Phosphorus containing cytisine derivatives

Details Phosphorus containing cytisine derivatives Phosphorus containing cytisine derivatives

1999-10-12

2001-02-27

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C546S023000

Reexamination Certificate

active

06194397

ABSTRACT:

CROSS REFERENCE
This application is a 371 of PCT/KZ96/00002 filed May 20, 1996.
BACKGROUND OF THE INVENTION
1. Technical Field
The invention is related to new chemical compounds, in particular to phosphorus containing cytisine derivatives showing their hepatoprotective and antienzyme activities.
2. Background Art
It is known that alkaloid cytisine (1) extracted firstly from the seeds of broom and thermopsis is now widely used in the medical practice in a state of 0.15% water solution (cytiton) as an analeptic agent (Mashkovsky, M. D., “Medicine remedies”, M., 1977, v.1, p.123).
A typical property of cytisine is its ability to arouse breathing that is connected with refectory stimulation of breathing center by intensified impulses coming from carotid balls. Simultaneous stimulation of sympathetic knots and adrenal glands leads to the rise of arterial pressure. In this connection, cytisine is recommended to be used in case of the stopping of breathing and heart activity at intoxication.
Cytisine is widespread in nature. It has been found in many plants and its extraction from a plant raw material by an ion exchange method is the main industrial way to obtain cytisine.
Synthesis of phosphorus containing N-[&bgr;-(dialkocsiphosphenyl) mercaptoethyl] cytisines (2) and their iodine methylates (3) has been described in works (Reports of the Uzbek SSR Academy of Sciences, 1978, No. 9, pp. 39-42; Reports of the Uzbek SSR Academy of Sciences, 1977, No. 7, pp. 40-43).
Authors have shown that all synthesized compounds have the irreversible inhibiting activity in a case of acetylcholinesterase and display the effect of selective inhibition of the butyrylcholinesterase catalytic activity.
Authors are aware of no evidences of other phosphorus containing cytisine derivatives in literature.
SUMMARY OF THE INVENTION
In connection with that the initial cytisine alkaloid displays considerable biological activity, one can assume that other phosphorus containing cytisine derivatives will also be of interest from this point of view.
An object of the present invention is to obtain new phosphorus containing cytisine derivatives that in particular have increased biological activity.
The object is attained by providing phosphorus containing cytisine derivatives of the general formula:
where n=0; 1;
at n=0 X=S; O
R=CH
3
(a); C
2
H
5
(b); C
3
H
7
(c); 1-C
3
H
7
(d); C
4
H
9
(e)
at n=1 X=O
R
1
=1-C
3
H
7
(a); C
6
H
5
(b); CH
3
—O—C
6
H
4
—(c)
Synthesis of O,O-dialkyl-N-cytisinylphosphates (n=0, X=O, compounds 4a-e) was carried out by means of the dialkylphosphite interaction with cytisine under the conditions of a Todde-Aterton's reaction according to the following scheme:
The synthesis of O,O-dialkyl-N-cytisinylthiophosphates (n=0, X=S, compounds 5a-e) was carried out in two stages. In the first stage, during the cytisine interaction with dialkylchlorphosphite (the synthesis was described in E. V. Nifantyev, “Chemistry of phosphorus containing compounds”, M. Science, 1983, p.85), the interaction being performed in the benzene medium in the flow of dry argon and in the presence of triethylamine, an intermediate 0,0-dialkyl-N-cytisinylphosphite is formed that then reacts with an equimolar amount of elementary sulfur giving O,O-dialkyl-N-cytisinylthiophosphate.
Dimethyl-(N-cytisinyl) alkyl (aryl) phosphonates (n=1, X=O, R=CH
3
, compounds 6a-c) have been obtained by means of the cytisine interaction with aldehydes and dimethylphosphite under the conditions of a Kabachnic-Fild's reaction
PREFERRED EMBODIMENTS OF THE INVENTION
The following examples explain the invention in more detail, without restricting it by this.


REFERENCES:
Chemical Abstracts, vol. 66(5),abst. No. 18,852(b), Jan. 1967.
Chemical Abstracts, vol. 125 (19),abst. No. 248,202f, Nov. 4, 1996.
“Silibinin”, Mashkovsky M.D. Medicinal remedies, Vilnius, v.l, 1994, p.450.
“Essentiale”, Mashkovsky M.D. Medicinal remedies, Vilnius, v.l, 1994, p.40.

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