DE1003214B - Process for the preparation of 4- (2,6-diamino-4-pyrimidylamino) phenylarsine oxide carbonate - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of 4- (2,6-diamino-4-pyrimidylamino) -phenylarsine oxide carbonate, animal studies found to be effective against infection by Trypanosoma rhodesiense is extremely effective. This substance is less toxic than the previously known compounds of this class and acts in non-toxic doses even in the advanced stages of infection in monkeys involving the central nervous system is already attacked, healing.

From US Pat. No. 2,435,393, in particular Example 5, it is known to use 4- (2-amino-4-pyrimidylamino) phenylarsine oxide hydrate by reducing 4- (2-amino-4-pyrimidylamino) phenylarsonic acid using sulfur dioxide and hydrochloric acid in the presence of potassium iodide and hydrolyzing the 4- (2-amino-4-pyrimidylaminoj-phenylarsine dichloride so formed) to represent. It is also mentioned there that 4- (2-amino-4-pyrirnidylamino) -phenylarsonic acid is carried out in this process a large number of other compounds, including 4- (2,6-diamino-4-pyrimidylamino) phenylarsonic acid, can replace. However, no data are given to show that the 4- (2,6-diamino-4-pyrimidylamino) phenylarsine oxide has actually been depicted.

It has now been found that this compound can be obtained if the crude mixture of the reduction products of 4- (2,6-diamino-4-pyrimidylamino) phenylarsonic acid is used further hydrolyzed, can easily be isolated in the form of the carbonate and that this is the previously shown Compounds compared to a much stronger therapeutic effect and less toxicity.

The process according to the invention for the preparation of 4 - (2,6 - diamino - 4 - pyrimidylamino) - phenyiarsinoxydcarbonate is characterized in that in a known manner by reducing 4- (2,6-diamino-4-pyrimidylamino) -phenylarsonic acid by means of sulfur dioxide and hydrochloric acid in the presence of potassium iodide and hydrolyzing the so formed, not further purified 4- (2,6-diamino-4-pyrimidylamino) -phenylarsine dichloride obtainable 4- (2,6-diamino-4-pyrimidylamino) -phenylarsine oxide is converted into the carbonate.

4- (2,6-Diamino-4-pyrimidylamino) -phenylarsine oxide carbonate can also be used also produce by converting p-aminophenylarsine oxide 4- (2,6-diamino-4-pyrimidylamino) phenylarsine oxide obtainable with 2,6-diamino-4-chloropyrimidine converted into the carbonate.

This reaction can preferably be carried out in an acidic medium, for example in dilute hydrochloric acid will.

The invention is illustrated in the following examples. The parts are parts by weight.

Method of manufacture

of 4- (2,6-diamino-4-pyrimidylamino) -

phenyl arsine carbonate

Applicant:

Imperial Chemical Industries Limited,
London

Representative:

Dipl.-Ing. A. Bohr, Dipl.-Ing. H. Bohr, Munich 5,

and Dr.-Ing. H. Fincke, Berlin-Lichterfelde West,

Freiwaldauer Weg 28, patent attorneys

Claimed, priority:
Great Britain December 15, 1952

Arthur Donald Ainley, Blackley, Lancashire

(Great Britain),
has been named as the inventor

example 1

14.4 parts of 4- (2,6-diamino-4-pyrimidylamino) phenylarsonic acid are dissolved in 500 parts of concentrated hydrochloric acid and 0.5 part of potassium iodide is added. The solution is heated to 40 ° and sulfur dioxide is passed through the mixture for 2 hours at this temperature. The reaction mixture is then left to stand, the supernatant liquid is decanted off and discarded, and 200 parts of water are added to the residue. The mixture 'was stirred and made alkaline by addition of 50 parts 10 ° / ₀ aqueous sodium carbonate solution to Brilliant Yellow paper. It is then filtered and the solid residue is dissolved in 250 parts of a 2 ° / ₀ aqueous sodium hydroxide solution. Then carbon dioxide is passed through the solution until it no longer reacts alkaline to clay yellow paper. It is then filtered and the solid residue is washed well with water and dried. It consists of 4- (2,6-diamino-4-pyrimidylamino) phenylarsine oxide carbonate and is a white powder that decomposes at 273 to 275 °.

Example 2

A mixture of 5 parts of p-aminophenylarsine oxide, 3.6 parts of 2,6-diamino-4-chloropyrimidine, 6 parts of concentrated aqueous hydrochloric acid and 44 parts of water is refluxed for 5 hours and then boiled

609 837/453

cooled to 20 ° and left at this temperature for 18 hours. Then 13.5 parts of 40 / _o aqueous sodium hydroxide solution was added °, and the mixture is filtered. Carbon dioxide is passed through the filtrate until it no longer reacts alkaline to clay yellow paper. The solution is then filtered and the solid residue dissolved in 20 parts of 8 _^0/0 aqueous sodium hydroxide solution. Carbon dioxide is passed through the solution until it no longer reacts alkaline to clay yellow paper. It is then filtered and the solid residue is washed well with water and dried. It consists of 4- (2,6-diamino-4-pyrimidylamino) phenylarsine oxide carbonate, which is in the form of a white powder that decomposes at 273 to 275 °.

The effectiveness of the compound prepared according to the invention against infections of mice by Trypanosoma rhodesiense was compared with that of the well-known 4 - (2 - amino - 4 - pyrimidylamino) - phenylarsine oxide dihydrochloride dihydrate.

Investigated connection Medium lethal dose
mg / kg Minimal
medicinal dose
mg / kg Chemo
thera
more peutic
index 4- (2,6-diamino-4-pyrimidylamino) phenylarsine oxide
carbonate dihydrate
4- (2-Amino-4-pyrimidylamino) phenylarsine oxide
dihydrochloride dihydrate 30 (intravenous)
50 (intraperitoneal)
125 (subcutaneous)
25 to 50 (subcutaneous) 1.25 (subcutaneous)
2 to 5 (subcutaneous) 24
40
100
about 10

It follows that the compound according to the invention is less toxic and has a curative effect on one lower minimum dose, therefore a significantly higher chemotherapeutic index (= ratio of mean lethal dose to the minimum medicinally effective dose). has than the above-mentioned analog known connection.

Claims (3)

Patent claims: 1. Process for the preparation of 4- (2,6-diamino-4-pyrimidylamino) -phenylarsinoxydcarbonat, characterized in that in a known manner by Reduction of 4- (2,6-diamino-4-pyrimidylamino) phenylarsonic acid using sulfur dioxide and hydrochloric acid in the presence of potassium iodide and hydrolyzing the so formed, not further purified 4- (2,6-diamino-4-pyrimidylamino) -phenylarsine dichloride available 4- (2,6-diamino-4-pvrimidylamino) -phenylarsine oxide is converted into the carbonate. 2. The method according to claim 1, characterized in that the reaction of p-aminophenylarsine oxide 4- (2,6-diamino-4-pyrimidylamino) -phenylarsine oxide obtainable with 2, δ-diamino ^ -chloropyrimidine is converted into the carbonate. 3. The method according to claim 2, characterized in that the reaction in an acidic medium, for example in dilute hydrochloric acid. Considered publications:
U.S. Patent No. 2,435,393. © 609 837/453 2.57