DE2125544C3 - 2H, 4H-U.4 Tnazin-33-dione - Google Patents

Description

The invention relates to 2 H.4 H-l, 2,4-triazine-3,5- <iione, as defined in the above claim, with pronounced diuretic and saluretic or natriuretic properties. You can therefore go to Treatment of edema and hypertension can be used.

Asymmetric triazine derivatives with a diuretic effect are not yet available, with one exception became known (Biochemical Pharmacology 15, 4 (Ml [1966], CA, 64, 18251 [1966]). The one described there However, 6-phenylthio-2 H.4 H-l, 2,4-tnazin-3,5-dione has only weak diuretic activity, as comparative experiments have shown (see table). It was therefore up so surprising that the 6- (2-aminophenylthio) -2 H, 4 Hl _t 2,4-triazine-3 _i 5-dione derivatives according to the invention are diuretically and saluretically highly effective.

In animal experiments, the compounds according to the invention have proven to be the known diuretic ones

ίο Chlorazanil hydrochloride (N-p-chlorophenyl-2,4-diamino-134-triazine hydrochloride - DT-PS 8 96 492 and 10 08 303) proved to be superior both in terms of their effectiveness and their sodium-potassium quotient.

The following table gives the diuretic activity over 24 hours of three of the new according to the invention Substances again and, in comparison, the values of chlorazanil hydrochloride and the above-described asymmetric triazine derivative 6-phenylth «rr2 H, 4 H- 1,2,4-triazine-3,5-dione. The attempts were made after the

Method by Lipschttz, Hadidian and Ker-

pezar (J. Pharmacol. 79, 97-110 [1943]) on rats carried out.

The table also contains the values of the Na and

IC excretion in the rat after oral administration (5 hour values). The Na / K quotient calculated from this shows that in the case of the compounds according to the invention, the K excretion clearly lags behind the Na excretion and, as a result, the K losses are low.

substance

O N Y- \ dose Hara Acute toxicity dose Na ⁺ mVal / kg Na / K- mg / kg volume LD ₅₀ (mg / kg). mg / kg mVal / kg (5 hours) quotient Rat p. O. ml / kg / mouse rat (5 hours) _N \ NH ₂
^N O
H ^U 24 hours p.o. 1.2 HN 10 23 364 (i.p.) 30th 6.8 1.2 5.7 j 100 87 5080 (p.o.) 100 10.2 8.5 300 125

6- (2-aminophenylthio) -

2H, 4H-1,2,4-triazine-3,5-dione

I. 19th 10 33 30th 35

(2-aminophenylH3,5-dioxo-

2H, 4H - !, 2,4-triazinyl-6) -

sulfoxide

2-carboxymethylene-6- (2-aminophenylthio) -2 H, 4 H-1,2,4-triazine-3,5-dione

72

> 1600 (Lp.)

1 5.1 1.3 3.9 10 8.1 1.5 5.4 100 8.3 1.6 5.2

100

12.2 2.2

5.5

continuation

substance

Dose hamtng'kg volume rat p. o. ml / kg / 24StA

Acuie toxicity LD ₅₀ (mg / kg), mouse

Pasis mg / kg rat p.o.

Na ⁺

mVal / kg

(Hour)

mVal / kg (5 hours)

Na / K ratio

N N

N H Chlorazinyl hydrochloride

3 IO

IO 100

28 70 42

6 9

20th

92 (sc) ') 300 (p of)

3.9

1.2

3.2

6-phenylthio-2H.4H-1,2,4-triazine-3,5-dione

Control - 7

') B. Z e m ρ I e η, Acta Pharm. Hung. 25, 77 (1955).

^z ) WB McKeon, Arch. InL Phannaco ^ m. 151, 225 (1964).

The new compounds according to the invention can be converted in a manner known per se of 6-bromo-2 H, 4 H-I, 2,4-triazine-3,5-dione with the corresponding 2-an / inothiophenols according to the following Reaction scheme can be prepared:

(D

(H)

R has the meaning given above.

The synthesis is preferably carried out in such a way that equimolar amounts of the two starting compounds, which are obtained by known methods, with the addition of 2 equivalents 2.6 0.9

2.9

jo sodium hydroxide in aqueous solution are refluxed for several hours. After the Reaction solution to room temperature and careful acidification, the new compounds precipitate as a fine crystalline precipitate.

i) Should the sulfur atom in connection III for Sulfoxy group are oxidized, this is advantageously done by heating III with sodium metaperiodate in aqueous solution. The following examples are intended to do just that Explain the production process for the compounds according to the invention in more detail.

example 1 6- (2-aminophenylthio) -2H, 4H-1,2,4-triazine-3,5-dione

27 grams (0.14 moles) of 6-bromo-2 H, 4 H-1,2,4-triazine-3,5-dione are dissolved in 280 ml of I n NaOH (0.28 mol) and mixed with 20 g (0.16 mol) of 2-aminothiophenol heated to boiling for 4 hours. It is filtered hot, cooled to room temperature.

V) temperature and acidify carefully with 50% acetic acid. The compound precipitates out as a pale yellow precipitate which, after filtration, is washed with water, dried and recrystallized from ethanol. Yield 23 g, m.p.> 300 ° C.

«Calculated: C 45.75, H 339, N 23.75; found: C 46.08, H 3.56. N 24.04.

Example 2

(2-aminophenyl) - (3,5-dioxo-2 H.4 H-t, 2,4-triazinyl-6) sulfoxide)

11.8 g (0.05 mol) 6- (2-aminophenylthio) -2 H, 4 H-1,2,4-triazine-3,5-dione are dissolved in 200 ml of 1% sodium hydroxide solution and a solution of 13.5 g Sodium metaperiodate heated to boiling in 200 ml of water for 1 hour. The reaction solution is then mixed with activated charcoal, acidified with glacial acetic acid and

filtered. The evaporated Fütrai is with ethanol extracted, the solution filtered and concentrated again. 2 g of the sulfoxide crystallize out, mp, 210-215 ° C (Z.), Calculated; C 42.85, H 3.20, N 22.21 j

found: C 42.54, H 3.40, N 21.93,

Example 3

2-carboxymethylene-6- (2-aminophenylthio) -2 H, 4 Hl _r 2,4-triazine-3,5-dione

4.5 g (0.016 mol) e-bromine ^ -carboxymethy-

len-2 H, 4 H-1,2,4-triazine-3,5-dione are in 32 ml Dissolved 1 η sodium hydroxide solution and with a solution of 2.5 g (0.020 mol) of 2-aminothiophenol in 16 ml of 1 N sodium hydroxide solution Heated to the boil for 4 hours. After cooling down

Room temperature is filtered and the 2-carboxymethylene-6- (2-aminophenylthio) -2 with dilute hydrochloric acid H, 4 H-1,2,4-triazine-3,5-dione precipitated. After recrystallization 1.5 g of the product are obtained from ethanol, melting point> 300 ° C,

Calculated: C 44.90, H 3.43, N 18.91;
Found: C 44.89, H 3.68, N 19.14.

The new 2 H, 4 H-1,2,4-triazine-3,5-diones can, if appropriate with suitable solid or liquid Mixed carriers of the customary type, for the preparation of solutions for injection purposes and in particular pharmaceutical preparations to be administered orally, such as coated tablets, pills or tablets, be used.

Claims (1)

Claim: 2 H, 4 H-1,2,4-triazine-3,5-diones of the general formula in which R is a hydrogen atom or a carboxymethylene group and A is a sulfur atom mean a sulfoxide group.