated from the residue twice extracted, each time with 10 ml of methanol. Both methanol extracts are combined and concentrated in vacuum. Thus obtained oily, colorless residue, which, together with the difficult methyl ether n-hexadecylphosphocholine acid contains more n-hexadecylamine, turn on 4.7 ml of anhydrous acetonitrile with trimethylsilylpropyne (1,02 g, 9.4 mmol) and sodium iodide (1.4 g, 9.4 mmol). Transformation occurs under stirring at room temperature and lasts 15 minutes

Formed by the reaction of sodium chloride is filtered off, the filtrate is concentrated in vacuo, the resulting residue is mixed with 4 ml of water, and the hydrolysis of the formed n-hexadecylphosphocholine acid. At the same time in the m) in vacuum. After treatment of the residue with 7 ml of acetone receive 346 mg of n-hexadecylphosphocholine acid 11. Thin layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol/water 65:25:4, vol/vol/vol/:Rf0,15.

Elemental analysis calculated for C16H35RHO3(306,42):

With 62,71, N 11,51; found 62,81, N 11,89 (%).

Complex benzhydrylamine ether n-hexadecylamine-N-tert.-butoxycarbonyl- -L-serine

A solution of 92 mg (0.3 mmol) n-hexadecylphosphocholine acid in 1 ml of pyridine, concentrated in vacuum, thus obtained pyridine salt, then dried over propeciacost phosphorus in vacuum. Then it was dissolved in 5 ml of anhydrous pyridine. 356 mg (0.95 mmol) of the protected serine (X SN (C6H5)2AT CO-O-C (CH3)3dried over propeciacost phosphorus, dissolved in 4 ml of anhydrous pyridine. Both solutions are mixed and to the mixture 581 mg (1.92 mmol) of triisopropylbenzenesulfonyl. The reaction mixture is stirred under anhydrous conditions at room temperature for 24 h then the mixture is concentrated in vacuo several times distilled with toluene, the residue is dried over propeciacost phosphorus in vacuum. The latter then extracted with 15 ml simple ditropis thus obtained residue by recrystallization from acetonitrile obtain 118 mg of the derivative n-hexadecylphosphocholine acid IV. Further purification is carried out using chromatography on a column with 8 g of silica gel 60 (grain size of 0.04-0,063 mm, 230-400 mesh mesh, Megs). Used for chromatography chloroform and a mixture of solvents for the elution containing 0.5% aqueous 25% ammonia. Elution produce 50 ml of chloroform, 50 ml of chloroform/methanol, 98: 2, vol/vol, 200 ml of chloroform/methanol, 95: 5, vol/vol, 200 ml of chloroform/methanol, 90:10, vol/vol. Particle size is 15 ml fractions 15-20 contains 72 mg of pure complex benzhydryl ether hexadecylamine-N-tert.-butoxycarbonyl-L-serine. Thin layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol, 80:20, vol/vol):Rf0,2.

Elementary analysis gives for C37H61N2PO7(NH-salt, 676,87): 65,65 remaining 9.08 N N 4,14 found 65,44, N 8,15, of 3.77 N (%).

n-hexadecylamine-L-serine.

69 mg (0.1 mmol) described compounds is dried in vacuum over propeciacost phosphorus and then dissolved in 13 ml of anhydrous chloroform. Through this solution passed 10 min dry nitrogen and then under anhydrous conditions at 0aboutWith 20 min of gaseous hydrogen chloride. After that the reaction vessel is tightly closed and stirred for 1 h at 0aboutC. To remove gazoobraznom. After that, the reaction mixture is concentrated under vacuum, the residue is stirred with a mixture of 10 ml of chloroform/methanol, 2:1, volume/volume, 1 ml of water and 0.02 ml of 25% aqueous ammonia, shake, after separation of the phases, separating the resulting organic phase. The aqueous phase is extracted three times, each time 5 ml of chloroform/methanol/ water, 2:1:0,18, volume/volume/volume, the organic solutions are combined and concentrated in vacuum. To remove residual water is distilled several times with 1 ml of benzene/ethanol, 2:3, vol/vol. The resulting product, hexadecylamine-L-serine 1,(NH4-salt), dried over propeciacost phosphorus in vacuum and then washed with acetone.

Yield 43 mg (95%).

To remove traces of ammonium chloride substance chromatographic 2.2 g of silica gel 60 (grain size of 0.04-0,063 mm, 230-400 mesh mesh. Megs). Column balance chloroform/methanol/aqueous 25% ammonia 80:20:0.5, the volume/volume/volume. Elution is done with 20 ml of chloroform/methanol/aqueous 25% ammonia 80:20:0.5, the volume/volume/volume, 20 ml of chloroform/methanol/aqueous 25% ammonia, 75:25:05, volume/volume/volume, 20 ml of chloroform/methanol/aqueous 25% ammonia, 70:3:0,5, volume/volume/volume, 20 ml of chloroform/methanol/aqueous 25% ammonia, 65: 35: 0.5, and volume/volume/objem thickening, (particle size 20 ml).

Thin layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol/acetone/acetic acid/ water, 10:2:4:2:1, volume/volume/volume/volume/volume Rf0,1).

The finding is performed with the molybdate reagent and reagent ninhydrin.

Elementary analysis gives for C19H45N2PO6(NH4-salt, monohydrate, 428,55);

With 53,24, N 10,57, N 6,54 found With 53,80, N 10,55, N 5,73 (%).

FAB-mass spectrometry (anionic spectrum): m/Z 414 (M-2H+Na)-m/Z 392 (M-H)-the m/Z 305 (M-CH2SN) (NH2)COOH)-;

cationic spectrum: m/Z 416 (M+Na)+m/Z 438 (M+2Na)+.

Analogously to example 1 there were obtained the following compounds.

P R I m m e R 2. n-decylphosphonic-L-serine.

From n-dodecylphosphonic acid and protected serine (formula III, X is CH(C6H5)2, CO-OC(CH3)3thin-layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol/ acetone/acetic acid/water 10: 2:4:2:1, volume/volume/volume/volume/volume),

Rf0,1.

Elemental analysis (diamontina salt)13H34N3PO5) (343,45).

Calculated:45,46, N 9,98, N 12,24.

Found: Sasesenage serine (formula H SN(C6H5)2, WITH-OC(CH3)3), thin layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol/acetone/acetic acid/water 10:2: 4:2:1, volume/volume/volume/volume/volume):

Rf0,1.

Elemental analysis (diamontina salt) C15H38NPO5(371,45)

Calculated: 48,50, N 10,31, N 11,31.

Found: 48,11, N 10,89, N 11,28.

P R I m e R 4. n-tetradecylphosphonic-L-serine.

From n-tetradecylphosphonic acid and protected serine (formula III, X is CH(C5H5)2, WITH-OC(CH3)3), thin layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol/acetone/acetic acid/water 10:2: 4:2:1, volume/volume/volume/volume/volume):

Rf0,1.

Elemental analysis (diamontina salt)17H42N3PO5(399,47).

Calculated: 51,11, N Or 10.60, N 10,52.

Found: 50,64, N 10,24, N 10,89.

P R I m e R 5. n-octadecylphosphonic-L-serine.

From n-octadecylphosphonic acid and protected serine (formula III, X= CH(C6H5)2, WITH-OC(CH3)3), thin layer chromatography (silica gel 60, Merck-ready plates, chloroform/methanol/ acetone/acetic acid/SUB>21H50N3PO5(455,01).

Calculated: 55,36, N 11,06, N Which 9.22.

Found, 55,18, N 11,37, N At 9.53.

P R I m e R 6. Archerphoto-L-serine.

From argillaceous acid and protected serine (formula III, X=CH (C6H5)2, WITH-OC (CH3)3), thin layer chromatography (silica gel 60, Merck-finished platinum, chloroform/methanol/acetone/acetic acid/ water 10:2: 4:2:1, volume/volume/volume/volume/volume:

Rf0,1.

Elemental analysis (diamontina salt)23H54N3PO5(483,66).

Calculated: 57,11, N 11,25, N 8,64.

Found, 57,48, N 11,68, N By 8.22.

1. PHOSPHORYLATED SERINE General formula

< / BR>
where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing from 6 to 30 carbon atoms which may be substituted with halogen, - OR1,-SR1or-NR1R2group, where R1and R2lowest alkali.

2. Phosphorylated serine General formula

< / BR>
where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing from 10 to 25 carbon atoms, which may be Sames">

3. N-Hexadecylamine-L-serine.

 

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