(3-r-1-adamantyl)-1-ethylamine hydrochlorides showing antiviral activity and a method for preparation thereof

FIELD: organic synthesis.

SUBSTANCE: invention provides group of novel antiviral nitrogen-containing compounds, in particular adamantane derivatives having general formula:

, wherein R represents chlorine or ethyl.

EFFECT: increased choice of biologically active compounds suitable for use in medicine as antiherpetic agents.

2 cl, 6 tbl, 3 ex

 

The invention relates to a new group of biologically active compounds adamantanol series, in particular hydrochloridum (3-R-1-substituted)-1-ethylamino, where R is Cl, C2H5the formula

R=Cl(a), C2H5(b)

The invention can find application in medicine.

The closest structure connection is rimantadine (hydrochloride α-methyl-1-adamantanemethylamine)

providing preventive effect against influenza caused by virus strains of type A. Although the compounds Ia-b are 3-adamantylamine rimantadine analogues, their anthropoda activity is quite weak, but all these compounds showed high biological activity against herpes virus simple, which rimantadine low activity, and compounds IB effectively inhibited both sensitive and resistant to acyclovir variants of the herpes virus simple.

If you compare the IB connection with efficiently used in medicine for the treatment of diseases herpes nature adamantane derivatives, it Antiherpes virus effect of the activity exceeds the activity of tromantadine (hydrochloride 1-(1-substituted)-2-[(2-dimethylamino)ethoxy]-ndimethylacetamide) 3 times, and admantine (1-(3-atinadamente)-1-ethylcarbamate) 1.5 times. (A.S. USSR №721048, 1992, bull. No. 11).

The purpose of the invention is a series of compounds with antiviral activity, hydrochloride (3-R-1-substituted)-1-ethylamino, where R=Cl, C2H5.

Physico-chemical properties and spectra of these compounds are given in tables 1 and 2.

According to the invention, the biological activity of patentable compounds is confirmed by examples 1-3.

Compounds Ia-b were tested for their toxicity in cell cultures and virus activity in models of influenza virus type a (classical swine fever bird (WCCP) strain Weybridge [Hav1N1] and human Aichi/2/68 [H3N2]) and herpes virus of simple type 1 (strain L2).

Example 1. The study of toxic action.

Table 3 presents the results of the study of toxic effects of derivatives of adamantane on the culture of primary trypsinization FEC and culture transplantable cells MDCK and Vero. Rimantadine was used as reference drug. As can be seen from the table, CD50IB was approximately 4 times less CD50of rimantadine, and the product Ia is even less toxic for the studied crops.

Example 2. Study of the biological activity against influenza A.

When studying the sensitivity of the influenza virus to the derivatives of adamantane inhibitory effect was assessed by the presence of cytopathic changes in the cell monolayer and the accumulation hemagglutinin is found in the culture fluid. It is shown that drugs Ia, IB had a weak effect on the reproduction of the virus: the values KTI were 10-12 times lower than rimantadine. The results are shown in table 4. The drugs did not provide a complete inhibition of the development of virusinduced cytopathic effect (the centre e) in the range nicitating concentrations.

Low anthropogeny effect of the studied compounds is also confirmed in the study of the ability of compounds to inhibit belascoaran with their introduction of the agrarian coverage (table 5). Inhibitory effect detected in the presence of concentrations of compounds, sharply exceeding the effective concentrations of rimantadine.

Example 3. Study of the biological activity against herpes virus simple type 1.

In the study of Antiherpes virus effect of effect of derivatives of adamantane in the culture of Vero cells (table 6) found that the Ia drug inhibits the development virusinduced effect in concentrations close to the value of CD50and the value of KTI approximately 2 times greater than KTI of rimantadine. IB showed a pronounced selective effect against HSV-1 (KTI=12,82). Similar results were obtained with HSV-1 with resistance to basic drug antiherpetic drug acyclovir.

The obtained results were confirmed when the research of influence of the most active compounds IB infectious titer of HSV-1. The maximum concentration used in this series of experiments did not exceed 1/2 CD50. In the presence of a concentration of 31.2 µg/ml (approximately 1/2 CD50) rimantadine reduced the infectious titer of the virus compared to control 0.9 lg PFU/ml, and IB in the same concentration - 1.55 lg. When increasing concentrations of IB to 62.5 μg/ml reduction in the caption amounted to 2.65 lg PFU/ml and were selective.

Thus patentable compounds, especially IB, represent a promising active principle for the development of more effective Antiherpes virus effect of the drug among the derivatives of adamantane.

Table 4

The study of the antiviral effect of adamantane derivatives in cell culture MDCK on the model of influenza a viruses
MedicationInfluenza virus a
 WCCPAichi/2/68
 ID50[µg/ml]KTIMAK [mg/ml]KTI
Ia

IB

rimantadine
96

48
4,78

to 3.58
192

96
2,39

1,79
 1,240,21,826,80
Note: MI OF 0.1 PFU/cell, incubation period of 72 hours Presents the results of three independent experiments. ID50and ID95the concentration of compounds that prevent the development of virusinduced the centre e, respectively, 50% and 95-100% at 95-100% of the centre e in control. The MACS (minimal active concentration) is the minimum concentration of a substance, completely preventing DSA. Chemotherapeutic index compounds (KTI) was calculated as the ratio of CD50to EID50(or MACS).
Table 5

Inhibition of the formation of plaques by rimantadine and a number of derivatives of adamantane, included in a solid agar floor, in the cell culture MDCK infected VCCP.
Concentration [µg/ml]Inhibition of belascoaran, % Medication
 rimantadineIaIB
0,57800
1,09000
5,09100
10,09307
20,01002019
50,0CT3426
100,0Ni3832
200,0Ni43CT
Note: MI OF 0.5 PFU/cell: duration of incubation 48 CST - cytotoxicity, N.I. - not investigated, as the concentration is close to or exceeds the amount of CD50.

ID95
Table 6

The study of the antiviral effect of adamantane derivatives in the culture of Vero cells on the model of HSV-1
MedicationID50KTI
Ia

IB
125/125

15,6/15,6
500/250

62,5/62,5
3,68/3,68

12,82/12,82
Rimantadine31,2/31,262,5/62,51,64/1,64
acyclovir0,45/1200,9/>120 
Note: MI OF 0.1 PFU/cell; incubation period of 48 hours EID50and ID95the concentration of compounds that prevent the development of virusinduced the centre e, respectively, 50% and 95-100% at 95-100% of the centre e in control. Chemotherapeutic index compounds (KTI) was calculated as the ratio of CD50to EID50. “*/*” for the reference sensitive to acyclovir HSV-1/S and resistant to acyclovir HSV-1/R(HSV/S/HSV/R)

1. Hydrochloride (3-R-1-substituted)-1-ethylamino, the formula

where R is Cl (Ia), (C2H5(IB),

possessing antiviral activity.

2. Method of preparing compounds according to claim 1, characterized in that the synthesis is carried out by the reaction of Lacerta-Vallaha with formamide in the environment of formic acid (3-R-1-substituted)methylketone.



 

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