NO127581B - - Google Patents

Description

Analogy method for the production of

new basic substituted derivatives of

(1H,3H)-ch<*>inazolin-2-thion-4-one with coronary vasodilatory action.

The invention relates to an analogue process for the preparation of new base-substituted derivatives of (1H,3H)-quinazolin-2-thion-4-one with coronary artery dilating action and with the general

formula

in which,

R^ means lower alkoxy groups with 1-4 C atoms, which are preferably in the 6,7- or 6,7,8-position,

R2 means alkoxy with 1-k C atoms,

m means the numbers 1, 2 or 3, and

n means the numbers 2 or. 3,

R^ and R^ independently mean lower alkyl, lower alkenyl, phenyl lower alkyl, cycloalkyl of up to Cg, or R^

and R^ together with the N atom form a 5, 6 or 7-membered heterocyclic ring, which optionally contains an O or N atom and optionally contains bound to the latter N atom a lower alkoxy-substituted phenyl-lower alkyl radical, or a halogen-substituted phenyl radical , as the method is characterized by (1H,3H)-quinazolin-2-thione-^-one méd

in which R1, R-j, Rjij and n have the above meaning, is acylated with an alkoxybenzoic acid of the general formula

where R2 and m have the above-mentioned meaning or a functional derivative thereof, possibly in the presence of an acid-binding agent.

The 3-(Y~amino-B-hydroxy-propyl)-(1H,3H)-quinazolin-2-thion-4-ones required as starting products can be prepared analogously to that in Heiv. 5£ (1967), lHMO described a method by reacting the correspondingly substituted o-alkoxycarbonyl-phenylisothiocyanates with 3-Y~amino"3~hydroxypropylamines.

The derivatives of (1H,3H)-quinazolin-2-thion-4-one which can be prepared according to the invention are valuable pharmaceuticals; they have a specific coronary artery dilating effect and are in this respect superior to known substances of this type.

The pharmacological investigation of coronary artery dilating effect was carried out using the change of the oxygen pressure in coronary venous blood according to that of W.K.A. Schaper and co-workers discussed the method on dogs (see W.K. Schaper, R. Xhonneux and J.B. Bogaard "Uber die continuous Messung des Sauerstoffdrucks im venosen Coronarblut" (Naunyn-Schmiedebergs Arch. exp. Path. und Pharmak. 2455 383-389 (1963)) .The drugged, spontaneously breathing

animals received the investigational preparations administered intravenously. With this test device, a dilation of the coronary arteries produced with the help of test substances and the associated increase in coronary flow leads to an increase in the oxygen pressure in coronary venous blood. The oxygen pressure was measured polarographically with a platinum electrode. according to Gleichmann-Lubbers (see U. Gleichmann and D.W. Lubbers "Die-Messung des Sauerstoffdruck in Gasen und Fliissigkeiten mit der Platin-Elektrode unter besonderer Berucksichtigung der Messung im Blut", Pflugers Arch. 271, 431-455

(1960)). The heart rate was continuously determined electronically from the systolic maxima of the arterial blood pressure. The arterial blood pressure was measured in a known manner with a Statham strain gauge electro-manometer in the Arteria femoralis.

The following table summarizes the results<;>of

they conducted pharmacological investigations. The preparations were each time examined in the form of their hydrochlorides.

When producing dragees and tablets with the derivatives of (1H,3H)-quinazolin-2-thion-4-one that can be prepared according to the invention as active ingredient, these substances can be mixed with the usual tableting aids such as starch, lactose, talc and the like. All tableting and coating materials common in pharmacy can be used. For the production of injection solutions, there is e.g. the hydrochlorides of the compounds in question are particularly suitable, as these are mostly well water-soluble. Of course, injection solutions of non-water-soluble products can also be prepared in a known manner with the co-use of known suspending agents, emulsifiers and/or dissolution agents.

Example.

39.7 g (0.1 mol) of 3-(Y-diethylamino-B-hydroxypropyl)-6,7>8-trimethoxy-(1H,3H)-quinazolin-2-thion-1|-one is dissolved in 250 ml chloroform and mixed with 11.1 g (0.11 mol) of triethylamine. Now add in drops while stirring at room temperature over the course of 30 minutes. a solution of 25.3 g (0.11 mol) of 3,4,5-trimethoxybenzoyl chloride in 80 ml of chloroform and after stirring for 1 hour at room temperature. It is then heated to boiling and stirred for 6 hours under reflux. After cooling, the reaction mixture is evaporated to dryness in vacuo. The residue is taken up in dilute hydrochloric acid and the solution thus formed is clearly filtered. The aqueous hydrochloric acid solution is then made alkaline with an aqueous soda solution and the reaction product, which separates out oily in vinegar, is taken up. After drying over pot ash, the hydrochloride of 3~/Y-diethylamino-8-(3,4,5-trimethoxy-benzoxy)-propyl7-6,7,8-trimethoxy-(1H ,3H)-quinazolin-2-thione-M-one in the form of colorless needles of m.p. 154-156°C.

Yield: 1+3 g (='68.5# of the theoretical).

The starting product 3-(Y-diethylamino-3-hydroxypropyl)-6,7,8-trimethoxy-(1H,3H)-chihazolin-2-thion-4-one can be prepared as follows;

28.3 g (0.1 mol) of 2,3,4-trimethoxy-6-methoxycarbonyl-phenyl isothiocyanate, prepared by reaction of 3,4,5-trimethoxy-anthranilic acid methyl ester with thiophosgene. analogously to the method stated in "Journal of Organic Chemistry" 27 (1962), 3702, dissolve

in 200 ml of anhydrous ether and is mixed with stirring at room temperature with a solution of 14.6 g (0.1 mol) of Y-dletylamino-g-hydroxypropylamine in 60 ml of anhydrous ether. Stirring is continued for 2 hours at room temperature.

temperature, desorbs the crystalline precipitated reaction product and thus obtains 3-(Y-diethylamino-B-hydroxypropyl)-6,7,8-trimethoxy-(1H,3H)-quinazolin-2-thion-4-one in the form of colorless needles of m.p. 146°C.

Yield: 33 g (= $3% of the theoretical).

Analogous to the above-mentioned method, the following output products can be produced:

General formula:

In an analogous way, as discussed in the introduction of this example, the following compounds according to the invention are produced from the above-mentioned starting products:

Claims (1)

Analogous process for the preparation of basic substituted derivatives of (1H,3H)-quinazolin-2-thion-4-one with coronary vasodilating action and having the general formula in which FL means lower alkoxy groups with 1-4 C atoms, which are preferably in the 6,7 or 6,7,8 position, R2 means alkoxy with 1-4 C atoms, m means the numbers 1, 2 or 3, and n means the numbers 2 or 3, R-j °S R|j means independently of each other lower alkyl, lower alkenyl, phenyl lower alkyl, cycloalkyl of C^ to Cg, or R^ and R^ together with the N atom form a 5, 6 or 7-member heterocyclic ring, which optionally contains an 0- or N-atom and optionally contains bound to the latter N-atom a lower alkoxy-substituted phenyl-lower alkyl residue, or a halogen-substituted phenyl residue, characterized in that (1H,3H)-quinazolin-2-thion-4- on with the general formula in which R^, R^, R^ and n have the above meaning, is acylated with an alkoxybenzoic acid of the general formula where R2 and m have the above-mentioned meaning or a functional derivative thereof, possibly in the presence of an acid-binding agent.