RU1363764C - N-2-fluorenesulfonyl-o-propionyl-threo-d,l-phenylserine ethyl ester showing antiviral activity with respect to echo 11 virus - Google Patents

Abstract

The invention relates to esters of substituted amino acids, in particular to ethyl ester M-2-fluorensulfonyl-0-propioNyl-threo-0, L-phenylserine (EPS), which may find application in medicine. The chain is the creation of new derivatives of this series it exhibits antiviral activity against ECHO virus G. The production of EPS is carried out from ethyl phosphate L-2-fluorensulfonyl-threo-0.1.-phen1llserine and propionic acid chloride with absolute chloroform upon boiling. Yield 93, 1%, mp 138-140 °; C. EFS is only active against ECHO P at a dose of 500 μg / mp and a therapeutic index of 2.);, -. | Mi 4 .. to @ s "-.1

Description

(loOOpffTeHi ie refers to i; the new XMivjM-; sc-.osMv with the ethyl ester N-2-f 1uoreisulfok; l -0-1pri lon 1.1G1-threo-O, 1-phenmlsarin, which can be used in biology and medicine .

The aim of the invention is the search for new derivatives in the phenylserine series. showing antiviral activity against ECHO 11 virus.

PRI me R. To a solution of 4.38 g (10.01 mmol)) of ethyl ester of N-2-fluorensulfonyl-gr8o-O, 1-phenylserines in 50 absolute chloroform, 0.93 g (10.05 mmol) are added dropwise with stirring ) propionic acid chloride in 10 MP absolute chloroform. The resulting solution was boiled for 5 hours, and then the solvent was removed under reduced pressure. The residue was recrystallized from a mixture of chloroform and petroleum ether (b.p. Q-VO C). Yield 4.60 g (93.1%) of N-2-fluorensulfonyl-0-propionyl-threo-0 ethyl ester and phenylserine; t, pl. 138-140 ° C. The product is white crystals, insoluble in water, slightly soluble in 13 ether, soluble in alcohol, chloroform, dimethyl sulfoxide.

Found. %: C 65.94; H, 5.70; N, 2.60; S b. 00.

Calcd for C27H27NC) sS,%: C 65.70: H 5.51-N 2.31; S6.50.

HK-cnescTpfKBr); CO vibrations at 1750 cm at ISO and 1340 cm

1 H-NMR spectrum (3 CDCts, Hitachi R-22, 90 F / iFi, HMDS., Ppm: 7.07-7.94 m (N, aromatic); 5.34 d (/ 3-CH), 4, 27 m (a-CH); 3.89 c (CH2 in -C (0) -OCH2CH3); 3.06 s. (CH2 in the fluorene core): 2.35 K. (CH2B-0-C (0) -CH2CH3 ); 1.09 t (СН; ш -С (0) -ОСН2СНз); 1.02 t (СНзз. 0-С (0) -СН2СНз.

Rf 0. 60- (SnufQ 254 UV; diisopropyl ether).

The activity of ethyl ester M-2-fluorensulfonyl O-propionyl-threo-оС-fenmelserin () was determined against viruses A13, Coxsackie B4, ECHO 11, aeecular stomatitis, influenza A and herpes simplex type 1.

The compound has antiviral activity only against ECHO 11 virus. Compared with 1/1 and using ribamidil as a reference preparation of a broad antiviral spectrum (Institute of Organic Synthesis, Academy of Sciences of Latvia), it was found that rbamidil did not affect the reproduction of ECHO 11 virus.

The toxicity of Compound I was determined in a culture of human embryo fibroblasts (PEC), for which various amounts of Compound i were added to the 1H9 pitageous medium. starting at 5000 mcg / ml or less. Observations of this culture by the PMF were carried out in

for 4 days with daily viewing. The maximum tolerated dose (MTD) of test compound I was taken to be its largest amount, which did not cause

degeneration of cells of the culture of PEF. Working

the dose (RD) was 1/2 MPD.

Determination of antiviral activity for RNA-containing viruses Koksaki A13 (Flores), Koksaki B4 (Powers), ECHO 11 (Upsala), vesicular stomatitis

(Indiana) and DNA virus

herpes simplex type I (L-2) was carried out by

De Clereg method. E. etai (J. Infect. Dis, 1980,

141 (3), 563-574). Test virus at a dose of 100 TCD

50 / 0.1 ml was introduced into the cell culture of the PSF and

Hep-2 and incubated for 1 hour at 37 ° C. Immediately after adsorption, the virus coalesced, the cells were washed with 199 medium, and a support medium containing various concentrations of the test drug was introduced into the tubes. The observation was carried out for 72 hours with daily viewing. The absence of the cytopathic effect of the virus. In the experiment, when it was triggered in the control, it was possible to consider the drug in this

focusing active. .

A study of the anti-influenza activity of Compound I was carried out in developing chicken embryos (G. A. Galegov et al. Questions of Virology, 1976.4, 503507) using virus A. (Vi1 (Tci) 35/72) (H3N2).

The experiments showed that N-2-fluorensulfonyl-0-propionyl-threo-DL-phenylserine (I) ethyl ester had MPD in PEC cells

and Ner-2 equal to 1000 μg / ml. At a working dose of 500 μg / ml, the compound delayed the preproduction of ECHO-11 virus with a value of XTI-2. The reference drug ribamidil in RD 50 µg / ml (MTD 1000 µg / ml) did not affect the reproduction of ECHO 11 virus.

As an analogue to the rio structure, the antiviral activity of the starting compound of ethyl ester N-2-fluorensulfonyl-threo-O-phenylserine (state registration 482-8482) was studied. As a result, it was found that, having toxicity similar to the claimed compound (MTD in human embryo fibroblast cultures

and Ner-2 1000 µg / ml, N-2-fluorensulfonyl-threo-oi-phenylserine ethyl ester did not show inhibitory activity against ECHO 11 and other test viruses used.

The antiviral activity of ethyl ester of N-2-fluorensulfonyl-O-propionyl-treo-DL-phenylcerin in relation to the ECHO 11 virus, taking into account the lack of effective anti-enterovirus agents, makes it promising for use in experimental biology and medicine, and can also serve as the basis

Claims (1)

SUMMARY OF THE INVENTION N-2-fluorensulfonyl-O-propionyl-threo-D ethyl ester. L-phenylseries formulas pine sn I about I S. II NH SO-f 2 Editor L. Gerasimova Compiled by L. Ioffe Tehred M. Morgenthal Order 3466 Circulation NGO Search for Rospatent 113035, Moscow, Zh-35, Rauska nab., 4/5 Production and Publishing Plant Matent, Uzhhorod, 101 Gagarin St. FOR directional snitez npoTMBoanp fc-funds. (56) USSR copyright certificate Nb 1140423.cl. C 07 C 103/46, 1985, USSR copyright certificate Nfe 1135150.cl. C 07 C 101/32, 1985. with antiviral activity against ECHO 11 virus. Proofreader N. Revska